User login
Durable responses to ADC sacituzumab in mTNBC
The novel antibody-drug conjugate sacituzumab govitecan was associated with durable clinical responses in one third of patients with heavily pretreated metastatic triple-negative breast cancer (TNBC), investigators in a multicenter study found.
Among a cohort of 108 patients with TNBC, the objective response rate (ORR) to treatment with sacituzumab govitecan was 33.3%, which included three complete and 33 partial responses (CR and PR), with a median duration of response of 7.7 months, reported Aditya Bardia, MD, from Massachusetts General Hospital in Boston and his colleagues.
“The duration of treatment with sacituzumab govitecan-hziy was longer than with the immediate previous antitumor therapy (5.1 months vs. 2.5 months); this provides further evidence of clinical activity in patients with difficult-to-treat metastatic triple-negative breast,” they wrote in The New England Journal of Medicine.
Sacituzumab govitecan (the suffix “hziy” used in the article is not sanctioned by the FDA, according to an editor’s note) is an antibody-drug conjugate consisting of SN-38, the active metabolite of the topoisomerase I inhibitor irinotecan, linked to a humanized monoclonal antibody targeted to Trop-2, a cell-surface glycoprotein expressed in triple-negative breast cancers and most other epithelial malignancies.
The study, preliminary results of which were previously reported at the San Antonio Breast Cancer Symposium in 2017, was part of a larger a phase 1/2 basket trial that resulted in sacituzumab govitecan receiving a breakthrough designation from the Food and Drug Administration.
The breast cancer cohort included 108 patients (107 women and one man; median age, 55 years) with TNBC who had received a median of 3 prior lines of anticancer therapies. Most had received taxanes (98%) and anthracyclines (86%).
At the time of data cutoff on December 1, 2017, the median duration of follow-up was 9.7 months. By that time, 100 of the 108 patients had discontinued therapy: 86 because of disease progression, three because of adverse events, 7 at the investigator’s discretion, and 2 for withdrawal of consent.
Four patients died during treatment; all of the deaths were judged to be caused by disease progression.
Grade 3 or 4 adverse events occurring in 10% or more of patients included neutropenia in 42% and anemia in 11%. Febrile neutropenia occurred in 9.3% of patients.
As noted before, the investigator-assessed ORR was 33.3%, and the median duration of response was 7.7 months. The ORR as assessed by independent central reviewers was 34.7%, and the median duration of response 9.1%. The clinical benefit rate, a composite of ORR plus stable disease of at a least 6 months duration, was 45.4%. The median progression-free survival was 5.5 months, and median overall survival was 13 months.
There were no significant differences in outcomes in a subgroup analysis broken down by patient age, metastatic disease, number of prior therapies, or presence of visceral metastases, the investigators noted, but they cautioned that the numbers were small, which led to wide confidence intervals, “and thus the homogeneity of clinical outcomes observed in these subgroups is weak and should be interpreted with caution,” they wrote.
The study was supported by Immunomedics. Dr. Bardia disclosed advisory board activities and institutional research grants from Immunomedics, Sanofi, and Radius Health. Multiple coauthors reported similar relationships with these and other companies.
SOURCE: Bardia A et al. NEJM 2019 Feb 20. doi: 10.1056/NEJMoa1814213.
The novel antibody-drug conjugate sacituzumab govitecan was associated with durable clinical responses in one third of patients with heavily pretreated metastatic triple-negative breast cancer (TNBC), investigators in a multicenter study found.
Among a cohort of 108 patients with TNBC, the objective response rate (ORR) to treatment with sacituzumab govitecan was 33.3%, which included three complete and 33 partial responses (CR and PR), with a median duration of response of 7.7 months, reported Aditya Bardia, MD, from Massachusetts General Hospital in Boston and his colleagues.
“The duration of treatment with sacituzumab govitecan-hziy was longer than with the immediate previous antitumor therapy (5.1 months vs. 2.5 months); this provides further evidence of clinical activity in patients with difficult-to-treat metastatic triple-negative breast,” they wrote in The New England Journal of Medicine.
Sacituzumab govitecan (the suffix “hziy” used in the article is not sanctioned by the FDA, according to an editor’s note) is an antibody-drug conjugate consisting of SN-38, the active metabolite of the topoisomerase I inhibitor irinotecan, linked to a humanized monoclonal antibody targeted to Trop-2, a cell-surface glycoprotein expressed in triple-negative breast cancers and most other epithelial malignancies.
The study, preliminary results of which were previously reported at the San Antonio Breast Cancer Symposium in 2017, was part of a larger a phase 1/2 basket trial that resulted in sacituzumab govitecan receiving a breakthrough designation from the Food and Drug Administration.
The breast cancer cohort included 108 patients (107 women and one man; median age, 55 years) with TNBC who had received a median of 3 prior lines of anticancer therapies. Most had received taxanes (98%) and anthracyclines (86%).
At the time of data cutoff on December 1, 2017, the median duration of follow-up was 9.7 months. By that time, 100 of the 108 patients had discontinued therapy: 86 because of disease progression, three because of adverse events, 7 at the investigator’s discretion, and 2 for withdrawal of consent.
Four patients died during treatment; all of the deaths were judged to be caused by disease progression.
Grade 3 or 4 adverse events occurring in 10% or more of patients included neutropenia in 42% and anemia in 11%. Febrile neutropenia occurred in 9.3% of patients.
As noted before, the investigator-assessed ORR was 33.3%, and the median duration of response was 7.7 months. The ORR as assessed by independent central reviewers was 34.7%, and the median duration of response 9.1%. The clinical benefit rate, a composite of ORR plus stable disease of at a least 6 months duration, was 45.4%. The median progression-free survival was 5.5 months, and median overall survival was 13 months.
There were no significant differences in outcomes in a subgroup analysis broken down by patient age, metastatic disease, number of prior therapies, or presence of visceral metastases, the investigators noted, but they cautioned that the numbers were small, which led to wide confidence intervals, “and thus the homogeneity of clinical outcomes observed in these subgroups is weak and should be interpreted with caution,” they wrote.
The study was supported by Immunomedics. Dr. Bardia disclosed advisory board activities and institutional research grants from Immunomedics, Sanofi, and Radius Health. Multiple coauthors reported similar relationships with these and other companies.
SOURCE: Bardia A et al. NEJM 2019 Feb 20. doi: 10.1056/NEJMoa1814213.
The novel antibody-drug conjugate sacituzumab govitecan was associated with durable clinical responses in one third of patients with heavily pretreated metastatic triple-negative breast cancer (TNBC), investigators in a multicenter study found.
Among a cohort of 108 patients with TNBC, the objective response rate (ORR) to treatment with sacituzumab govitecan was 33.3%, which included three complete and 33 partial responses (CR and PR), with a median duration of response of 7.7 months, reported Aditya Bardia, MD, from Massachusetts General Hospital in Boston and his colleagues.
“The duration of treatment with sacituzumab govitecan-hziy was longer than with the immediate previous antitumor therapy (5.1 months vs. 2.5 months); this provides further evidence of clinical activity in patients with difficult-to-treat metastatic triple-negative breast,” they wrote in The New England Journal of Medicine.
Sacituzumab govitecan (the suffix “hziy” used in the article is not sanctioned by the FDA, according to an editor’s note) is an antibody-drug conjugate consisting of SN-38, the active metabolite of the topoisomerase I inhibitor irinotecan, linked to a humanized monoclonal antibody targeted to Trop-2, a cell-surface glycoprotein expressed in triple-negative breast cancers and most other epithelial malignancies.
The study, preliminary results of which were previously reported at the San Antonio Breast Cancer Symposium in 2017, was part of a larger a phase 1/2 basket trial that resulted in sacituzumab govitecan receiving a breakthrough designation from the Food and Drug Administration.
The breast cancer cohort included 108 patients (107 women and one man; median age, 55 years) with TNBC who had received a median of 3 prior lines of anticancer therapies. Most had received taxanes (98%) and anthracyclines (86%).
At the time of data cutoff on December 1, 2017, the median duration of follow-up was 9.7 months. By that time, 100 of the 108 patients had discontinued therapy: 86 because of disease progression, three because of adverse events, 7 at the investigator’s discretion, and 2 for withdrawal of consent.
Four patients died during treatment; all of the deaths were judged to be caused by disease progression.
Grade 3 or 4 adverse events occurring in 10% or more of patients included neutropenia in 42% and anemia in 11%. Febrile neutropenia occurred in 9.3% of patients.
As noted before, the investigator-assessed ORR was 33.3%, and the median duration of response was 7.7 months. The ORR as assessed by independent central reviewers was 34.7%, and the median duration of response 9.1%. The clinical benefit rate, a composite of ORR plus stable disease of at a least 6 months duration, was 45.4%. The median progression-free survival was 5.5 months, and median overall survival was 13 months.
There were no significant differences in outcomes in a subgroup analysis broken down by patient age, metastatic disease, number of prior therapies, or presence of visceral metastases, the investigators noted, but they cautioned that the numbers were small, which led to wide confidence intervals, “and thus the homogeneity of clinical outcomes observed in these subgroups is weak and should be interpreted with caution,” they wrote.
The study was supported by Immunomedics. Dr. Bardia disclosed advisory board activities and institutional research grants from Immunomedics, Sanofi, and Radius Health. Multiple coauthors reported similar relationships with these and other companies.
SOURCE: Bardia A et al. NEJM 2019 Feb 20. doi: 10.1056/NEJMoa1814213.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Sacituzumab govitecan induced responses in patients with heavily pretreated TNBC.
Major finding: The objective response rate among 108 patients with metastatic TNBC was 33.3%.
Study details: Phase 1/2 trial cohort of 107 women and one man with advanced triple-negative breast cancer.
Disclosures: The study was supported by Immunomedics. Dr. Bardia disclosed advisory board activities with and institutional research grants from Immunomedics, Sanofi, and Radius Health. Multiple coauthors reported similar relationships with these and other companies.
Source: Bardia A et al. NEJM. 2019 Feb 20. doi: 10.1056/NEJMoa1814213.
Breast Cancer Tumor Board
Case Presentation
This case represents a composite of many different patients and is not meant to represent an individual. Any resemblance to an actual patient is coincidental.
A 32-year-old African American woman presented with a self-palpated left breast mass (axillary tail at 9 o’clock position). The patient was a nonsmoker, was otherwise healthy, and had no family history of breast or any other cancer. She had never used oral contraceptives or hormones, was never pregnant, her menarche was at age 12 years, and she had regular menstrual periods. On physical examination she had a 1-cm left breast mass and a palpable left axillary lymph node. A complete diagnostic workup revealed a 2-cm left breast mass. An ultrasound-guided biopsy of the axillary lymph node was positive for invasive ductal carcinoma (IDC). The final diagnosis was left breast cancer, stage IIB IDC, T1N1M0, ER+, PR+, HER2 2+ by immunohistochemistry, fluorescence in situ hybridization (FISH) was 2.4, confirming a HER2+ tumor.
Anita Aggarwal, DO, PhD. What is the role of genetic counseling and testing in this young patient who does not have a family history of breast cancer?
Vickie L. Venne, MS. This patient absolutely would be a candidate for counseling and testing. From a genetic counseling perspective, one of the first points has to do with what “no family history of cancer” means. Typically, in a fast-paced clinic, a patient will be asked “Does anybody else in your family have cancer?” And it’s not uncommon to get the answer “no.” Genetic counselors collect specific information on at least the first- and second-degree relatives, so we end up with 3 generations. This includes both the maternal and the paternal histories. We find that people who initially report no family history of cancer are often just thinking of breast cancer, even if the provider’s question is broad. When we start digging, we often find other cancers because cancer is common.
The other issue is that she was diagnosed at a young age. Clearly, 32 years is much younger than we typically see in breast cancer, and we know that individuals with hereditary cancers often have an earlier age of onset. With no other information, her a priori risk of having a BRCA1/2 mutation would be < 2.5%.
Regardless, based on current National Comprehensive Cancer Network (NCCN) guidelines, she would be a testing candidate. We would also recommend testing for more than just BRCA1/2. In the last few decades, there have been many genes identified that are associated with an increased susceptibility to cancer. Many of these genes are part of syndromes, so if you had a mutation, that also would increase the risk for a cancer in another organ. If this woman’s mother and father lived into their 70s or 80s and she had a number of aunts on both sides who never developed breast cancer, it would be less likely to be BRCA1/2. However, P53 also can present in young women and as a de novo mutation. Therefore, we would offer her a panel of actionable genes. Genes that if, in fact, we identified a mutation in one of them, would mean we could do something different for this young lady.
JoAnn Manning, MD. Let’s say she does have testing, and she comes back BRCA+. Then what would be the recommendations or guidance?
Ms. Venne. Women (and men as well!) with mutations have an increased risk for a second primary breast cancer as well as cancer in other organs. Focusing first on the breast story and all the media around BRCA1/2 mutations and surgery, this is a woman who may consider a more aggressive surgery, including prophylactic contralateral mastectomy, if she is concerned. She is young, so we also would explore her fertility plans. While her next few months will be filled with breast cancer treatment choices, women with BRCA mutations also are at an increased risk to develop ovarian cancer, so that might be a decision she makes as well. Her health care team may also eventually discuss chemotherapeutic options available specifically to women with mutations.
However, we often see young women who are extremely nervous because there is a sense that if you’re younger, your cancer must be inherited. Part of the pretest counseling is to explore psychosocial issues and help these young ladies understand that, especially if she does not have a family history of cancer and the only indication is her age, then it’s highly likely that we’re not going to find an identifiable mutation. And in that circumstance, she probably could consider a more conservative surgical decision.
Dr. Aggarwal. How common is a BRCA1 or BRCA2 mutation in African American females?
Ms. Venne. I have not paid attention to the prevalence of mutations based on ethnicity, so I don’t know. While many of the initial mutations were discovered in women of European ancestry, there are large cohorts of women with African ancestry whose specimens are now available for identifying genetic markers that will improve breast cancer risk assessment in them.1 However, because those mutations are still being characterized, it is more common to find a variant of uncertain significance (VUS) in African American women. A VUS is an alteration—a change in the gene—that we simply don’t know what it means yet. Clinicians don’t have enough information to know if that alteration is pathogenic or benign. The problem is that people try to make sense out of everything in their lives, so they also will try to make a VUS mean something. We try hard to help people understand that a VUS is really no more significant than if we had not tested in the first place, and they should not act on that information. They should use their family history, their age, their other psychosocial concerns about their experiences with cancer as they make their treatment decisions. But they also should check back periodically with their genetic counselor because VUSs can be reclassified. And if that happens, the information might be more useful for not only them, but their family members.
Dr. Manning. Would you consider this patient for any neoadjuvant chemotherapy?
Dr. Aggarwal. The patient is a young female with a small tumor that is HER2+. The indication for neoadjuvant chemotherapy is typically a big tumor or inoperable disease. Neoadjuvant chemotherapy is considered the standard of care for patients with inflammatory breast cancer and may confer a survival benefit in these patients. Of all the breast cancer subtypes, triple negative and HER2+ are considered the most chemosensitive and may benefit from neoadjuvant therapy. This patient has a small tumor, and I don’t think she’s a candidate for neoadjuvant chemotherapy unless the patient wants to see if her tumor is chemosensitive or not.
Dr. Manning, What’s the role and benefit of lumpectomy vs mastectomy?
Dr. Manning. Historically, mastectomy would have been considered the standard of care, but luckily, in the 1970s and the 1980s, we had a significant number of randomized controlled trials that demonstrated that certain women with particular characteristics would get the same overall survival if they chose mastectomy vs lumpectomy, the removal of the tumor with negative margin and whole-breast radiation. The key thing to understand is that breast-conserving surgery is now very well established with more than 20 years of data to support it. And that breast irradiation after breast-conserving surgery is essential to maximizing the local control and the overall survival (OS).
There have been a lot of major studies, but the one with the greatest follow-up now is the National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 protocol, which was the only trial to compare mastectomy to lumpectomy and radiation or lumpectomy alone. It required negative margins. With 20 years of follow-up, the data still support that mastectomy or lumpectomy with radiation offers equivalent OS and local control. It’s really about patient preference if they are candidates.
Who is a candidate? Clearly, there are contraindications. We tend to look primarily at the size of the tumor. However, removing an average-sized tumor (< 2 cm) with a margin may not have a good cosmetic result for a patient with very small breasts. That patient may opt to go forward with a mastectomy instead. Young patients who are candidates must have to have negative margins. If they have persistently positive resection margins after excision or reexcision, then they need to go forward with mastectomy.
A patient who has imaging evidence of multicentric disease with 2 or more primary tumors in separate quadrants would not be a candidate for breast-conserving therapy. Diffuse malignant-appearing microcalcifications on a mammogram also would suggest multicentric disease. And a patient with a prior history of radiation therapy to the breast or chest wall cannot go through breast-conserving therapy.
In the case we are discussing, we also should make sure this young lady is not pregnant. If the patient is adamant about breast-conserving surgery and pregnant, especially in the third trimester, radiation could be deferred until after delivery. Another relative contraindication is for patients who have connective tissue disorders. Sometimes if they are given whole-breast radiation, the cosmetic result is poor. So if you’re doing this procedure to save the breast, then having a good cosmetic result is an important consideration for many patients.
When you look at the size of the tumor for this patient, she seems to be a good candidate for breast-conserving surgery. I would recommend that she go forward with lumpectomy followed by whole-breast radiation.
Ms. Venne. Although the numbers aren’t nearly as large as they were in the original trials looking at the lumpectomy vs mastectomy, there are now survival data for women with BRCA1/2 mutations. With all of the caveats that Dr. Manning mentioned, even if you have an identifiable mutation, you may not necessarily need that more aggressive surgery.2 Clearly, individuals with identifiable mutations would have a higher chance of a contralateral breast cancer, a second primary, so some individuals consider a prophylactic bilateral mastectomy. But from a survival perspective, there are a fair amount of data now available that say that lumpectomy vs mastectomy should really be the conversation based on all of the information that Dr. Manning outlines rather than using primarily the mutation status
Dr. Manning. I agree.
Dr. Aggarwal. This patient had a lumpectomy and axillary lymph node dissection. Pathology reported 1.5-cm mass, grade 3 IDC; the margins were negative. There was no skin involvement, 27 lymph nodes removed were all negative. Dr. Manning, can you please discuss the role of radiation in early stage breast cancer in patients like this case?
Dr. Manning. One of the questions that is always controversial for radiation in these early stage breast cancer cases is what do you do with the nodal irradiation? Previously, radiation oncologists based treatment plans on retrospective data, but in 2015, there were 2 major studies, 1 from Canada, and 1 from the European Organisation for Research and Treatment of Cancer (EORTC).3,4 Both studies tried to determine whether there was an advantage to doing regional nodal irradiation in early breast cancer cases. That encompassed axillary, supraclavicular, and internal mammary nodes. The studies showed that there was no survival advantage, but there was a statistically significant improvement in disease free survival and in local regional recurrence and distant mets.
Unfortunately, there are still a lot of unanswered questions, like what group potentially would benefit the most? In the MA.20 Study, some observers questioned that maybe the ER-/PR- women had the most benefit, but then, in the other study the benefit wasn’t clear.4,5 One question is which lymph node group is having the most impact? Was the benefit from radiating the supraclavicular nodes or was it from radiating the internal mammary nodes? Determining the answer is important from a technical point of view because when you radiate the internal mammary nodes, you have the potential to expose more heart and lung to radiation. You have to put all these together and make a recommendation.
Clearly, for a patient with negative nodes there is no question: You would not treat the regional nodes. However, for a patient with positive nodes you really have to individualize the approach and consider age, anatomy, tumor location, and burden of axillary disease.
I would sit down and have a discussion with this young woman to weigh the risks and the benefits. There is a slight increased risk of lymphedema in these patients, and radiation pneumonitis increases, but not significantly. A key concern is to minimize the total dose of radiation to the heart. There have been great developments in radiation oncology technology and capabilities, so the cardiac dose is now less. But when you think about a 32-year-old patient and weigh the benefit of a 2% to 3% decrease in the incidence of distant metastases and no OS advantage, then you really need to have a conversation about how to safely treat her. At a minimum, I would treat the high axilla and the supraclavicular nodes because she had a pretty extensive lymph node dissection with more than 20 nodes, and then with her getting systemic therapy, that should be more than adequate.
Dr. Aggarwal. Is there any cutoff for age or size of the tumor where you would not do any radiation to the breast?
Dr. Manning. In this particular patient absolutely not because of the lymph node. She had breast-conserving therapy, and she’s only 32-years-old. The PRIME 2 study offered lumpectomy alone vs lumpectomy and radiation for women aged ≥ 65 years with tumors ≤ 3 cm, low grade.6 The study participants had to have negative lymph nodes, be ER+, and low grade. It was a very select group. The lumpectomy patients had a recurrence rate around 4%, and the other was closer to 1.3%.
You have to look at the whole picture. Is this a healthy 70-year-old woman? Is it an inconvenience for her to get treatment? Is she going to get hormone therapy and will she be adherent? There’s a very small group of women who underwent breast-conserving surgery that I would feel safe about not offering radiation.
Dr. Aggarwal. About 15% to 20% of all breast cancers are HER2 over expressors, which used to be a poor prognostic characteristic. However, the development of anti-HER2 therapies has changed the picture of HER2 prognosis. After the initial discovery of activity, the pivotal study by Slamon et al showed benefit in terms of progression-free survival (PFS) and OS with chemotherapy and trastuzumab. The NCCN guideline recommends anti-HER2 antibody trastuzumab in combination with chemotherapy.7
Patients with tumor < 0.5 cm who are HER2+ and ER+ may not benefit from trastuzumab, but those who are ER- and HER2+ will still benefit from trastuzumab. The combination is adriamycin/cyclophosphamide followed by a taxane with trastuzumab and to complete 1 year of trastuzumab or trastuzumab in combination with carboplatin and taxanes.
Pertuzumab, in combination with trastuzumab and docetaxel (PHT) has been FDA-approved in neoadjuvant and metastatic HER2+ disease, but is not FDA approved yet in the adjuvant setting. However, these are expensive drugs, and we don’t know how long these drugs should be given.
Mr. Crawford, What are the adverse effects (AEs) of an anti-HER2 or trastuzumab treatment, and what is the cost of trastuzumab?
Russell Crawford, BPharm. The anti-HER2 antibodies have certainly changed treatment plans and outcomes for patients with breast cancer who test HER2+. There are actually 3 of these anti-HER2 drugs on the U.S. market, and they can be used in a variety of settings. Trastuzumab and pertuzumab are indicated in women or patients who have HER2+ disease, and they work by binding to the extracellular domain of the HER2 proteins and mediate antibody-dependent cellular toxicity by inhibiting proliferation of the cells that overexpress HER2.
In this patient, we would be looking at using adjuvant trastuzumab to complete a 1-year course of therapy while she’s getting her dose-dense doxorubicin and cyclophosphamide (AC) on a weekly basis for the first 12 weeks. Trastuzumab is dosed with an initial loading dose of 4 mg/kg as the first dose, and then it’s 2 mg/kg/wk until adjuvant chemotherapy is completed. We usually extend the dosing out to 6 mg/kg every 3 weeks to complete the year of treatment.
These drugs are fairly well tolerated. They are monoclonal proteins, so a lot of the AEs that patients experience are the things that we’re used to seeing with other monoclonal proteins like the infusion-related reactions and some flulike symptoms. The biggest concern with these patients is that being on the drug for a year, there is a risk of decreasing the left ventricular ejection fraction (LVEF) of the heart. That risk is increased when these drugs are combined with anthracyclines that we know are cardiotoxic. As a single agent, the impact on left ventricular function is not significant, but when it is combined with chemotherapy, it does become a problem. Usually, we recommend routine and periodic monitoring of the LVEF with a multiple-gated acquisition or an echocardiogram to make sure that we’re not causing harm related to this treatment.
The cost of these drugs depends on the frequency, is it every week, every 2 weeks, or every 3 weeks? There are different ways to give trastuzumab, but for most patients, we prefer the every 3-week dose. And it’s estimated that for a 70-kg patient, a dose of trastuzumab at 6 mg/kg at the rate of every 3 weeks costs about $2,500 per dose. The VA pays about $6 a milligram, but it’s certainly money well spent because it has changed the playing field and the outcomes for these patients.
The cost of pertuzumab is dosed a little bit differently. It’s a flat dose not a weight-based dose. Patients get an initial loading dose of 840 mg and a continuation dose of 420 mg every 3 weeks. The cost of the 420-mg dose of pertuzumab is just under $3,000, so that first-time loading dose would be a $6,000 dose, and the continuing doses are about $3,000 per dose every 3 weeks. The AE profile is no different from what you would expect with trastuzumab. There is a similar toxicity profile for these 2 drugs. It does not appear that there is any additional cardiotoxicity if you are using the combination in the neoadjuvant setting.
The third targeted agent that goes after the HER2 is ado-trastuzumab, but it is only used in the metastatic setting, so we’ll reserve that for down the road for this patient should we ever need it.
Dr. Aggarwal. The patient received adriamycin/cyclophosphamide followed by paclitaxel weekly for 12 weeks with trastuzumab. After the 12 weekly doses, she went on trastuzumab every 3 weeks. Because she was ER+, she was a candidate for additional endocrine ablation therapy. She was started on tamoxifen and leuprolide acetate for complete hormonal ablation.
Tamoxifen was the first targeted therapy for breast cancer. In women with ER+ breast cancer, with tamoxifen given for 5 years as adjuvant treatment, the odds of recurrences decreased by 39%, and death decreased by 30% in both pre- and postmenopausal women.8 Then the ATLAS data came, which randomly allocated patients to continue another 5 years of tamoxifen vs placebo, for a total of 10 years of treatment with tamoxifen. With a mean of 7.6 years of further follow-up after entry at year 5 in this trial showed that recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.9 The current recommendation for pre- and postmenopausal is 10 years of tamoxifen.
In addition we have 3 aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, which block the production of estrogen in postmenopausal females. Anastrozole and letrozole are nonsteroidal, and exemestane is steroidal. There are countless big randomized trials using all of these drug in different combinations. In most of these trials, AIs are shown to be equal to tamoxifen when they are compared with each other, but their AE profile is different.
The recommendation by the American Society of Clinical Oncology and NCCN guidelines is to use only AIs for 5 years. There are different combinations: You can give tamoxifen for 2 to 3 years, followed by 5 years of an AI, or 5 years of tamoxifen and 5 years of an AI. Some patients wants to stop because of AEs, but others want to continue. Patients can develop osteoporosis and arthritis from an AI and hot flashes from tamoxifen.
Mr. Crawford, How would you manage of these AEs from these treatments?
Mr. Crawford. Because this woman is young, age 32, and premenopausal, tamoxifen would be the recommended endocrine therapy for her being ER+/PR+. But the role of the leuprolide acetate is to induce a chemical oophorectomy. We are putting her into ovarian ablation by using the leuprolide acetate.
The tamoxifen is relatively well tolerated, but as an ER blocker, it has a different AE profile than does an estrogen production decreaser. With tamoxifen patients tend to complain about hot flashes, edema, fluid retention, altered menses, spotting vaginal discharge, vaginal bleeding, and dryness. These medications also increase the risk of venous thromboembolism (VTE), and there is some concern about increased risk of developing endometrial cancers with these medications. We can give it either once or twice daily. There’s nothing that really says 10 mg twice daily vs 20 mg once daily is any different. So we may play with dosing to see if patients tolerate it better one way or the other.
There are medications that we can offer to help manage the hot flashes. These medications don’t necessarily make the hot flashes go away, but they can decrease the hot flash intensity or and/or frequency. Many medications have been evaluated for hot flashes. The best data are for venlafaxine, which is usually given once a day at bedtime (dosage 37.5-75.0 mg). There has been success with gabapentin titrated up to a dose of about 300 mg 3 times daily. They are fairly similar for decreasing hot flash scores and intensities, but the patient preferences were more favorable toward the venlafaxine than for the gabapentin.
The AIs, on the other hand, have a different AE profile. With tamoxifen we see vaginal discharges, bleeding, endometrial cancer risk, and VTE risk, but these are not significant problems with any of the AIs. The AE profiles for AIs include hot flashes, but more often it is complaints of bone pain, arthralgias, and myalgias. Probably the top reason why most patients discontinue taking AIs is arthralgia and myalgia.
Because we have shut off estrogen production with the AIs, and estrogen is an important component of maintaining good bone health and bone homeostasis, patients are at an increased risked of losing or declining bone mineral density (BMD). It is recommended that these patients get placed on routine calcium and vitamin D supplementation with routine dual-energy X-ray absorptiometry scans, so we know whether we will need to initiate osteoporosis treatment, whether with oral bisphosphonates, intravenous bisphosphonates, or subcutaneous rank ligand inhibitors.
With bisphosphonates there may be a slight increase in fracture rates. But we have to balance that with the BMD concerns. If the patient progresses into the metastatic setting and we know that there’s a fair chance that there’s going to be some skeletal involvement, those people are also at an increased risk of fracture. While there is a slight concern about the increased risk of fractures with bisphosphonates, I tend to believe that the benefits outweigh the risks.
Go to www.fedprac.com/AVAHO for a discussion of the next steps in the treatment for the patient after she returned 2 years later with nausea, vomiting, acute onset headache, and 2 brain lesions that were about 2 cm.
Click here to read the digital edition.
1. Feng Y, Rhie SK, Huo D, et al. Characterizing genetic susceptibility to breast cancer in women of african ancestry. Cancer Epidemiol Biomarkers. 2017;26(7):1016-1026.
2. Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19(2):169-180.
3. Poortmans PM, Collette S, Kirkove C, et al; EORTC Radiation Oncology and Breast Cancer Groups. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373(4):317-327.
4. Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373(4):307-316.
5. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383(9935):2127-2135.
6. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015;16(3):266-273.
7. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182.
8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
9. Davies C, Pan H, Godwin J, et al; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805-816.
Case Presentation
This case represents a composite of many different patients and is not meant to represent an individual. Any resemblance to an actual patient is coincidental.
A 32-year-old African American woman presented with a self-palpated left breast mass (axillary tail at 9 o’clock position). The patient was a nonsmoker, was otherwise healthy, and had no family history of breast or any other cancer. She had never used oral contraceptives or hormones, was never pregnant, her menarche was at age 12 years, and she had regular menstrual periods. On physical examination she had a 1-cm left breast mass and a palpable left axillary lymph node. A complete diagnostic workup revealed a 2-cm left breast mass. An ultrasound-guided biopsy of the axillary lymph node was positive for invasive ductal carcinoma (IDC). The final diagnosis was left breast cancer, stage IIB IDC, T1N1M0, ER+, PR+, HER2 2+ by immunohistochemistry, fluorescence in situ hybridization (FISH) was 2.4, confirming a HER2+ tumor.
Anita Aggarwal, DO, PhD. What is the role of genetic counseling and testing in this young patient who does not have a family history of breast cancer?
Vickie L. Venne, MS. This patient absolutely would be a candidate for counseling and testing. From a genetic counseling perspective, one of the first points has to do with what “no family history of cancer” means. Typically, in a fast-paced clinic, a patient will be asked “Does anybody else in your family have cancer?” And it’s not uncommon to get the answer “no.” Genetic counselors collect specific information on at least the first- and second-degree relatives, so we end up with 3 generations. This includes both the maternal and the paternal histories. We find that people who initially report no family history of cancer are often just thinking of breast cancer, even if the provider’s question is broad. When we start digging, we often find other cancers because cancer is common.
The other issue is that she was diagnosed at a young age. Clearly, 32 years is much younger than we typically see in breast cancer, and we know that individuals with hereditary cancers often have an earlier age of onset. With no other information, her a priori risk of having a BRCA1/2 mutation would be < 2.5%.
Regardless, based on current National Comprehensive Cancer Network (NCCN) guidelines, she would be a testing candidate. We would also recommend testing for more than just BRCA1/2. In the last few decades, there have been many genes identified that are associated with an increased susceptibility to cancer. Many of these genes are part of syndromes, so if you had a mutation, that also would increase the risk for a cancer in another organ. If this woman’s mother and father lived into their 70s or 80s and she had a number of aunts on both sides who never developed breast cancer, it would be less likely to be BRCA1/2. However, P53 also can present in young women and as a de novo mutation. Therefore, we would offer her a panel of actionable genes. Genes that if, in fact, we identified a mutation in one of them, would mean we could do something different for this young lady.
JoAnn Manning, MD. Let’s say she does have testing, and she comes back BRCA+. Then what would be the recommendations or guidance?
Ms. Venne. Women (and men as well!) with mutations have an increased risk for a second primary breast cancer as well as cancer in other organs. Focusing first on the breast story and all the media around BRCA1/2 mutations and surgery, this is a woman who may consider a more aggressive surgery, including prophylactic contralateral mastectomy, if she is concerned. She is young, so we also would explore her fertility plans. While her next few months will be filled with breast cancer treatment choices, women with BRCA mutations also are at an increased risk to develop ovarian cancer, so that might be a decision she makes as well. Her health care team may also eventually discuss chemotherapeutic options available specifically to women with mutations.
However, we often see young women who are extremely nervous because there is a sense that if you’re younger, your cancer must be inherited. Part of the pretest counseling is to explore psychosocial issues and help these young ladies understand that, especially if she does not have a family history of cancer and the only indication is her age, then it’s highly likely that we’re not going to find an identifiable mutation. And in that circumstance, she probably could consider a more conservative surgical decision.
Dr. Aggarwal. How common is a BRCA1 or BRCA2 mutation in African American females?
Ms. Venne. I have not paid attention to the prevalence of mutations based on ethnicity, so I don’t know. While many of the initial mutations were discovered in women of European ancestry, there are large cohorts of women with African ancestry whose specimens are now available for identifying genetic markers that will improve breast cancer risk assessment in them.1 However, because those mutations are still being characterized, it is more common to find a variant of uncertain significance (VUS) in African American women. A VUS is an alteration—a change in the gene—that we simply don’t know what it means yet. Clinicians don’t have enough information to know if that alteration is pathogenic or benign. The problem is that people try to make sense out of everything in their lives, so they also will try to make a VUS mean something. We try hard to help people understand that a VUS is really no more significant than if we had not tested in the first place, and they should not act on that information. They should use their family history, their age, their other psychosocial concerns about their experiences with cancer as they make their treatment decisions. But they also should check back periodically with their genetic counselor because VUSs can be reclassified. And if that happens, the information might be more useful for not only them, but their family members.
Dr. Manning. Would you consider this patient for any neoadjuvant chemotherapy?
Dr. Aggarwal. The patient is a young female with a small tumor that is HER2+. The indication for neoadjuvant chemotherapy is typically a big tumor or inoperable disease. Neoadjuvant chemotherapy is considered the standard of care for patients with inflammatory breast cancer and may confer a survival benefit in these patients. Of all the breast cancer subtypes, triple negative and HER2+ are considered the most chemosensitive and may benefit from neoadjuvant therapy. This patient has a small tumor, and I don’t think she’s a candidate for neoadjuvant chemotherapy unless the patient wants to see if her tumor is chemosensitive or not.
Dr. Manning, What’s the role and benefit of lumpectomy vs mastectomy?
Dr. Manning. Historically, mastectomy would have been considered the standard of care, but luckily, in the 1970s and the 1980s, we had a significant number of randomized controlled trials that demonstrated that certain women with particular characteristics would get the same overall survival if they chose mastectomy vs lumpectomy, the removal of the tumor with negative margin and whole-breast radiation. The key thing to understand is that breast-conserving surgery is now very well established with more than 20 years of data to support it. And that breast irradiation after breast-conserving surgery is essential to maximizing the local control and the overall survival (OS).
There have been a lot of major studies, but the one with the greatest follow-up now is the National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 protocol, which was the only trial to compare mastectomy to lumpectomy and radiation or lumpectomy alone. It required negative margins. With 20 years of follow-up, the data still support that mastectomy or lumpectomy with radiation offers equivalent OS and local control. It’s really about patient preference if they are candidates.
Who is a candidate? Clearly, there are contraindications. We tend to look primarily at the size of the tumor. However, removing an average-sized tumor (< 2 cm) with a margin may not have a good cosmetic result for a patient with very small breasts. That patient may opt to go forward with a mastectomy instead. Young patients who are candidates must have to have negative margins. If they have persistently positive resection margins after excision or reexcision, then they need to go forward with mastectomy.
A patient who has imaging evidence of multicentric disease with 2 or more primary tumors in separate quadrants would not be a candidate for breast-conserving therapy. Diffuse malignant-appearing microcalcifications on a mammogram also would suggest multicentric disease. And a patient with a prior history of radiation therapy to the breast or chest wall cannot go through breast-conserving therapy.
In the case we are discussing, we also should make sure this young lady is not pregnant. If the patient is adamant about breast-conserving surgery and pregnant, especially in the third trimester, radiation could be deferred until after delivery. Another relative contraindication is for patients who have connective tissue disorders. Sometimes if they are given whole-breast radiation, the cosmetic result is poor. So if you’re doing this procedure to save the breast, then having a good cosmetic result is an important consideration for many patients.
When you look at the size of the tumor for this patient, she seems to be a good candidate for breast-conserving surgery. I would recommend that she go forward with lumpectomy followed by whole-breast radiation.
Ms. Venne. Although the numbers aren’t nearly as large as they were in the original trials looking at the lumpectomy vs mastectomy, there are now survival data for women with BRCA1/2 mutations. With all of the caveats that Dr. Manning mentioned, even if you have an identifiable mutation, you may not necessarily need that more aggressive surgery.2 Clearly, individuals with identifiable mutations would have a higher chance of a contralateral breast cancer, a second primary, so some individuals consider a prophylactic bilateral mastectomy. But from a survival perspective, there are a fair amount of data now available that say that lumpectomy vs mastectomy should really be the conversation based on all of the information that Dr. Manning outlines rather than using primarily the mutation status
Dr. Manning. I agree.
Dr. Aggarwal. This patient had a lumpectomy and axillary lymph node dissection. Pathology reported 1.5-cm mass, grade 3 IDC; the margins were negative. There was no skin involvement, 27 lymph nodes removed were all negative. Dr. Manning, can you please discuss the role of radiation in early stage breast cancer in patients like this case?
Dr. Manning. One of the questions that is always controversial for radiation in these early stage breast cancer cases is what do you do with the nodal irradiation? Previously, radiation oncologists based treatment plans on retrospective data, but in 2015, there were 2 major studies, 1 from Canada, and 1 from the European Organisation for Research and Treatment of Cancer (EORTC).3,4 Both studies tried to determine whether there was an advantage to doing regional nodal irradiation in early breast cancer cases. That encompassed axillary, supraclavicular, and internal mammary nodes. The studies showed that there was no survival advantage, but there was a statistically significant improvement in disease free survival and in local regional recurrence and distant mets.
Unfortunately, there are still a lot of unanswered questions, like what group potentially would benefit the most? In the MA.20 Study, some observers questioned that maybe the ER-/PR- women had the most benefit, but then, in the other study the benefit wasn’t clear.4,5 One question is which lymph node group is having the most impact? Was the benefit from radiating the supraclavicular nodes or was it from radiating the internal mammary nodes? Determining the answer is important from a technical point of view because when you radiate the internal mammary nodes, you have the potential to expose more heart and lung to radiation. You have to put all these together and make a recommendation.
Clearly, for a patient with negative nodes there is no question: You would not treat the regional nodes. However, for a patient with positive nodes you really have to individualize the approach and consider age, anatomy, tumor location, and burden of axillary disease.
I would sit down and have a discussion with this young woman to weigh the risks and the benefits. There is a slight increased risk of lymphedema in these patients, and radiation pneumonitis increases, but not significantly. A key concern is to minimize the total dose of radiation to the heart. There have been great developments in radiation oncology technology and capabilities, so the cardiac dose is now less. But when you think about a 32-year-old patient and weigh the benefit of a 2% to 3% decrease in the incidence of distant metastases and no OS advantage, then you really need to have a conversation about how to safely treat her. At a minimum, I would treat the high axilla and the supraclavicular nodes because she had a pretty extensive lymph node dissection with more than 20 nodes, and then with her getting systemic therapy, that should be more than adequate.
Dr. Aggarwal. Is there any cutoff for age or size of the tumor where you would not do any radiation to the breast?
Dr. Manning. In this particular patient absolutely not because of the lymph node. She had breast-conserving therapy, and she’s only 32-years-old. The PRIME 2 study offered lumpectomy alone vs lumpectomy and radiation for women aged ≥ 65 years with tumors ≤ 3 cm, low grade.6 The study participants had to have negative lymph nodes, be ER+, and low grade. It was a very select group. The lumpectomy patients had a recurrence rate around 4%, and the other was closer to 1.3%.
You have to look at the whole picture. Is this a healthy 70-year-old woman? Is it an inconvenience for her to get treatment? Is she going to get hormone therapy and will she be adherent? There’s a very small group of women who underwent breast-conserving surgery that I would feel safe about not offering radiation.
Dr. Aggarwal. About 15% to 20% of all breast cancers are HER2 over expressors, which used to be a poor prognostic characteristic. However, the development of anti-HER2 therapies has changed the picture of HER2 prognosis. After the initial discovery of activity, the pivotal study by Slamon et al showed benefit in terms of progression-free survival (PFS) and OS with chemotherapy and trastuzumab. The NCCN guideline recommends anti-HER2 antibody trastuzumab in combination with chemotherapy.7
Patients with tumor < 0.5 cm who are HER2+ and ER+ may not benefit from trastuzumab, but those who are ER- and HER2+ will still benefit from trastuzumab. The combination is adriamycin/cyclophosphamide followed by a taxane with trastuzumab and to complete 1 year of trastuzumab or trastuzumab in combination with carboplatin and taxanes.
Pertuzumab, in combination with trastuzumab and docetaxel (PHT) has been FDA-approved in neoadjuvant and metastatic HER2+ disease, but is not FDA approved yet in the adjuvant setting. However, these are expensive drugs, and we don’t know how long these drugs should be given.
Mr. Crawford, What are the adverse effects (AEs) of an anti-HER2 or trastuzumab treatment, and what is the cost of trastuzumab?
Russell Crawford, BPharm. The anti-HER2 antibodies have certainly changed treatment plans and outcomes for patients with breast cancer who test HER2+. There are actually 3 of these anti-HER2 drugs on the U.S. market, and they can be used in a variety of settings. Trastuzumab and pertuzumab are indicated in women or patients who have HER2+ disease, and they work by binding to the extracellular domain of the HER2 proteins and mediate antibody-dependent cellular toxicity by inhibiting proliferation of the cells that overexpress HER2.
In this patient, we would be looking at using adjuvant trastuzumab to complete a 1-year course of therapy while she’s getting her dose-dense doxorubicin and cyclophosphamide (AC) on a weekly basis for the first 12 weeks. Trastuzumab is dosed with an initial loading dose of 4 mg/kg as the first dose, and then it’s 2 mg/kg/wk until adjuvant chemotherapy is completed. We usually extend the dosing out to 6 mg/kg every 3 weeks to complete the year of treatment.
These drugs are fairly well tolerated. They are monoclonal proteins, so a lot of the AEs that patients experience are the things that we’re used to seeing with other monoclonal proteins like the infusion-related reactions and some flulike symptoms. The biggest concern with these patients is that being on the drug for a year, there is a risk of decreasing the left ventricular ejection fraction (LVEF) of the heart. That risk is increased when these drugs are combined with anthracyclines that we know are cardiotoxic. As a single agent, the impact on left ventricular function is not significant, but when it is combined with chemotherapy, it does become a problem. Usually, we recommend routine and periodic monitoring of the LVEF with a multiple-gated acquisition or an echocardiogram to make sure that we’re not causing harm related to this treatment.
The cost of these drugs depends on the frequency, is it every week, every 2 weeks, or every 3 weeks? There are different ways to give trastuzumab, but for most patients, we prefer the every 3-week dose. And it’s estimated that for a 70-kg patient, a dose of trastuzumab at 6 mg/kg at the rate of every 3 weeks costs about $2,500 per dose. The VA pays about $6 a milligram, but it’s certainly money well spent because it has changed the playing field and the outcomes for these patients.
The cost of pertuzumab is dosed a little bit differently. It’s a flat dose not a weight-based dose. Patients get an initial loading dose of 840 mg and a continuation dose of 420 mg every 3 weeks. The cost of the 420-mg dose of pertuzumab is just under $3,000, so that first-time loading dose would be a $6,000 dose, and the continuing doses are about $3,000 per dose every 3 weeks. The AE profile is no different from what you would expect with trastuzumab. There is a similar toxicity profile for these 2 drugs. It does not appear that there is any additional cardiotoxicity if you are using the combination in the neoadjuvant setting.
The third targeted agent that goes after the HER2 is ado-trastuzumab, but it is only used in the metastatic setting, so we’ll reserve that for down the road for this patient should we ever need it.
Dr. Aggarwal. The patient received adriamycin/cyclophosphamide followed by paclitaxel weekly for 12 weeks with trastuzumab. After the 12 weekly doses, she went on trastuzumab every 3 weeks. Because she was ER+, she was a candidate for additional endocrine ablation therapy. She was started on tamoxifen and leuprolide acetate for complete hormonal ablation.
Tamoxifen was the first targeted therapy for breast cancer. In women with ER+ breast cancer, with tamoxifen given for 5 years as adjuvant treatment, the odds of recurrences decreased by 39%, and death decreased by 30% in both pre- and postmenopausal women.8 Then the ATLAS data came, which randomly allocated patients to continue another 5 years of tamoxifen vs placebo, for a total of 10 years of treatment with tamoxifen. With a mean of 7.6 years of further follow-up after entry at year 5 in this trial showed that recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.9 The current recommendation for pre- and postmenopausal is 10 years of tamoxifen.
In addition we have 3 aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, which block the production of estrogen in postmenopausal females. Anastrozole and letrozole are nonsteroidal, and exemestane is steroidal. There are countless big randomized trials using all of these drug in different combinations. In most of these trials, AIs are shown to be equal to tamoxifen when they are compared with each other, but their AE profile is different.
The recommendation by the American Society of Clinical Oncology and NCCN guidelines is to use only AIs for 5 years. There are different combinations: You can give tamoxifen for 2 to 3 years, followed by 5 years of an AI, or 5 years of tamoxifen and 5 years of an AI. Some patients wants to stop because of AEs, but others want to continue. Patients can develop osteoporosis and arthritis from an AI and hot flashes from tamoxifen.
Mr. Crawford, How would you manage of these AEs from these treatments?
Mr. Crawford. Because this woman is young, age 32, and premenopausal, tamoxifen would be the recommended endocrine therapy for her being ER+/PR+. But the role of the leuprolide acetate is to induce a chemical oophorectomy. We are putting her into ovarian ablation by using the leuprolide acetate.
The tamoxifen is relatively well tolerated, but as an ER blocker, it has a different AE profile than does an estrogen production decreaser. With tamoxifen patients tend to complain about hot flashes, edema, fluid retention, altered menses, spotting vaginal discharge, vaginal bleeding, and dryness. These medications also increase the risk of venous thromboembolism (VTE), and there is some concern about increased risk of developing endometrial cancers with these medications. We can give it either once or twice daily. There’s nothing that really says 10 mg twice daily vs 20 mg once daily is any different. So we may play with dosing to see if patients tolerate it better one way or the other.
There are medications that we can offer to help manage the hot flashes. These medications don’t necessarily make the hot flashes go away, but they can decrease the hot flash intensity or and/or frequency. Many medications have been evaluated for hot flashes. The best data are for venlafaxine, which is usually given once a day at bedtime (dosage 37.5-75.0 mg). There has been success with gabapentin titrated up to a dose of about 300 mg 3 times daily. They are fairly similar for decreasing hot flash scores and intensities, but the patient preferences were more favorable toward the venlafaxine than for the gabapentin.
The AIs, on the other hand, have a different AE profile. With tamoxifen we see vaginal discharges, bleeding, endometrial cancer risk, and VTE risk, but these are not significant problems with any of the AIs. The AE profiles for AIs include hot flashes, but more often it is complaints of bone pain, arthralgias, and myalgias. Probably the top reason why most patients discontinue taking AIs is arthralgia and myalgia.
Because we have shut off estrogen production with the AIs, and estrogen is an important component of maintaining good bone health and bone homeostasis, patients are at an increased risked of losing or declining bone mineral density (BMD). It is recommended that these patients get placed on routine calcium and vitamin D supplementation with routine dual-energy X-ray absorptiometry scans, so we know whether we will need to initiate osteoporosis treatment, whether with oral bisphosphonates, intravenous bisphosphonates, or subcutaneous rank ligand inhibitors.
With bisphosphonates there may be a slight increase in fracture rates. But we have to balance that with the BMD concerns. If the patient progresses into the metastatic setting and we know that there’s a fair chance that there’s going to be some skeletal involvement, those people are also at an increased risk of fracture. While there is a slight concern about the increased risk of fractures with bisphosphonates, I tend to believe that the benefits outweigh the risks.
Go to www.fedprac.com/AVAHO for a discussion of the next steps in the treatment for the patient after she returned 2 years later with nausea, vomiting, acute onset headache, and 2 brain lesions that were about 2 cm.
Click here to read the digital edition.
Case Presentation
This case represents a composite of many different patients and is not meant to represent an individual. Any resemblance to an actual patient is coincidental.
A 32-year-old African American woman presented with a self-palpated left breast mass (axillary tail at 9 o’clock position). The patient was a nonsmoker, was otherwise healthy, and had no family history of breast or any other cancer. She had never used oral contraceptives or hormones, was never pregnant, her menarche was at age 12 years, and she had regular menstrual periods. On physical examination she had a 1-cm left breast mass and a palpable left axillary lymph node. A complete diagnostic workup revealed a 2-cm left breast mass. An ultrasound-guided biopsy of the axillary lymph node was positive for invasive ductal carcinoma (IDC). The final diagnosis was left breast cancer, stage IIB IDC, T1N1M0, ER+, PR+, HER2 2+ by immunohistochemistry, fluorescence in situ hybridization (FISH) was 2.4, confirming a HER2+ tumor.
Anita Aggarwal, DO, PhD. What is the role of genetic counseling and testing in this young patient who does not have a family history of breast cancer?
Vickie L. Venne, MS. This patient absolutely would be a candidate for counseling and testing. From a genetic counseling perspective, one of the first points has to do with what “no family history of cancer” means. Typically, in a fast-paced clinic, a patient will be asked “Does anybody else in your family have cancer?” And it’s not uncommon to get the answer “no.” Genetic counselors collect specific information on at least the first- and second-degree relatives, so we end up with 3 generations. This includes both the maternal and the paternal histories. We find that people who initially report no family history of cancer are often just thinking of breast cancer, even if the provider’s question is broad. When we start digging, we often find other cancers because cancer is common.
The other issue is that she was diagnosed at a young age. Clearly, 32 years is much younger than we typically see in breast cancer, and we know that individuals with hereditary cancers often have an earlier age of onset. With no other information, her a priori risk of having a BRCA1/2 mutation would be < 2.5%.
Regardless, based on current National Comprehensive Cancer Network (NCCN) guidelines, she would be a testing candidate. We would also recommend testing for more than just BRCA1/2. In the last few decades, there have been many genes identified that are associated with an increased susceptibility to cancer. Many of these genes are part of syndromes, so if you had a mutation, that also would increase the risk for a cancer in another organ. If this woman’s mother and father lived into their 70s or 80s and she had a number of aunts on both sides who never developed breast cancer, it would be less likely to be BRCA1/2. However, P53 also can present in young women and as a de novo mutation. Therefore, we would offer her a panel of actionable genes. Genes that if, in fact, we identified a mutation in one of them, would mean we could do something different for this young lady.
JoAnn Manning, MD. Let’s say she does have testing, and she comes back BRCA+. Then what would be the recommendations or guidance?
Ms. Venne. Women (and men as well!) with mutations have an increased risk for a second primary breast cancer as well as cancer in other organs. Focusing first on the breast story and all the media around BRCA1/2 mutations and surgery, this is a woman who may consider a more aggressive surgery, including prophylactic contralateral mastectomy, if she is concerned. She is young, so we also would explore her fertility plans. While her next few months will be filled with breast cancer treatment choices, women with BRCA mutations also are at an increased risk to develop ovarian cancer, so that might be a decision she makes as well. Her health care team may also eventually discuss chemotherapeutic options available specifically to women with mutations.
However, we often see young women who are extremely nervous because there is a sense that if you’re younger, your cancer must be inherited. Part of the pretest counseling is to explore psychosocial issues and help these young ladies understand that, especially if she does not have a family history of cancer and the only indication is her age, then it’s highly likely that we’re not going to find an identifiable mutation. And in that circumstance, she probably could consider a more conservative surgical decision.
Dr. Aggarwal. How common is a BRCA1 or BRCA2 mutation in African American females?
Ms. Venne. I have not paid attention to the prevalence of mutations based on ethnicity, so I don’t know. While many of the initial mutations were discovered in women of European ancestry, there are large cohorts of women with African ancestry whose specimens are now available for identifying genetic markers that will improve breast cancer risk assessment in them.1 However, because those mutations are still being characterized, it is more common to find a variant of uncertain significance (VUS) in African American women. A VUS is an alteration—a change in the gene—that we simply don’t know what it means yet. Clinicians don’t have enough information to know if that alteration is pathogenic or benign. The problem is that people try to make sense out of everything in their lives, so they also will try to make a VUS mean something. We try hard to help people understand that a VUS is really no more significant than if we had not tested in the first place, and they should not act on that information. They should use their family history, their age, their other psychosocial concerns about their experiences with cancer as they make their treatment decisions. But they also should check back periodically with their genetic counselor because VUSs can be reclassified. And if that happens, the information might be more useful for not only them, but their family members.
Dr. Manning. Would you consider this patient for any neoadjuvant chemotherapy?
Dr. Aggarwal. The patient is a young female with a small tumor that is HER2+. The indication for neoadjuvant chemotherapy is typically a big tumor or inoperable disease. Neoadjuvant chemotherapy is considered the standard of care for patients with inflammatory breast cancer and may confer a survival benefit in these patients. Of all the breast cancer subtypes, triple negative and HER2+ are considered the most chemosensitive and may benefit from neoadjuvant therapy. This patient has a small tumor, and I don’t think she’s a candidate for neoadjuvant chemotherapy unless the patient wants to see if her tumor is chemosensitive or not.
Dr. Manning, What’s the role and benefit of lumpectomy vs mastectomy?
Dr. Manning. Historically, mastectomy would have been considered the standard of care, but luckily, in the 1970s and the 1980s, we had a significant number of randomized controlled trials that demonstrated that certain women with particular characteristics would get the same overall survival if they chose mastectomy vs lumpectomy, the removal of the tumor with negative margin and whole-breast radiation. The key thing to understand is that breast-conserving surgery is now very well established with more than 20 years of data to support it. And that breast irradiation after breast-conserving surgery is essential to maximizing the local control and the overall survival (OS).
There have been a lot of major studies, but the one with the greatest follow-up now is the National Surgical Adjuvant Breast and Bowel Project (NSABP) B06 protocol, which was the only trial to compare mastectomy to lumpectomy and radiation or lumpectomy alone. It required negative margins. With 20 years of follow-up, the data still support that mastectomy or lumpectomy with radiation offers equivalent OS and local control. It’s really about patient preference if they are candidates.
Who is a candidate? Clearly, there are contraindications. We tend to look primarily at the size of the tumor. However, removing an average-sized tumor (< 2 cm) with a margin may not have a good cosmetic result for a patient with very small breasts. That patient may opt to go forward with a mastectomy instead. Young patients who are candidates must have to have negative margins. If they have persistently positive resection margins after excision or reexcision, then they need to go forward with mastectomy.
A patient who has imaging evidence of multicentric disease with 2 or more primary tumors in separate quadrants would not be a candidate for breast-conserving therapy. Diffuse malignant-appearing microcalcifications on a mammogram also would suggest multicentric disease. And a patient with a prior history of radiation therapy to the breast or chest wall cannot go through breast-conserving therapy.
In the case we are discussing, we also should make sure this young lady is not pregnant. If the patient is adamant about breast-conserving surgery and pregnant, especially in the third trimester, radiation could be deferred until after delivery. Another relative contraindication is for patients who have connective tissue disorders. Sometimes if they are given whole-breast radiation, the cosmetic result is poor. So if you’re doing this procedure to save the breast, then having a good cosmetic result is an important consideration for many patients.
When you look at the size of the tumor for this patient, she seems to be a good candidate for breast-conserving surgery. I would recommend that she go forward with lumpectomy followed by whole-breast radiation.
Ms. Venne. Although the numbers aren’t nearly as large as they were in the original trials looking at the lumpectomy vs mastectomy, there are now survival data for women with BRCA1/2 mutations. With all of the caveats that Dr. Manning mentioned, even if you have an identifiable mutation, you may not necessarily need that more aggressive surgery.2 Clearly, individuals with identifiable mutations would have a higher chance of a contralateral breast cancer, a second primary, so some individuals consider a prophylactic bilateral mastectomy. But from a survival perspective, there are a fair amount of data now available that say that lumpectomy vs mastectomy should really be the conversation based on all of the information that Dr. Manning outlines rather than using primarily the mutation status
Dr. Manning. I agree.
Dr. Aggarwal. This patient had a lumpectomy and axillary lymph node dissection. Pathology reported 1.5-cm mass, grade 3 IDC; the margins were negative. There was no skin involvement, 27 lymph nodes removed were all negative. Dr. Manning, can you please discuss the role of radiation in early stage breast cancer in patients like this case?
Dr. Manning. One of the questions that is always controversial for radiation in these early stage breast cancer cases is what do you do with the nodal irradiation? Previously, radiation oncologists based treatment plans on retrospective data, but in 2015, there were 2 major studies, 1 from Canada, and 1 from the European Organisation for Research and Treatment of Cancer (EORTC).3,4 Both studies tried to determine whether there was an advantage to doing regional nodal irradiation in early breast cancer cases. That encompassed axillary, supraclavicular, and internal mammary nodes. The studies showed that there was no survival advantage, but there was a statistically significant improvement in disease free survival and in local regional recurrence and distant mets.
Unfortunately, there are still a lot of unanswered questions, like what group potentially would benefit the most? In the MA.20 Study, some observers questioned that maybe the ER-/PR- women had the most benefit, but then, in the other study the benefit wasn’t clear.4,5 One question is which lymph node group is having the most impact? Was the benefit from radiating the supraclavicular nodes or was it from radiating the internal mammary nodes? Determining the answer is important from a technical point of view because when you radiate the internal mammary nodes, you have the potential to expose more heart and lung to radiation. You have to put all these together and make a recommendation.
Clearly, for a patient with negative nodes there is no question: You would not treat the regional nodes. However, for a patient with positive nodes you really have to individualize the approach and consider age, anatomy, tumor location, and burden of axillary disease.
I would sit down and have a discussion with this young woman to weigh the risks and the benefits. There is a slight increased risk of lymphedema in these patients, and radiation pneumonitis increases, but not significantly. A key concern is to minimize the total dose of radiation to the heart. There have been great developments in radiation oncology technology and capabilities, so the cardiac dose is now less. But when you think about a 32-year-old patient and weigh the benefit of a 2% to 3% decrease in the incidence of distant metastases and no OS advantage, then you really need to have a conversation about how to safely treat her. At a minimum, I would treat the high axilla and the supraclavicular nodes because she had a pretty extensive lymph node dissection with more than 20 nodes, and then with her getting systemic therapy, that should be more than adequate.
Dr. Aggarwal. Is there any cutoff for age or size of the tumor where you would not do any radiation to the breast?
Dr. Manning. In this particular patient absolutely not because of the lymph node. She had breast-conserving therapy, and she’s only 32-years-old. The PRIME 2 study offered lumpectomy alone vs lumpectomy and radiation for women aged ≥ 65 years with tumors ≤ 3 cm, low grade.6 The study participants had to have negative lymph nodes, be ER+, and low grade. It was a very select group. The lumpectomy patients had a recurrence rate around 4%, and the other was closer to 1.3%.
You have to look at the whole picture. Is this a healthy 70-year-old woman? Is it an inconvenience for her to get treatment? Is she going to get hormone therapy and will she be adherent? There’s a very small group of women who underwent breast-conserving surgery that I would feel safe about not offering radiation.
Dr. Aggarwal. About 15% to 20% of all breast cancers are HER2 over expressors, which used to be a poor prognostic characteristic. However, the development of anti-HER2 therapies has changed the picture of HER2 prognosis. After the initial discovery of activity, the pivotal study by Slamon et al showed benefit in terms of progression-free survival (PFS) and OS with chemotherapy and trastuzumab. The NCCN guideline recommends anti-HER2 antibody trastuzumab in combination with chemotherapy.7
Patients with tumor < 0.5 cm who are HER2+ and ER+ may not benefit from trastuzumab, but those who are ER- and HER2+ will still benefit from trastuzumab. The combination is adriamycin/cyclophosphamide followed by a taxane with trastuzumab and to complete 1 year of trastuzumab or trastuzumab in combination with carboplatin and taxanes.
Pertuzumab, in combination with trastuzumab and docetaxel (PHT) has been FDA-approved in neoadjuvant and metastatic HER2+ disease, but is not FDA approved yet in the adjuvant setting. However, these are expensive drugs, and we don’t know how long these drugs should be given.
Mr. Crawford, What are the adverse effects (AEs) of an anti-HER2 or trastuzumab treatment, and what is the cost of trastuzumab?
Russell Crawford, BPharm. The anti-HER2 antibodies have certainly changed treatment plans and outcomes for patients with breast cancer who test HER2+. There are actually 3 of these anti-HER2 drugs on the U.S. market, and they can be used in a variety of settings. Trastuzumab and pertuzumab are indicated in women or patients who have HER2+ disease, and they work by binding to the extracellular domain of the HER2 proteins and mediate antibody-dependent cellular toxicity by inhibiting proliferation of the cells that overexpress HER2.
In this patient, we would be looking at using adjuvant trastuzumab to complete a 1-year course of therapy while she’s getting her dose-dense doxorubicin and cyclophosphamide (AC) on a weekly basis for the first 12 weeks. Trastuzumab is dosed with an initial loading dose of 4 mg/kg as the first dose, and then it’s 2 mg/kg/wk until adjuvant chemotherapy is completed. We usually extend the dosing out to 6 mg/kg every 3 weeks to complete the year of treatment.
These drugs are fairly well tolerated. They are monoclonal proteins, so a lot of the AEs that patients experience are the things that we’re used to seeing with other monoclonal proteins like the infusion-related reactions and some flulike symptoms. The biggest concern with these patients is that being on the drug for a year, there is a risk of decreasing the left ventricular ejection fraction (LVEF) of the heart. That risk is increased when these drugs are combined with anthracyclines that we know are cardiotoxic. As a single agent, the impact on left ventricular function is not significant, but when it is combined with chemotherapy, it does become a problem. Usually, we recommend routine and periodic monitoring of the LVEF with a multiple-gated acquisition or an echocardiogram to make sure that we’re not causing harm related to this treatment.
The cost of these drugs depends on the frequency, is it every week, every 2 weeks, or every 3 weeks? There are different ways to give trastuzumab, but for most patients, we prefer the every 3-week dose. And it’s estimated that for a 70-kg patient, a dose of trastuzumab at 6 mg/kg at the rate of every 3 weeks costs about $2,500 per dose. The VA pays about $6 a milligram, but it’s certainly money well spent because it has changed the playing field and the outcomes for these patients.
The cost of pertuzumab is dosed a little bit differently. It’s a flat dose not a weight-based dose. Patients get an initial loading dose of 840 mg and a continuation dose of 420 mg every 3 weeks. The cost of the 420-mg dose of pertuzumab is just under $3,000, so that first-time loading dose would be a $6,000 dose, and the continuing doses are about $3,000 per dose every 3 weeks. The AE profile is no different from what you would expect with trastuzumab. There is a similar toxicity profile for these 2 drugs. It does not appear that there is any additional cardiotoxicity if you are using the combination in the neoadjuvant setting.
The third targeted agent that goes after the HER2 is ado-trastuzumab, but it is only used in the metastatic setting, so we’ll reserve that for down the road for this patient should we ever need it.
Dr. Aggarwal. The patient received adriamycin/cyclophosphamide followed by paclitaxel weekly for 12 weeks with trastuzumab. After the 12 weekly doses, she went on trastuzumab every 3 weeks. Because she was ER+, she was a candidate for additional endocrine ablation therapy. She was started on tamoxifen and leuprolide acetate for complete hormonal ablation.
Tamoxifen was the first targeted therapy for breast cancer. In women with ER+ breast cancer, with tamoxifen given for 5 years as adjuvant treatment, the odds of recurrences decreased by 39%, and death decreased by 30% in both pre- and postmenopausal women.8 Then the ATLAS data came, which randomly allocated patients to continue another 5 years of tamoxifen vs placebo, for a total of 10 years of treatment with tamoxifen. With a mean of 7.6 years of further follow-up after entry at year 5 in this trial showed that recurrence and breast cancer mortality during the second decade after diagnosis are reduced more effectively by 10 years of adjuvant tamoxifen than by 5 years.9 The current recommendation for pre- and postmenopausal is 10 years of tamoxifen.
In addition we have 3 aromatase inhibitors (AIs), anastrozole, letrozole, and exemestane, which block the production of estrogen in postmenopausal females. Anastrozole and letrozole are nonsteroidal, and exemestane is steroidal. There are countless big randomized trials using all of these drug in different combinations. In most of these trials, AIs are shown to be equal to tamoxifen when they are compared with each other, but their AE profile is different.
The recommendation by the American Society of Clinical Oncology and NCCN guidelines is to use only AIs for 5 years. There are different combinations: You can give tamoxifen for 2 to 3 years, followed by 5 years of an AI, or 5 years of tamoxifen and 5 years of an AI. Some patients wants to stop because of AEs, but others want to continue. Patients can develop osteoporosis and arthritis from an AI and hot flashes from tamoxifen.
Mr. Crawford, How would you manage of these AEs from these treatments?
Mr. Crawford. Because this woman is young, age 32, and premenopausal, tamoxifen would be the recommended endocrine therapy for her being ER+/PR+. But the role of the leuprolide acetate is to induce a chemical oophorectomy. We are putting her into ovarian ablation by using the leuprolide acetate.
The tamoxifen is relatively well tolerated, but as an ER blocker, it has a different AE profile than does an estrogen production decreaser. With tamoxifen patients tend to complain about hot flashes, edema, fluid retention, altered menses, spotting vaginal discharge, vaginal bleeding, and dryness. These medications also increase the risk of venous thromboembolism (VTE), and there is some concern about increased risk of developing endometrial cancers with these medications. We can give it either once or twice daily. There’s nothing that really says 10 mg twice daily vs 20 mg once daily is any different. So we may play with dosing to see if patients tolerate it better one way or the other.
There are medications that we can offer to help manage the hot flashes. These medications don’t necessarily make the hot flashes go away, but they can decrease the hot flash intensity or and/or frequency. Many medications have been evaluated for hot flashes. The best data are for venlafaxine, which is usually given once a day at bedtime (dosage 37.5-75.0 mg). There has been success with gabapentin titrated up to a dose of about 300 mg 3 times daily. They are fairly similar for decreasing hot flash scores and intensities, but the patient preferences were more favorable toward the venlafaxine than for the gabapentin.
The AIs, on the other hand, have a different AE profile. With tamoxifen we see vaginal discharges, bleeding, endometrial cancer risk, and VTE risk, but these are not significant problems with any of the AIs. The AE profiles for AIs include hot flashes, but more often it is complaints of bone pain, arthralgias, and myalgias. Probably the top reason why most patients discontinue taking AIs is arthralgia and myalgia.
Because we have shut off estrogen production with the AIs, and estrogen is an important component of maintaining good bone health and bone homeostasis, patients are at an increased risked of losing or declining bone mineral density (BMD). It is recommended that these patients get placed on routine calcium and vitamin D supplementation with routine dual-energy X-ray absorptiometry scans, so we know whether we will need to initiate osteoporosis treatment, whether with oral bisphosphonates, intravenous bisphosphonates, or subcutaneous rank ligand inhibitors.
With bisphosphonates there may be a slight increase in fracture rates. But we have to balance that with the BMD concerns. If the patient progresses into the metastatic setting and we know that there’s a fair chance that there’s going to be some skeletal involvement, those people are also at an increased risk of fracture. While there is a slight concern about the increased risk of fractures with bisphosphonates, I tend to believe that the benefits outweigh the risks.
Go to www.fedprac.com/AVAHO for a discussion of the next steps in the treatment for the patient after she returned 2 years later with nausea, vomiting, acute onset headache, and 2 brain lesions that were about 2 cm.
Click here to read the digital edition.
1. Feng Y, Rhie SK, Huo D, et al. Characterizing genetic susceptibility to breast cancer in women of african ancestry. Cancer Epidemiol Biomarkers. 2017;26(7):1016-1026.
2. Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19(2):169-180.
3. Poortmans PM, Collette S, Kirkove C, et al; EORTC Radiation Oncology and Breast Cancer Groups. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373(4):317-327.
4. Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373(4):307-316.
5. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383(9935):2127-2135.
6. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015;16(3):266-273.
7. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182.
8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
9. Davies C, Pan H, Godwin J, et al; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805-816.
1. Feng Y, Rhie SK, Huo D, et al. Characterizing genetic susceptibility to breast cancer in women of african ancestry. Cancer Epidemiol Biomarkers. 2017;26(7):1016-1026.
2. Copson ER, Maishman TC, Tapper WJ, et al. Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol. 2018;19(2):169-180.
3. Poortmans PM, Collette S, Kirkove C, et al; EORTC Radiation Oncology and Breast Cancer Groups. Internal mammary and medial supraclavicular irradiation in breast cancer. N Engl J Med. 2015;373(4):317-327.
4. Whelan TJ, Olivotto IA, Parulekar WR, et al; MA.20 Study Investigators. Regional nodal irradiation in early-stage breast cancer. N Engl J Med. 2015;373(4):307-316.
5. EBCTCG (Early Breast Cancer Trialists’ Collaborative Group), McGale P, Taylor C, Correa C, et al. Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials. Lancet. 2014;383(9935):2127-2135.
6. Kunkler IH, Williams LJ, Jack WJ, Cameron DA, Dixon JM; PRIME II investigators. Breast-conserving surgery with or without irradiation in women aged 65 years or older with early breast cancer (PRIME II): a randomised controlled trial. Lancet Oncol. 2015;16(3):266-273.
7. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182.
8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15 year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
9. Davies C, Pan H, Godwin J, et al; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013;381(9869):805-816.
Breast cancer recurrence lower, survival better with dose-intensified regimens
Dose-intense adjuvant chemotherapy is associated with significant if modest improvements in recurrence-free, breast cancer–specific, and overall survival among women with early breast cancer, results of a meta-analysis of data on individual patients showed.
Among more than 37,000 patients treated in 26 clinical trials with a median follow-up of 7.4 years, there was a 14% reduction in relative risk and 3.4% reduction in absolute 10-year risk of breast cancer recurrence for women who were treated either with accelerated-schedule or sequential chemotherapy, reported members of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
There were no differences in deaths from cardiovascular disease, acute myeloid leukemia, or other cancers between patients treated with dose-intense regimens or schedules and those treated with standard chemotherapy, although patients on dose-intense regimens had higher incidence of grade 3 or 4 anemia, and more did not complete the prescribed courses compared with standard chemotherapy, the investigators noted.
“The balance of benefit versus toxicity, therefore, appears to favor more dose-intense chemotherapy. A further advantage of 2-weekly versus 3-weekly chemotherapy – but not of sequential versus concurrent chemotherapy – is treatment is completed sooner,” they wrote in The Lancet.
The investigators examined individual patient data for 26 of 33 trials comparing either 2-weekly chemotherapy with 3-weekly therapy, or sequential vs. concurrent anthracycline and taxane-based chemotherapy.
The trials comprised a total cohort of 37,297 women randomized, most of whom were younger than 70 years at the time of diagnose and had node-positive disease.
The 10 year-risk for breast cancer recurrence, one of two primary endpoints, was 28% with dose intensification vs. 31.4% with standard dosing, translating into a first-event rate ratio (RR) for recurrence of 0.86 (P less than .0001).
Ten-year breast-cancer mortality, the other primary endpoint, was 18.9% among patients treated with dose-intensified regimens or schedules, compared with 21.3% for patients treated under standard protocols.
All-cause mortality was lower with dose intensification (22.1% vs. 24.8%, P less than .0001), and death without recurrence was also slightly but significantly lower (4.1% vs. 4.6%, respectively, P = .034).
The reductions in recurrence rates were similar among trials comparing 2-week vs. 3-week chemotherapy cycles, sequential vs. concurrent schedules, and both strategies together.
“The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant [P less than .0001) in estrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumor characteristics,” the investigators wrote.
“The present findings are of limited relevance to the question of which women with early breast cancer should be offered chemotherapy, although they do indicate that chemotherapy can reduce breast cancer mortality rates by 40% rather than a third. The absolute gain from this proportional reduction in recurrence depends chiefly on what the risk of distant recurrence would be without chemotherapy, which varies greatly from one woman to another, and is the subject of much ongoing research,” the investigators wrote.
“The findings are, however, directly relevant to selection of what regimen to use, and they show that, if chemotherapy is to be given, a dose-intense regimen should at least be considered,” they wrote.
The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
SOURCE: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
Although these results are meaningful, several limitations should be recognized as we translate these findings into practice. First, the benefits of dose intensification have not been established in the era of targeted therapy. Given that these studies enrolled women from 1985 to 2011, HER2 status was known for only 50% of tumors. Of those tested, 16% (n = 2,994) were HER2 positive. Use of trastuzumab was not reported but was probably uncommon since adjuvant trastuzumab was not approved until 2006. The remaining 18,625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. Therefore, the majority of patients with HER2- positive breast cancer did not receive targeted therapy.
Although the authors report that women with HER2-positive and HER2-negative disease benefit similarly from dose intensification, it is impossible to know whether dose intensification benefits trastuzumab-treated patients or those who receive more than one HER2-targeted therapy (pertuzumab, neratinib, or trastuzumab-emtansine). Similarly, if other targeted therapies such as CDK4/6 inhibitors and PARP inhibitors show significant benefit in the curative setting for high-risk estrogen receptor (ER)-positive or BRCA-mutated breast cancer, prospective studies will be required to establish whether dose-intensive chemotherapy is better than standard chemotherapy in those settings.
Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. Moreover, gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. Finally, the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.
With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important. In modern practice, if anthracycline-based chemotherapy is warranted, these data provide convincing evidence that a dose-intense approach should be considered.
Sara A Hurvitz, MD, is from the David Geffen School of Medicine at UCLA, Santa Monica, Calif. Her remarks are excerpted from an editorial accompanying the study. She reports institutional research funding and fees for abstract and manuscript writing from several pharmaceutical companies outside of the submitted work, and travel reimbursement from Lilly outside of the submitted work.
Although these results are meaningful, several limitations should be recognized as we translate these findings into practice. First, the benefits of dose intensification have not been established in the era of targeted therapy. Given that these studies enrolled women from 1985 to 2011, HER2 status was known for only 50% of tumors. Of those tested, 16% (n = 2,994) were HER2 positive. Use of trastuzumab was not reported but was probably uncommon since adjuvant trastuzumab was not approved until 2006. The remaining 18,625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. Therefore, the majority of patients with HER2- positive breast cancer did not receive targeted therapy.
Although the authors report that women with HER2-positive and HER2-negative disease benefit similarly from dose intensification, it is impossible to know whether dose intensification benefits trastuzumab-treated patients or those who receive more than one HER2-targeted therapy (pertuzumab, neratinib, or trastuzumab-emtansine). Similarly, if other targeted therapies such as CDK4/6 inhibitors and PARP inhibitors show significant benefit in the curative setting for high-risk estrogen receptor (ER)-positive or BRCA-mutated breast cancer, prospective studies will be required to establish whether dose-intensive chemotherapy is better than standard chemotherapy in those settings.
Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. Moreover, gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. Finally, the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.
With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important. In modern practice, if anthracycline-based chemotherapy is warranted, these data provide convincing evidence that a dose-intense approach should be considered.
Sara A Hurvitz, MD, is from the David Geffen School of Medicine at UCLA, Santa Monica, Calif. Her remarks are excerpted from an editorial accompanying the study. She reports institutional research funding and fees for abstract and manuscript writing from several pharmaceutical companies outside of the submitted work, and travel reimbursement from Lilly outside of the submitted work.
Although these results are meaningful, several limitations should be recognized as we translate these findings into practice. First, the benefits of dose intensification have not been established in the era of targeted therapy. Given that these studies enrolled women from 1985 to 2011, HER2 status was known for only 50% of tumors. Of those tested, 16% (n = 2,994) were HER2 positive. Use of trastuzumab was not reported but was probably uncommon since adjuvant trastuzumab was not approved until 2006. The remaining 18,625 patients did not have HER2 testing; thus, no HER2-directed therapy would have been given. Therefore, the majority of patients with HER2- positive breast cancer did not receive targeted therapy.
Although the authors report that women with HER2-positive and HER2-negative disease benefit similarly from dose intensification, it is impossible to know whether dose intensification benefits trastuzumab-treated patients or those who receive more than one HER2-targeted therapy (pertuzumab, neratinib, or trastuzumab-emtansine). Similarly, if other targeted therapies such as CDK4/6 inhibitors and PARP inhibitors show significant benefit in the curative setting for high-risk estrogen receptor (ER)-positive or BRCA-mutated breast cancer, prospective studies will be required to establish whether dose-intensive chemotherapy is better than standard chemotherapy in those settings.
Second, it is premature to conclude that patients older than 70 years or those with node-negative disease benefit from dose intensification, given the small number of patients in those groups and the fact that no significant benefit was observed for these patients. Moreover, gene-expression profiling was not used in these studies; thus, the benefit, if any, of a dose-intense approach for women with lymph-node-negative, high-risk, ER-positive disease is impossible to know. Finally, the use of dose intensification has not been studied in non-anthracycline, taxane-based regimens, which are being increasingly evaluated and used in women with node-negative, ER-positive disease.
With these caveats in mind, the results of this meta-analysis are undoubtedly clinically important. In modern practice, if anthracycline-based chemotherapy is warranted, these data provide convincing evidence that a dose-intense approach should be considered.
Sara A Hurvitz, MD, is from the David Geffen School of Medicine at UCLA, Santa Monica, Calif. Her remarks are excerpted from an editorial accompanying the study. She reports institutional research funding and fees for abstract and manuscript writing from several pharmaceutical companies outside of the submitted work, and travel reimbursement from Lilly outside of the submitted work.
Dose-intense adjuvant chemotherapy is associated with significant if modest improvements in recurrence-free, breast cancer–specific, and overall survival among women with early breast cancer, results of a meta-analysis of data on individual patients showed.
Among more than 37,000 patients treated in 26 clinical trials with a median follow-up of 7.4 years, there was a 14% reduction in relative risk and 3.4% reduction in absolute 10-year risk of breast cancer recurrence for women who were treated either with accelerated-schedule or sequential chemotherapy, reported members of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
There were no differences in deaths from cardiovascular disease, acute myeloid leukemia, or other cancers between patients treated with dose-intense regimens or schedules and those treated with standard chemotherapy, although patients on dose-intense regimens had higher incidence of grade 3 or 4 anemia, and more did not complete the prescribed courses compared with standard chemotherapy, the investigators noted.
“The balance of benefit versus toxicity, therefore, appears to favor more dose-intense chemotherapy. A further advantage of 2-weekly versus 3-weekly chemotherapy – but not of sequential versus concurrent chemotherapy – is treatment is completed sooner,” they wrote in The Lancet.
The investigators examined individual patient data for 26 of 33 trials comparing either 2-weekly chemotherapy with 3-weekly therapy, or sequential vs. concurrent anthracycline and taxane-based chemotherapy.
The trials comprised a total cohort of 37,297 women randomized, most of whom were younger than 70 years at the time of diagnose and had node-positive disease.
The 10 year-risk for breast cancer recurrence, one of two primary endpoints, was 28% with dose intensification vs. 31.4% with standard dosing, translating into a first-event rate ratio (RR) for recurrence of 0.86 (P less than .0001).
Ten-year breast-cancer mortality, the other primary endpoint, was 18.9% among patients treated with dose-intensified regimens or schedules, compared with 21.3% for patients treated under standard protocols.
All-cause mortality was lower with dose intensification (22.1% vs. 24.8%, P less than .0001), and death without recurrence was also slightly but significantly lower (4.1% vs. 4.6%, respectively, P = .034).
The reductions in recurrence rates were similar among trials comparing 2-week vs. 3-week chemotherapy cycles, sequential vs. concurrent schedules, and both strategies together.
“The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant [P less than .0001) in estrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumor characteristics,” the investigators wrote.
“The present findings are of limited relevance to the question of which women with early breast cancer should be offered chemotherapy, although they do indicate that chemotherapy can reduce breast cancer mortality rates by 40% rather than a third. The absolute gain from this proportional reduction in recurrence depends chiefly on what the risk of distant recurrence would be without chemotherapy, which varies greatly from one woman to another, and is the subject of much ongoing research,” the investigators wrote.
“The findings are, however, directly relevant to selection of what regimen to use, and they show that, if chemotherapy is to be given, a dose-intense regimen should at least be considered,” they wrote.
The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
SOURCE: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
Dose-intense adjuvant chemotherapy is associated with significant if modest improvements in recurrence-free, breast cancer–specific, and overall survival among women with early breast cancer, results of a meta-analysis of data on individual patients showed.
Among more than 37,000 patients treated in 26 clinical trials with a median follow-up of 7.4 years, there was a 14% reduction in relative risk and 3.4% reduction in absolute 10-year risk of breast cancer recurrence for women who were treated either with accelerated-schedule or sequential chemotherapy, reported members of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG).
There were no differences in deaths from cardiovascular disease, acute myeloid leukemia, or other cancers between patients treated with dose-intense regimens or schedules and those treated with standard chemotherapy, although patients on dose-intense regimens had higher incidence of grade 3 or 4 anemia, and more did not complete the prescribed courses compared with standard chemotherapy, the investigators noted.
“The balance of benefit versus toxicity, therefore, appears to favor more dose-intense chemotherapy. A further advantage of 2-weekly versus 3-weekly chemotherapy – but not of sequential versus concurrent chemotherapy – is treatment is completed sooner,” they wrote in The Lancet.
The investigators examined individual patient data for 26 of 33 trials comparing either 2-weekly chemotherapy with 3-weekly therapy, or sequential vs. concurrent anthracycline and taxane-based chemotherapy.
The trials comprised a total cohort of 37,297 women randomized, most of whom were younger than 70 years at the time of diagnose and had node-positive disease.
The 10 year-risk for breast cancer recurrence, one of two primary endpoints, was 28% with dose intensification vs. 31.4% with standard dosing, translating into a first-event rate ratio (RR) for recurrence of 0.86 (P less than .0001).
Ten-year breast-cancer mortality, the other primary endpoint, was 18.9% among patients treated with dose-intensified regimens or schedules, compared with 21.3% for patients treated under standard protocols.
All-cause mortality was lower with dose intensification (22.1% vs. 24.8%, P less than .0001), and death without recurrence was also slightly but significantly lower (4.1% vs. 4.6%, respectively, P = .034).
The reductions in recurrence rates were similar among trials comparing 2-week vs. 3-week chemotherapy cycles, sequential vs. concurrent schedules, and both strategies together.
“The proportional reductions in recurrence with dose-intense chemotherapy were similar and highly significant [P less than .0001) in estrogen receptor (ER)-positive and ER-negative disease and did not differ significantly by other patient or tumor characteristics,” the investigators wrote.
“The present findings are of limited relevance to the question of which women with early breast cancer should be offered chemotherapy, although they do indicate that chemotherapy can reduce breast cancer mortality rates by 40% rather than a third. The absolute gain from this proportional reduction in recurrence depends chiefly on what the risk of distant recurrence would be without chemotherapy, which varies greatly from one woman to another, and is the subject of much ongoing research,” the investigators wrote.
“The findings are, however, directly relevant to selection of what regimen to use, and they show that, if chemotherapy is to be given, a dose-intense regimen should at least be considered,” they wrote.
The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
SOURCE: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
FROM THE LANCET
Key clinical point: Consider dose-intensification or sequential therapy for patients undergoing chemotherapy.
Major finding: Ten-year recurrence rates were 28% with dose intensification vs. 31.4% for standard dosing.
Study details: Meta-analysis of individual data on 37,298 women enrolled in 26 randomized trials.
Disclosures: The meta-analysis was funded by Cancer Research UK and the Medical Research Council. All authors reported having no relevant disclosures.
Source: EBCTCG. The Lancet. 2019 Feb 7. doi: 10.1016/S0140-6736(18)33137-4.
Why Am I Being Treated Like a Female Breast Cancer Patient? (FULL)
Patient Perspective
Breast cancer has been one of my life’s greatest blessings. Its highs and lows, prospects, and disappointments have only strengthened my faith and turned me more to God.
In March 2012, I had a bad cold, and while I was coughing and grabbing my chest, I discovered a small knot in my left breast, and for whatever reason, I suspected it was cancer. I immediately woke my wife. She, groggy and in usual humor exclaimed, “Oh great! You have breast cancer! Well guess what? I have prostate cancer…now go back to sleep!” I laughed at the prospect of her having prostate cancer. It certainly would’ve changed a few dynamics in our relationship.
Two weeks later my fears were confirmed. I was told that I needed to have a mastectomy of my left breast. I wanted nothing but to have this poison removed. Yesterday would not have been too soon.
My surgery was scheduled a month later; it was a long wait. And it soon became clear that as I recovered from the impending mastectomy, I also would be in line for open-heart surgery.
The mastectomy was a textbook procedure with no complications. My surgeon apprehensively warned me that follow-up visits would be at the Women’s Health Center. I must admit, it was awkward every time I went. Realistically though, I cared more about my health than about others’ perceptions.
While I prepared for my cardiac surgery, the blood test revealed triglyceride levels that were through the roof. In fact, the cardiac surgeon described them as “industrial strength.” After an exhaustive review, it was determined that my adjuvant therapy with tamoxifen was the culprit! I immediately stopped taking it, and within days my levels returned to normal. I was now left to fight any future bouts of cancer with just my body’s own defenses.
It probably seems strange, but if I had not found the breast lump, the problems with my heart would have gone undetected. I most likely would’ve died. Had the cancer not been a part of my life, I wouldn’t have been able to keep on living.
In the middle of March 2016, during preliminary testing for surgery to remove a skin tag, my chest X-ray displayed abnormalities. The workup showed that my breast cancer had returned. Worse yet, it had metastasized to my lungs. It had gone into my lymph nodes and lower spine.
The fight was on. A treatment plan was outlined; 12 weeks of chemotherapy infusions was a reasonable plan of attack. A second opinion was not necessarily an opportunity to find a differing plan, but as in my case, it was comforting affirmation of a good plan. I remember wondering if the rest of my life was going to be a mix of hospital visits, blood transfusions, chemotherapies, and injections.
While fear of the unknown works on one’s psyche, I made a decision to focus on my faith and God. My cancer experiences are probably no worse or different from the experiences of most other patients. I do believe that my perception of how cancer affected me psychologically is a different story. I know and trust that I am in the capable and knowledgeable hands of my doctor.
While the experience of good health care is remarkable, living with cancer does not end with medical care. I am blessed to have a partner who loves me infinitely. I cannot imagine my life without her.
I am grateful my cancer has allowed me to remain alive. The prospect of death does not shake me. I plan on living my life to the fullest.
Oncologist Perspective
Yes, men do get breast cancer! Unlike female breast cancer (FBC), male breast cancer (MBC) makes up about 1% of all cases in the U.S. The lifetime risk of a man developing breast cancer is about 1 in 1,000 vs 1 in 8 women.1 Little is known about MBC because its rarity renders prospective randomized trials problematic. As a result, the management of breast cancer in males from diagnosis to treatment is based on research on FBC. Patients with MBC have higher mortality, and the incidence is rising 1.1% per year; by comparison both trends are decreasing for females with breast cancer.2,3
Males are usually older and present with an advanced stage of the disease at the time of the diagnosis. Most MBC is ER+/PR+ and HER2−.4 Comparison data of 1,123 male veterans with 5,320 females revealed that the mean age at diagnosis was 70 years for MBC and 57 years for FBC, respectively (P < .01); 95% of patients with MBC and 72% of patients with FBC were aged > 50 years (P < .01). Patients with MBC were more likely to present with stage III or IV disease (40% vs 24%, respectively). Eighty percent of patients with MBC had ER+/PR+ tumors. Mortality was 31.6% in males vs 14.9% in females.
Given the high prevalence of ER/PR positivity, MBC usually is considered to have a better prognosis, but that does not explain the high mortality. Unlike FBC, delay in diagnosis due to lack of MBC awareness and no screening guidelines for MBC, older age at diagnosis, and comorbidities have been considered the etiology of higher mortality in MBC, but there has to be more than that. I believe that the differences in MBC biology and pathology also have to be contributing factors to MBC mortality.
As a VA oncologist, I have treated a number of patients with MBC. Surprisingly, my experience treating these patients has been different from treating FBC. In 2011, when I first met Mr. Lewis, he laughed and questioned his diagnosis—how could he have breast cancer if males don’t have breasts, and none of his family member had any type of cancer. Prior to his cancer diagnoses, he had gone through multiple cardiac stents and had a history of hypertriglyceridemia. His cancer workup and treatment plan were the same as that of females with breast cancer, and he questioned me again, “Why am I being treated like a female breast cancer patient?”
Unlike females with breast cancer, he had to have a complete mastectomy given the small breast tissue. His final diagnosis was stage IIA invasive ductal carcinoma of the left breast.
Because of Mr. Lewis’ cardiac history and recent stent placement, I was hesitant to give him first-line adjuvant anthracycline. The Oncotype DX test is highly recommended and easily done for FBC, but I had to go through great difficulty to order this test for him. The Oncotype Dx RS score for him was 17 (a so-called low score) with distant recurrence risk of 11%. I interpreted the test the same way as I would for a patient with FBC. We were happy that he did not have to be exposed to toxic chemotherapies.
Because of the lack of data for aromatase inhibitors (AIs) use in males, adjuvant tamoxifen was given but had to be stopped after a month because of hypertriglyceridemia > 8,000 mg/dL and cholesterol > 700 mg/dL. Tamoxifen as well as an AI was deemed not to be the right adjuvant treatment for him. There were no data on adjuvant fulvestrant; not even for females in 2012. Mr. Lewis was among the unlucky 11% and presented with stage IV disease in his lungs and bones 4 years after the initial diagnosis. He has not had a great response to taxanes and now is being treated with fulvestrant. He remains positive and hopeful, he told me only God—not medical science—has the power to take back the gift of life.
My experience with Mr. Lewis and others has underscored that MBC is not the same disease as FBC. I am hopeful we will see more clinical trials to further identify MBC biology and genomics.
Click here to read the digital edition.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. American Cancer Society. Cancer facts and figures 2014. Atlanta, GA: American Cancer Society; 2014.
2. Anderson WF, Jatoi I, Tse J, Rosenberg PS. Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol. 2010;28(2):232-239.
3. Howlander N, Noone AM, Krapcho M, et al. eds. SEER cancer statistics review, 1975-2009: fast stats. http://seer.cancer.gov/csr/1975_2009_pops09. Updated April 2012. Accessed January 20, 2018.
4. Ly D, Forman D, Ferlay J, Brinton LA, Cook MB. An international comparison of male and female breast cancer incidence rates. Int J Cancer. 2013;132(8):1918-1926.
Patient Perspective
Breast cancer has been one of my life’s greatest blessings. Its highs and lows, prospects, and disappointments have only strengthened my faith and turned me more to God.
In March 2012, I had a bad cold, and while I was coughing and grabbing my chest, I discovered a small knot in my left breast, and for whatever reason, I suspected it was cancer. I immediately woke my wife. She, groggy and in usual humor exclaimed, “Oh great! You have breast cancer! Well guess what? I have prostate cancer…now go back to sleep!” I laughed at the prospect of her having prostate cancer. It certainly would’ve changed a few dynamics in our relationship.
Two weeks later my fears were confirmed. I was told that I needed to have a mastectomy of my left breast. I wanted nothing but to have this poison removed. Yesterday would not have been too soon.
My surgery was scheduled a month later; it was a long wait. And it soon became clear that as I recovered from the impending mastectomy, I also would be in line for open-heart surgery.
The mastectomy was a textbook procedure with no complications. My surgeon apprehensively warned me that follow-up visits would be at the Women’s Health Center. I must admit, it was awkward every time I went. Realistically though, I cared more about my health than about others’ perceptions.
While I prepared for my cardiac surgery, the blood test revealed triglyceride levels that were through the roof. In fact, the cardiac surgeon described them as “industrial strength.” After an exhaustive review, it was determined that my adjuvant therapy with tamoxifen was the culprit! I immediately stopped taking it, and within days my levels returned to normal. I was now left to fight any future bouts of cancer with just my body’s own defenses.
It probably seems strange, but if I had not found the breast lump, the problems with my heart would have gone undetected. I most likely would’ve died. Had the cancer not been a part of my life, I wouldn’t have been able to keep on living.
In the middle of March 2016, during preliminary testing for surgery to remove a skin tag, my chest X-ray displayed abnormalities. The workup showed that my breast cancer had returned. Worse yet, it had metastasized to my lungs. It had gone into my lymph nodes and lower spine.
The fight was on. A treatment plan was outlined; 12 weeks of chemotherapy infusions was a reasonable plan of attack. A second opinion was not necessarily an opportunity to find a differing plan, but as in my case, it was comforting affirmation of a good plan. I remember wondering if the rest of my life was going to be a mix of hospital visits, blood transfusions, chemotherapies, and injections.
While fear of the unknown works on one’s psyche, I made a decision to focus on my faith and God. My cancer experiences are probably no worse or different from the experiences of most other patients. I do believe that my perception of how cancer affected me psychologically is a different story. I know and trust that I am in the capable and knowledgeable hands of my doctor.
While the experience of good health care is remarkable, living with cancer does not end with medical care. I am blessed to have a partner who loves me infinitely. I cannot imagine my life without her.
I am grateful my cancer has allowed me to remain alive. The prospect of death does not shake me. I plan on living my life to the fullest.
Oncologist Perspective
Yes, men do get breast cancer! Unlike female breast cancer (FBC), male breast cancer (MBC) makes up about 1% of all cases in the U.S. The lifetime risk of a man developing breast cancer is about 1 in 1,000 vs 1 in 8 women.1 Little is known about MBC because its rarity renders prospective randomized trials problematic. As a result, the management of breast cancer in males from diagnosis to treatment is based on research on FBC. Patients with MBC have higher mortality, and the incidence is rising 1.1% per year; by comparison both trends are decreasing for females with breast cancer.2,3
Males are usually older and present with an advanced stage of the disease at the time of the diagnosis. Most MBC is ER+/PR+ and HER2−.4 Comparison data of 1,123 male veterans with 5,320 females revealed that the mean age at diagnosis was 70 years for MBC and 57 years for FBC, respectively (P < .01); 95% of patients with MBC and 72% of patients with FBC were aged > 50 years (P < .01). Patients with MBC were more likely to present with stage III or IV disease (40% vs 24%, respectively). Eighty percent of patients with MBC had ER+/PR+ tumors. Mortality was 31.6% in males vs 14.9% in females.
Given the high prevalence of ER/PR positivity, MBC usually is considered to have a better prognosis, but that does not explain the high mortality. Unlike FBC, delay in diagnosis due to lack of MBC awareness and no screening guidelines for MBC, older age at diagnosis, and comorbidities have been considered the etiology of higher mortality in MBC, but there has to be more than that. I believe that the differences in MBC biology and pathology also have to be contributing factors to MBC mortality.
As a VA oncologist, I have treated a number of patients with MBC. Surprisingly, my experience treating these patients has been different from treating FBC. In 2011, when I first met Mr. Lewis, he laughed and questioned his diagnosis—how could he have breast cancer if males don’t have breasts, and none of his family member had any type of cancer. Prior to his cancer diagnoses, he had gone through multiple cardiac stents and had a history of hypertriglyceridemia. His cancer workup and treatment plan were the same as that of females with breast cancer, and he questioned me again, “Why am I being treated like a female breast cancer patient?”
Unlike females with breast cancer, he had to have a complete mastectomy given the small breast tissue. His final diagnosis was stage IIA invasive ductal carcinoma of the left breast.
Because of Mr. Lewis’ cardiac history and recent stent placement, I was hesitant to give him first-line adjuvant anthracycline. The Oncotype DX test is highly recommended and easily done for FBC, but I had to go through great difficulty to order this test for him. The Oncotype Dx RS score for him was 17 (a so-called low score) with distant recurrence risk of 11%. I interpreted the test the same way as I would for a patient with FBC. We were happy that he did not have to be exposed to toxic chemotherapies.
Because of the lack of data for aromatase inhibitors (AIs) use in males, adjuvant tamoxifen was given but had to be stopped after a month because of hypertriglyceridemia > 8,000 mg/dL and cholesterol > 700 mg/dL. Tamoxifen as well as an AI was deemed not to be the right adjuvant treatment for him. There were no data on adjuvant fulvestrant; not even for females in 2012. Mr. Lewis was among the unlucky 11% and presented with stage IV disease in his lungs and bones 4 years after the initial diagnosis. He has not had a great response to taxanes and now is being treated with fulvestrant. He remains positive and hopeful, he told me only God—not medical science—has the power to take back the gift of life.
My experience with Mr. Lewis and others has underscored that MBC is not the same disease as FBC. I am hopeful we will see more clinical trials to further identify MBC biology and genomics.
Click here to read the digital edition.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
Patient Perspective
Breast cancer has been one of my life’s greatest blessings. Its highs and lows, prospects, and disappointments have only strengthened my faith and turned me more to God.
In March 2012, I had a bad cold, and while I was coughing and grabbing my chest, I discovered a small knot in my left breast, and for whatever reason, I suspected it was cancer. I immediately woke my wife. She, groggy and in usual humor exclaimed, “Oh great! You have breast cancer! Well guess what? I have prostate cancer…now go back to sleep!” I laughed at the prospect of her having prostate cancer. It certainly would’ve changed a few dynamics in our relationship.
Two weeks later my fears were confirmed. I was told that I needed to have a mastectomy of my left breast. I wanted nothing but to have this poison removed. Yesterday would not have been too soon.
My surgery was scheduled a month later; it was a long wait. And it soon became clear that as I recovered from the impending mastectomy, I also would be in line for open-heart surgery.
The mastectomy was a textbook procedure with no complications. My surgeon apprehensively warned me that follow-up visits would be at the Women’s Health Center. I must admit, it was awkward every time I went. Realistically though, I cared more about my health than about others’ perceptions.
While I prepared for my cardiac surgery, the blood test revealed triglyceride levels that were through the roof. In fact, the cardiac surgeon described them as “industrial strength.” After an exhaustive review, it was determined that my adjuvant therapy with tamoxifen was the culprit! I immediately stopped taking it, and within days my levels returned to normal. I was now left to fight any future bouts of cancer with just my body’s own defenses.
It probably seems strange, but if I had not found the breast lump, the problems with my heart would have gone undetected. I most likely would’ve died. Had the cancer not been a part of my life, I wouldn’t have been able to keep on living.
In the middle of March 2016, during preliminary testing for surgery to remove a skin tag, my chest X-ray displayed abnormalities. The workup showed that my breast cancer had returned. Worse yet, it had metastasized to my lungs. It had gone into my lymph nodes and lower spine.
The fight was on. A treatment plan was outlined; 12 weeks of chemotherapy infusions was a reasonable plan of attack. A second opinion was not necessarily an opportunity to find a differing plan, but as in my case, it was comforting affirmation of a good plan. I remember wondering if the rest of my life was going to be a mix of hospital visits, blood transfusions, chemotherapies, and injections.
While fear of the unknown works on one’s psyche, I made a decision to focus on my faith and God. My cancer experiences are probably no worse or different from the experiences of most other patients. I do believe that my perception of how cancer affected me psychologically is a different story. I know and trust that I am in the capable and knowledgeable hands of my doctor.
While the experience of good health care is remarkable, living with cancer does not end with medical care. I am blessed to have a partner who loves me infinitely. I cannot imagine my life without her.
I am grateful my cancer has allowed me to remain alive. The prospect of death does not shake me. I plan on living my life to the fullest.
Oncologist Perspective
Yes, men do get breast cancer! Unlike female breast cancer (FBC), male breast cancer (MBC) makes up about 1% of all cases in the U.S. The lifetime risk of a man developing breast cancer is about 1 in 1,000 vs 1 in 8 women.1 Little is known about MBC because its rarity renders prospective randomized trials problematic. As a result, the management of breast cancer in males from diagnosis to treatment is based on research on FBC. Patients with MBC have higher mortality, and the incidence is rising 1.1% per year; by comparison both trends are decreasing for females with breast cancer.2,3
Males are usually older and present with an advanced stage of the disease at the time of the diagnosis. Most MBC is ER+/PR+ and HER2−.4 Comparison data of 1,123 male veterans with 5,320 females revealed that the mean age at diagnosis was 70 years for MBC and 57 years for FBC, respectively (P < .01); 95% of patients with MBC and 72% of patients with FBC were aged > 50 years (P < .01). Patients with MBC were more likely to present with stage III or IV disease (40% vs 24%, respectively). Eighty percent of patients with MBC had ER+/PR+ tumors. Mortality was 31.6% in males vs 14.9% in females.
Given the high prevalence of ER/PR positivity, MBC usually is considered to have a better prognosis, but that does not explain the high mortality. Unlike FBC, delay in diagnosis due to lack of MBC awareness and no screening guidelines for MBC, older age at diagnosis, and comorbidities have been considered the etiology of higher mortality in MBC, but there has to be more than that. I believe that the differences in MBC biology and pathology also have to be contributing factors to MBC mortality.
As a VA oncologist, I have treated a number of patients with MBC. Surprisingly, my experience treating these patients has been different from treating FBC. In 2011, when I first met Mr. Lewis, he laughed and questioned his diagnosis—how could he have breast cancer if males don’t have breasts, and none of his family member had any type of cancer. Prior to his cancer diagnoses, he had gone through multiple cardiac stents and had a history of hypertriglyceridemia. His cancer workup and treatment plan were the same as that of females with breast cancer, and he questioned me again, “Why am I being treated like a female breast cancer patient?”
Unlike females with breast cancer, he had to have a complete mastectomy given the small breast tissue. His final diagnosis was stage IIA invasive ductal carcinoma of the left breast.
Because of Mr. Lewis’ cardiac history and recent stent placement, I was hesitant to give him first-line adjuvant anthracycline. The Oncotype DX test is highly recommended and easily done for FBC, but I had to go through great difficulty to order this test for him. The Oncotype Dx RS score for him was 17 (a so-called low score) with distant recurrence risk of 11%. I interpreted the test the same way as I would for a patient with FBC. We were happy that he did not have to be exposed to toxic chemotherapies.
Because of the lack of data for aromatase inhibitors (AIs) use in males, adjuvant tamoxifen was given but had to be stopped after a month because of hypertriglyceridemia > 8,000 mg/dL and cholesterol > 700 mg/dL. Tamoxifen as well as an AI was deemed not to be the right adjuvant treatment for him. There were no data on adjuvant fulvestrant; not even for females in 2012. Mr. Lewis was among the unlucky 11% and presented with stage IV disease in his lungs and bones 4 years after the initial diagnosis. He has not had a great response to taxanes and now is being treated with fulvestrant. He remains positive and hopeful, he told me only God—not medical science—has the power to take back the gift of life.
My experience with Mr. Lewis and others has underscored that MBC is not the same disease as FBC. I am hopeful we will see more clinical trials to further identify MBC biology and genomics.
Click here to read the digital edition.
Author disclosures
The authors report no actual or potential conflicts of interest with regard to this article.
Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the U.S. Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.
1. American Cancer Society. Cancer facts and figures 2014. Atlanta, GA: American Cancer Society; 2014.
2. Anderson WF, Jatoi I, Tse J, Rosenberg PS. Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol. 2010;28(2):232-239.
3. Howlander N, Noone AM, Krapcho M, et al. eds. SEER cancer statistics review, 1975-2009: fast stats. http://seer.cancer.gov/csr/1975_2009_pops09. Updated April 2012. Accessed January 20, 2018.
4. Ly D, Forman D, Ferlay J, Brinton LA, Cook MB. An international comparison of male and female breast cancer incidence rates. Int J Cancer. 2013;132(8):1918-1926.
1. American Cancer Society. Cancer facts and figures 2014. Atlanta, GA: American Cancer Society; 2014.
2. Anderson WF, Jatoi I, Tse J, Rosenberg PS. Male breast cancer: a population-based comparison with female breast cancer. J Clin Oncol. 2010;28(2):232-239.
3. Howlander N, Noone AM, Krapcho M, et al. eds. SEER cancer statistics review, 1975-2009: fast stats. http://seer.cancer.gov/csr/1975_2009_pops09. Updated April 2012. Accessed January 20, 2018.
4. Ly D, Forman D, Ferlay J, Brinton LA, Cook MB. An international comparison of male and female breast cancer incidence rates. Int J Cancer. 2013;132(8):1918-1926.
Therapy ups breast cancer survivors’ cardiac risks
WASHINGTON – Oncologists and cardiologists need to work hand-in-hand when managing the care of women with breast cancer whose treatment plan includes cardiotoxic therapies and breast irradiation, reported specialists.
Depending on the cancer subtype, women with breast cancer may receive chemotherapy with a cardiotoxic anthracycline such as doxorubicin or epirubicin, or a HER2-targeted agent such as trastuzumab (Herceptin), pertuzumab (Perjeta), or ado-trastuzumab emtansine (Kadcyla).
“The cardiotoxicity related to breast cancer has been a well publicized issue, and chances are your patients know about it and are concerned as well,” Jennifer E. Liu, MD, director of cardiovascular laboratories at Memorial Sloan Kettering Cancer Center in New York, said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Anthracyclines, trastuzumab, and HF
In large adjuvant therapy trials of anthracyclines and trastuzumab in women with breast cancer, doxorubicin alone was associated with an asymptomatic decline in left ventricular ejection fraction (LVEF) of 4% to 11%, and a less than 1% incidence of heart failure (HF), Dr. Liu noted.
When patients received an anthracycline followed by trastuzumab, the incidence of asymptomatic LVEF decline ranged from 4% to 19%, the incidence of clinical HF was 2% to 4%, and the rate of trastuzumab interruption for cardiac adverse events ranged from 5% to 18%.
In comparison, in trials with trastuzumab in combination therapy that did not contain an anthracycline, the risk of cardiovascular complications was lower, with asymptomatic decline in LVEF ranging from 3.2% to 9.4%, and class III/IV HF occurring in just 0.5% of patients. In trials combining trastuzumab and pertuzumab, there were no increases in cardiac toxicity over trastuzumab alone.
Although with longer follow-up, the approximately 4% rate of HF in patients treated with anthracycline-based chemotherapy, paclitaxel, and trastuzumab in the NSABP B-31 trial has not changed significantly; retrospective claims-based studies reflecting daily practice have shown significantly higher rates of HF and or cardiomyopathy, Dr. Liu said.
She cited a 2012 study showing that among 45,537 women with a mean age of 76 years who were treated for breast cancer, the 3-year incidence rates of HF and/or cardiomyopathy were 32% for patients treated with trastuzumab alone, and 41.9% for those treated with an anthracycline followed by trastuzumab. Other, smaller studies also showed lower but significantly elevated risks for the drugs.
The discrepancy between clinical trial and “real world” results may be chalked up to the fact that claims-based data rely on diagnostic codes that may not accurately reflect the actual cardiac diagnosis, and by the fact that clinical trials have strict entry criteria that exclude patients with cardiovascular disease, she said.
Radiation risks
Radiation therapy is associated with a more than 7% increase in major coronary events per Gy of mean heart dose, Dr. Liu noted, citing a 2013 study (N Engl J Med. 2013;368:987-98).
Paul Nguyen, MD, a radiation oncologist at the Dana-Farber/Brigham and Women’s Cancer Center in Boston, said that risk factors for radiation-induced heart disease include anterior or left chest irradiation, cumulative doses above 30 Gy, patient age younger than 50 years, doses of more than 2 Gy per fraction, presence and extent of tumor in or near the heart, lack of radiation shielding, concomitant chemotherapy (especially with anthracyclines), and preexisting cardiovascular disease or risk factors.
For patients with breast cancer, the risk of developing radiation-induced heart disease has diminished considerably with the adoption of heart-sparing techniques over the last several decades, including 3-D conformal techniques, intensity-modulated radiation therapy, proton beam therapy, novel patient positioning techniques that allow radiation only to the cancer-involved breast, and deep inspiration breath holds in which the radiation beam is gated to turn on only when the patient is holding a deep breath, Dr. Nguyen noted.
Treatment options for LVEF decline
The package insert for trastuzumab recommends withholding the drug for a minimum of 4 weeks if the patient has a 16% or greater decline in LVEF from baseline, or a 10% or greater decline from baseline to below the lower limit of normal. The insert recommends LVEF monitoring every 3 or 4 weeks, and says that trastuzumab can be resumed if LVEF improves to above the lower limit of normal with an absolute decrease from baseline of not more than 15%. The insert also states, however, that “the safety of continuation or resumption of trastuzumab in patients with trastuzumab induced LV dysfunction has never been studied, “ Dr. Liu noted.
She cited an American Society of Clinical Oncology guideline on the prevention and monitoring of cardiac dysfunction in survivors of adult cancers, which states in part that the decision to continue or discontinue cancer therapy in patients with evidence of cardiac dysfunction “made by the oncologist, should be informed by close collaboration with a cardiologist, fully evaluating the clinical circumstances and considering the risks and benefits of continuation of therapy responsible for the cardiac dysfunction.”
“I want to emphasize the importance of accepting and managing cardiovascular risk in patients priors to and during potentially cardiotoxic therapy. To optimize cardiologic and oncologic outcomes, we need to avoid or minimize treatment interruptions of life-saving therapy, and mitigate cardiac events with aggressive cardiovascular risk-factor modification,” Dr. Liu said.
She called for development of better risk stratification tools to tailor cardiac surveillance during therapy, based on both patient-specific and treatment-specific risk factors.
Dr. Liu reported nothing to disclose. Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics. Cota, Dendreon, Ferring Pharmaceuticals. GenomeDx, Janssen, and Nanobiotix.
WASHINGTON – Oncologists and cardiologists need to work hand-in-hand when managing the care of women with breast cancer whose treatment plan includes cardiotoxic therapies and breast irradiation, reported specialists.
Depending on the cancer subtype, women with breast cancer may receive chemotherapy with a cardiotoxic anthracycline such as doxorubicin or epirubicin, or a HER2-targeted agent such as trastuzumab (Herceptin), pertuzumab (Perjeta), or ado-trastuzumab emtansine (Kadcyla).
“The cardiotoxicity related to breast cancer has been a well publicized issue, and chances are your patients know about it and are concerned as well,” Jennifer E. Liu, MD, director of cardiovascular laboratories at Memorial Sloan Kettering Cancer Center in New York, said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Anthracyclines, trastuzumab, and HF
In large adjuvant therapy trials of anthracyclines and trastuzumab in women with breast cancer, doxorubicin alone was associated with an asymptomatic decline in left ventricular ejection fraction (LVEF) of 4% to 11%, and a less than 1% incidence of heart failure (HF), Dr. Liu noted.
When patients received an anthracycline followed by trastuzumab, the incidence of asymptomatic LVEF decline ranged from 4% to 19%, the incidence of clinical HF was 2% to 4%, and the rate of trastuzumab interruption for cardiac adverse events ranged from 5% to 18%.
In comparison, in trials with trastuzumab in combination therapy that did not contain an anthracycline, the risk of cardiovascular complications was lower, with asymptomatic decline in LVEF ranging from 3.2% to 9.4%, and class III/IV HF occurring in just 0.5% of patients. In trials combining trastuzumab and pertuzumab, there were no increases in cardiac toxicity over trastuzumab alone.
Although with longer follow-up, the approximately 4% rate of HF in patients treated with anthracycline-based chemotherapy, paclitaxel, and trastuzumab in the NSABP B-31 trial has not changed significantly; retrospective claims-based studies reflecting daily practice have shown significantly higher rates of HF and or cardiomyopathy, Dr. Liu said.
She cited a 2012 study showing that among 45,537 women with a mean age of 76 years who were treated for breast cancer, the 3-year incidence rates of HF and/or cardiomyopathy were 32% for patients treated with trastuzumab alone, and 41.9% for those treated with an anthracycline followed by trastuzumab. Other, smaller studies also showed lower but significantly elevated risks for the drugs.
The discrepancy between clinical trial and “real world” results may be chalked up to the fact that claims-based data rely on diagnostic codes that may not accurately reflect the actual cardiac diagnosis, and by the fact that clinical trials have strict entry criteria that exclude patients with cardiovascular disease, she said.
Radiation risks
Radiation therapy is associated with a more than 7% increase in major coronary events per Gy of mean heart dose, Dr. Liu noted, citing a 2013 study (N Engl J Med. 2013;368:987-98).
Paul Nguyen, MD, a radiation oncologist at the Dana-Farber/Brigham and Women’s Cancer Center in Boston, said that risk factors for radiation-induced heart disease include anterior or left chest irradiation, cumulative doses above 30 Gy, patient age younger than 50 years, doses of more than 2 Gy per fraction, presence and extent of tumor in or near the heart, lack of radiation shielding, concomitant chemotherapy (especially with anthracyclines), and preexisting cardiovascular disease or risk factors.
For patients with breast cancer, the risk of developing radiation-induced heart disease has diminished considerably with the adoption of heart-sparing techniques over the last several decades, including 3-D conformal techniques, intensity-modulated radiation therapy, proton beam therapy, novel patient positioning techniques that allow radiation only to the cancer-involved breast, and deep inspiration breath holds in which the radiation beam is gated to turn on only when the patient is holding a deep breath, Dr. Nguyen noted.
Treatment options for LVEF decline
The package insert for trastuzumab recommends withholding the drug for a minimum of 4 weeks if the patient has a 16% or greater decline in LVEF from baseline, or a 10% or greater decline from baseline to below the lower limit of normal. The insert recommends LVEF monitoring every 3 or 4 weeks, and says that trastuzumab can be resumed if LVEF improves to above the lower limit of normal with an absolute decrease from baseline of not more than 15%. The insert also states, however, that “the safety of continuation or resumption of trastuzumab in patients with trastuzumab induced LV dysfunction has never been studied, “ Dr. Liu noted.
She cited an American Society of Clinical Oncology guideline on the prevention and monitoring of cardiac dysfunction in survivors of adult cancers, which states in part that the decision to continue or discontinue cancer therapy in patients with evidence of cardiac dysfunction “made by the oncologist, should be informed by close collaboration with a cardiologist, fully evaluating the clinical circumstances and considering the risks and benefits of continuation of therapy responsible for the cardiac dysfunction.”
“I want to emphasize the importance of accepting and managing cardiovascular risk in patients priors to and during potentially cardiotoxic therapy. To optimize cardiologic and oncologic outcomes, we need to avoid or minimize treatment interruptions of life-saving therapy, and mitigate cardiac events with aggressive cardiovascular risk-factor modification,” Dr. Liu said.
She called for development of better risk stratification tools to tailor cardiac surveillance during therapy, based on both patient-specific and treatment-specific risk factors.
Dr. Liu reported nothing to disclose. Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics. Cota, Dendreon, Ferring Pharmaceuticals. GenomeDx, Janssen, and Nanobiotix.
WASHINGTON – Oncologists and cardiologists need to work hand-in-hand when managing the care of women with breast cancer whose treatment plan includes cardiotoxic therapies and breast irradiation, reported specialists.
Depending on the cancer subtype, women with breast cancer may receive chemotherapy with a cardiotoxic anthracycline such as doxorubicin or epirubicin, or a HER2-targeted agent such as trastuzumab (Herceptin), pertuzumab (Perjeta), or ado-trastuzumab emtansine (Kadcyla).
“The cardiotoxicity related to breast cancer has been a well publicized issue, and chances are your patients know about it and are concerned as well,” Jennifer E. Liu, MD, director of cardiovascular laboratories at Memorial Sloan Kettering Cancer Center in New York, said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.
Anthracyclines, trastuzumab, and HF
In large adjuvant therapy trials of anthracyclines and trastuzumab in women with breast cancer, doxorubicin alone was associated with an asymptomatic decline in left ventricular ejection fraction (LVEF) of 4% to 11%, and a less than 1% incidence of heart failure (HF), Dr. Liu noted.
When patients received an anthracycline followed by trastuzumab, the incidence of asymptomatic LVEF decline ranged from 4% to 19%, the incidence of clinical HF was 2% to 4%, and the rate of trastuzumab interruption for cardiac adverse events ranged from 5% to 18%.
In comparison, in trials with trastuzumab in combination therapy that did not contain an anthracycline, the risk of cardiovascular complications was lower, with asymptomatic decline in LVEF ranging from 3.2% to 9.4%, and class III/IV HF occurring in just 0.5% of patients. In trials combining trastuzumab and pertuzumab, there were no increases in cardiac toxicity over trastuzumab alone.
Although with longer follow-up, the approximately 4% rate of HF in patients treated with anthracycline-based chemotherapy, paclitaxel, and trastuzumab in the NSABP B-31 trial has not changed significantly; retrospective claims-based studies reflecting daily practice have shown significantly higher rates of HF and or cardiomyopathy, Dr. Liu said.
She cited a 2012 study showing that among 45,537 women with a mean age of 76 years who were treated for breast cancer, the 3-year incidence rates of HF and/or cardiomyopathy were 32% for patients treated with trastuzumab alone, and 41.9% for those treated with an anthracycline followed by trastuzumab. Other, smaller studies also showed lower but significantly elevated risks for the drugs.
The discrepancy between clinical trial and “real world” results may be chalked up to the fact that claims-based data rely on diagnostic codes that may not accurately reflect the actual cardiac diagnosis, and by the fact that clinical trials have strict entry criteria that exclude patients with cardiovascular disease, she said.
Radiation risks
Radiation therapy is associated with a more than 7% increase in major coronary events per Gy of mean heart dose, Dr. Liu noted, citing a 2013 study (N Engl J Med. 2013;368:987-98).
Paul Nguyen, MD, a radiation oncologist at the Dana-Farber/Brigham and Women’s Cancer Center in Boston, said that risk factors for radiation-induced heart disease include anterior or left chest irradiation, cumulative doses above 30 Gy, patient age younger than 50 years, doses of more than 2 Gy per fraction, presence and extent of tumor in or near the heart, lack of radiation shielding, concomitant chemotherapy (especially with anthracyclines), and preexisting cardiovascular disease or risk factors.
For patients with breast cancer, the risk of developing radiation-induced heart disease has diminished considerably with the adoption of heart-sparing techniques over the last several decades, including 3-D conformal techniques, intensity-modulated radiation therapy, proton beam therapy, novel patient positioning techniques that allow radiation only to the cancer-involved breast, and deep inspiration breath holds in which the radiation beam is gated to turn on only when the patient is holding a deep breath, Dr. Nguyen noted.
Treatment options for LVEF decline
The package insert for trastuzumab recommends withholding the drug for a minimum of 4 weeks if the patient has a 16% or greater decline in LVEF from baseline, or a 10% or greater decline from baseline to below the lower limit of normal. The insert recommends LVEF monitoring every 3 or 4 weeks, and says that trastuzumab can be resumed if LVEF improves to above the lower limit of normal with an absolute decrease from baseline of not more than 15%. The insert also states, however, that “the safety of continuation or resumption of trastuzumab in patients with trastuzumab induced LV dysfunction has never been studied, “ Dr. Liu noted.
She cited an American Society of Clinical Oncology guideline on the prevention and monitoring of cardiac dysfunction in survivors of adult cancers, which states in part that the decision to continue or discontinue cancer therapy in patients with evidence of cardiac dysfunction “made by the oncologist, should be informed by close collaboration with a cardiologist, fully evaluating the clinical circumstances and considering the risks and benefits of continuation of therapy responsible for the cardiac dysfunction.”
“I want to emphasize the importance of accepting and managing cardiovascular risk in patients priors to and during potentially cardiotoxic therapy. To optimize cardiologic and oncologic outcomes, we need to avoid or minimize treatment interruptions of life-saving therapy, and mitigate cardiac events with aggressive cardiovascular risk-factor modification,” Dr. Liu said.
She called for development of better risk stratification tools to tailor cardiac surveillance during therapy, based on both patient-specific and treatment-specific risk factors.
Dr. Liu reported nothing to disclose. Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics. Cota, Dendreon, Ferring Pharmaceuticals. GenomeDx, Janssen, and Nanobiotix.
REPORTING FROM ACC CARDIO-ONCOLOGY
Key clinical point: Oncologists should work with cardiologists to mitigate heart disease risk.
Major finding: Anthracyclines followed by trastuzumab significantly increase risk of HF.
Study details: Review of risk for heart disease in breast cancer survivors.
Disclosures: Dr. Liu reported nothing to disclose. Dr. Nguyen reported consulting fees/honoraria from Astellas, Augmenix, Blue Earth Diagnostics, Cota, Dendreon, Ferring Pharmaceuticals, GenomeDx, Janssen, and Nanobiotix.
Clinical relevance of tamoxifen pharmacogenetics in question
The clinical relevance of tamoxifen pharmacogenetics and therapeutic drug monitoring has been challenged, according to findings from an observational study.
“The objective of the prospective CYPTAM study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome[s] in patients with early-stage breast cancer receiving tamoxifen,” wrote Anabel Sanchez-Spitman, PharmD, of the Leiden University Medical Center, the Netherlands, and her colleagues in the Journal of Clinical Oncology.
“Although, in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy [has been] described, confirmation based on prospective studies is lacking,” they wrote.
The researchers followed 667 patients with early-stage breast malignancy who were treated with 20 mg of oral tamoxifen daily.
Dr. Sanchez-Spitman and her colleagues performed CYP2D6 genotype testing and measured blood levels of endoxifen, an active metabolite of tamoxifen, in study participants. Both of these measures were linked with relapse-free survival via statistical analysis.
After analysis, no significant association was found between endoxifen concentrations (P = .691) or CYP2D6 genotyping (P = .799) and relapse-free survival. These data were the same in both univariable and multivariable regression analysis.
“Neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results,” they wrote.
The authors acknowledged that a key limitation of the study was the absence of tamoxifen adherence testing, but the availability of persistence data was well collected, lessening this drawback.
“Our data do not justify therapeutic drug monitoring based on endoxifen concentrations in patients with breast cancer receiving tamoxifen,” they concluded.
The study was supported by grant funding provided by ZOLEON. The authors reported no conflicts of interest.
SOURCE: Sanchez-Spitman A et al. J Clin Oncol. 2019 Jan 24. doi: 10.1200/JCO.18.00307.
The clinical relevance of tamoxifen pharmacogenetics and therapeutic drug monitoring has been challenged, according to findings from an observational study.
“The objective of the prospective CYPTAM study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome[s] in patients with early-stage breast cancer receiving tamoxifen,” wrote Anabel Sanchez-Spitman, PharmD, of the Leiden University Medical Center, the Netherlands, and her colleagues in the Journal of Clinical Oncology.
“Although, in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy [has been] described, confirmation based on prospective studies is lacking,” they wrote.
The researchers followed 667 patients with early-stage breast malignancy who were treated with 20 mg of oral tamoxifen daily.
Dr. Sanchez-Spitman and her colleagues performed CYP2D6 genotype testing and measured blood levels of endoxifen, an active metabolite of tamoxifen, in study participants. Both of these measures were linked with relapse-free survival via statistical analysis.
After analysis, no significant association was found between endoxifen concentrations (P = .691) or CYP2D6 genotyping (P = .799) and relapse-free survival. These data were the same in both univariable and multivariable regression analysis.
“Neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results,” they wrote.
The authors acknowledged that a key limitation of the study was the absence of tamoxifen adherence testing, but the availability of persistence data was well collected, lessening this drawback.
“Our data do not justify therapeutic drug monitoring based on endoxifen concentrations in patients with breast cancer receiving tamoxifen,” they concluded.
The study was supported by grant funding provided by ZOLEON. The authors reported no conflicts of interest.
SOURCE: Sanchez-Spitman A et al. J Clin Oncol. 2019 Jan 24. doi: 10.1200/JCO.18.00307.
The clinical relevance of tamoxifen pharmacogenetics and therapeutic drug monitoring has been challenged, according to findings from an observational study.
“The objective of the prospective CYPTAM study was to associate endoxifen concentrations and CYP2D6 genotypes with clinical outcome[s] in patients with early-stage breast cancer receiving tamoxifen,” wrote Anabel Sanchez-Spitman, PharmD, of the Leiden University Medical Center, the Netherlands, and her colleagues in the Journal of Clinical Oncology.
“Although, in a retrospective study, an endoxifen threshold of 5.9 ng/mL for efficacy [has been] described, confirmation based on prospective studies is lacking,” they wrote.
The researchers followed 667 patients with early-stage breast malignancy who were treated with 20 mg of oral tamoxifen daily.
Dr. Sanchez-Spitman and her colleagues performed CYP2D6 genotype testing and measured blood levels of endoxifen, an active metabolite of tamoxifen, in study participants. Both of these measures were linked with relapse-free survival via statistical analysis.
After analysis, no significant association was found between endoxifen concentrations (P = .691) or CYP2D6 genotyping (P = .799) and relapse-free survival. These data were the same in both univariable and multivariable regression analysis.
“Neither categorizing endoxifen concentrations into quartiles nor using 5.9 ng/mL as threshold altered these results,” they wrote.
The authors acknowledged that a key limitation of the study was the absence of tamoxifen adherence testing, but the availability of persistence data was well collected, lessening this drawback.
“Our data do not justify therapeutic drug monitoring based on endoxifen concentrations in patients with breast cancer receiving tamoxifen,” they concluded.
The study was supported by grant funding provided by ZOLEON. The authors reported no conflicts of interest.
SOURCE: Sanchez-Spitman A et al. J Clin Oncol. 2019 Jan 24. doi: 10.1200/JCO.18.00307.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point:
Major finding: An endoxifen concentration of greater than 5.9 ng/mL was not linked with clinical efficacy in patients with breast malignancy.
Study details: A prospective study of 667 patients with early-stage breast malignancy treated with adjuvant tamoxifen.
Disclosures: The study was supported by grant funding provided by ZOLEON. The authors reported no conflicts of interest.
Source: Sanchez-Spitman A et al. J Clin Oncol. 2019 Jan 24. doi: 10.1200/JCO.18.00307.
Single-cell genomics drive progress toward human breast cell atlas development
SAN ANTONIO – Researchers at MD Anderson Cancer Center in Houston and the University of New South Wales (UNSW) in Sydney are among teams from around the world working toward human breast cell atlas development using single-cell genomics, and their efforts to date have yielded new understanding of both the normal breast cell ecosystem and the breast cancer tumor microenvironment.
The work at MD Anderson, for example, has led to the identification of a number of new gene markers and multiple cell states within breast cell types, according to Tapsi Kumar Seth, who reported early findings from an analysis of more than 32,000 cells from normal breast tissue during a presentation at the San Antonio Breast Cancer Symposium.
At the UNSW’s Garvan Institute of Medical Research, Alexander Swarbrick, PhD, and his colleagues are working to better define the tumor microenvironment at the single-cell level. At the symposium, Dr. Swarbrick presented interim findings from cellular analyses in the first 23 breast cancer cases of about 200 that will be studied in the course of the project.
Improved understanding of the cellular landscape of both normal breast tissue and breast cancer tissue should lead to new stromal- and immune-based therapies for the treatment of breast cancer, the investigators said.
The normal breast cell ecosystem
The MD Anderson researchers studied 32,148 stromal cells from pathologically normal breast tissues collected from 11 women who underwent mastectomy at the center.
Unbiased expression analysis identified three major cell types, including epithelial cells, fibroblasts, and endothelial cells, as well as several minor cell types such as macrophages, T-cells, apocrine cells, pericytes, and others, said Ms. Seth, a graduate student in the department of genetics at the center and a member of the Navin Laboratory there.
The work is designed to help identify the presence and function of cells and explain how they behave in a normal breast ecosystem, she said.
“We know that a female breast undergoes a lot of changes due to age, pregnancy, or when there is a disease such as cancer, so it’s essential to chart out what a normal cell reference would look like,” she said.
Toward that goal, a protocol was developed to dissociate the tissue samples within 2 hours due to the decline in viability seen in cells and RNA over time. Analysis of the cell states revealed different transcriptional programs in luminal epithelial cells (hormone receptor positive and secretory), basal epithelial cells (myoepithelial or basement-like), endothelial cells (lymphatic or vascular), macrophages (M1 or M2) and fibroblasts (three subgroups) and provided insight into progenitors of each cell types, she said.
A map was created to show gene expression and to identify transcriptomally similar cells.
“We were able to identify most of the major cell types that are present in human breasts,” she said. “What was interesting was that the composition of these cells also varied across women.”
For example, the proportion of fibroblasts was lower in 3 of the 11 patients, and even though the cells were pathologically normal, immune cell populations, including T-cells and macrophages, were also seen.
Adipocytes cannot be evaluated using this technology because they are large and the layer of fat cells must be removed during dissociation to prevent clogging of the machines, she noted, adding that “this is really a limitation of our technology.”
A closer look was taken at each of the major cell types identified.
Epithelial cells
Both canonical and new gene markers were used to identify luminal and basal epithelial cells, Ms. Seth noted.
Among the known markers were KRT18 for luminal epithelial cells and KRT5, KRT6B, KRT14, and KRT15 for basal epithelial cells. Among the new markers were SLC39A6, EFHD1 and HES1 for the luminal epithelial cells, and CITED4, CCK28, MMP7, and MDRG2 for the basal epithelial cells.
“We went on and validated these markers on the tissue section using methods like spatial transcriptomics,” she said, explaining that this “really helps capture the RNA expression spatially,” and can resolve the localization of cell types markers in anatomical structures.
For these cells, the expression of the newly identified gene markers was mostly confined to ducts and lobules.
In addition, an analysis of cell states within the luminal epithelial cells showed four different cell states, each of which have “different kinds of genes that they express, and also different pathways that they express, suggesting that these might be transcriptomally different,” Ms. Seth said.
Of note, these cells and cells states are not biased to a specific condition or patient, suggesting that they are coming from all of the patients, she added.
Two of the four cell states – the secretory and hormone responsive states – have previously been reported, but Ms. Seth and her colleagues identified two additional cell states that may have different biological functions and are present in the different anatomical regions of the breast.
Fibroblasts
Fibroblasts, the cells of the connective tissue, were the most abundant cell type. Like the epithelial cells, both canonical collagen markers (COL6A3, MMP2, FBN1, FBLN2, FBN, and COL1A1) and newly identified gene markers (TNXB, AEBP1, CFH, CTSK, TPPP3, MEG3, HTRA1, LHFP, and OGN) were used to identify them.
Endothelial cells
Breast tissue is highly vascular, so endothelial cells, which line the walls of veins, arteries, and lymphatic vessels, are plentiful.
“Again, for both these cell types, we identified them using the canonical marker CD31, and we identified some new gene markers,” she said, noting that the new markers include CCL21, CLDN5, MMRN1, LYVE1, and PROX1 for lymphatic endothelial cells, and RNASE1 and IFI27 for vascular endothelial cells.
Two different groups – or states – of vascular endothelial cells were identified, with each expressing “very different genes as well as very different pathways, again suggesting that they might have different biological functions, which we are still investigating,” she said.
Additional findings and future directions
In addition to stromal cells, some immune cells were also seen. These included T cells that came mostly from two patients, as well as macrophages and monocytes, which comprised the most abundant immune cell population.
Of note, all of these cells are also found in the tumor microenvironment, but they are in a transformed state. For example cancer-associated fibroblasts, tumor endothelial cells, tumor-associated macrophages, and tumor-associated adipocytes have been seen in that environment, she said.
“So what we are trying to do with this project is ... learn how these cells are, and how these cells behave in the normal ecosystem,” she explained, noting that the hope is to provide a valuable reference for the research community with new insights about how normal cell types are transformed in the tumor microenvironment.
In an effort to overcome the adipocyte-associated limitation of the technology, adipocytes are “now being isolated by single nucleus RNA sequencing.”
“This [sequencing] technology has helped us identify multiple cell states within a cell type; and most of these cell states may have different biological functions, which probably can be investigated by spatial transcriptomic methods,” she said.
Spatial transcriptomics also continue to be used for validation of the new gene markers identified in the course of this research, she noted.
The breast tumor microenvironment
At the Garvan Institute, current work is focusing more on defining the landscape of the breast tumor microenvironment at single-cell resolution, according to Dr. Swarbrick, a senior research fellow and head of the Tumour Progression Laboratory there.
“Breast cancers ... are complex cellular ecosystems, and it’s really the sum of the interactions between the cell types that play major roles in determining the etiology of disease and its response to therapy,” he said. “So I think that going forward toward a new age of diagnostics and therapeutics, there’s wonderful potential in capitalizing on the tumor microenvironment for new developments, but this has to be built on a really deep understanding of the tumor microenvironment, and – I might say – a new taxonomy of the breast cellular environment.”
Therefore, in an effort to address “this limitation in our knowledge base,” his lab is also working toward development of a breast cell atlas.
A fresh tissue collection program was established to collect early breast cancer tissues at the time of surgery, metastatic biopsies, and metastatic lesions from autopsies. The tissues are quickly dissociated into their cellular components and they undergo massively parallel capture and sequencing using the 10x genomics platform, he said.
Thousands of cells per case are analyzed using single-cell RNA sequencing (RNA-seq), as well as “RAGE-seq” and “CITE-seq,” which are performed in parallel to the RNA sequencing to address some of the limitations of the RNA sequencing alone and to “try to gain a multi-omic insight into the cell biology,” he explained.
RAGE-seq, which Dr. Swarbrick and his team developed, “is essentially a method to do targeted long-read sequencing in parallel to the short-read sequencing that we use for RNA-seq,” and CITE-seq is “a really fantastic method developed at the New York Genome Center that essentially allows us to gather proteomic data in parallel to the RNA data,” he said.
Based on findings from the analyses of about 125,000 cells from 25 patients, a map was created that showed the cell clusters identified by both canonical markers and gene expression signatures.
“We find the cell types we would expect to be present in a breast cancer,” he said.
The map shows clusters of myeloid, epithelial-1 and -2, cancer-associated fibroblast (CAF)-1 and -2, endothelial, T Reg, B, and CD8 and CD4 T cells.
Next, each cell type is quantified in each patient, and a graphic representation of the findings shows large variability in the proportions of each cell type in each patient.
“Ultimately, our goal is to be able to relate the frequencies of cell types and molecular features to each other, but also to clinical-pathological features from these patients,” he noted.
A closer look at the findings on an individual case level demonstrates the potential for development of better therapies.
For example, a case involving a high-grade triple-negative invasive ductal carcinoma exhibited each of the cell types found overall.
“One of the things that strikes us early on is we see a number of malignant epithelial populations,” he said, noting that proliferation is one of the drivers of the heterogeneity, but that heterogeneity was also seen for “other clinically relevant features such as basal cytokeratins,” which were heterogeneously expressed in different cell-type clusters.
“This was kind of paralleled in the immunohistochemistry results that we obtained from this patient,” he said. “We could also apply other clinically used tests that we’ve developed on bulk (such as PAM50 intrinsic subtyping) and ask whether they can be applied at the single-cell resolution.
“We think that these are going to be great tools to try to now get in and understand the significance of this heterogeneity and try to identify the lethal cells within this patient, and potentially therapeutic strategies to eradicate those cells,” he added.
Fibroblasts
A notable finding of this project was the presence of “not one, but two populations of fibroblasts,” Dr. Swarbrick said, noting that fibroblasts are typically discussed as a single entity.
“This is arguing that there are at least two major types present within the breast, and almost every case has these populations present at roughly equal amounts,” he said.
This is of particular interest, because it has been shown in prior studies that targeting fibroblasts can have therapeutic outcomes.
“So we think this is a very important population within the tumor microenvironment,” he added.
With respect to gene expression features, CAF-1 is dominated by signatures of extracellular matrix deposition and remodeling, which “look like the classic myofibroblasts that we typically think of when we study cancer-associated fibroblasts.”
“In contrast, the CAF-2 population ... have what appears to be quite a predominant secretory function, so we see a lot of cytokines being produced by these cells, but we also see a very high level of expression of a number immune checkpoint ligands,” he said, adding that his team is actively pursuing whether these cells may be undergoing signaling events with infiltrating lymphocytes in the tumor microenvironment.
The signatures for both CAF types are prognostic within large breast cancer data sets, suggesting that they do actually have an important role in disease, he noted.
Markers for these cells include ACTA2, which was previously known to be a marker, and which is almost exclusively restricted to CAF-1, and the cell surface protein CD34 – a progenitor marker in many different cellular systems, “which is actually beautifully expressed on the CAF-2 population” as demonstrated using CITE-seq.
“So we’re now using this as a way to prospectively identify these cells, pull them out of tumors, and conduct biologic assays to learn more about them,” he said.
The immune milieu
“We’re in the age of immunotherapy, and this is an area of huge interest, but we have a long way to go in making it as effective as possible for breast cancer patients,” Dr. Swarbrick said. “I believe part of that is through a very deep understanding of the taxonomy.”
RNA data alone are useful but insufficient to fully identify subsets of immune cells due to a “relatively low-resolution ability to resolve T cells.”
“But because we’re now using the panel of 125 antibodies in parallel, we can now start to use protein levels to split up these populations and we can start to now identify, with higher resolution, more unique populations within the environment,” he said, noting that the availability of protein data not only helps identify subtypes, but is also therapeutically important as it allows for certainty regarding whether the protein target of therapeutic antibodies is expressed on the surface of cells.
Ultimately the hope is that this effort to build a multi-omic breast cancer atlas will continue to drive new discoveries in personalized medicine for breast cancer, Dr. Swarbrick concluded, adding that the field is moving fast, and it will be very important for labs like his and the Navin Lab to communicate to avoid needlessly duplicating efforts.
“I think it’s going to be really exciting to start to put some of these [findings] together,” he said.
The MD Anderson project is funded by the Chan Zuckerberg Initiative as part of its work in supporting the Human Cell Atlas project. Ms. Seth reported having no disclosures. Dr. Swarbrick’s research is funded by the Australian Government/National Health and Medical Research Council and the National Breast Cancer Foundation. He reported having no relevant disclosures.
SOURCE: Seth T et al. SABCS 2018, Abstract GS1-02; Swarbrick A et al. SABCS 2018, Abstract GS1-01
SAN ANTONIO – Researchers at MD Anderson Cancer Center in Houston and the University of New South Wales (UNSW) in Sydney are among teams from around the world working toward human breast cell atlas development using single-cell genomics, and their efforts to date have yielded new understanding of both the normal breast cell ecosystem and the breast cancer tumor microenvironment.
The work at MD Anderson, for example, has led to the identification of a number of new gene markers and multiple cell states within breast cell types, according to Tapsi Kumar Seth, who reported early findings from an analysis of more than 32,000 cells from normal breast tissue during a presentation at the San Antonio Breast Cancer Symposium.
At the UNSW’s Garvan Institute of Medical Research, Alexander Swarbrick, PhD, and his colleagues are working to better define the tumor microenvironment at the single-cell level. At the symposium, Dr. Swarbrick presented interim findings from cellular analyses in the first 23 breast cancer cases of about 200 that will be studied in the course of the project.
Improved understanding of the cellular landscape of both normal breast tissue and breast cancer tissue should lead to new stromal- and immune-based therapies for the treatment of breast cancer, the investigators said.
The normal breast cell ecosystem
The MD Anderson researchers studied 32,148 stromal cells from pathologically normal breast tissues collected from 11 women who underwent mastectomy at the center.
Unbiased expression analysis identified three major cell types, including epithelial cells, fibroblasts, and endothelial cells, as well as several minor cell types such as macrophages, T-cells, apocrine cells, pericytes, and others, said Ms. Seth, a graduate student in the department of genetics at the center and a member of the Navin Laboratory there.
The work is designed to help identify the presence and function of cells and explain how they behave in a normal breast ecosystem, she said.
“We know that a female breast undergoes a lot of changes due to age, pregnancy, or when there is a disease such as cancer, so it’s essential to chart out what a normal cell reference would look like,” she said.
Toward that goal, a protocol was developed to dissociate the tissue samples within 2 hours due to the decline in viability seen in cells and RNA over time. Analysis of the cell states revealed different transcriptional programs in luminal epithelial cells (hormone receptor positive and secretory), basal epithelial cells (myoepithelial or basement-like), endothelial cells (lymphatic or vascular), macrophages (M1 or M2) and fibroblasts (three subgroups) and provided insight into progenitors of each cell types, she said.
A map was created to show gene expression and to identify transcriptomally similar cells.
“We were able to identify most of the major cell types that are present in human breasts,” she said. “What was interesting was that the composition of these cells also varied across women.”
For example, the proportion of fibroblasts was lower in 3 of the 11 patients, and even though the cells were pathologically normal, immune cell populations, including T-cells and macrophages, were also seen.
Adipocytes cannot be evaluated using this technology because they are large and the layer of fat cells must be removed during dissociation to prevent clogging of the machines, she noted, adding that “this is really a limitation of our technology.”
A closer look was taken at each of the major cell types identified.
Epithelial cells
Both canonical and new gene markers were used to identify luminal and basal epithelial cells, Ms. Seth noted.
Among the known markers were KRT18 for luminal epithelial cells and KRT5, KRT6B, KRT14, and KRT15 for basal epithelial cells. Among the new markers were SLC39A6, EFHD1 and HES1 for the luminal epithelial cells, and CITED4, CCK28, MMP7, and MDRG2 for the basal epithelial cells.
“We went on and validated these markers on the tissue section using methods like spatial transcriptomics,” she said, explaining that this “really helps capture the RNA expression spatially,” and can resolve the localization of cell types markers in anatomical structures.
For these cells, the expression of the newly identified gene markers was mostly confined to ducts and lobules.
In addition, an analysis of cell states within the luminal epithelial cells showed four different cell states, each of which have “different kinds of genes that they express, and also different pathways that they express, suggesting that these might be transcriptomally different,” Ms. Seth said.
Of note, these cells and cells states are not biased to a specific condition or patient, suggesting that they are coming from all of the patients, she added.
Two of the four cell states – the secretory and hormone responsive states – have previously been reported, but Ms. Seth and her colleagues identified two additional cell states that may have different biological functions and are present in the different anatomical regions of the breast.
Fibroblasts
Fibroblasts, the cells of the connective tissue, were the most abundant cell type. Like the epithelial cells, both canonical collagen markers (COL6A3, MMP2, FBN1, FBLN2, FBN, and COL1A1) and newly identified gene markers (TNXB, AEBP1, CFH, CTSK, TPPP3, MEG3, HTRA1, LHFP, and OGN) were used to identify them.
Endothelial cells
Breast tissue is highly vascular, so endothelial cells, which line the walls of veins, arteries, and lymphatic vessels, are plentiful.
“Again, for both these cell types, we identified them using the canonical marker CD31, and we identified some new gene markers,” she said, noting that the new markers include CCL21, CLDN5, MMRN1, LYVE1, and PROX1 for lymphatic endothelial cells, and RNASE1 and IFI27 for vascular endothelial cells.
Two different groups – or states – of vascular endothelial cells were identified, with each expressing “very different genes as well as very different pathways, again suggesting that they might have different biological functions, which we are still investigating,” she said.
Additional findings and future directions
In addition to stromal cells, some immune cells were also seen. These included T cells that came mostly from two patients, as well as macrophages and monocytes, which comprised the most abundant immune cell population.
Of note, all of these cells are also found in the tumor microenvironment, but they are in a transformed state. For example cancer-associated fibroblasts, tumor endothelial cells, tumor-associated macrophages, and tumor-associated adipocytes have been seen in that environment, she said.
“So what we are trying to do with this project is ... learn how these cells are, and how these cells behave in the normal ecosystem,” she explained, noting that the hope is to provide a valuable reference for the research community with new insights about how normal cell types are transformed in the tumor microenvironment.
In an effort to overcome the adipocyte-associated limitation of the technology, adipocytes are “now being isolated by single nucleus RNA sequencing.”
“This [sequencing] technology has helped us identify multiple cell states within a cell type; and most of these cell states may have different biological functions, which probably can be investigated by spatial transcriptomic methods,” she said.
Spatial transcriptomics also continue to be used for validation of the new gene markers identified in the course of this research, she noted.
The breast tumor microenvironment
At the Garvan Institute, current work is focusing more on defining the landscape of the breast tumor microenvironment at single-cell resolution, according to Dr. Swarbrick, a senior research fellow and head of the Tumour Progression Laboratory there.
“Breast cancers ... are complex cellular ecosystems, and it’s really the sum of the interactions between the cell types that play major roles in determining the etiology of disease and its response to therapy,” he said. “So I think that going forward toward a new age of diagnostics and therapeutics, there’s wonderful potential in capitalizing on the tumor microenvironment for new developments, but this has to be built on a really deep understanding of the tumor microenvironment, and – I might say – a new taxonomy of the breast cellular environment.”
Therefore, in an effort to address “this limitation in our knowledge base,” his lab is also working toward development of a breast cell atlas.
A fresh tissue collection program was established to collect early breast cancer tissues at the time of surgery, metastatic biopsies, and metastatic lesions from autopsies. The tissues are quickly dissociated into their cellular components and they undergo massively parallel capture and sequencing using the 10x genomics platform, he said.
Thousands of cells per case are analyzed using single-cell RNA sequencing (RNA-seq), as well as “RAGE-seq” and “CITE-seq,” which are performed in parallel to the RNA sequencing to address some of the limitations of the RNA sequencing alone and to “try to gain a multi-omic insight into the cell biology,” he explained.
RAGE-seq, which Dr. Swarbrick and his team developed, “is essentially a method to do targeted long-read sequencing in parallel to the short-read sequencing that we use for RNA-seq,” and CITE-seq is “a really fantastic method developed at the New York Genome Center that essentially allows us to gather proteomic data in parallel to the RNA data,” he said.
Based on findings from the analyses of about 125,000 cells from 25 patients, a map was created that showed the cell clusters identified by both canonical markers and gene expression signatures.
“We find the cell types we would expect to be present in a breast cancer,” he said.
The map shows clusters of myeloid, epithelial-1 and -2, cancer-associated fibroblast (CAF)-1 and -2, endothelial, T Reg, B, and CD8 and CD4 T cells.
Next, each cell type is quantified in each patient, and a graphic representation of the findings shows large variability in the proportions of each cell type in each patient.
“Ultimately, our goal is to be able to relate the frequencies of cell types and molecular features to each other, but also to clinical-pathological features from these patients,” he noted.
A closer look at the findings on an individual case level demonstrates the potential for development of better therapies.
For example, a case involving a high-grade triple-negative invasive ductal carcinoma exhibited each of the cell types found overall.
“One of the things that strikes us early on is we see a number of malignant epithelial populations,” he said, noting that proliferation is one of the drivers of the heterogeneity, but that heterogeneity was also seen for “other clinically relevant features such as basal cytokeratins,” which were heterogeneously expressed in different cell-type clusters.
“This was kind of paralleled in the immunohistochemistry results that we obtained from this patient,” he said. “We could also apply other clinically used tests that we’ve developed on bulk (such as PAM50 intrinsic subtyping) and ask whether they can be applied at the single-cell resolution.
“We think that these are going to be great tools to try to now get in and understand the significance of this heterogeneity and try to identify the lethal cells within this patient, and potentially therapeutic strategies to eradicate those cells,” he added.
Fibroblasts
A notable finding of this project was the presence of “not one, but two populations of fibroblasts,” Dr. Swarbrick said, noting that fibroblasts are typically discussed as a single entity.
“This is arguing that there are at least two major types present within the breast, and almost every case has these populations present at roughly equal amounts,” he said.
This is of particular interest, because it has been shown in prior studies that targeting fibroblasts can have therapeutic outcomes.
“So we think this is a very important population within the tumor microenvironment,” he added.
With respect to gene expression features, CAF-1 is dominated by signatures of extracellular matrix deposition and remodeling, which “look like the classic myofibroblasts that we typically think of when we study cancer-associated fibroblasts.”
“In contrast, the CAF-2 population ... have what appears to be quite a predominant secretory function, so we see a lot of cytokines being produced by these cells, but we also see a very high level of expression of a number immune checkpoint ligands,” he said, adding that his team is actively pursuing whether these cells may be undergoing signaling events with infiltrating lymphocytes in the tumor microenvironment.
The signatures for both CAF types are prognostic within large breast cancer data sets, suggesting that they do actually have an important role in disease, he noted.
Markers for these cells include ACTA2, which was previously known to be a marker, and which is almost exclusively restricted to CAF-1, and the cell surface protein CD34 – a progenitor marker in many different cellular systems, “which is actually beautifully expressed on the CAF-2 population” as demonstrated using CITE-seq.
“So we’re now using this as a way to prospectively identify these cells, pull them out of tumors, and conduct biologic assays to learn more about them,” he said.
The immune milieu
“We’re in the age of immunotherapy, and this is an area of huge interest, but we have a long way to go in making it as effective as possible for breast cancer patients,” Dr. Swarbrick said. “I believe part of that is through a very deep understanding of the taxonomy.”
RNA data alone are useful but insufficient to fully identify subsets of immune cells due to a “relatively low-resolution ability to resolve T cells.”
“But because we’re now using the panel of 125 antibodies in parallel, we can now start to use protein levels to split up these populations and we can start to now identify, with higher resolution, more unique populations within the environment,” he said, noting that the availability of protein data not only helps identify subtypes, but is also therapeutically important as it allows for certainty regarding whether the protein target of therapeutic antibodies is expressed on the surface of cells.
Ultimately the hope is that this effort to build a multi-omic breast cancer atlas will continue to drive new discoveries in personalized medicine for breast cancer, Dr. Swarbrick concluded, adding that the field is moving fast, and it will be very important for labs like his and the Navin Lab to communicate to avoid needlessly duplicating efforts.
“I think it’s going to be really exciting to start to put some of these [findings] together,” he said.
The MD Anderson project is funded by the Chan Zuckerberg Initiative as part of its work in supporting the Human Cell Atlas project. Ms. Seth reported having no disclosures. Dr. Swarbrick’s research is funded by the Australian Government/National Health and Medical Research Council and the National Breast Cancer Foundation. He reported having no relevant disclosures.
SOURCE: Seth T et al. SABCS 2018, Abstract GS1-02; Swarbrick A et al. SABCS 2018, Abstract GS1-01
SAN ANTONIO – Researchers at MD Anderson Cancer Center in Houston and the University of New South Wales (UNSW) in Sydney are among teams from around the world working toward human breast cell atlas development using single-cell genomics, and their efforts to date have yielded new understanding of both the normal breast cell ecosystem and the breast cancer tumor microenvironment.
The work at MD Anderson, for example, has led to the identification of a number of new gene markers and multiple cell states within breast cell types, according to Tapsi Kumar Seth, who reported early findings from an analysis of more than 32,000 cells from normal breast tissue during a presentation at the San Antonio Breast Cancer Symposium.
At the UNSW’s Garvan Institute of Medical Research, Alexander Swarbrick, PhD, and his colleagues are working to better define the tumor microenvironment at the single-cell level. At the symposium, Dr. Swarbrick presented interim findings from cellular analyses in the first 23 breast cancer cases of about 200 that will be studied in the course of the project.
Improved understanding of the cellular landscape of both normal breast tissue and breast cancer tissue should lead to new stromal- and immune-based therapies for the treatment of breast cancer, the investigators said.
The normal breast cell ecosystem
The MD Anderson researchers studied 32,148 stromal cells from pathologically normal breast tissues collected from 11 women who underwent mastectomy at the center.
Unbiased expression analysis identified three major cell types, including epithelial cells, fibroblasts, and endothelial cells, as well as several minor cell types such as macrophages, T-cells, apocrine cells, pericytes, and others, said Ms. Seth, a graduate student in the department of genetics at the center and a member of the Navin Laboratory there.
The work is designed to help identify the presence and function of cells and explain how they behave in a normal breast ecosystem, she said.
“We know that a female breast undergoes a lot of changes due to age, pregnancy, or when there is a disease such as cancer, so it’s essential to chart out what a normal cell reference would look like,” she said.
Toward that goal, a protocol was developed to dissociate the tissue samples within 2 hours due to the decline in viability seen in cells and RNA over time. Analysis of the cell states revealed different transcriptional programs in luminal epithelial cells (hormone receptor positive and secretory), basal epithelial cells (myoepithelial or basement-like), endothelial cells (lymphatic or vascular), macrophages (M1 or M2) and fibroblasts (three subgroups) and provided insight into progenitors of each cell types, she said.
A map was created to show gene expression and to identify transcriptomally similar cells.
“We were able to identify most of the major cell types that are present in human breasts,” she said. “What was interesting was that the composition of these cells also varied across women.”
For example, the proportion of fibroblasts was lower in 3 of the 11 patients, and even though the cells were pathologically normal, immune cell populations, including T-cells and macrophages, were also seen.
Adipocytes cannot be evaluated using this technology because they are large and the layer of fat cells must be removed during dissociation to prevent clogging of the machines, she noted, adding that “this is really a limitation of our technology.”
A closer look was taken at each of the major cell types identified.
Epithelial cells
Both canonical and new gene markers were used to identify luminal and basal epithelial cells, Ms. Seth noted.
Among the known markers were KRT18 for luminal epithelial cells and KRT5, KRT6B, KRT14, and KRT15 for basal epithelial cells. Among the new markers were SLC39A6, EFHD1 and HES1 for the luminal epithelial cells, and CITED4, CCK28, MMP7, and MDRG2 for the basal epithelial cells.
“We went on and validated these markers on the tissue section using methods like spatial transcriptomics,” she said, explaining that this “really helps capture the RNA expression spatially,” and can resolve the localization of cell types markers in anatomical structures.
For these cells, the expression of the newly identified gene markers was mostly confined to ducts and lobules.
In addition, an analysis of cell states within the luminal epithelial cells showed four different cell states, each of which have “different kinds of genes that they express, and also different pathways that they express, suggesting that these might be transcriptomally different,” Ms. Seth said.
Of note, these cells and cells states are not biased to a specific condition or patient, suggesting that they are coming from all of the patients, she added.
Two of the four cell states – the secretory and hormone responsive states – have previously been reported, but Ms. Seth and her colleagues identified two additional cell states that may have different biological functions and are present in the different anatomical regions of the breast.
Fibroblasts
Fibroblasts, the cells of the connective tissue, were the most abundant cell type. Like the epithelial cells, both canonical collagen markers (COL6A3, MMP2, FBN1, FBLN2, FBN, and COL1A1) and newly identified gene markers (TNXB, AEBP1, CFH, CTSK, TPPP3, MEG3, HTRA1, LHFP, and OGN) were used to identify them.
Endothelial cells
Breast tissue is highly vascular, so endothelial cells, which line the walls of veins, arteries, and lymphatic vessels, are plentiful.
“Again, for both these cell types, we identified them using the canonical marker CD31, and we identified some new gene markers,” she said, noting that the new markers include CCL21, CLDN5, MMRN1, LYVE1, and PROX1 for lymphatic endothelial cells, and RNASE1 and IFI27 for vascular endothelial cells.
Two different groups – or states – of vascular endothelial cells were identified, with each expressing “very different genes as well as very different pathways, again suggesting that they might have different biological functions, which we are still investigating,” she said.
Additional findings and future directions
In addition to stromal cells, some immune cells were also seen. These included T cells that came mostly from two patients, as well as macrophages and monocytes, which comprised the most abundant immune cell population.
Of note, all of these cells are also found in the tumor microenvironment, but they are in a transformed state. For example cancer-associated fibroblasts, tumor endothelial cells, tumor-associated macrophages, and tumor-associated adipocytes have been seen in that environment, she said.
“So what we are trying to do with this project is ... learn how these cells are, and how these cells behave in the normal ecosystem,” she explained, noting that the hope is to provide a valuable reference for the research community with new insights about how normal cell types are transformed in the tumor microenvironment.
In an effort to overcome the adipocyte-associated limitation of the technology, adipocytes are “now being isolated by single nucleus RNA sequencing.”
“This [sequencing] technology has helped us identify multiple cell states within a cell type; and most of these cell states may have different biological functions, which probably can be investigated by spatial transcriptomic methods,” she said.
Spatial transcriptomics also continue to be used for validation of the new gene markers identified in the course of this research, she noted.
The breast tumor microenvironment
At the Garvan Institute, current work is focusing more on defining the landscape of the breast tumor microenvironment at single-cell resolution, according to Dr. Swarbrick, a senior research fellow and head of the Tumour Progression Laboratory there.
“Breast cancers ... are complex cellular ecosystems, and it’s really the sum of the interactions between the cell types that play major roles in determining the etiology of disease and its response to therapy,” he said. “So I think that going forward toward a new age of diagnostics and therapeutics, there’s wonderful potential in capitalizing on the tumor microenvironment for new developments, but this has to be built on a really deep understanding of the tumor microenvironment, and – I might say – a new taxonomy of the breast cellular environment.”
Therefore, in an effort to address “this limitation in our knowledge base,” his lab is also working toward development of a breast cell atlas.
A fresh tissue collection program was established to collect early breast cancer tissues at the time of surgery, metastatic biopsies, and metastatic lesions from autopsies. The tissues are quickly dissociated into their cellular components and they undergo massively parallel capture and sequencing using the 10x genomics platform, he said.
Thousands of cells per case are analyzed using single-cell RNA sequencing (RNA-seq), as well as “RAGE-seq” and “CITE-seq,” which are performed in parallel to the RNA sequencing to address some of the limitations of the RNA sequencing alone and to “try to gain a multi-omic insight into the cell biology,” he explained.
RAGE-seq, which Dr. Swarbrick and his team developed, “is essentially a method to do targeted long-read sequencing in parallel to the short-read sequencing that we use for RNA-seq,” and CITE-seq is “a really fantastic method developed at the New York Genome Center that essentially allows us to gather proteomic data in parallel to the RNA data,” he said.
Based on findings from the analyses of about 125,000 cells from 25 patients, a map was created that showed the cell clusters identified by both canonical markers and gene expression signatures.
“We find the cell types we would expect to be present in a breast cancer,” he said.
The map shows clusters of myeloid, epithelial-1 and -2, cancer-associated fibroblast (CAF)-1 and -2, endothelial, T Reg, B, and CD8 and CD4 T cells.
Next, each cell type is quantified in each patient, and a graphic representation of the findings shows large variability in the proportions of each cell type in each patient.
“Ultimately, our goal is to be able to relate the frequencies of cell types and molecular features to each other, but also to clinical-pathological features from these patients,” he noted.
A closer look at the findings on an individual case level demonstrates the potential for development of better therapies.
For example, a case involving a high-grade triple-negative invasive ductal carcinoma exhibited each of the cell types found overall.
“One of the things that strikes us early on is we see a number of malignant epithelial populations,” he said, noting that proliferation is one of the drivers of the heterogeneity, but that heterogeneity was also seen for “other clinically relevant features such as basal cytokeratins,” which were heterogeneously expressed in different cell-type clusters.
“This was kind of paralleled in the immunohistochemistry results that we obtained from this patient,” he said. “We could also apply other clinically used tests that we’ve developed on bulk (such as PAM50 intrinsic subtyping) and ask whether they can be applied at the single-cell resolution.
“We think that these are going to be great tools to try to now get in and understand the significance of this heterogeneity and try to identify the lethal cells within this patient, and potentially therapeutic strategies to eradicate those cells,” he added.
Fibroblasts
A notable finding of this project was the presence of “not one, but two populations of fibroblasts,” Dr. Swarbrick said, noting that fibroblasts are typically discussed as a single entity.
“This is arguing that there are at least two major types present within the breast, and almost every case has these populations present at roughly equal amounts,” he said.
This is of particular interest, because it has been shown in prior studies that targeting fibroblasts can have therapeutic outcomes.
“So we think this is a very important population within the tumor microenvironment,” he added.
With respect to gene expression features, CAF-1 is dominated by signatures of extracellular matrix deposition and remodeling, which “look like the classic myofibroblasts that we typically think of when we study cancer-associated fibroblasts.”
“In contrast, the CAF-2 population ... have what appears to be quite a predominant secretory function, so we see a lot of cytokines being produced by these cells, but we also see a very high level of expression of a number immune checkpoint ligands,” he said, adding that his team is actively pursuing whether these cells may be undergoing signaling events with infiltrating lymphocytes in the tumor microenvironment.
The signatures for both CAF types are prognostic within large breast cancer data sets, suggesting that they do actually have an important role in disease, he noted.
Markers for these cells include ACTA2, which was previously known to be a marker, and which is almost exclusively restricted to CAF-1, and the cell surface protein CD34 – a progenitor marker in many different cellular systems, “which is actually beautifully expressed on the CAF-2 population” as demonstrated using CITE-seq.
“So we’re now using this as a way to prospectively identify these cells, pull them out of tumors, and conduct biologic assays to learn more about them,” he said.
The immune milieu
“We’re in the age of immunotherapy, and this is an area of huge interest, but we have a long way to go in making it as effective as possible for breast cancer patients,” Dr. Swarbrick said. “I believe part of that is through a very deep understanding of the taxonomy.”
RNA data alone are useful but insufficient to fully identify subsets of immune cells due to a “relatively low-resolution ability to resolve T cells.”
“But because we’re now using the panel of 125 antibodies in parallel, we can now start to use protein levels to split up these populations and we can start to now identify, with higher resolution, more unique populations within the environment,” he said, noting that the availability of protein data not only helps identify subtypes, but is also therapeutically important as it allows for certainty regarding whether the protein target of therapeutic antibodies is expressed on the surface of cells.
Ultimately the hope is that this effort to build a multi-omic breast cancer atlas will continue to drive new discoveries in personalized medicine for breast cancer, Dr. Swarbrick concluded, adding that the field is moving fast, and it will be very important for labs like his and the Navin Lab to communicate to avoid needlessly duplicating efforts.
“I think it’s going to be really exciting to start to put some of these [findings] together,” he said.
The MD Anderson project is funded by the Chan Zuckerberg Initiative as part of its work in supporting the Human Cell Atlas project. Ms. Seth reported having no disclosures. Dr. Swarbrick’s research is funded by the Australian Government/National Health and Medical Research Council and the National Breast Cancer Foundation. He reported having no relevant disclosures.
SOURCE: Seth T et al. SABCS 2018, Abstract GS1-02; Swarbrick A et al. SABCS 2018, Abstract GS1-01
REPORTING FROM SABCS 2018
Key clinical point: Improved understanding of the cellular landscape of both normal breast tissue and breast cancer could lead to new stromal- and immune-based therapies.
Major finding: From pathologically normal breast tissues expression, investigators identified three major cell types, as well as several minor cell types. In analyses of cells from breast cancer patients, a map was created that showed the cell clusters identified by both canonical markers and gene expression signatures.
Study details: An analysis of 32,138 breast cells from 11 women, and another of about 125,000 cells from 25 patients.
Disclosures: The MD Anderson research is part of the Human Cell Atlas project and is funded by the Chan Zuckerberg Initiative. Ms. Seth reported having no disclosures. Dr. Swarbrick’s research is funded by the Australian Government/National Health and Medical Research Council and the National Breast Cancer Foundation. He reported having no relevant disclosures.
Source: Seth T et al. SABCS 2018: Abstract GS1-02; Swarbrick A et al. SABCS 2018: Abstract GS1-01.
AML, myeloma risk higher for breast cancer survivors
Breast cancer survivors should continue to be monitored for hematologic malignancies, especially acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), results of a population-based study from France suggest.
Among nearly 440,000 women with an incident breast cancer diagnosis, the incidence of AML was nearly three times higher and the incidence of MDS was five times higher than that of women in the general population. Women with breast cancer also were at higher risk for multiple myeloma (MM) and acute lymphoblastic leukemia/lymphocytic lymphoma (ALL/LL) compared with the background population, reported Marie Joelle Jabagi, PharmD, MPH, of the University of Paris Sud, France, and her colleagues.
“These findings serve to better inform practicing oncologists, and breast cancer survivors should be advised of the increased risk of developing certain hematologic malignant neoplasms after their first cancer diagnosis,” they wrote in JAMA Network Open.
Breast cancers are the malignant solid tumors most frequently associated with risk for myeloid neoplasms, but there is little information on the risk for secondary lymphoid malignancies among breast cancer patients, the investigators stated.
“In addition, real-life data on secondary hematologic malignant neoplasm incidence are scarce, especially in the recent period marked by major advances in breast cancer treatments,” they wrote.
To get better estimates of the incidence of myeloid and lymphoid neoplasms in this population, they conducted a retrospective review of information from the French National Health Data System on all French women from the ages of 20 to 85 years who had an incident breast cancer diagnosis from July 1, 2006, through Dec. 31, 2015.
In all, 439,704 women with a median age of 59 years were identified. They were followed until a diagnosis of a hematologic malignancy, death, or loss to follow-up, or until Dec. 31, 2016.
Data on the breast cancer patients were compared with those for all French women in the general population who were registered in the general national health insurance program from January 2007 through the end of 2016.
During a median follow-up of 5 years, there were 3,046 cases of hematologic neoplasms among the breast cancer patients, including 509 cases of AML, for a crude incidence rate (CIR) of 24.5 per 100,000 person-years (py); 832 cases of MDS for a CIR of 40.1/100,000 py; and 267 cases of myeloproliferative neoplasms (MPN), for a CIR of 12.8/100,000 py.
In addition, there were 420 cases of MM for a CIR of 20.3/100,000 py; 912 cases of Hodgkin or non-Hodgkin lymphoma (HL/NHL) for a CIR of 44.4/100,000 py, and 106 cases of ALL/LL for a CIR of 5.1/100,000 py.
Breast cancer survivors had significantly higher incidences, compared with the general population, of AML (standardized incidence ratio [SIR] 2.8, 95% confidence interval [CI], 2.5-3.2), MDS (SIR 5.0, CI, 4.4-5.7), MM (SIR 1.5, CI, 1.3-17), and ALL/LL (SIR 2.0, CI, 1.3-3.0). There was a trend toward significance for both MPN and HL/NHL, but the lower limit of the confidence intervals for these conditions either crossed or touched 1.
In a review of the literature, the authors found that “[s]everal studies linked AML and MDS to chemotherapeutic agents, radiation treatment, and supportive treatment with granulocyte colony-stimulating factor. These results are consistent with other available data showing a 2½-fold to 3½-fold increased risk of AML.”
They noted that their estimate of a five-fold increase in risk for MDS was higher than the 3.7-fold risk reported in a previous registry cohort analysis, suggesting that risk for MDS among breast cancer patients may be underestimated.
“The recent discovery of the gene signatures that guide treatment decisions in early-stage breast cancer might reduce the number of patients exposed to cytotoxic chemotherapy and its complications, including hematologic malignant neoplasm. Therefore, continuing to monitor hematologic malignant neoplasm trends is necessary, especially given that approaches to cancer treatment are rapidly evolving. Further research is also required to assess the modality of treatment for and the genetic predisposition to these secondary malignant neoplasms,” the authors concluded.
SOURCE: Jabagi MJ et al. JAMA Network Open. 2019 Jan 18. doi: 10.1001/jamanetworkopen.2018.7147.
Breast cancer survivors should continue to be monitored for hematologic malignancies, especially acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), results of a population-based study from France suggest.
Among nearly 440,000 women with an incident breast cancer diagnosis, the incidence of AML was nearly three times higher and the incidence of MDS was five times higher than that of women in the general population. Women with breast cancer also were at higher risk for multiple myeloma (MM) and acute lymphoblastic leukemia/lymphocytic lymphoma (ALL/LL) compared with the background population, reported Marie Joelle Jabagi, PharmD, MPH, of the University of Paris Sud, France, and her colleagues.
“These findings serve to better inform practicing oncologists, and breast cancer survivors should be advised of the increased risk of developing certain hematologic malignant neoplasms after their first cancer diagnosis,” they wrote in JAMA Network Open.
Breast cancers are the malignant solid tumors most frequently associated with risk for myeloid neoplasms, but there is little information on the risk for secondary lymphoid malignancies among breast cancer patients, the investigators stated.
“In addition, real-life data on secondary hematologic malignant neoplasm incidence are scarce, especially in the recent period marked by major advances in breast cancer treatments,” they wrote.
To get better estimates of the incidence of myeloid and lymphoid neoplasms in this population, they conducted a retrospective review of information from the French National Health Data System on all French women from the ages of 20 to 85 years who had an incident breast cancer diagnosis from July 1, 2006, through Dec. 31, 2015.
In all, 439,704 women with a median age of 59 years were identified. They were followed until a diagnosis of a hematologic malignancy, death, or loss to follow-up, or until Dec. 31, 2016.
Data on the breast cancer patients were compared with those for all French women in the general population who were registered in the general national health insurance program from January 2007 through the end of 2016.
During a median follow-up of 5 years, there were 3,046 cases of hematologic neoplasms among the breast cancer patients, including 509 cases of AML, for a crude incidence rate (CIR) of 24.5 per 100,000 person-years (py); 832 cases of MDS for a CIR of 40.1/100,000 py; and 267 cases of myeloproliferative neoplasms (MPN), for a CIR of 12.8/100,000 py.
In addition, there were 420 cases of MM for a CIR of 20.3/100,000 py; 912 cases of Hodgkin or non-Hodgkin lymphoma (HL/NHL) for a CIR of 44.4/100,000 py, and 106 cases of ALL/LL for a CIR of 5.1/100,000 py.
Breast cancer survivors had significantly higher incidences, compared with the general population, of AML (standardized incidence ratio [SIR] 2.8, 95% confidence interval [CI], 2.5-3.2), MDS (SIR 5.0, CI, 4.4-5.7), MM (SIR 1.5, CI, 1.3-17), and ALL/LL (SIR 2.0, CI, 1.3-3.0). There was a trend toward significance for both MPN and HL/NHL, but the lower limit of the confidence intervals for these conditions either crossed or touched 1.
In a review of the literature, the authors found that “[s]everal studies linked AML and MDS to chemotherapeutic agents, radiation treatment, and supportive treatment with granulocyte colony-stimulating factor. These results are consistent with other available data showing a 2½-fold to 3½-fold increased risk of AML.”
They noted that their estimate of a five-fold increase in risk for MDS was higher than the 3.7-fold risk reported in a previous registry cohort analysis, suggesting that risk for MDS among breast cancer patients may be underestimated.
“The recent discovery of the gene signatures that guide treatment decisions in early-stage breast cancer might reduce the number of patients exposed to cytotoxic chemotherapy and its complications, including hematologic malignant neoplasm. Therefore, continuing to monitor hematologic malignant neoplasm trends is necessary, especially given that approaches to cancer treatment are rapidly evolving. Further research is also required to assess the modality of treatment for and the genetic predisposition to these secondary malignant neoplasms,” the authors concluded.
SOURCE: Jabagi MJ et al. JAMA Network Open. 2019 Jan 18. doi: 10.1001/jamanetworkopen.2018.7147.
Breast cancer survivors should continue to be monitored for hematologic malignancies, especially acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), results of a population-based study from France suggest.
Among nearly 440,000 women with an incident breast cancer diagnosis, the incidence of AML was nearly three times higher and the incidence of MDS was five times higher than that of women in the general population. Women with breast cancer also were at higher risk for multiple myeloma (MM) and acute lymphoblastic leukemia/lymphocytic lymphoma (ALL/LL) compared with the background population, reported Marie Joelle Jabagi, PharmD, MPH, of the University of Paris Sud, France, and her colleagues.
“These findings serve to better inform practicing oncologists, and breast cancer survivors should be advised of the increased risk of developing certain hematologic malignant neoplasms after their first cancer diagnosis,” they wrote in JAMA Network Open.
Breast cancers are the malignant solid tumors most frequently associated with risk for myeloid neoplasms, but there is little information on the risk for secondary lymphoid malignancies among breast cancer patients, the investigators stated.
“In addition, real-life data on secondary hematologic malignant neoplasm incidence are scarce, especially in the recent period marked by major advances in breast cancer treatments,” they wrote.
To get better estimates of the incidence of myeloid and lymphoid neoplasms in this population, they conducted a retrospective review of information from the French National Health Data System on all French women from the ages of 20 to 85 years who had an incident breast cancer diagnosis from July 1, 2006, through Dec. 31, 2015.
In all, 439,704 women with a median age of 59 years were identified. They were followed until a diagnosis of a hematologic malignancy, death, or loss to follow-up, or until Dec. 31, 2016.
Data on the breast cancer patients were compared with those for all French women in the general population who were registered in the general national health insurance program from January 2007 through the end of 2016.
During a median follow-up of 5 years, there were 3,046 cases of hematologic neoplasms among the breast cancer patients, including 509 cases of AML, for a crude incidence rate (CIR) of 24.5 per 100,000 person-years (py); 832 cases of MDS for a CIR of 40.1/100,000 py; and 267 cases of myeloproliferative neoplasms (MPN), for a CIR of 12.8/100,000 py.
In addition, there were 420 cases of MM for a CIR of 20.3/100,000 py; 912 cases of Hodgkin or non-Hodgkin lymphoma (HL/NHL) for a CIR of 44.4/100,000 py, and 106 cases of ALL/LL for a CIR of 5.1/100,000 py.
Breast cancer survivors had significantly higher incidences, compared with the general population, of AML (standardized incidence ratio [SIR] 2.8, 95% confidence interval [CI], 2.5-3.2), MDS (SIR 5.0, CI, 4.4-5.7), MM (SIR 1.5, CI, 1.3-17), and ALL/LL (SIR 2.0, CI, 1.3-3.0). There was a trend toward significance for both MPN and HL/NHL, but the lower limit of the confidence intervals for these conditions either crossed or touched 1.
In a review of the literature, the authors found that “[s]everal studies linked AML and MDS to chemotherapeutic agents, radiation treatment, and supportive treatment with granulocyte colony-stimulating factor. These results are consistent with other available data showing a 2½-fold to 3½-fold increased risk of AML.”
They noted that their estimate of a five-fold increase in risk for MDS was higher than the 3.7-fold risk reported in a previous registry cohort analysis, suggesting that risk for MDS among breast cancer patients may be underestimated.
“The recent discovery of the gene signatures that guide treatment decisions in early-stage breast cancer might reduce the number of patients exposed to cytotoxic chemotherapy and its complications, including hematologic malignant neoplasm. Therefore, continuing to monitor hematologic malignant neoplasm trends is necessary, especially given that approaches to cancer treatment are rapidly evolving. Further research is also required to assess the modality of treatment for and the genetic predisposition to these secondary malignant neoplasms,” the authors concluded.
SOURCE: Jabagi MJ et al. JAMA Network Open. 2019 Jan 18. doi: 10.1001/jamanetworkopen.2018.7147.
FROM JAMA NETWORK OPEN
Key clinical point: Breast cancer survivors should be monitored for hematologic malignancies.
Major finding: The standardized incidence ratio for AML was 2.8 and the SIR for multiple myeloma was 5.0 among French breast cancer survivors compared with women in the general French population.
Study details: Retrospective analysis of data on 439,704 women aged 20-85 years with a breast cancer diagnosis.
Disclosures: The authors did not report a study funding source. Coauthor Anthony Goncalves, MD, reported nonfinancial support from Roche, Novartis, Pfizer, Celgene, MSD, Lilly, and Astra Zeneca outside of the submitted work. No other disclosures were reported.
Source: Jabagi MJ et al. JAMA Network Open. 2019 Jan 18. doi: 10.1001/jamanetworkopen.2018.7147.
FDA approves third trastuzumab biosimilar
The Food and Drug Administration .
Ontruzant (trastuzumab-dttb), marketed by Samsung Bioepis, is the third approved biosimilar to Genentech’s Herceptin in the United States.
Patients should be selected for treatment with Ontruzant using an FDA-approved companion diagnostic for a trastuzumab product.
The prescribing information for the newly approved biosimilar includes a boxed warning highlighting the risk of cardiomyopathy, infusion reactions, embryo-fetal toxicity, and pulmonary toxicity associated with the drug.
Ontruzant was shown to be equivalent to Herceptin in a phase 3 study (Eur J Cancer. 2018 Apr;93:19-27).
The trial included 875 patients with HER2-positive early breast cancer. Patients were randomized to receive Ontruzant or Herceptin for eight cycles concurrently with chemotherapy. The chemotherapy consisted of four cycles of docetaxel followed by four cycles of 5-fluorouracil/epirubicin/cyclophosphamide.
The patients then underwent surgery, which was followed by 10 cycles of Ontruzant (n=380) or Herceptin (n=384).
The median follow-up was 437 days in the Ontruzant arm and 438 days in the Herceptin arm. Safety and efficacy results were similar between the treatment arms.
Treatment-emergent adverse events occurred in 97.5% of patients in the Ontruzant arm and 96.1% of those in the Herceptin arm.
The 12-month event-free survival rate was 93.7% in the Ontruzant arm and 93.4% in the Herceptin arm.
The Food and Drug Administration .
Ontruzant (trastuzumab-dttb), marketed by Samsung Bioepis, is the third approved biosimilar to Genentech’s Herceptin in the United States.
Patients should be selected for treatment with Ontruzant using an FDA-approved companion diagnostic for a trastuzumab product.
The prescribing information for the newly approved biosimilar includes a boxed warning highlighting the risk of cardiomyopathy, infusion reactions, embryo-fetal toxicity, and pulmonary toxicity associated with the drug.
Ontruzant was shown to be equivalent to Herceptin in a phase 3 study (Eur J Cancer. 2018 Apr;93:19-27).
The trial included 875 patients with HER2-positive early breast cancer. Patients were randomized to receive Ontruzant or Herceptin for eight cycles concurrently with chemotherapy. The chemotherapy consisted of four cycles of docetaxel followed by four cycles of 5-fluorouracil/epirubicin/cyclophosphamide.
The patients then underwent surgery, which was followed by 10 cycles of Ontruzant (n=380) or Herceptin (n=384).
The median follow-up was 437 days in the Ontruzant arm and 438 days in the Herceptin arm. Safety and efficacy results were similar between the treatment arms.
Treatment-emergent adverse events occurred in 97.5% of patients in the Ontruzant arm and 96.1% of those in the Herceptin arm.
The 12-month event-free survival rate was 93.7% in the Ontruzant arm and 93.4% in the Herceptin arm.
The Food and Drug Administration .
Ontruzant (trastuzumab-dttb), marketed by Samsung Bioepis, is the third approved biosimilar to Genentech’s Herceptin in the United States.
Patients should be selected for treatment with Ontruzant using an FDA-approved companion diagnostic for a trastuzumab product.
The prescribing information for the newly approved biosimilar includes a boxed warning highlighting the risk of cardiomyopathy, infusion reactions, embryo-fetal toxicity, and pulmonary toxicity associated with the drug.
Ontruzant was shown to be equivalent to Herceptin in a phase 3 study (Eur J Cancer. 2018 Apr;93:19-27).
The trial included 875 patients with HER2-positive early breast cancer. Patients were randomized to receive Ontruzant or Herceptin for eight cycles concurrently with chemotherapy. The chemotherapy consisted of four cycles of docetaxel followed by four cycles of 5-fluorouracil/epirubicin/cyclophosphamide.
The patients then underwent surgery, which was followed by 10 cycles of Ontruzant (n=380) or Herceptin (n=384).
The median follow-up was 437 days in the Ontruzant arm and 438 days in the Herceptin arm. Safety and efficacy results were similar between the treatment arms.
Treatment-emergent adverse events occurred in 97.5% of patients in the Ontruzant arm and 96.1% of those in the Herceptin arm.
The 12-month event-free survival rate was 93.7% in the Ontruzant arm and 93.4% in the Herceptin arm.
High postpartum breast cancer metastasis risk may persist for a decade
Increased risk of metastasis associated with postpartum breast cancer (PPBC) in women 45 years or younger may persist for 10 years after childbirth, a finding that may give reason to extend the 5-year window currently defining PPBC.
Analysis of more than 700 patients showed that risk of metastasis was approximately twofold higher for a decade after childbirth, with risks about 3.5- to fivefold higher in women diagnosed with stage I or II disease, reported lead author Erica Goddard, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and her colleagues. Regardless of parity status, patients diagnosed with stage III disease had poor outcomes.
“The high risk for metastasis is independent of poor prognostic indicators, including biological subtype, stage, age, or year of diagnosis,” the investigators wrote in JAMA Network Open. “Yet, PPBC is an underrecognized subset of breast cancer, and few studies address the associated high risk for metastasis.”
The cohort study involved 701 women 45 years or younger who were diagnosed with breast cancer between 1981 and 2014. Early cases were retrospective, until the study switched to a prospective method in 2004. The investigators analyzed rates of distant metastasis and looked for associations with tumor cell proliferation, lymphovascular invasion, lymph node involvement, and other clinical attributes. Distant metastasis was defined by spread beyond the ipsilateral breast or local draining lymph node, as detected by physical exam, imaging, and/or pathological testing. The investigators also stained available tumor samples for Ki67 positivity, which is used for prognostic purposes, and to distinguish between ER-positive luminal A versus ER-positive luminal B disease.
Compared with nulliparous patients, women under 45 who were diagnosed with PPBC within 5 years of childbirth were 2.13 times as likely to develop metastasis (P = .009). This risk persisted for 5 more years. Women diagnosed within 5-10 years of childbirth showed a similar hazard ratio, of 2.23 (P = .006). After 10 years, the hazard ratio dropped to 1.6, but this value was statistically insignificant (P = .13). Patients identified with stage I or II disease had more dramatic risk profiles, with hazard ratios of 3.5 and 5.2, for diagnoses up to 5 years postpartum, and diagnoses 5-10 years postpartum, respectively. These findings suggest that, for some patients, the 5- to 10-year window may be the riskiest time for metastasis, and, incidentally, one that has historically been excluded from the definition of PPBC.
In addition, patients diagnosed with estrogen receptor–positive breast cancer within 10 years of childbirth had outcomes similar to those of nulliparous women with estrogen receptor–negative breast cancer, and postpartum women with estrogen receptor–negative breast cancer had worse outcomes than did nulliparous women with the same subtype. Furthermore, PPBC was associated with higher rates of lymph node involvement and lymphovascular invasion. Collectively, these findings suggest that PPBC is generally more aggressive than nulliparous breast cancer. In contrast, Ki67 positivity, identifying the luminal B subtype, was associated with worse outcome regardless of parity status, but this finding was statistically insignificant.
“[T]hese data suggest that stages I and II breast cancer in patients with PPBC diagnosed within 10 years of parturition may be underestimated in their risk for metastasis, as parity status is not currently factored into clinical decision-making algorithms, such as the National Comprehensive Cancer Network guidelines,” the investigators concluded. “In sum, we suggest that poor-prognostic PPBC is an increasing problem that merits more dedicated research.”
The study was funded by the National Cancer Institute, the National Institutes of Health, the U.S. Department of Defense, and other organizations. Dr. Goddard reported funding from the NCI and NIH. Dr. Mori reported financial support from the Department of Defense.
SOURCE: Goddard et al. JAMA Netw Open. 2019 Jan 11. doi: 10.1001/jamanetworkopen.2018.
Increased risk of metastasis associated with postpartum breast cancer (PPBC) in women 45 years or younger may persist for 10 years after childbirth, a finding that may give reason to extend the 5-year window currently defining PPBC.
Analysis of more than 700 patients showed that risk of metastasis was approximately twofold higher for a decade after childbirth, with risks about 3.5- to fivefold higher in women diagnosed with stage I or II disease, reported lead author Erica Goddard, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and her colleagues. Regardless of parity status, patients diagnosed with stage III disease had poor outcomes.
“The high risk for metastasis is independent of poor prognostic indicators, including biological subtype, stage, age, or year of diagnosis,” the investigators wrote in JAMA Network Open. “Yet, PPBC is an underrecognized subset of breast cancer, and few studies address the associated high risk for metastasis.”
The cohort study involved 701 women 45 years or younger who were diagnosed with breast cancer between 1981 and 2014. Early cases were retrospective, until the study switched to a prospective method in 2004. The investigators analyzed rates of distant metastasis and looked for associations with tumor cell proliferation, lymphovascular invasion, lymph node involvement, and other clinical attributes. Distant metastasis was defined by spread beyond the ipsilateral breast or local draining lymph node, as detected by physical exam, imaging, and/or pathological testing. The investigators also stained available tumor samples for Ki67 positivity, which is used for prognostic purposes, and to distinguish between ER-positive luminal A versus ER-positive luminal B disease.
Compared with nulliparous patients, women under 45 who were diagnosed with PPBC within 5 years of childbirth were 2.13 times as likely to develop metastasis (P = .009). This risk persisted for 5 more years. Women diagnosed within 5-10 years of childbirth showed a similar hazard ratio, of 2.23 (P = .006). After 10 years, the hazard ratio dropped to 1.6, but this value was statistically insignificant (P = .13). Patients identified with stage I or II disease had more dramatic risk profiles, with hazard ratios of 3.5 and 5.2, for diagnoses up to 5 years postpartum, and diagnoses 5-10 years postpartum, respectively. These findings suggest that, for some patients, the 5- to 10-year window may be the riskiest time for metastasis, and, incidentally, one that has historically been excluded from the definition of PPBC.
In addition, patients diagnosed with estrogen receptor–positive breast cancer within 10 years of childbirth had outcomes similar to those of nulliparous women with estrogen receptor–negative breast cancer, and postpartum women with estrogen receptor–negative breast cancer had worse outcomes than did nulliparous women with the same subtype. Furthermore, PPBC was associated with higher rates of lymph node involvement and lymphovascular invasion. Collectively, these findings suggest that PPBC is generally more aggressive than nulliparous breast cancer. In contrast, Ki67 positivity, identifying the luminal B subtype, was associated with worse outcome regardless of parity status, but this finding was statistically insignificant.
“[T]hese data suggest that stages I and II breast cancer in patients with PPBC diagnosed within 10 years of parturition may be underestimated in their risk for metastasis, as parity status is not currently factored into clinical decision-making algorithms, such as the National Comprehensive Cancer Network guidelines,” the investigators concluded. “In sum, we suggest that poor-prognostic PPBC is an increasing problem that merits more dedicated research.”
The study was funded by the National Cancer Institute, the National Institutes of Health, the U.S. Department of Defense, and other organizations. Dr. Goddard reported funding from the NCI and NIH. Dr. Mori reported financial support from the Department of Defense.
SOURCE: Goddard et al. JAMA Netw Open. 2019 Jan 11. doi: 10.1001/jamanetworkopen.2018.
Increased risk of metastasis associated with postpartum breast cancer (PPBC) in women 45 years or younger may persist for 10 years after childbirth, a finding that may give reason to extend the 5-year window currently defining PPBC.
Analysis of more than 700 patients showed that risk of metastasis was approximately twofold higher for a decade after childbirth, with risks about 3.5- to fivefold higher in women diagnosed with stage I or II disease, reported lead author Erica Goddard, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and her colleagues. Regardless of parity status, patients diagnosed with stage III disease had poor outcomes.
“The high risk for metastasis is independent of poor prognostic indicators, including biological subtype, stage, age, or year of diagnosis,” the investigators wrote in JAMA Network Open. “Yet, PPBC is an underrecognized subset of breast cancer, and few studies address the associated high risk for metastasis.”
The cohort study involved 701 women 45 years or younger who were diagnosed with breast cancer between 1981 and 2014. Early cases were retrospective, until the study switched to a prospective method in 2004. The investigators analyzed rates of distant metastasis and looked for associations with tumor cell proliferation, lymphovascular invasion, lymph node involvement, and other clinical attributes. Distant metastasis was defined by spread beyond the ipsilateral breast or local draining lymph node, as detected by physical exam, imaging, and/or pathological testing. The investigators also stained available tumor samples for Ki67 positivity, which is used for prognostic purposes, and to distinguish between ER-positive luminal A versus ER-positive luminal B disease.
Compared with nulliparous patients, women under 45 who were diagnosed with PPBC within 5 years of childbirth were 2.13 times as likely to develop metastasis (P = .009). This risk persisted for 5 more years. Women diagnosed within 5-10 years of childbirth showed a similar hazard ratio, of 2.23 (P = .006). After 10 years, the hazard ratio dropped to 1.6, but this value was statistically insignificant (P = .13). Patients identified with stage I or II disease had more dramatic risk profiles, with hazard ratios of 3.5 and 5.2, for diagnoses up to 5 years postpartum, and diagnoses 5-10 years postpartum, respectively. These findings suggest that, for some patients, the 5- to 10-year window may be the riskiest time for metastasis, and, incidentally, one that has historically been excluded from the definition of PPBC.
In addition, patients diagnosed with estrogen receptor–positive breast cancer within 10 years of childbirth had outcomes similar to those of nulliparous women with estrogen receptor–negative breast cancer, and postpartum women with estrogen receptor–negative breast cancer had worse outcomes than did nulliparous women with the same subtype. Furthermore, PPBC was associated with higher rates of lymph node involvement and lymphovascular invasion. Collectively, these findings suggest that PPBC is generally more aggressive than nulliparous breast cancer. In contrast, Ki67 positivity, identifying the luminal B subtype, was associated with worse outcome regardless of parity status, but this finding was statistically insignificant.
“[T]hese data suggest that stages I and II breast cancer in patients with PPBC diagnosed within 10 years of parturition may be underestimated in their risk for metastasis, as parity status is not currently factored into clinical decision-making algorithms, such as the National Comprehensive Cancer Network guidelines,” the investigators concluded. “In sum, we suggest that poor-prognostic PPBC is an increasing problem that merits more dedicated research.”
The study was funded by the National Cancer Institute, the National Institutes of Health, the U.S. Department of Defense, and other organizations. Dr. Goddard reported funding from the NCI and NIH. Dr. Mori reported financial support from the Department of Defense.
SOURCE: Goddard et al. JAMA Netw Open. 2019 Jan 11. doi: 10.1001/jamanetworkopen.2018.
FROM JAMA NETWORK OPEN
Key clinical point: Increased risk of metastasis associated with postpartum breast cancer in women 45 years or younger may persist for 10 years after childbirth, instead of 5 years, as previously reported.
Major finding: Compared with nulliparous breast cancer patients, women 45 years or younger diagnosed with breast cancer within 5-10 years of childbirth were 2.23 times as likely to develop metastasis.
Study details: A retrospective and prospective cohort study involving 701 women with stage I, II, or III breast cancer who were 45 years or younger at time of diagnosis.
Disclosures: The study was funded by the National Cancer Institute, the National Institutes of Health, the U.S. Department of Defense, and other organizations. Dr. Goddard reported funding from the NCI and NIH. Dr. Mori reported financial support from the Department of Defense.
Source: Goddard et al. JAMA Netw Open. 2019 Jan 11. doi: 10.1001/jamanetworkopen.2018.6997.