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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.
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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.
Progress in cancer research slowed by broken system
NEW YORK – Conflicts of interest, whether reported or unreported, are just one component of a broken system that has misaligned incentives with meaningful advances in breast cancer research, agreed a panel of experts who participated in an evening program sponsored by SHARE, a breast cancer patient advocacy group.
“The issue of disclosures, while it is important, is not really the key issue. The key issue for me is about the amazing amount of money that is changing hands,” said Fran Visco, president of the National Breast Cancer Coalition, Washington. She contended not enough money in breast cancer research is being applied to save women’s lives rather than driving profits for institutions, physicians, and the pharmaceutical industry.
The other two participants in this panel, called Conflicts of Interest in Research and Treatment: What Breast Cancer Patients Should Know, largely agreed. In turn, they each explained that major sums of money in play for physicians and institutions collaborating with industry are earmarked for generating income much more than improving outcomes.
“Most of where this money is going is for these little tiny improvements and there is no association between the outcome increment that you get and what you pay for that outcome increment,” said Robert Cook-Deegan, MD, a bioethicist and a professor at the School for Innovation in Society, Arizona State University, Tempe.
Leaving aside whether physician-scientists working at nonprofit research institutions can avoid conflicts of interest when money is funneled to them from start-up investment opportunities, pharmaceutical board memberships, and direct compensation deals for consultancies and other services, Dr. Cook-Deegan was referring to the bigger problem of misaligned incentives. Large financial rewards are available for any drug with market potential instead of being limited to those that save lives, he said.
Tracing the current system to the Bayh-Dole Act in 1980, which permitted researchers to claim patents for intellectual property developed with federal funding, Dr. Cook-Deegan described a system of minnows, fish, and sharks. Researchers, who are the minnows, seek potential new therapeutics to be developed by for-profit startups or other commercial entities, which are the fish. If the drug continues to show promise, it brings investors, who are the sharks.
Once the new therapy reaches the sharks, the excitement about a new and more effective treatment has been overshadowed by the excitement about profits, which are essential to pay for the large investment required for the clinical development that brings new drugs to market. If the drug is marketable, it is considered a success even when the clinical benefits barely register.
“There have been about 20 new [cancer] drugs approved by the [Food and Drug Administration] in the last 2 years. The increased median disease-free survival is usually about 3 months,” said Otis W. Brawley, MD, who recently joined the Kimmel Cancer Center at Johns Hopkins University after resigning his position as chief medical officer at the American Cancer Society (ACS).
Dr. Brawley joined the others in declaring: “The system is broken.” The flow of money is not the only incentive for researchers to participate in clinical development programs focused on minor advances rather than blockbuster discoveries. Unrestricted research grants are now much harder to obtain, according to Dr. Brawley, making collaboration with industry essential not just for research funding but career advancement. Research at major cancer centers is still being conducted at the highest level, but there are unavoidable interdependent relationships for nonprofit institutions and for-profit enterprises.
“The doc who prescribes the drug to the average patient probably does not have this conflict of interest,” he said. “However, they are influenced by people who have these conflicts.”
The SHARE panel on conflicts of interest was convened after a series of articles co-reported by ProPublica and the New York Times described the failure of the chief medical officer at Memorial Sloan Kettering Cancer Center, José Baselga, MD, to disclose his financial conflicts of interest in publications, such as the New England Journal of Medicine, where they are required. Dr. Baselga resigned his position.
However, the failure to disclose financial relationships with industry was a minor topic during the SHARE panel. Robert Bazell, PhD, an adjunct professor in the division of molecular, cellular, and developmental biology at Yale University, New Haven, Conn., moderated the panel. He said in his opening remarks that the issues “go much deeper.”
While the articles did not reveal “anything illegal, it opened a lot of peoples’ eyes as to how much money there was in the system,” said Dr. Bazell, who was for many years the chief science and health correspondent for NBC News.
Specifically, it has heightened concern about whether profit motives are subverting the goals of science, according to Dr. Bazell. “This money bomb has fallen on a lot of science but it has particularly fallen on oncology,” he said.
Not everyone, including the bioethicist, agreed that profits by themselves are the problem. Big rewards may be a reasonable price for discoveries that save lives, but all agreed that the system does not necessarily reserve big rewards for life-saving advances.
“The focus isn’t really on drugs that will save lives, its just on more drugs,” said Ms. Visco, echoing the incentive system described by Dr. Cook-Deegan. She believes the current system handsomely rewards scientists and physicians for developing drugs with little or no significant clinical benefit. When a drug shows a progression-free survival benefit relative to a previous standard, even of modest statistical or clinical significance, it will be prescribed and profits will be generated.
Early in her tenure at the National Breast Cancer Coalition, Ms. Visco, who was a practicing lawyer prior to taking the helm of the coalition, considered fund raising for research the primary goal. She hoped that the coalition could help the breast cancer research community identify and fund priorities, but her perspective has changed.
“I used to think that we should be collaborators but now I am coming to the conclusion that we should be in charge. Educated, trained patient advocates with a constituency should be in charge, because our only agenda is to save lives and end breast cancer,” Ms. Visco said. She no longer believes in simply increasing funding even at research centers such as the National Cancer Institute without a fundamental reorganization of priorities.
Many leaders in medicine are aware of the problem, according to Dr. Brawley, who cited a recent statement by the American Society of Clinical Oncology that expressed concern about the plethora of cancer trials showing very small gains. He did agree with the others, however, that incentives are now misaligned.
“We are designing clinical trials not to look for big gains,” Dr. Brawley agreed. But he also cautioned that the system is complex. One reason that drugs offering modest or little gain over a previous standard are highly marketable is that patients themselves demand them. Direct-to-consumer marketing supports drugs with little or even nothing to offer.
“I see patients who want drugs that they should not get,” said Dr. Brawley, who indicated that clinicians are under pressure to offer something to desperate patients even when options are expensive and not shown to provide any change in outcome.
Overall, in the shake-up at Memorial Sloan Kettering, it was the failure to disclose significant financial relationships rather than the financial relationships themselves that represented an important breach in ethics, according to Dr. Brawley, who indicated that researcher relationships with industry are not inherently wrong. In an article published in November 2018, the New York Times reported that Dr. Brawley left his post at the ACS because of “his dismay” over some partnerships the ACS had formed with industry, but Dr. Brawley would not confirm or deny this report.
Relative to conflicts of interest at major research institutions, Dr. Cook-Deegan was more circumspect about whether disclosure is enough. Although he agreed with the premise that close collaboration with industry might be clinically valuable, which one investigator at Memorial Sloan Kettering claimed when speaking with the New York Times, he questioned whether there is a line over which the relationship is too intertwined.
“Do you really need to serve on the board? Do you really need the types of financial ties that have the potential to influence clinical decisions?” he asked.
Although Dr. Cook-Deegan agreed with the others that he does not know exactly how best to fix the system, he believes a fix may be coming.
“I think we are at an inflection point,” he said. “The symptoms of a system that has been running off the rails for a while are getting severe enough that we are starting to pay attention,” he said. One sign of movement is that both political parties have “introduced bills to address pricing, which is directly related to the problems we are talking about.”
NEW YORK – Conflicts of interest, whether reported or unreported, are just one component of a broken system that has misaligned incentives with meaningful advances in breast cancer research, agreed a panel of experts who participated in an evening program sponsored by SHARE, a breast cancer patient advocacy group.
“The issue of disclosures, while it is important, is not really the key issue. The key issue for me is about the amazing amount of money that is changing hands,” said Fran Visco, president of the National Breast Cancer Coalition, Washington. She contended not enough money in breast cancer research is being applied to save women’s lives rather than driving profits for institutions, physicians, and the pharmaceutical industry.
The other two participants in this panel, called Conflicts of Interest in Research and Treatment: What Breast Cancer Patients Should Know, largely agreed. In turn, they each explained that major sums of money in play for physicians and institutions collaborating with industry are earmarked for generating income much more than improving outcomes.
“Most of where this money is going is for these little tiny improvements and there is no association between the outcome increment that you get and what you pay for that outcome increment,” said Robert Cook-Deegan, MD, a bioethicist and a professor at the School for Innovation in Society, Arizona State University, Tempe.
Leaving aside whether physician-scientists working at nonprofit research institutions can avoid conflicts of interest when money is funneled to them from start-up investment opportunities, pharmaceutical board memberships, and direct compensation deals for consultancies and other services, Dr. Cook-Deegan was referring to the bigger problem of misaligned incentives. Large financial rewards are available for any drug with market potential instead of being limited to those that save lives, he said.
Tracing the current system to the Bayh-Dole Act in 1980, which permitted researchers to claim patents for intellectual property developed with federal funding, Dr. Cook-Deegan described a system of minnows, fish, and sharks. Researchers, who are the minnows, seek potential new therapeutics to be developed by for-profit startups or other commercial entities, which are the fish. If the drug continues to show promise, it brings investors, who are the sharks.
Once the new therapy reaches the sharks, the excitement about a new and more effective treatment has been overshadowed by the excitement about profits, which are essential to pay for the large investment required for the clinical development that brings new drugs to market. If the drug is marketable, it is considered a success even when the clinical benefits barely register.
“There have been about 20 new [cancer] drugs approved by the [Food and Drug Administration] in the last 2 years. The increased median disease-free survival is usually about 3 months,” said Otis W. Brawley, MD, who recently joined the Kimmel Cancer Center at Johns Hopkins University after resigning his position as chief medical officer at the American Cancer Society (ACS).
Dr. Brawley joined the others in declaring: “The system is broken.” The flow of money is not the only incentive for researchers to participate in clinical development programs focused on minor advances rather than blockbuster discoveries. Unrestricted research grants are now much harder to obtain, according to Dr. Brawley, making collaboration with industry essential not just for research funding but career advancement. Research at major cancer centers is still being conducted at the highest level, but there are unavoidable interdependent relationships for nonprofit institutions and for-profit enterprises.
“The doc who prescribes the drug to the average patient probably does not have this conflict of interest,” he said. “However, they are influenced by people who have these conflicts.”
The SHARE panel on conflicts of interest was convened after a series of articles co-reported by ProPublica and the New York Times described the failure of the chief medical officer at Memorial Sloan Kettering Cancer Center, José Baselga, MD, to disclose his financial conflicts of interest in publications, such as the New England Journal of Medicine, where they are required. Dr. Baselga resigned his position.
However, the failure to disclose financial relationships with industry was a minor topic during the SHARE panel. Robert Bazell, PhD, an adjunct professor in the division of molecular, cellular, and developmental biology at Yale University, New Haven, Conn., moderated the panel. He said in his opening remarks that the issues “go much deeper.”
While the articles did not reveal “anything illegal, it opened a lot of peoples’ eyes as to how much money there was in the system,” said Dr. Bazell, who was for many years the chief science and health correspondent for NBC News.
Specifically, it has heightened concern about whether profit motives are subverting the goals of science, according to Dr. Bazell. “This money bomb has fallen on a lot of science but it has particularly fallen on oncology,” he said.
Not everyone, including the bioethicist, agreed that profits by themselves are the problem. Big rewards may be a reasonable price for discoveries that save lives, but all agreed that the system does not necessarily reserve big rewards for life-saving advances.
“The focus isn’t really on drugs that will save lives, its just on more drugs,” said Ms. Visco, echoing the incentive system described by Dr. Cook-Deegan. She believes the current system handsomely rewards scientists and physicians for developing drugs with little or no significant clinical benefit. When a drug shows a progression-free survival benefit relative to a previous standard, even of modest statistical or clinical significance, it will be prescribed and profits will be generated.
Early in her tenure at the National Breast Cancer Coalition, Ms. Visco, who was a practicing lawyer prior to taking the helm of the coalition, considered fund raising for research the primary goal. She hoped that the coalition could help the breast cancer research community identify and fund priorities, but her perspective has changed.
“I used to think that we should be collaborators but now I am coming to the conclusion that we should be in charge. Educated, trained patient advocates with a constituency should be in charge, because our only agenda is to save lives and end breast cancer,” Ms. Visco said. She no longer believes in simply increasing funding even at research centers such as the National Cancer Institute without a fundamental reorganization of priorities.
Many leaders in medicine are aware of the problem, according to Dr. Brawley, who cited a recent statement by the American Society of Clinical Oncology that expressed concern about the plethora of cancer trials showing very small gains. He did agree with the others, however, that incentives are now misaligned.
“We are designing clinical trials not to look for big gains,” Dr. Brawley agreed. But he also cautioned that the system is complex. One reason that drugs offering modest or little gain over a previous standard are highly marketable is that patients themselves demand them. Direct-to-consumer marketing supports drugs with little or even nothing to offer.
“I see patients who want drugs that they should not get,” said Dr. Brawley, who indicated that clinicians are under pressure to offer something to desperate patients even when options are expensive and not shown to provide any change in outcome.
Overall, in the shake-up at Memorial Sloan Kettering, it was the failure to disclose significant financial relationships rather than the financial relationships themselves that represented an important breach in ethics, according to Dr. Brawley, who indicated that researcher relationships with industry are not inherently wrong. In an article published in November 2018, the New York Times reported that Dr. Brawley left his post at the ACS because of “his dismay” over some partnerships the ACS had formed with industry, but Dr. Brawley would not confirm or deny this report.
Relative to conflicts of interest at major research institutions, Dr. Cook-Deegan was more circumspect about whether disclosure is enough. Although he agreed with the premise that close collaboration with industry might be clinically valuable, which one investigator at Memorial Sloan Kettering claimed when speaking with the New York Times, he questioned whether there is a line over which the relationship is too intertwined.
“Do you really need to serve on the board? Do you really need the types of financial ties that have the potential to influence clinical decisions?” he asked.
Although Dr. Cook-Deegan agreed with the others that he does not know exactly how best to fix the system, he believes a fix may be coming.
“I think we are at an inflection point,” he said. “The symptoms of a system that has been running off the rails for a while are getting severe enough that we are starting to pay attention,” he said. One sign of movement is that both political parties have “introduced bills to address pricing, which is directly related to the problems we are talking about.”
NEW YORK – Conflicts of interest, whether reported or unreported, are just one component of a broken system that has misaligned incentives with meaningful advances in breast cancer research, agreed a panel of experts who participated in an evening program sponsored by SHARE, a breast cancer patient advocacy group.
“The issue of disclosures, while it is important, is not really the key issue. The key issue for me is about the amazing amount of money that is changing hands,” said Fran Visco, president of the National Breast Cancer Coalition, Washington. She contended not enough money in breast cancer research is being applied to save women’s lives rather than driving profits for institutions, physicians, and the pharmaceutical industry.
The other two participants in this panel, called Conflicts of Interest in Research and Treatment: What Breast Cancer Patients Should Know, largely agreed. In turn, they each explained that major sums of money in play for physicians and institutions collaborating with industry are earmarked for generating income much more than improving outcomes.
“Most of where this money is going is for these little tiny improvements and there is no association between the outcome increment that you get and what you pay for that outcome increment,” said Robert Cook-Deegan, MD, a bioethicist and a professor at the School for Innovation in Society, Arizona State University, Tempe.
Leaving aside whether physician-scientists working at nonprofit research institutions can avoid conflicts of interest when money is funneled to them from start-up investment opportunities, pharmaceutical board memberships, and direct compensation deals for consultancies and other services, Dr. Cook-Deegan was referring to the bigger problem of misaligned incentives. Large financial rewards are available for any drug with market potential instead of being limited to those that save lives, he said.
Tracing the current system to the Bayh-Dole Act in 1980, which permitted researchers to claim patents for intellectual property developed with federal funding, Dr. Cook-Deegan described a system of minnows, fish, and sharks. Researchers, who are the minnows, seek potential new therapeutics to be developed by for-profit startups or other commercial entities, which are the fish. If the drug continues to show promise, it brings investors, who are the sharks.
Once the new therapy reaches the sharks, the excitement about a new and more effective treatment has been overshadowed by the excitement about profits, which are essential to pay for the large investment required for the clinical development that brings new drugs to market. If the drug is marketable, it is considered a success even when the clinical benefits barely register.
“There have been about 20 new [cancer] drugs approved by the [Food and Drug Administration] in the last 2 years. The increased median disease-free survival is usually about 3 months,” said Otis W. Brawley, MD, who recently joined the Kimmel Cancer Center at Johns Hopkins University after resigning his position as chief medical officer at the American Cancer Society (ACS).
Dr. Brawley joined the others in declaring: “The system is broken.” The flow of money is not the only incentive for researchers to participate in clinical development programs focused on minor advances rather than blockbuster discoveries. Unrestricted research grants are now much harder to obtain, according to Dr. Brawley, making collaboration with industry essential not just for research funding but career advancement. Research at major cancer centers is still being conducted at the highest level, but there are unavoidable interdependent relationships for nonprofit institutions and for-profit enterprises.
“The doc who prescribes the drug to the average patient probably does not have this conflict of interest,” he said. “However, they are influenced by people who have these conflicts.”
The SHARE panel on conflicts of interest was convened after a series of articles co-reported by ProPublica and the New York Times described the failure of the chief medical officer at Memorial Sloan Kettering Cancer Center, José Baselga, MD, to disclose his financial conflicts of interest in publications, such as the New England Journal of Medicine, where they are required. Dr. Baselga resigned his position.
However, the failure to disclose financial relationships with industry was a minor topic during the SHARE panel. Robert Bazell, PhD, an adjunct professor in the division of molecular, cellular, and developmental biology at Yale University, New Haven, Conn., moderated the panel. He said in his opening remarks that the issues “go much deeper.”
While the articles did not reveal “anything illegal, it opened a lot of peoples’ eyes as to how much money there was in the system,” said Dr. Bazell, who was for many years the chief science and health correspondent for NBC News.
Specifically, it has heightened concern about whether profit motives are subverting the goals of science, according to Dr. Bazell. “This money bomb has fallen on a lot of science but it has particularly fallen on oncology,” he said.
Not everyone, including the bioethicist, agreed that profits by themselves are the problem. Big rewards may be a reasonable price for discoveries that save lives, but all agreed that the system does not necessarily reserve big rewards for life-saving advances.
“The focus isn’t really on drugs that will save lives, its just on more drugs,” said Ms. Visco, echoing the incentive system described by Dr. Cook-Deegan. She believes the current system handsomely rewards scientists and physicians for developing drugs with little or no significant clinical benefit. When a drug shows a progression-free survival benefit relative to a previous standard, even of modest statistical or clinical significance, it will be prescribed and profits will be generated.
Early in her tenure at the National Breast Cancer Coalition, Ms. Visco, who was a practicing lawyer prior to taking the helm of the coalition, considered fund raising for research the primary goal. She hoped that the coalition could help the breast cancer research community identify and fund priorities, but her perspective has changed.
“I used to think that we should be collaborators but now I am coming to the conclusion that we should be in charge. Educated, trained patient advocates with a constituency should be in charge, because our only agenda is to save lives and end breast cancer,” Ms. Visco said. She no longer believes in simply increasing funding even at research centers such as the National Cancer Institute without a fundamental reorganization of priorities.
Many leaders in medicine are aware of the problem, according to Dr. Brawley, who cited a recent statement by the American Society of Clinical Oncology that expressed concern about the plethora of cancer trials showing very small gains. He did agree with the others, however, that incentives are now misaligned.
“We are designing clinical trials not to look for big gains,” Dr. Brawley agreed. But he also cautioned that the system is complex. One reason that drugs offering modest or little gain over a previous standard are highly marketable is that patients themselves demand them. Direct-to-consumer marketing supports drugs with little or even nothing to offer.
“I see patients who want drugs that they should not get,” said Dr. Brawley, who indicated that clinicians are under pressure to offer something to desperate patients even when options are expensive and not shown to provide any change in outcome.
Overall, in the shake-up at Memorial Sloan Kettering, it was the failure to disclose significant financial relationships rather than the financial relationships themselves that represented an important breach in ethics, according to Dr. Brawley, who indicated that researcher relationships with industry are not inherently wrong. In an article published in November 2018, the New York Times reported that Dr. Brawley left his post at the ACS because of “his dismay” over some partnerships the ACS had formed with industry, but Dr. Brawley would not confirm or deny this report.
Relative to conflicts of interest at major research institutions, Dr. Cook-Deegan was more circumspect about whether disclosure is enough. Although he agreed with the premise that close collaboration with industry might be clinically valuable, which one investigator at Memorial Sloan Kettering claimed when speaking with the New York Times, he questioned whether there is a line over which the relationship is too intertwined.
“Do you really need to serve on the board? Do you really need the types of financial ties that have the potential to influence clinical decisions?” he asked.
Although Dr. Cook-Deegan agreed with the others that he does not know exactly how best to fix the system, he believes a fix may be coming.
“I think we are at an inflection point,” he said. “The symptoms of a system that has been running off the rails for a while are getting severe enough that we are starting to pay attention,” he said. One sign of movement is that both political parties have “introduced bills to address pricing, which is directly related to the problems we are talking about.”
Soy didn’t up all-cause mortality in breast cancer survivors
A cohort of Chinese women who are breast cancer survivors had no increased mortality from soy intake, according to a new study.
The work adds to the existing body of evidence that women with breast cancer, or risk for breast cancer, don’t need to modify their soy intake to mitigate risk, said the study’s first author, Suzanne C. Ho, PhD.
Speaking at the annual meeting of the North American Menopause Society, Dr. Ho noted that the combination of increasing breast cancer incidence and improved outcome has resulted in larger numbers of breast cancer survivors in Hong Kong, where she is professor emerita at the Chinese University of Hong Kong.
The prospective, ongoing study examines the association between soy intake pre- and postdiagnosis and total mortality for Chinese women who are breast cancer survivors. Dr. Ho said that she and her colleagues hypothesized that they would not see higher mortality among women who had higher soy intake – and this was the case.
Of 1,497 breast cancer survivors drawn from two facilities in Hong Kong, those who consumed higher quantities of dietary soy did not have increased risk of all-cause mortality, compared with those in the lowest tertile of soy consumption.
There are theoretical underpinnings for thinking that soy could be a player in cancer risk, but the biochemistry and epidemiology behind the studies are complicated. Estrogen plays a role in human breast cancer, and many modern breast cancer treatments actually dampen endogenous estrogens.
However, epidemiologic data have shown that consumption of soy-based foods – which contain phytoestrogens, primarily in the form of isoflavones – is inversely associated with developing breast cancer.
This is all part of why soy-based foods have been thought of as a mixed bag with regard to breast cancer: Soy isoflavones are, said Dr. Ho, “Natural estrogen receptor modulators that possess both estrogenlike and antiestrogenic properties.”
Other chemicals contained in soy may fight cancer, with effects that are antioxidative and strengthen immune response. Soy constituents also inhibit DNA topoisomerase I and II, proteases, tyrosine kinases, and inositol phosphate, effects that can slow tumor growth. Still, one soy isoflavone, genistein, actually can promote growth of estrogen-dependent tumors in rats, said Dr. Ho
Dr. Ho and her colleagues enrolled Hong Kong residents for the study of mortality among breast cancer survivors. Participants were included if they were Chinese, female, aged 24-77 years, and had their first primary breast cancer histologically confirmed within 12 months of entering the study. Cancer had to be graded below stage III.
Using a 109-item validated food questionnaire, investigators gathered information about participants’ soy intake and general diet for the year prior to breast cancer diagnosis. Other patient characteristics, relevant prognostic information from medical records, and anthropometric data were collected at baseline, and repeated at 18, 36, and 60 months.
The primary outcome measure – all-cause mortality during the follow-up period – was tracked for a mean 50.9 months, with a 78% retention rate for study participants, said Dr. Ho. In total, 96 patients died during follow-up, making up 5.9% of the premenopausal and 7% of the postmenopausal participants.
Statistical analysis corrected for potential confounders, including patient and disease characteristics and treatment modalities, as well as overall energy consumption.
Patients were evenly divided into tertiles of soy isoflavone intake, with cutpoints of 3.77 mg/1,000 kcal and 10.05 mg/1,000 kcal for the lower limit of the two higher tertiles. For the highest tertile, though, mean isoflavone intake was actually 20.87 mg/1,000 kcal.
Patient, disease, and treatment characteristics did not differ significantly among the tertiles.
An adjusted statistical analysis looked at pre- and postmenopausal women separately by tertile of soy isoflavone consumption, setting the hazard ratio for all-cause mortality at 1.00 for women in the lowest tertile of soy consumption.
For premenopausal women in the middle tertile, the HR was 0.45 (95% confidence interval, 0.20-1.00), and 0.86 for those in the highest tertile (95% CI, 0.43-1.72); 782 participants, in all, were premenopausal.
For the 715 postmenopausal women, the HR for those in the middle tertile of soy consumption was 0.94 (95% CI, 0.43-2.05), and 1.11 in the highest (95% CI, 0.54-2.29).
Taking all pre- and postmenopausal participants together, those in the middle tertile of soy isoflavone intake had an all-cause mortality HR of 0.63 (95% CI, 0.37-1.09). For the highest tertile of the full cohort, the HR was 0.95 (95% CI, 0.58-1.55).
Confidence intervals were wide in these findings, but Dr. Ho noted that “moderate soy food intake might be associated with better survival.”
“Prediagnosis soy intake did not increase the risk of all-cause mortality in breast cancer survivors,” said Dr. Ho, findings she called “consistent with the literature that soy consumption does not adversely effect breast cancer survival.”
The study is ongoing, she explained, and “longer follow-up will provide further evidence on the effect of pre- and postdiagnosis soy intake on breast cancer outcomes.”
The study had a homogeneous population of southern Chinese women, with fairly good retention and robust statistical adjustment for confounders. However, it wasn’t possible to assess bioavailability of isoflavones and their metabolites, which can vary according to individual microbiota. Also, researchers did not track whether patients used traditional Chinese medicine.
The World Cancer Research Fund International supported the study. Dr. Ho reported no conflicts of interest.
SOURCE: Ho S et al. NAMS 2018, Abstract S-23.
A cohort of Chinese women who are breast cancer survivors had no increased mortality from soy intake, according to a new study.
The work adds to the existing body of evidence that women with breast cancer, or risk for breast cancer, don’t need to modify their soy intake to mitigate risk, said the study’s first author, Suzanne C. Ho, PhD.
Speaking at the annual meeting of the North American Menopause Society, Dr. Ho noted that the combination of increasing breast cancer incidence and improved outcome has resulted in larger numbers of breast cancer survivors in Hong Kong, where she is professor emerita at the Chinese University of Hong Kong.
The prospective, ongoing study examines the association between soy intake pre- and postdiagnosis and total mortality for Chinese women who are breast cancer survivors. Dr. Ho said that she and her colleagues hypothesized that they would not see higher mortality among women who had higher soy intake – and this was the case.
Of 1,497 breast cancer survivors drawn from two facilities in Hong Kong, those who consumed higher quantities of dietary soy did not have increased risk of all-cause mortality, compared with those in the lowest tertile of soy consumption.
There are theoretical underpinnings for thinking that soy could be a player in cancer risk, but the biochemistry and epidemiology behind the studies are complicated. Estrogen plays a role in human breast cancer, and many modern breast cancer treatments actually dampen endogenous estrogens.
However, epidemiologic data have shown that consumption of soy-based foods – which contain phytoestrogens, primarily in the form of isoflavones – is inversely associated with developing breast cancer.
This is all part of why soy-based foods have been thought of as a mixed bag with regard to breast cancer: Soy isoflavones are, said Dr. Ho, “Natural estrogen receptor modulators that possess both estrogenlike and antiestrogenic properties.”
Other chemicals contained in soy may fight cancer, with effects that are antioxidative and strengthen immune response. Soy constituents also inhibit DNA topoisomerase I and II, proteases, tyrosine kinases, and inositol phosphate, effects that can slow tumor growth. Still, one soy isoflavone, genistein, actually can promote growth of estrogen-dependent tumors in rats, said Dr. Ho
Dr. Ho and her colleagues enrolled Hong Kong residents for the study of mortality among breast cancer survivors. Participants were included if they were Chinese, female, aged 24-77 years, and had their first primary breast cancer histologically confirmed within 12 months of entering the study. Cancer had to be graded below stage III.
Using a 109-item validated food questionnaire, investigators gathered information about participants’ soy intake and general diet for the year prior to breast cancer diagnosis. Other patient characteristics, relevant prognostic information from medical records, and anthropometric data were collected at baseline, and repeated at 18, 36, and 60 months.
The primary outcome measure – all-cause mortality during the follow-up period – was tracked for a mean 50.9 months, with a 78% retention rate for study participants, said Dr. Ho. In total, 96 patients died during follow-up, making up 5.9% of the premenopausal and 7% of the postmenopausal participants.
Statistical analysis corrected for potential confounders, including patient and disease characteristics and treatment modalities, as well as overall energy consumption.
Patients were evenly divided into tertiles of soy isoflavone intake, with cutpoints of 3.77 mg/1,000 kcal and 10.05 mg/1,000 kcal for the lower limit of the two higher tertiles. For the highest tertile, though, mean isoflavone intake was actually 20.87 mg/1,000 kcal.
Patient, disease, and treatment characteristics did not differ significantly among the tertiles.
An adjusted statistical analysis looked at pre- and postmenopausal women separately by tertile of soy isoflavone consumption, setting the hazard ratio for all-cause mortality at 1.00 for women in the lowest tertile of soy consumption.
For premenopausal women in the middle tertile, the HR was 0.45 (95% confidence interval, 0.20-1.00), and 0.86 for those in the highest tertile (95% CI, 0.43-1.72); 782 participants, in all, were premenopausal.
For the 715 postmenopausal women, the HR for those in the middle tertile of soy consumption was 0.94 (95% CI, 0.43-2.05), and 1.11 in the highest (95% CI, 0.54-2.29).
Taking all pre- and postmenopausal participants together, those in the middle tertile of soy isoflavone intake had an all-cause mortality HR of 0.63 (95% CI, 0.37-1.09). For the highest tertile of the full cohort, the HR was 0.95 (95% CI, 0.58-1.55).
Confidence intervals were wide in these findings, but Dr. Ho noted that “moderate soy food intake might be associated with better survival.”
“Prediagnosis soy intake did not increase the risk of all-cause mortality in breast cancer survivors,” said Dr. Ho, findings she called “consistent with the literature that soy consumption does not adversely effect breast cancer survival.”
The study is ongoing, she explained, and “longer follow-up will provide further evidence on the effect of pre- and postdiagnosis soy intake on breast cancer outcomes.”
The study had a homogeneous population of southern Chinese women, with fairly good retention and robust statistical adjustment for confounders. However, it wasn’t possible to assess bioavailability of isoflavones and their metabolites, which can vary according to individual microbiota. Also, researchers did not track whether patients used traditional Chinese medicine.
The World Cancer Research Fund International supported the study. Dr. Ho reported no conflicts of interest.
SOURCE: Ho S et al. NAMS 2018, Abstract S-23.
A cohort of Chinese women who are breast cancer survivors had no increased mortality from soy intake, according to a new study.
The work adds to the existing body of evidence that women with breast cancer, or risk for breast cancer, don’t need to modify their soy intake to mitigate risk, said the study’s first author, Suzanne C. Ho, PhD.
Speaking at the annual meeting of the North American Menopause Society, Dr. Ho noted that the combination of increasing breast cancer incidence and improved outcome has resulted in larger numbers of breast cancer survivors in Hong Kong, where she is professor emerita at the Chinese University of Hong Kong.
The prospective, ongoing study examines the association between soy intake pre- and postdiagnosis and total mortality for Chinese women who are breast cancer survivors. Dr. Ho said that she and her colleagues hypothesized that they would not see higher mortality among women who had higher soy intake – and this was the case.
Of 1,497 breast cancer survivors drawn from two facilities in Hong Kong, those who consumed higher quantities of dietary soy did not have increased risk of all-cause mortality, compared with those in the lowest tertile of soy consumption.
There are theoretical underpinnings for thinking that soy could be a player in cancer risk, but the biochemistry and epidemiology behind the studies are complicated. Estrogen plays a role in human breast cancer, and many modern breast cancer treatments actually dampen endogenous estrogens.
However, epidemiologic data have shown that consumption of soy-based foods – which contain phytoestrogens, primarily in the form of isoflavones – is inversely associated with developing breast cancer.
This is all part of why soy-based foods have been thought of as a mixed bag with regard to breast cancer: Soy isoflavones are, said Dr. Ho, “Natural estrogen receptor modulators that possess both estrogenlike and antiestrogenic properties.”
Other chemicals contained in soy may fight cancer, with effects that are antioxidative and strengthen immune response. Soy constituents also inhibit DNA topoisomerase I and II, proteases, tyrosine kinases, and inositol phosphate, effects that can slow tumor growth. Still, one soy isoflavone, genistein, actually can promote growth of estrogen-dependent tumors in rats, said Dr. Ho
Dr. Ho and her colleagues enrolled Hong Kong residents for the study of mortality among breast cancer survivors. Participants were included if they were Chinese, female, aged 24-77 years, and had their first primary breast cancer histologically confirmed within 12 months of entering the study. Cancer had to be graded below stage III.
Using a 109-item validated food questionnaire, investigators gathered information about participants’ soy intake and general diet for the year prior to breast cancer diagnosis. Other patient characteristics, relevant prognostic information from medical records, and anthropometric data were collected at baseline, and repeated at 18, 36, and 60 months.
The primary outcome measure – all-cause mortality during the follow-up period – was tracked for a mean 50.9 months, with a 78% retention rate for study participants, said Dr. Ho. In total, 96 patients died during follow-up, making up 5.9% of the premenopausal and 7% of the postmenopausal participants.
Statistical analysis corrected for potential confounders, including patient and disease characteristics and treatment modalities, as well as overall energy consumption.
Patients were evenly divided into tertiles of soy isoflavone intake, with cutpoints of 3.77 mg/1,000 kcal and 10.05 mg/1,000 kcal for the lower limit of the two higher tertiles. For the highest tertile, though, mean isoflavone intake was actually 20.87 mg/1,000 kcal.
Patient, disease, and treatment characteristics did not differ significantly among the tertiles.
An adjusted statistical analysis looked at pre- and postmenopausal women separately by tertile of soy isoflavone consumption, setting the hazard ratio for all-cause mortality at 1.00 for women in the lowest tertile of soy consumption.
For premenopausal women in the middle tertile, the HR was 0.45 (95% confidence interval, 0.20-1.00), and 0.86 for those in the highest tertile (95% CI, 0.43-1.72); 782 participants, in all, were premenopausal.
For the 715 postmenopausal women, the HR for those in the middle tertile of soy consumption was 0.94 (95% CI, 0.43-2.05), and 1.11 in the highest (95% CI, 0.54-2.29).
Taking all pre- and postmenopausal participants together, those in the middle tertile of soy isoflavone intake had an all-cause mortality HR of 0.63 (95% CI, 0.37-1.09). For the highest tertile of the full cohort, the HR was 0.95 (95% CI, 0.58-1.55).
Confidence intervals were wide in these findings, but Dr. Ho noted that “moderate soy food intake might be associated with better survival.”
“Prediagnosis soy intake did not increase the risk of all-cause mortality in breast cancer survivors,” said Dr. Ho, findings she called “consistent with the literature that soy consumption does not adversely effect breast cancer survival.”
The study is ongoing, she explained, and “longer follow-up will provide further evidence on the effect of pre- and postdiagnosis soy intake on breast cancer outcomes.”
The study had a homogeneous population of southern Chinese women, with fairly good retention and robust statistical adjustment for confounders. However, it wasn’t possible to assess bioavailability of isoflavones and their metabolites, which can vary according to individual microbiota. Also, researchers did not track whether patients used traditional Chinese medicine.
The World Cancer Research Fund International supported the study. Dr. Ho reported no conflicts of interest.
SOURCE: Ho S et al. NAMS 2018, Abstract S-23.
REPORTING FROM NAMS 2018
Key clinical point: Soy consumption did not increase mortality risk in breast cancer survivors.
Major finding: The hazard ratios for all-cause mortality were 0.63 and 0.95 for the two highest tertiles of soy consumption.
Study details: An ongoing prospective cohort study of 1,497 female breast cancer survivors in Hong Kong.
Disclosures: The World Cancer Research Fund International supported the study. Dr. Ho reported no conflicts of interest.
Source: Ho S et al. NAMS 2018, Abstract S-23.