Breast Cancer

A record-setting 40,000-plus oncology professionals attended this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The outstanding education and scientific program, with the theme of Delivering Discoveries: Expanding the Reach of Precision Medicine, was planned and led by ASCO President Dr Bruce Johnson, professor and director of Thoracic Oncology at the Dana Farber Cancer Institute in Boston, and chaired by Sarah Cannon’s Dr David Spigel and Harvard’s Dr Ann Partridge. A recurring finding throughout the meeting was that “less is more” in several key areas of cancer therapy. From small molecules targeting driver mutations across various tumors to the application of immunotherapy in subsets of common cancers, it is clear that more patients are experiencing dramatic results from novel approaches.

A featured plenary session trial was TAILORx, a study of 10,273 women with hormone-receptor–positive, surgically resected breast cancer that had not spread to the lymph nodes, was less than 5 cm, and was not positive for the HER2 gene amplification. This clinical trial was sponsored by the NCI and initiated in 2006. It used the OncotypeDX genetic test to stratify patients into groups of low, intermediate, or high risk for recurrence. The low-risk patients received only hormonal therapy, and the high-risk patients were treated with hormonal therapy plus chemotherapy.

Dr Joseph Sparano, professor of Medicine and Women’s Health at the Albert Einstein College of Medicine in New York, presented the results from the group of 6,700 intermediate risk women who were randomized to receive hormonal therapy alone or in combination with chemotherapy. After 9 years of follow-up, 83.3% of the volunteers, as Dr Sparano appropriately referred to them, who were treated with hormonal therapy were still cancer free, compared with 84.3% of those who also received chemotherapy, demonstrating no statistical benefit for the addition of chemotherapy. Of note, breast cancer experts discussing the trial, including Dr Lisa Carey, professor of Breast Cancer Research at the UNC Lineberger Cancer Institute in Chapel Hill, urged that younger women, under the age of 50, with recurrence scores (RS) toward the higher end of the intermediate risk group (RS, 16-25) should still discuss and consider chemotherapy with their physicians. In summary, all patients fitting the study criteria with low (
These landmark and practice changing results mean that each year about 60,000 women in the United States will be spared the side effects of toxic drugs. These 10,273 study volunteers are true heroes to the women who will be diagnosed with breast cancer in coming years.

In the field of lung cancer, many new trial results using immunotherapy were presented, with the most talked about being single-agent pembrolizumab, a PD1 inhibitor, improving survival over traditional chemotherapy in patients with PD-L1 positive tumors, which comprise the majority of squamous cell and adenocarcinomas of the lung. Also in the plenary, Dr Gilberto Lopes of the Sylvester Cancer Center at the University of Miami, presented these results from the KEYNOTE-042 study. In patients with PD-L1 tumor proportion score (TPS) of >1%, the benefit in overall survival (OS) of pembrolizumab compared with chemotherapy was 16.7 versus 12.1 months, respectively (HR, 0.81). In those patients with a TPS of >20%, the OS benefit was 17.7 versus 1.0 months (HR, 0.77), and in the group with a TPS of >50%, the benefit was 20.0 versus 12.2 months (HR, 0.69). Overall, the quality of life and the occurrence of side effects were substantially better for those patients receiving immunotherapy alone. Other findings presented at the meeting demonstrated the benefit of adding immunotherapy to chemotherapy and of treating with combination immunotherapy (PD-1 and CTLA-4 inhibitors). Many options now exist, much work remains to be done, and accrual to clinical trials is more important than ever.

Another plenary session trial evaluated the benefit of performing a nephrectomy in patients with advanced or metastatic renal cell carcinoma (RCC), a long-held and practiced standard of care. Dr Arnaud Mejean of Paris Descartes University presented findings from the CARMENA trial, which randomized 450 patients with metastatic clear cell RCC to receive cytoreductive nephrectomy followed by sunitinib, or sunitinib alone. The OS results of 18.4 versus 13.9 months, respectively (HR, 0.89) favored sunitinib alone in this noninferiority analysis. Other endpoints lined up in favor of not removing the cancerous kidney, and the presenter and discussants were united in their opinion of the results and the resulting change in doing less surgery in these patients.

In a step away from less therapy, the European Pediatric Soft Tissue Sarcoma Study showed that adding 6 months of low-dose maintenance chemotherapy after standard intensive therapy improves survival in children with high-risk rhabdomyosarcoma. The addition of a vinorelbine and cyclophosphamide low-dose regimen improved 5-year disease-free survival from 69.8% to 77.6% (HR, 0.68) and OS from 73.7% to 86.5% (HR, 0.52) as presented by Dr Gianni Bisogno, University of Padovani, Italy. The maintenance regimen showed no increase in toxicity and actually fewer infections were noted.

In the area of molecular profiling, multiple studies at the meeting demonstrated the importance of assessing cancers for mutations as outstanding results were seen with therapies for NTRK, RET, ROS, and MSI-high driven tumors. In a debate on the role of molecular profiling, I had the opportunity to declare and support our position at Sarah Cannon that all patients with relapsed or metastatic cancers should have this testing performed. It will be through better understanding of the biology of these cancers that we will advance the field for all patients while sometimes finding a target or mutation that will dramatically change the life of a patient.

In keeping with the meeting’s theme, Delivering Discoveries: Expanding the Reach of Precision Medicine, the presentations and the discussions clearly demonstrated that through the use of precision medicine techniques such as prognostic gene assays and molecular profiling, patients can receive the best therapy, even “tailored” therapy, which may often actually be less therapy. It is an exciting time in cancer research, and I have never been more optimistic about the future of cancer treatment for our patients.

A record-setting 40,000-plus oncology professionals attended this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The outstanding education and scientific program, with the theme of Delivering Discoveries: Expanding the Reach of Precision Medicine, was planned and led by ASCO President Dr Bruce Johnson, professor and director of Thoracic Oncology at the Dana Farber Cancer Institute in Boston, and chaired by Sarah Cannon’s Dr David Spigel and Harvard’s Dr Ann Partridge. A recurring finding throughout the meeting was that “less is more” in several key areas of cancer therapy. From small molecules targeting driver mutations across various tumors to the application of immunotherapy in subsets of common cancers, it is clear that more patients are experiencing dramatic results from novel approaches.

A featured plenary session trial was TAILORx, a study of 10,273 women with hormone-receptor–positive, surgically resected breast cancer that had not spread to the lymph nodes, was less than 5 cm, and was not positive for the HER2 gene amplification. This clinical trial was sponsored by the NCI and initiated in 2006. It used the OncotypeDX genetic test to stratify patients into groups of low, intermediate, or high risk for recurrence. The low-risk patients received only hormonal therapy, and the high-risk patients were treated with hormonal therapy plus chemotherapy.

Dr Joseph Sparano, professor of Medicine and Women’s Health at the Albert Einstein College of Medicine in New York, presented the results from the group of 6,700 intermediate risk women who were randomized to receive hormonal therapy alone or in combination with chemotherapy. After 9 years of follow-up, 83.3% of the volunteers, as Dr Sparano appropriately referred to them, who were treated with hormonal therapy were still cancer free, compared with 84.3% of those who also received chemotherapy, demonstrating no statistical benefit for the addition of chemotherapy. Of note, breast cancer experts discussing the trial, including Dr Lisa Carey, professor of Breast Cancer Research at the UNC Lineberger Cancer Institute in Chapel Hill, urged that younger women, under the age of 50, with recurrence scores (RS) toward the higher end of the intermediate risk group (RS, 16-25) should still discuss and consider chemotherapy with their physicians. In summary, all patients fitting the study criteria with low (
These landmark and practice changing results mean that each year about 60,000 women in the United States will be spared the side effects of toxic drugs. These 10,273 study volunteers are true heroes to the women who will be diagnosed with breast cancer in coming years.

In the field of lung cancer, many new trial results using immunotherapy were presented, with the most talked about being single-agent pembrolizumab, a PD1 inhibitor, improving survival over traditional chemotherapy in patients with PD-L1 positive tumors, which comprise the majority of squamous cell and adenocarcinomas of the lung. Also in the plenary, Dr Gilberto Lopes of the Sylvester Cancer Center at the University of Miami, presented these results from the KEYNOTE-042 study. In patients with PD-L1 tumor proportion score (TPS) of >1%, the benefit in overall survival (OS) of pembrolizumab compared with chemotherapy was 16.7 versus 12.1 months, respectively (HR, 0.81). In those patients with a TPS of >20%, the OS benefit was 17.7 versus 1.0 months (HR, 0.77), and in the group with a TPS of >50%, the benefit was 20.0 versus 12.2 months (HR, 0.69). Overall, the quality of life and the occurrence of side effects were substantially better for those patients receiving immunotherapy alone. Other findings presented at the meeting demonstrated the benefit of adding immunotherapy to chemotherapy and of treating with combination immunotherapy (PD-1 and CTLA-4 inhibitors). Many options now exist, much work remains to be done, and accrual to clinical trials is more important than ever.

Another plenary session trial evaluated the benefit of performing a nephrectomy in patients with advanced or metastatic renal cell carcinoma (RCC), a long-held and practiced standard of care. Dr Arnaud Mejean of Paris Descartes University presented findings from the CARMENA trial, which randomized 450 patients with metastatic clear cell RCC to receive cytoreductive nephrectomy followed by sunitinib, or sunitinib alone. The OS results of 18.4 versus 13.9 months, respectively (HR, 0.89) favored sunitinib alone in this noninferiority analysis. Other endpoints lined up in favor of not removing the cancerous kidney, and the presenter and discussants were united in their opinion of the results and the resulting change in doing less surgery in these patients.

In a step away from less therapy, the European Pediatric Soft Tissue Sarcoma Study showed that adding 6 months of low-dose maintenance chemotherapy after standard intensive therapy improves survival in children with high-risk rhabdomyosarcoma. The addition of a vinorelbine and cyclophosphamide low-dose regimen improved 5-year disease-free survival from 69.8% to 77.6% (HR, 0.68) and OS from 73.7% to 86.5% (HR, 0.52) as presented by Dr Gianni Bisogno, University of Padovani, Italy. The maintenance regimen showed no increase in toxicity and actually fewer infections were noted.

In the area of molecular profiling, multiple studies at the meeting demonstrated the importance of assessing cancers for mutations as outstanding results were seen with therapies for NTRK, RET, ROS, and MSI-high driven tumors. In a debate on the role of molecular profiling, I had the opportunity to declare and support our position at Sarah Cannon that all patients with relapsed or metastatic cancers should have this testing performed. It will be through better understanding of the biology of these cancers that we will advance the field for all patients while sometimes finding a target or mutation that will dramatically change the life of a patient.

In keeping with the meeting’s theme, Delivering Discoveries: Expanding the Reach of Precision Medicine, the presentations and the discussions clearly demonstrated that through the use of precision medicine techniques such as prognostic gene assays and molecular profiling, patients can receive the best therapy, even “tailored” therapy, which may often actually be less therapy. It is an exciting time in cancer research, and I have never been more optimistic about the future of cancer treatment for our patients.

A record-setting 40,000-plus oncology professionals attended this year’s annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago. The outstanding education and scientific program, with the theme of Delivering Discoveries: Expanding the Reach of Precision Medicine, was planned and led by ASCO President Dr Bruce Johnson, professor and director of Thoracic Oncology at the Dana Farber Cancer Institute in Boston, and chaired by Sarah Cannon’s Dr David Spigel and Harvard’s Dr Ann Partridge. A recurring finding throughout the meeting was that “less is more” in several key areas of cancer therapy. From small molecules targeting driver mutations across various tumors to the application of immunotherapy in subsets of common cancers, it is clear that more patients are experiencing dramatic results from novel approaches.

A featured plenary session trial was TAILORx, a study of 10,273 women with hormone-receptor–positive, surgically resected breast cancer that had not spread to the lymph nodes, was less than 5 cm, and was not positive for the HER2 gene amplification. This clinical trial was sponsored by the NCI and initiated in 2006. It used the OncotypeDX genetic test to stratify patients into groups of low, intermediate, or high risk for recurrence. The low-risk patients received only hormonal therapy, and the high-risk patients were treated with hormonal therapy plus chemotherapy.

Dr Joseph Sparano, professor of Medicine and Women’s Health at the Albert Einstein College of Medicine in New York, presented the results from the group of 6,700 intermediate risk women who were randomized to receive hormonal therapy alone or in combination with chemotherapy. After 9 years of follow-up, 83.3% of the volunteers, as Dr Sparano appropriately referred to them, who were treated with hormonal therapy were still cancer free, compared with 84.3% of those who also received chemotherapy, demonstrating no statistical benefit for the addition of chemotherapy. Of note, breast cancer experts discussing the trial, including Dr Lisa Carey, professor of Breast Cancer Research at the UNC Lineberger Cancer Institute in Chapel Hill, urged that younger women, under the age of 50, with recurrence scores (RS) toward the higher end of the intermediate risk group (RS, 16-25) should still discuss and consider chemotherapy with their physicians. In summary, all patients fitting the study criteria with low (
These landmark and practice changing results mean that each year about 60,000 women in the United States will be spared the side effects of toxic drugs. These 10,273 study volunteers are true heroes to the women who will be diagnosed with breast cancer in coming years.

In the field of lung cancer, many new trial results using immunotherapy were presented, with the most talked about being single-agent pembrolizumab, a PD1 inhibitor, improving survival over traditional chemotherapy in patients with PD-L1 positive tumors, which comprise the majority of squamous cell and adenocarcinomas of the lung. Also in the plenary, Dr Gilberto Lopes of the Sylvester Cancer Center at the University of Miami, presented these results from the KEYNOTE-042 study. In patients with PD-L1 tumor proportion score (TPS) of >1%, the benefit in overall survival (OS) of pembrolizumab compared with chemotherapy was 16.7 versus 12.1 months, respectively (HR, 0.81). In those patients with a TPS of >20%, the OS benefit was 17.7 versus 1.0 months (HR, 0.77), and in the group with a TPS of >50%, the benefit was 20.0 versus 12.2 months (HR, 0.69). Overall, the quality of life and the occurrence of side effects were substantially better for those patients receiving immunotherapy alone. Other findings presented at the meeting demonstrated the benefit of adding immunotherapy to chemotherapy and of treating with combination immunotherapy (PD-1 and CTLA-4 inhibitors). Many options now exist, much work remains to be done, and accrual to clinical trials is more important than ever.

Another plenary session trial evaluated the benefit of performing a nephrectomy in patients with advanced or metastatic renal cell carcinoma (RCC), a long-held and practiced standard of care. Dr Arnaud Mejean of Paris Descartes University presented findings from the CARMENA trial, which randomized 450 patients with metastatic clear cell RCC to receive cytoreductive nephrectomy followed by sunitinib, or sunitinib alone. The OS results of 18.4 versus 13.9 months, respectively (HR, 0.89) favored sunitinib alone in this noninferiority analysis. Other endpoints lined up in favor of not removing the cancerous kidney, and the presenter and discussants were united in their opinion of the results and the resulting change in doing less surgery in these patients.

In a step away from less therapy, the European Pediatric Soft Tissue Sarcoma Study showed that adding 6 months of low-dose maintenance chemotherapy after standard intensive therapy improves survival in children with high-risk rhabdomyosarcoma. The addition of a vinorelbine and cyclophosphamide low-dose regimen improved 5-year disease-free survival from 69.8% to 77.6% (HR, 0.68) and OS from 73.7% to 86.5% (HR, 0.52) as presented by Dr Gianni Bisogno, University of Padovani, Italy. The maintenance regimen showed no increase in toxicity and actually fewer infections were noted.

In the area of molecular profiling, multiple studies at the meeting demonstrated the importance of assessing cancers for mutations as outstanding results were seen with therapies for NTRK, RET, ROS, and MSI-high driven tumors. In a debate on the role of molecular profiling, I had the opportunity to declare and support our position at Sarah Cannon that all patients with relapsed or metastatic cancers should have this testing performed. It will be through better understanding of the biology of these cancers that we will advance the field for all patients while sometimes finding a target or mutation that will dramatically change the life of a patient.

In keeping with the meeting’s theme, Delivering Discoveries: Expanding the Reach of Precision Medicine, the presentations and the discussions clearly demonstrated that through the use of precision medicine techniques such as prognostic gene assays and molecular profiling, patients can receive the best therapy, even “tailored” therapy, which may often actually be less therapy. It is an exciting time in cancer research, and I have never been more optimistic about the future of cancer treatment for our patients.

Breast cancer is one of the most prevalent cancers in women worldwide, with more than 1 million new cases diagnosed annually.¹ Prognosis for the disease has improved significantly, but 25% to 60% of women living with breast cancer experience some level of pain ranging from mild to severe, the nature of which can evolve from acute to chronic.² Pre-, intra-, and post-treatment risk factors have been found to correlate with the development of acute and chronic pain and include young age, type of breast surgery (lumpectomy or total mastectomy), axillary node dissection, radiation therapy, and hormonal therapy.^3-5 Chemotherapy, particularly anthracycline- and taxane-based regimens, has also been shown to induce pain, arthralgia, myalgia, and peripheral neuropathy during treatment.⁶ In particular, postradiation pain may result from subcutaneous fibrosis with fixation to underlying musculature and the development of fibrous flaps in the internal axilla.⁷ These tissue changes are commonly subclinical, occurring 4 to 12 months postradiation,⁸ and can progress undetected until pain and upper-limb disability develop.

The presence of persistent pain has a considerable impact on the quality of life in survivors of breast cancer: psychological distress is prevalent (anxiety, depression, worry, fear), the performance of daily activities is diminished (eg, bathing, dressing, preparing meals, shopping), and economic independence is compromised by the inability to work or reduced employment and income. These factors directly and indirectly contribute to an increase in the use of health care services.^9,10

The management of pain is often characterized by pharmacologic-related treatment, such as the use of opioids and nonsteroidal anti-inflammatory medications, and nonpharmacologic-related treatment, such as exercise. Empirical evidence has shown that rehabilitative exercise programs, which commonly include a combination of resistance training and aerobic exercises, can effectively reduce pain in breast cancer survivors.^10-12 Women living with breast cancer who are directed to rehabilitative exercise programs experience an improvement not only in pain levels but also in their ability to engage in activities of daily living, in their psychological health, and in their overall quality of life.^13-15 However, despite evidence to support exercise programs to reduce pain related to breast cancer treatment, residual pain and upper-limb discomfort are common complaints in breast cancer survivors, and there is little focus on the duration of effectiveness of such programs for reducing pain after treatment for breast cancer. The objective of this study was to determine if an exercise program initiated postradiation would improve long-term pain levels in a carefully selected population of young women who were living with breast cancer and had no history of shoulder pathology or significant treatment complications.
 

Methods

Design

We used a pilot randomized control trial to compare the long-term effectiveness of a 12-week postradiation exercise program versus standard care on residual pain levels in young women (aged 18-45 years) living with breast cancer. The program was initiated 3 to 4 weeks postradiation to allow for acute inflammatory reactions to subside. Pain severity and interference were assessed using the Brief Pain Inventory-Short Form (BPI-SF), a tool for assessing cancer pain.^16,17 Pain levels for isolated shoulder movements were also recorded on examination by a physical therapist. All measures were collected at 6 time points (T1-T6): postsurgery and preradiation (T1, baseline), postradiation and preintervention (T2), and 4 points during an 18-month period postradiation (T3-T6 at 3, 6, 12, and 18 months postradiation).
 

Sample

Young women living with breast cancer who met our eligibility criteria were identified from 2 clinics at the Jewish General Hospital – the Segal Cancer Center and the Department of Radiation Oncology in Montréal, Québec, Canada. Inclusion criteria included women with a diagnosis of stage I to stage III breast cancer, who were 18 to 45 years old, were scheduled for postoperative adjuvant radiation therapy, had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (normal ambulatory function, minimal symptoms), and who consented to participate in the study. Exclusion criteria included women with a metastatic (stage IV) diagnosis; significant musculoskeletal, cardiac, pulmonary, or metabolic comorbidities that would not allow for participation in physical activity; a previous breast cancer diagnosis with treatment to the ipsilateral or contralateral sides; postsurgical lymphedema; postsurgical capsulitis, tendonitis, or other shoulder inflammatory complications; and any contraindication to exercise. The recruitment goal was outlined as 50 patients per group; however, a protracted accrual time because of the stringent study criteria yielded a sample of 29 and 30 patients for the intervention and control groups, respectively, which was sufficient for significant testing of differences between the 2 study groups.¹⁸
 

Variables and measures

Clinical characteristics. We used standardized questions and chart review to document the participants’ clinical characteristics and to capture information on the following: the stage and subtype of breast cancer, hormonal and human epidermal growth factor receptors (HER2) (estrogen receptor, progesterone receptor, and HER2 status), extent of surgery (lumpectomy or total mastectomy), and other modalities of treatment (eg, chemotherapy, radiation therapy).

Pain assessment. The BPI-SF was used to assess participants’ cancer-related pain. Pain severity ranged from 0 (no pain), 1 to 4 (mild pain), 5 to 6 (moderate pain), to 7 to 10 (severe pain).^18,19 The questionnaire also identifies the pain interference in daily activities using a Likert scale ranging from 0 (Does not interfere) to 10 (Completely interferes) in the following 7 domains or subscales: General Activity, Walking, Mood, Sleep, Work, Relations with Others, and Enjoyment of Life.¹⁶ For the purpose of this study, mean scores were tabulated using both pain intensity and interference scales.

Another important component of the BPI-SF instructs participants to localize pain by means of a body diagram. For purpose of analysis, 3 pain regions were established: shoulder girdle/chest wall on the affected side; neck and other upper extremity, including hand(s), forearm(s), wrist(s), and finger(s); and other regions, including abdominal discomfort, leg(s), hip(s), knee(s), ankle(s), lower back, and feet. In addition, pain levels on movement (Yes/No) were recorded for isolated shoulder flexion, abduction, and horizontal abduction (sitting and standing). The measurements were completed by a single physical therapist throughout the course of the study to minimize variance.

Procedure

The study protocol was approved by the Research Ethics Board at the Jewish General Hospital. Recruitment occurred from 2011 through 2015. The research was in accordance with the ethical standards of the responsible committee on human experimentation. Eligible women were recruited by the research coordinator who described the purpose, risks, and benefits of the study; advised on confidentiality, data collection, and intervention allocation procedures; and highlighted voluntary participation. The research coordinator addressed any concerns on the part of the participants before obtaining their written informed consent. Random allocation to the intervention and control groups was established using a web-based randomization plan generator (www.randomization.com). A single individual was responsible for the randomization process, and treatment assignments were revealed after each participant’s name had been entered. A physical therapist performed 6 sequential evaluations (T1-T6) at the time of participants’ medical follow-up appointments.

Intervention

The 12-week exercise intervention started 3 weeks postradiation and was composed of an initial 6-week program of low-level cardiovascular and resistance exercises that progressed to a set of more advanced exercises for the remaining 6 weeks. Participants were instructed to warm up for at least 10 minutes with a cardiovascular exercise of their choice (eg, a recumbent cross trainer, walking, or stairs) before doing a combined strength, endurance, and stretching exercise program for the upper body.²⁰ The final portion of the exercise intervention included a period of light cool-down. Weight training resistance levels were based on a maximum 8 to 10 repetitions for strength and a maximum of 20 repetitions for endurance training exercises, which progressed gradually over the course of the 12-week exercise program to ensure participant safety.^21,22 Participants in the intervention group were supervised at least once a week by an exercise physiologist at a center for oncology patients (Hope & Cope Wellness Centre), and patients were encouraged to perform the program at home 2 to 3 times a week. Those who were not able to exercise consistently at the center were provided with equipment and instructed on how to do the program safely at home.

By comparison, the control group received standard care, which included advice on the benefits of an active lifestyle, including exercise, but without a specific intervention. Participants were not restricted in their physical activity and/or sport participation levels, and their weekly activity levels were calculated using the Metabolic Equivalent of Task and recorded at each of the 6 time points.

Statistical analysis

Descriptive statistics were used to examine participant characteristics. The quantitative data collected through the BPI-SF measures were analyzed with JMP software (version 11.2; SAS Institute, Cary, NC). Continuous variables were tested for statistical significance (P ≤ .05) through the chi-square (categorical), analysis of variance, and nonparametric Wilcoxon tests. The analyses did not include missing data.

Results

A total of 59 young women were randomized into the intervention (n = 29) and control (n = 30) groups. Of those, 2 participants dropped out of the study because of family and time constraints, and 3 participants died, 2 from the control and 1 from the intervention group, after subsequently developing metastatic disease. Baseline data including comparative tumor characteristics, surgical interventions, and treatment interventions have been published in relation to other elements of this study.^23,24 The participants had a mean age of 39.2 years (standard deviation [SD], 5.0). More than half of them had an invasive ductal carcinoma (69.5%) and were estrogen positive (78.0%), progesterone positive (74.6%), or HER2 positive (20.3%), whereas 10.2% were triple negative. Most of the participants had undergone breast-sparing procedures (86.4% lumpectomy), and 18.6% had a total mastectomy. By random chance, the intervention group had higher rates of total mastectomy (24.4% and 13.3%, respectively) and surgical reconstruction (12.2% and 6.7%, respectively) compared with the control group. Most of the women (71.2%) received chemotherapy, and all received radiation therapy. In the intervention group, 37.2% received radiation therapy localized to the axilla, and 88% received a boost of radiation to the surgical bed. Self-reported exercise diaries were returned by 15 of the 29 intervention participants, and training frequencies among them varied significantly (1-6 times a week).

The findings showed that there was little variance between the intervention and control groups in BPI-SF severity scores from T1 to T6, so the means and SDs of the BPI-SF scores were grouped at 6 time points (Table 1). There was no statistically significant difference between baseline measures at T1 (1.68; SD, 1.17) and measures at 18 months postintervention (T6: 1.46; SD, 1.37). At baseline, 87.7% of the women reported no pain (31.5%) or mild levels of pain (55.6%), and 13% reported moderate or severe pain. Over the duration of the study from T1 to T6, these primarily low levels of pain (BPI-SF, 0-4) remained consistent with a favorable shift toward having no pain (T1: 31.5%; T6: 24.4%). By 18 months postintervention, 95.7% of women reported no or mild pain, with 4.9% reporting moderate pain.

Discussion

Previous studies have hypothesized that younger age (18-39 years), adjuvant radiotherapy, and axillary node dissection are risk factors for chronic pain in breast cancer survivors.^22,25 Persistent pain is prevalent in 12% to 51% of breast cancer survivors, with up to one-third experiencing some pain more than 5 years after treatment,^26,27 and our study outcomes concur with those findings. In our study, pain, as measured by the BPI-SF, was found to persist for most participants (75.6%) after the 18-month follow-up. The results of our trial showed that a 12-week exercise intervention administered postsurgery and postradiation had no statistically significant effect on long-term (18 months) pain severity and its interference in daily life. It is worth noting that body regions that had not been directly related to either surgical or radiation treatment for breast cancer were commonly identified as areas of pain but were not specifically targeted by our intervention. However, focusing on pain severity (BPI-SF), our findings suggest that the benefits of targeted upper-extremity exercise on pain in the intermediate time course of follow-up (T3, T4, and T5) was notable compared with the control group, which received standard care. The apparent recurrence of pain at 18 months in both groups was not anticipated and needs to be further investigated.

More specific objective assessments of pain on active shoulder movement identified distinct patterns of pain that could not be isolated using the BPI-SF alone. The incidence and localization of pain on movement differed between the population of women who received a specific exercise intervention and those who received standard care (Figure 2). Patterns of pain over time fluctuated in the control group, whereas the intervention group reported a linear decrease in pain. Residual pain on shoulder movement remained apparent in both groups at 18-months postradiation, but that finding was not reflected in the BPI-SF results. The literature supports our findings on persistent pain among breast cancer survivors,^3,7,8,28-30 and in our study of young women carefully screened and excluded for pre-existent shoulder conditions or comorbid medical conditions, recurrent articular pain was nonetheless prevalent. It seems that unidentified or multiple factors may be part of the etiology of pain in this young adult cohort.

Although the BPI-SF is a generic measurement tool commonly used to assess and measure cancer patients’ pain levels, the lack of variance in our BPI-SF severity and interference outcomes over time (T1-T6) (Table 1, Table 2), the variety of “other” unrelated regions (Figure 1) identified by the BPI-SF, and the contrast in our findings on specific physical examination emphasize the potential limitations of this clinical tool.

Limitations

Recruitment of young adult women was difficult because of our stringent inclusion criteria, the long-term follow-up, and the relatively small population of breast cancer patients in this age demographic. Therefore, the duration of the recruitment phase, despite our having access to a specialized young adult and adolescent clinic in our institute, greatly surpassed the expectations we had when we designed the study. In addition, there remains an inherent bias in participants who accept participation in a study that includes exercise interventions. Potential participants who exercise regularly or have a positive inclination toward doing exercise are more likely to participate. Despite the prescription of a targeted 12-week upper-limb intervention in this study, the general activity levels of both groups may have had an impact on the significance of this study. In addition, the low adherence to the use of self-reported logs failed to capture the true compliance rates of our participants because their lack of tracking does not indicate failure to comply with the program. The use of weekly or biweekly telephone calls to monitor compliance rates of activity more vigilantly may be used in future studies.

Conclusions

Advances in clinical management of breast cancer have improved survival outcomes, and morbidity over recent years, yet symptoms such as pain remain prevalent in this population. The results of this study showed that a targeted, 12-week upper-limb exercise intervention postradiation transiently improved levels of shoulder pain without a concomitant impact on chronic pain or any positive influence on activities of daily living 18 months posttreatment. Furthermore, future studies should use a variety of measurement tools to evaluate trunk and upper-limb pain in women with breast cancer and investigate the optimal timing of postradiation exercise interventions.

Acknowledgments

The authors thank Hope & Cope, the CURE foundation, and the Jewish General Hospital Foundation/Weekend to End Breast Cancer for providing the financial resources needed to sustain this research study. They also thank the McGill Adolescent and Young Adult program for its continued support. Previous oral presentations of research Muanza TM, et al. Randomized clinical trial of a progressive exercise program for young women with breast cancer undergoing radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(3):s35-s36.

Breast cancer is one of the most prevalent cancers in women worldwide, with more than 1 million new cases diagnosed annually.¹ Prognosis for the disease has improved significantly, but 25% to 60% of women living with breast cancer experience some level of pain ranging from mild to severe, the nature of which can evolve from acute to chronic.² Pre-, intra-, and post-treatment risk factors have been found to correlate with the development of acute and chronic pain and include young age, type of breast surgery (lumpectomy or total mastectomy), axillary node dissection, radiation therapy, and hormonal therapy.^3-5 Chemotherapy, particularly anthracycline- and taxane-based regimens, has also been shown to induce pain, arthralgia, myalgia, and peripheral neuropathy during treatment.⁶ In particular, postradiation pain may result from subcutaneous fibrosis with fixation to underlying musculature and the development of fibrous flaps in the internal axilla.⁷ These tissue changes are commonly subclinical, occurring 4 to 12 months postradiation,⁸ and can progress undetected until pain and upper-limb disability develop.

The presence of persistent pain has a considerable impact on the quality of life in survivors of breast cancer: psychological distress is prevalent (anxiety, depression, worry, fear), the performance of daily activities is diminished (eg, bathing, dressing, preparing meals, shopping), and economic independence is compromised by the inability to work or reduced employment and income. These factors directly and indirectly contribute to an increase in the use of health care services.^9,10

The management of pain is often characterized by pharmacologic-related treatment, such as the use of opioids and nonsteroidal anti-inflammatory medications, and nonpharmacologic-related treatment, such as exercise. Empirical evidence has shown that rehabilitative exercise programs, which commonly include a combination of resistance training and aerobic exercises, can effectively reduce pain in breast cancer survivors.^10-12 Women living with breast cancer who are directed to rehabilitative exercise programs experience an improvement not only in pain levels but also in their ability to engage in activities of daily living, in their psychological health, and in their overall quality of life.^13-15 However, despite evidence to support exercise programs to reduce pain related to breast cancer treatment, residual pain and upper-limb discomfort are common complaints in breast cancer survivors, and there is little focus on the duration of effectiveness of such programs for reducing pain after treatment for breast cancer. The objective of this study was to determine if an exercise program initiated postradiation would improve long-term pain levels in a carefully selected population of young women who were living with breast cancer and had no history of shoulder pathology or significant treatment complications.
 

Methods

Design

We used a pilot randomized control trial to compare the long-term effectiveness of a 12-week postradiation exercise program versus standard care on residual pain levels in young women (aged 18-45 years) living with breast cancer. The program was initiated 3 to 4 weeks postradiation to allow for acute inflammatory reactions to subside. Pain severity and interference were assessed using the Brief Pain Inventory-Short Form (BPI-SF), a tool for assessing cancer pain.^16,17 Pain levels for isolated shoulder movements were also recorded on examination by a physical therapist. All measures were collected at 6 time points (T1-T6): postsurgery and preradiation (T1, baseline), postradiation and preintervention (T2), and 4 points during an 18-month period postradiation (T3-T6 at 3, 6, 12, and 18 months postradiation).
 

Sample

Young women living with breast cancer who met our eligibility criteria were identified from 2 clinics at the Jewish General Hospital – the Segal Cancer Center and the Department of Radiation Oncology in Montréal, Québec, Canada. Inclusion criteria included women with a diagnosis of stage I to stage III breast cancer, who were 18 to 45 years old, were scheduled for postoperative adjuvant radiation therapy, had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (normal ambulatory function, minimal symptoms), and who consented to participate in the study. Exclusion criteria included women with a metastatic (stage IV) diagnosis; significant musculoskeletal, cardiac, pulmonary, or metabolic comorbidities that would not allow for participation in physical activity; a previous breast cancer diagnosis with treatment to the ipsilateral or contralateral sides; postsurgical lymphedema; postsurgical capsulitis, tendonitis, or other shoulder inflammatory complications; and any contraindication to exercise. The recruitment goal was outlined as 50 patients per group; however, a protracted accrual time because of the stringent study criteria yielded a sample of 29 and 30 patients for the intervention and control groups, respectively, which was sufficient for significant testing of differences between the 2 study groups.¹⁸
 

Variables and measures

Clinical characteristics. We used standardized questions and chart review to document the participants’ clinical characteristics and to capture information on the following: the stage and subtype of breast cancer, hormonal and human epidermal growth factor receptors (HER2) (estrogen receptor, progesterone receptor, and HER2 status), extent of surgery (lumpectomy or total mastectomy), and other modalities of treatment (eg, chemotherapy, radiation therapy).

Pain assessment. The BPI-SF was used to assess participants’ cancer-related pain. Pain severity ranged from 0 (no pain), 1 to 4 (mild pain), 5 to 6 (moderate pain), to 7 to 10 (severe pain).^18,19 The questionnaire also identifies the pain interference in daily activities using a Likert scale ranging from 0 (Does not interfere) to 10 (Completely interferes) in the following 7 domains or subscales: General Activity, Walking, Mood, Sleep, Work, Relations with Others, and Enjoyment of Life.¹⁶ For the purpose of this study, mean scores were tabulated using both pain intensity and interference scales.

Another important component of the BPI-SF instructs participants to localize pain by means of a body diagram. For purpose of analysis, 3 pain regions were established: shoulder girdle/chest wall on the affected side; neck and other upper extremity, including hand(s), forearm(s), wrist(s), and finger(s); and other regions, including abdominal discomfort, leg(s), hip(s), knee(s), ankle(s), lower back, and feet. In addition, pain levels on movement (Yes/No) were recorded for isolated shoulder flexion, abduction, and horizontal abduction (sitting and standing). The measurements were completed by a single physical therapist throughout the course of the study to minimize variance.

Procedure

The study protocol was approved by the Research Ethics Board at the Jewish General Hospital. Recruitment occurred from 2011 through 2015. The research was in accordance with the ethical standards of the responsible committee on human experimentation. Eligible women were recruited by the research coordinator who described the purpose, risks, and benefits of the study; advised on confidentiality, data collection, and intervention allocation procedures; and highlighted voluntary participation. The research coordinator addressed any concerns on the part of the participants before obtaining their written informed consent. Random allocation to the intervention and control groups was established using a web-based randomization plan generator (www.randomization.com). A single individual was responsible for the randomization process, and treatment assignments were revealed after each participant’s name had been entered. A physical therapist performed 6 sequential evaluations (T1-T6) at the time of participants’ medical follow-up appointments.

Intervention

The 12-week exercise intervention started 3 weeks postradiation and was composed of an initial 6-week program of low-level cardiovascular and resistance exercises that progressed to a set of more advanced exercises for the remaining 6 weeks. Participants were instructed to warm up for at least 10 minutes with a cardiovascular exercise of their choice (eg, a recumbent cross trainer, walking, or stairs) before doing a combined strength, endurance, and stretching exercise program for the upper body.²⁰ The final portion of the exercise intervention included a period of light cool-down. Weight training resistance levels were based on a maximum 8 to 10 repetitions for strength and a maximum of 20 repetitions for endurance training exercises, which progressed gradually over the course of the 12-week exercise program to ensure participant safety.^21,22 Participants in the intervention group were supervised at least once a week by an exercise physiologist at a center for oncology patients (Hope & Cope Wellness Centre), and patients were encouraged to perform the program at home 2 to 3 times a week. Those who were not able to exercise consistently at the center were provided with equipment and instructed on how to do the program safely at home.

By comparison, the control group received standard care, which included advice on the benefits of an active lifestyle, including exercise, but without a specific intervention. Participants were not restricted in their physical activity and/or sport participation levels, and their weekly activity levels were calculated using the Metabolic Equivalent of Task and recorded at each of the 6 time points.

Statistical analysis

Descriptive statistics were used to examine participant characteristics. The quantitative data collected through the BPI-SF measures were analyzed with JMP software (version 11.2; SAS Institute, Cary, NC). Continuous variables were tested for statistical significance (P ≤ .05) through the chi-square (categorical), analysis of variance, and nonparametric Wilcoxon tests. The analyses did not include missing data.

Results

A total of 59 young women were randomized into the intervention (n = 29) and control (n = 30) groups. Of those, 2 participants dropped out of the study because of family and time constraints, and 3 participants died, 2 from the control and 1 from the intervention group, after subsequently developing metastatic disease. Baseline data including comparative tumor characteristics, surgical interventions, and treatment interventions have been published in relation to other elements of this study.^23,24 The participants had a mean age of 39.2 years (standard deviation [SD], 5.0). More than half of them had an invasive ductal carcinoma (69.5%) and were estrogen positive (78.0%), progesterone positive (74.6%), or HER2 positive (20.3%), whereas 10.2% were triple negative. Most of the participants had undergone breast-sparing procedures (86.4% lumpectomy), and 18.6% had a total mastectomy. By random chance, the intervention group had higher rates of total mastectomy (24.4% and 13.3%, respectively) and surgical reconstruction (12.2% and 6.7%, respectively) compared with the control group. Most of the women (71.2%) received chemotherapy, and all received radiation therapy. In the intervention group, 37.2% received radiation therapy localized to the axilla, and 88% received a boost of radiation to the surgical bed. Self-reported exercise diaries were returned by 15 of the 29 intervention participants, and training frequencies among them varied significantly (1-6 times a week).

The findings showed that there was little variance between the intervention and control groups in BPI-SF severity scores from T1 to T6, so the means and SDs of the BPI-SF scores were grouped at 6 time points (Table 1). There was no statistically significant difference between baseline measures at T1 (1.68; SD, 1.17) and measures at 18 months postintervention (T6: 1.46; SD, 1.37). At baseline, 87.7% of the women reported no pain (31.5%) or mild levels of pain (55.6%), and 13% reported moderate or severe pain. Over the duration of the study from T1 to T6, these primarily low levels of pain (BPI-SF, 0-4) remained consistent with a favorable shift toward having no pain (T1: 31.5%; T6: 24.4%). By 18 months postintervention, 95.7% of women reported no or mild pain, with 4.9% reporting moderate pain.

Discussion

Previous studies have hypothesized that younger age (18-39 years), adjuvant radiotherapy, and axillary node dissection are risk factors for chronic pain in breast cancer survivors.^22,25 Persistent pain is prevalent in 12% to 51% of breast cancer survivors, with up to one-third experiencing some pain more than 5 years after treatment,^26,27 and our study outcomes concur with those findings. In our study, pain, as measured by the BPI-SF, was found to persist for most participants (75.6%) after the 18-month follow-up. The results of our trial showed that a 12-week exercise intervention administered postsurgery and postradiation had no statistically significant effect on long-term (18 months) pain severity and its interference in daily life. It is worth noting that body regions that had not been directly related to either surgical or radiation treatment for breast cancer were commonly identified as areas of pain but were not specifically targeted by our intervention. However, focusing on pain severity (BPI-SF), our findings suggest that the benefits of targeted upper-extremity exercise on pain in the intermediate time course of follow-up (T3, T4, and T5) was notable compared with the control group, which received standard care. The apparent recurrence of pain at 18 months in both groups was not anticipated and needs to be further investigated.

More specific objective assessments of pain on active shoulder movement identified distinct patterns of pain that could not be isolated using the BPI-SF alone. The incidence and localization of pain on movement differed between the population of women who received a specific exercise intervention and those who received standard care (Figure 2). Patterns of pain over time fluctuated in the control group, whereas the intervention group reported a linear decrease in pain. Residual pain on shoulder movement remained apparent in both groups at 18-months postradiation, but that finding was not reflected in the BPI-SF results. The literature supports our findings on persistent pain among breast cancer survivors,^3,7,8,28-30 and in our study of young women carefully screened and excluded for pre-existent shoulder conditions or comorbid medical conditions, recurrent articular pain was nonetheless prevalent. It seems that unidentified or multiple factors may be part of the etiology of pain in this young adult cohort.

Although the BPI-SF is a generic measurement tool commonly used to assess and measure cancer patients’ pain levels, the lack of variance in our BPI-SF severity and interference outcomes over time (T1-T6) (Table 1, Table 2), the variety of “other” unrelated regions (Figure 1) identified by the BPI-SF, and the contrast in our findings on specific physical examination emphasize the potential limitations of this clinical tool.

Limitations

Recruitment of young adult women was difficult because of our stringent inclusion criteria, the long-term follow-up, and the relatively small population of breast cancer patients in this age demographic. Therefore, the duration of the recruitment phase, despite our having access to a specialized young adult and adolescent clinic in our institute, greatly surpassed the expectations we had when we designed the study. In addition, there remains an inherent bias in participants who accept participation in a study that includes exercise interventions. Potential participants who exercise regularly or have a positive inclination toward doing exercise are more likely to participate. Despite the prescription of a targeted 12-week upper-limb intervention in this study, the general activity levels of both groups may have had an impact on the significance of this study. In addition, the low adherence to the use of self-reported logs failed to capture the true compliance rates of our participants because their lack of tracking does not indicate failure to comply with the program. The use of weekly or biweekly telephone calls to monitor compliance rates of activity more vigilantly may be used in future studies.

Conclusions

Advances in clinical management of breast cancer have improved survival outcomes, and morbidity over recent years, yet symptoms such as pain remain prevalent in this population. The results of this study showed that a targeted, 12-week upper-limb exercise intervention postradiation transiently improved levels of shoulder pain without a concomitant impact on chronic pain or any positive influence on activities of daily living 18 months posttreatment. Furthermore, future studies should use a variety of measurement tools to evaluate trunk and upper-limb pain in women with breast cancer and investigate the optimal timing of postradiation exercise interventions.

Acknowledgments

The authors thank Hope & Cope, the CURE foundation, and the Jewish General Hospital Foundation/Weekend to End Breast Cancer for providing the financial resources needed to sustain this research study. They also thank the McGill Adolescent and Young Adult program for its continued support. Previous oral presentations of research Muanza TM, et al. Randomized clinical trial of a progressive exercise program for young women with breast cancer undergoing radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(3):s35-s36.

Breast cancer is one of the most prevalent cancers in women worldwide, with more than 1 million new cases diagnosed annually.¹ Prognosis for the disease has improved significantly, but 25% to 60% of women living with breast cancer experience some level of pain ranging from mild to severe, the nature of which can evolve from acute to chronic.² Pre-, intra-, and post-treatment risk factors have been found to correlate with the development of acute and chronic pain and include young age, type of breast surgery (lumpectomy or total mastectomy), axillary node dissection, radiation therapy, and hormonal therapy.^3-5 Chemotherapy, particularly anthracycline- and taxane-based regimens, has also been shown to induce pain, arthralgia, myalgia, and peripheral neuropathy during treatment.⁶ In particular, postradiation pain may result from subcutaneous fibrosis with fixation to underlying musculature and the development of fibrous flaps in the internal axilla.⁷ These tissue changes are commonly subclinical, occurring 4 to 12 months postradiation,⁸ and can progress undetected until pain and upper-limb disability develop.

The presence of persistent pain has a considerable impact on the quality of life in survivors of breast cancer: psychological distress is prevalent (anxiety, depression, worry, fear), the performance of daily activities is diminished (eg, bathing, dressing, preparing meals, shopping), and economic independence is compromised by the inability to work or reduced employment and income. These factors directly and indirectly contribute to an increase in the use of health care services.^9,10

The management of pain is often characterized by pharmacologic-related treatment, such as the use of opioids and nonsteroidal anti-inflammatory medications, and nonpharmacologic-related treatment, such as exercise. Empirical evidence has shown that rehabilitative exercise programs, which commonly include a combination of resistance training and aerobic exercises, can effectively reduce pain in breast cancer survivors.^10-12 Women living with breast cancer who are directed to rehabilitative exercise programs experience an improvement not only in pain levels but also in their ability to engage in activities of daily living, in their psychological health, and in their overall quality of life.^13-15 However, despite evidence to support exercise programs to reduce pain related to breast cancer treatment, residual pain and upper-limb discomfort are common complaints in breast cancer survivors, and there is little focus on the duration of effectiveness of such programs for reducing pain after treatment for breast cancer. The objective of this study was to determine if an exercise program initiated postradiation would improve long-term pain levels in a carefully selected population of young women who were living with breast cancer and had no history of shoulder pathology or significant treatment complications.
 

Methods

Design

We used a pilot randomized control trial to compare the long-term effectiveness of a 12-week postradiation exercise program versus standard care on residual pain levels in young women (aged 18-45 years) living with breast cancer. The program was initiated 3 to 4 weeks postradiation to allow for acute inflammatory reactions to subside. Pain severity and interference were assessed using the Brief Pain Inventory-Short Form (BPI-SF), a tool for assessing cancer pain.^16,17 Pain levels for isolated shoulder movements were also recorded on examination by a physical therapist. All measures were collected at 6 time points (T1-T6): postsurgery and preradiation (T1, baseline), postradiation and preintervention (T2), and 4 points during an 18-month period postradiation (T3-T6 at 3, 6, 12, and 18 months postradiation).
 

Sample

Young women living with breast cancer who met our eligibility criteria were identified from 2 clinics at the Jewish General Hospital – the Segal Cancer Center and the Department of Radiation Oncology in Montréal, Québec, Canada. Inclusion criteria included women with a diagnosis of stage I to stage III breast cancer, who were 18 to 45 years old, were scheduled for postoperative adjuvant radiation therapy, had an Eastern Cooperative Oncology Group Performance Status of 0 or 1 (normal ambulatory function, minimal symptoms), and who consented to participate in the study. Exclusion criteria included women with a metastatic (stage IV) diagnosis; significant musculoskeletal, cardiac, pulmonary, or metabolic comorbidities that would not allow for participation in physical activity; a previous breast cancer diagnosis with treatment to the ipsilateral or contralateral sides; postsurgical lymphedema; postsurgical capsulitis, tendonitis, or other shoulder inflammatory complications; and any contraindication to exercise. The recruitment goal was outlined as 50 patients per group; however, a protracted accrual time because of the stringent study criteria yielded a sample of 29 and 30 patients for the intervention and control groups, respectively, which was sufficient for significant testing of differences between the 2 study groups.¹⁸
 

Variables and measures

Clinical characteristics. We used standardized questions and chart review to document the participants’ clinical characteristics and to capture information on the following: the stage and subtype of breast cancer, hormonal and human epidermal growth factor receptors (HER2) (estrogen receptor, progesterone receptor, and HER2 status), extent of surgery (lumpectomy or total mastectomy), and other modalities of treatment (eg, chemotherapy, radiation therapy).

Pain assessment. The BPI-SF was used to assess participants’ cancer-related pain. Pain severity ranged from 0 (no pain), 1 to 4 (mild pain), 5 to 6 (moderate pain), to 7 to 10 (severe pain).^18,19 The questionnaire also identifies the pain interference in daily activities using a Likert scale ranging from 0 (Does not interfere) to 10 (Completely interferes) in the following 7 domains or subscales: General Activity, Walking, Mood, Sleep, Work, Relations with Others, and Enjoyment of Life.¹⁶ For the purpose of this study, mean scores were tabulated using both pain intensity and interference scales.

Another important component of the BPI-SF instructs participants to localize pain by means of a body diagram. For purpose of analysis, 3 pain regions were established: shoulder girdle/chest wall on the affected side; neck and other upper extremity, including hand(s), forearm(s), wrist(s), and finger(s); and other regions, including abdominal discomfort, leg(s), hip(s), knee(s), ankle(s), lower back, and feet. In addition, pain levels on movement (Yes/No) were recorded for isolated shoulder flexion, abduction, and horizontal abduction (sitting and standing). The measurements were completed by a single physical therapist throughout the course of the study to minimize variance.

Procedure

The study protocol was approved by the Research Ethics Board at the Jewish General Hospital. Recruitment occurred from 2011 through 2015. The research was in accordance with the ethical standards of the responsible committee on human experimentation. Eligible women were recruited by the research coordinator who described the purpose, risks, and benefits of the study; advised on confidentiality, data collection, and intervention allocation procedures; and highlighted voluntary participation. The research coordinator addressed any concerns on the part of the participants before obtaining their written informed consent. Random allocation to the intervention and control groups was established using a web-based randomization plan generator (www.randomization.com). A single individual was responsible for the randomization process, and treatment assignments were revealed after each participant’s name had been entered. A physical therapist performed 6 sequential evaluations (T1-T6) at the time of participants’ medical follow-up appointments.

Intervention

The 12-week exercise intervention started 3 weeks postradiation and was composed of an initial 6-week program of low-level cardiovascular and resistance exercises that progressed to a set of more advanced exercises for the remaining 6 weeks. Participants were instructed to warm up for at least 10 minutes with a cardiovascular exercise of their choice (eg, a recumbent cross trainer, walking, or stairs) before doing a combined strength, endurance, and stretching exercise program for the upper body.²⁰ The final portion of the exercise intervention included a period of light cool-down. Weight training resistance levels were based on a maximum 8 to 10 repetitions for strength and a maximum of 20 repetitions for endurance training exercises, which progressed gradually over the course of the 12-week exercise program to ensure participant safety.^21,22 Participants in the intervention group were supervised at least once a week by an exercise physiologist at a center for oncology patients (Hope & Cope Wellness Centre), and patients were encouraged to perform the program at home 2 to 3 times a week. Those who were not able to exercise consistently at the center were provided with equipment and instructed on how to do the program safely at home.

By comparison, the control group received standard care, which included advice on the benefits of an active lifestyle, including exercise, but without a specific intervention. Participants were not restricted in their physical activity and/or sport participation levels, and their weekly activity levels were calculated using the Metabolic Equivalent of Task and recorded at each of the 6 time points.

Statistical analysis

Descriptive statistics were used to examine participant characteristics. The quantitative data collected through the BPI-SF measures were analyzed with JMP software (version 11.2; SAS Institute, Cary, NC). Continuous variables were tested for statistical significance (P ≤ .05) through the chi-square (categorical), analysis of variance, and nonparametric Wilcoxon tests. The analyses did not include missing data.

Results

A total of 59 young women were randomized into the intervention (n = 29) and control (n = 30) groups. Of those, 2 participants dropped out of the study because of family and time constraints, and 3 participants died, 2 from the control and 1 from the intervention group, after subsequently developing metastatic disease. Baseline data including comparative tumor characteristics, surgical interventions, and treatment interventions have been published in relation to other elements of this study.^23,24 The participants had a mean age of 39.2 years (standard deviation [SD], 5.0). More than half of them had an invasive ductal carcinoma (69.5%) and were estrogen positive (78.0%), progesterone positive (74.6%), or HER2 positive (20.3%), whereas 10.2% were triple negative. Most of the participants had undergone breast-sparing procedures (86.4% lumpectomy), and 18.6% had a total mastectomy. By random chance, the intervention group had higher rates of total mastectomy (24.4% and 13.3%, respectively) and surgical reconstruction (12.2% and 6.7%, respectively) compared with the control group. Most of the women (71.2%) received chemotherapy, and all received radiation therapy. In the intervention group, 37.2% received radiation therapy localized to the axilla, and 88% received a boost of radiation to the surgical bed. Self-reported exercise diaries were returned by 15 of the 29 intervention participants, and training frequencies among them varied significantly (1-6 times a week).

The findings showed that there was little variance between the intervention and control groups in BPI-SF severity scores from T1 to T6, so the means and SDs of the BPI-SF scores were grouped at 6 time points (Table 1). There was no statistically significant difference between baseline measures at T1 (1.68; SD, 1.17) and measures at 18 months postintervention (T6: 1.46; SD, 1.37). At baseline, 87.7% of the women reported no pain (31.5%) or mild levels of pain (55.6%), and 13% reported moderate or severe pain. Over the duration of the study from T1 to T6, these primarily low levels of pain (BPI-SF, 0-4) remained consistent with a favorable shift toward having no pain (T1: 31.5%; T6: 24.4%). By 18 months postintervention, 95.7% of women reported no or mild pain, with 4.9% reporting moderate pain.

Discussion

Previous studies have hypothesized that younger age (18-39 years), adjuvant radiotherapy, and axillary node dissection are risk factors for chronic pain in breast cancer survivors.^22,25 Persistent pain is prevalent in 12% to 51% of breast cancer survivors, with up to one-third experiencing some pain more than 5 years after treatment,^26,27 and our study outcomes concur with those findings. In our study, pain, as measured by the BPI-SF, was found to persist for most participants (75.6%) after the 18-month follow-up. The results of our trial showed that a 12-week exercise intervention administered postsurgery and postradiation had no statistically significant effect on long-term (18 months) pain severity and its interference in daily life. It is worth noting that body regions that had not been directly related to either surgical or radiation treatment for breast cancer were commonly identified as areas of pain but were not specifically targeted by our intervention. However, focusing on pain severity (BPI-SF), our findings suggest that the benefits of targeted upper-extremity exercise on pain in the intermediate time course of follow-up (T3, T4, and T5) was notable compared with the control group, which received standard care. The apparent recurrence of pain at 18 months in both groups was not anticipated and needs to be further investigated.

More specific objective assessments of pain on active shoulder movement identified distinct patterns of pain that could not be isolated using the BPI-SF alone. The incidence and localization of pain on movement differed between the population of women who received a specific exercise intervention and those who received standard care (Figure 2). Patterns of pain over time fluctuated in the control group, whereas the intervention group reported a linear decrease in pain. Residual pain on shoulder movement remained apparent in both groups at 18-months postradiation, but that finding was not reflected in the BPI-SF results. The literature supports our findings on persistent pain among breast cancer survivors,^3,7,8,28-30 and in our study of young women carefully screened and excluded for pre-existent shoulder conditions or comorbid medical conditions, recurrent articular pain was nonetheless prevalent. It seems that unidentified or multiple factors may be part of the etiology of pain in this young adult cohort.

Although the BPI-SF is a generic measurement tool commonly used to assess and measure cancer patients’ pain levels, the lack of variance in our BPI-SF severity and interference outcomes over time (T1-T6) (Table 1, Table 2), the variety of “other” unrelated regions (Figure 1) identified by the BPI-SF, and the contrast in our findings on specific physical examination emphasize the potential limitations of this clinical tool.

Limitations

Recruitment of young adult women was difficult because of our stringent inclusion criteria, the long-term follow-up, and the relatively small population of breast cancer patients in this age demographic. Therefore, the duration of the recruitment phase, despite our having access to a specialized young adult and adolescent clinic in our institute, greatly surpassed the expectations we had when we designed the study. In addition, there remains an inherent bias in participants who accept participation in a study that includes exercise interventions. Potential participants who exercise regularly or have a positive inclination toward doing exercise are more likely to participate. Despite the prescription of a targeted 12-week upper-limb intervention in this study, the general activity levels of both groups may have had an impact on the significance of this study. In addition, the low adherence to the use of self-reported logs failed to capture the true compliance rates of our participants because their lack of tracking does not indicate failure to comply with the program. The use of weekly or biweekly telephone calls to monitor compliance rates of activity more vigilantly may be used in future studies.

Conclusions

Advances in clinical management of breast cancer have improved survival outcomes, and morbidity over recent years, yet symptoms such as pain remain prevalent in this population. The results of this study showed that a targeted, 12-week upper-limb exercise intervention postradiation transiently improved levels of shoulder pain without a concomitant impact on chronic pain or any positive influence on activities of daily living 18 months posttreatment. Furthermore, future studies should use a variety of measurement tools to evaluate trunk and upper-limb pain in women with breast cancer and investigate the optimal timing of postradiation exercise interventions.

Acknowledgments

The authors thank Hope & Cope, the CURE foundation, and the Jewish General Hospital Foundation/Weekend to End Breast Cancer for providing the financial resources needed to sustain this research study. They also thank the McGill Adolescent and Young Adult program for its continued support. Previous oral presentations of research Muanza TM, et al. Randomized clinical trial of a progressive exercise program for young women with breast cancer undergoing radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(3):s35-s36.

Rural cancer survivors reported more timely care than did urban cancer survivors in a survey of 6,826 Medicare beneficiaries.

Taken as a whole, a similar quality of care was reported between the two groups, but the picture changed when racial/ethnic subgroups were considered. Non-Hispanic black and Hispanic patients in rural locations reported inferior care to their urban counterparts, investigators wrote in Cancer.

“Cancer patients living in rural areas are vulnerable and have unique health care needs,” wrote lead author Michelle A. Mollica, PhD, of the National Cancer Institute, and her colleagues. “To our knowledge, this is the first study to explore the patient’s perception of the timeliness of care in such a large, multiregion sample of cancer patients.”

In 2003, the National Academy of Medicine concluded that living in a rural environment was associated with poorer health. Existing research surrounding cancer has echoed this concern, showing that rural patients have higher rates of cancer and mortality, longer delays in diagnosis, and limited access to care.

The current, retrospective study involved 6,140 urban and 686 rural Medicare beneficiaries who were aged at least 65 years when diagnosed with either breast, lung, colorectal, or prostate cancer. Consumer Assessment of Healthcare Providers and Systems surveys were conducted between 1998 and 2013, then linked with data from the Surveillance, Epidemiology, and End Results registry program.

Surveys were conducted within 12 months of diagnosis, during which time patients were asked about their access to care as defined by two composites: “Getting Needed Care” and “Getting Care Quickly.” Getting Needed Care included ease of making appointments and receiving treatments and Getting Care Quickly questions asked about appointment delays and time spent waiting at the doctor’s office. Answers were converted to a numerical score from 0 to 100, with 0 being the worst and 100 being the best.

For both composites, mean scores for urban and rural locations were greater than 85 out of 100.

In contrast to previous studies, urban patients reported longer delays in care, scoring Getting Care Quickly 2.27 points lower than rural patients (P = .02). Pacific Islanders and non-Hispanic Asian patients from rural places reported even faster care, ranking about 8 points higher than urban patients of the same race/ethnicity.

Locality did not have a significant impact on Getting Needed Care unless race/ethnicity was also considered (P = .04). Non-Hispanic white patients from rural locations scored Getting Needed Care about 2 points higher than urban white patients, while Hispanic and non-Hispanic black patients had an opposite trend, with this rural cohort ranking Getting Needed Care lower than urban patients of the same race/ethnicity.

“Geographic residence is but one important factor in cancer care delivery,” the authors noted. “There is a need for fine-grained research looking at specific barriers for urban residents, experiences of racial/ethnic minority survivors residing in rural areas, and rural-urban differences in the clinic settings in which medical care is delivered.”

The authors had no disclosures to report.

SOURCE: Mollica MA et al. Cancer. 2018 Jun 7. doi: 10.1002/cncr.31541.

Rural cancer survivors reported more timely care than did urban cancer survivors in a survey of 6,826 Medicare beneficiaries.

Taken as a whole, a similar quality of care was reported between the two groups, but the picture changed when racial/ethnic subgroups were considered. Non-Hispanic black and Hispanic patients in rural locations reported inferior care to their urban counterparts, investigators wrote in Cancer.

“Cancer patients living in rural areas are vulnerable and have unique health care needs,” wrote lead author Michelle A. Mollica, PhD, of the National Cancer Institute, and her colleagues. “To our knowledge, this is the first study to explore the patient’s perception of the timeliness of care in such a large, multiregion sample of cancer patients.”

In 2003, the National Academy of Medicine concluded that living in a rural environment was associated with poorer health. Existing research surrounding cancer has echoed this concern, showing that rural patients have higher rates of cancer and mortality, longer delays in diagnosis, and limited access to care.

The current, retrospective study involved 6,140 urban and 686 rural Medicare beneficiaries who were aged at least 65 years when diagnosed with either breast, lung, colorectal, or prostate cancer. Consumer Assessment of Healthcare Providers and Systems surveys were conducted between 1998 and 2013, then linked with data from the Surveillance, Epidemiology, and End Results registry program.

Surveys were conducted within 12 months of diagnosis, during which time patients were asked about their access to care as defined by two composites: “Getting Needed Care” and “Getting Care Quickly.” Getting Needed Care included ease of making appointments and receiving treatments and Getting Care Quickly questions asked about appointment delays and time spent waiting at the doctor’s office. Answers were converted to a numerical score from 0 to 100, with 0 being the worst and 100 being the best.

For both composites, mean scores for urban and rural locations were greater than 85 out of 100.

In contrast to previous studies, urban patients reported longer delays in care, scoring Getting Care Quickly 2.27 points lower than rural patients (P = .02). Pacific Islanders and non-Hispanic Asian patients from rural places reported even faster care, ranking about 8 points higher than urban patients of the same race/ethnicity.

Locality did not have a significant impact on Getting Needed Care unless race/ethnicity was also considered (P = .04). Non-Hispanic white patients from rural locations scored Getting Needed Care about 2 points higher than urban white patients, while Hispanic and non-Hispanic black patients had an opposite trend, with this rural cohort ranking Getting Needed Care lower than urban patients of the same race/ethnicity.

“Geographic residence is but one important factor in cancer care delivery,” the authors noted. “There is a need for fine-grained research looking at specific barriers for urban residents, experiences of racial/ethnic minority survivors residing in rural areas, and rural-urban differences in the clinic settings in which medical care is delivered.”

The authors had no disclosures to report.

SOURCE: Mollica MA et al. Cancer. 2018 Jun 7. doi: 10.1002/cncr.31541.

Rural cancer survivors reported more timely care than did urban cancer survivors in a survey of 6,826 Medicare beneficiaries.

Taken as a whole, a similar quality of care was reported between the two groups, but the picture changed when racial/ethnic subgroups were considered. Non-Hispanic black and Hispanic patients in rural locations reported inferior care to their urban counterparts, investigators wrote in Cancer.

“Cancer patients living in rural areas are vulnerable and have unique health care needs,” wrote lead author Michelle A. Mollica, PhD, of the National Cancer Institute, and her colleagues. “To our knowledge, this is the first study to explore the patient’s perception of the timeliness of care in such a large, multiregion sample of cancer patients.”

In 2003, the National Academy of Medicine concluded that living in a rural environment was associated with poorer health. Existing research surrounding cancer has echoed this concern, showing that rural patients have higher rates of cancer and mortality, longer delays in diagnosis, and limited access to care.

The current, retrospective study involved 6,140 urban and 686 rural Medicare beneficiaries who were aged at least 65 years when diagnosed with either breast, lung, colorectal, or prostate cancer. Consumer Assessment of Healthcare Providers and Systems surveys were conducted between 1998 and 2013, then linked with data from the Surveillance, Epidemiology, and End Results registry program.

Surveys were conducted within 12 months of diagnosis, during which time patients were asked about their access to care as defined by two composites: “Getting Needed Care” and “Getting Care Quickly.” Getting Needed Care included ease of making appointments and receiving treatments and Getting Care Quickly questions asked about appointment delays and time spent waiting at the doctor’s office. Answers were converted to a numerical score from 0 to 100, with 0 being the worst and 100 being the best.

For both composites, mean scores for urban and rural locations were greater than 85 out of 100.

In contrast to previous studies, urban patients reported longer delays in care, scoring Getting Care Quickly 2.27 points lower than rural patients (P = .02). Pacific Islanders and non-Hispanic Asian patients from rural places reported even faster care, ranking about 8 points higher than urban patients of the same race/ethnicity.

Locality did not have a significant impact on Getting Needed Care unless race/ethnicity was also considered (P = .04). Non-Hispanic white patients from rural locations scored Getting Needed Care about 2 points higher than urban white patients, while Hispanic and non-Hispanic black patients had an opposite trend, with this rural cohort ranking Getting Needed Care lower than urban patients of the same race/ethnicity.

“Geographic residence is but one important factor in cancer care delivery,” the authors noted. “There is a need for fine-grained research looking at specific barriers for urban residents, experiences of racial/ethnic minority survivors residing in rural areas, and rural-urban differences in the clinic settings in which medical care is delivered.”

The authors had no disclosures to report.

SOURCE: Mollica MA et al. Cancer. 2018 Jun 7. doi: 10.1002/cncr.31541.

Platinum-based chemotherapy is effective in metastatic triple negative breast cancer (mTNBC), but predictive biomarkers would help identify the best candidates for the treatment. Two sets of parameters—neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)—have already demonstrated their prognostic prowess in many malignancies, but how well will they do in platinum-treated mTNBC patients? Researchers from Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy conducted a retrospective, single-center study to evaluate the association between baseline NLR or PLR and progression-free survival (PFS) in 57 mTNBC patients treated with carboplatin-paclitaxel or carboplatin-gemcitabine between 2007 and 2017, compared with 148 patients with hormone receptor-positive HER2-negative metastatic breast cancer.

Response was assessed every 3 chemotherapy cycles. Among platinum-treated patients, high NLR and PLR were associated with significantly lower PFS. Median PFS was 304 days in patients with NLR < 2.5, and 158 days in those with NLR ≥ 2.5. Progression-free survival was longer in patients with baseline PLR < 200, compared with PLR ≥ 200. The researchers found no significant association between NLR or PLR and the PFS of control patients.

When the same parameters were evaluated before the administration of the third treatment cycle, NLR < 2.5 was still associated with reduced risk of disease progression, although PLR < 200 was not.

In patients with mTNBC, median overall survival was significantly longer in patients with NLR < 2.5 compared with NLR ≥ 2.5. Platelet-to-lymphocyte ratio values were not associated with overall survival. The ratios also appeared to have a generally prognostic role independently from tumor biology.

The hormone receptors for NLR and PLR in multivariable analysis for PFS were similar, and the parameters correlated with each other, the researchers say, suggesting that both NLR and PLR “well reflect the inflammatory/immune contexture in mTNBC, and may be redundant as predictive biomarkers.”

Source:
Vernieri C, Mennitto A, Prisciandaro M, et al. Sci Rep. 2018;8(1):8703.

Platinum-based chemotherapy is effective in metastatic triple negative breast cancer (mTNBC), but predictive biomarkers would help identify the best candidates for the treatment. Two sets of parameters—neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)—have already demonstrated their prognostic prowess in many malignancies, but how well will they do in platinum-treated mTNBC patients? Researchers from Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy conducted a retrospective, single-center study to evaluate the association between baseline NLR or PLR and progression-free survival (PFS) in 57 mTNBC patients treated with carboplatin-paclitaxel or carboplatin-gemcitabine between 2007 and 2017, compared with 148 patients with hormone receptor-positive HER2-negative metastatic breast cancer.

Response was assessed every 3 chemotherapy cycles. Among platinum-treated patients, high NLR and PLR were associated with significantly lower PFS. Median PFS was 304 days in patients with NLR < 2.5, and 158 days in those with NLR ≥ 2.5. Progression-free survival was longer in patients with baseline PLR < 200, compared with PLR ≥ 200. The researchers found no significant association between NLR or PLR and the PFS of control patients.

When the same parameters were evaluated before the administration of the third treatment cycle, NLR < 2.5 was still associated with reduced risk of disease progression, although PLR < 200 was not.

In patients with mTNBC, median overall survival was significantly longer in patients with NLR < 2.5 compared with NLR ≥ 2.5. Platelet-to-lymphocyte ratio values were not associated with overall survival. The ratios also appeared to have a generally prognostic role independently from tumor biology.

The hormone receptors for NLR and PLR in multivariable analysis for PFS were similar, and the parameters correlated with each other, the researchers say, suggesting that both NLR and PLR “well reflect the inflammatory/immune contexture in mTNBC, and may be redundant as predictive biomarkers.”

Source:
Vernieri C, Mennitto A, Prisciandaro M, et al. Sci Rep. 2018;8(1):8703.

Platinum-based chemotherapy is effective in metastatic triple negative breast cancer (mTNBC), but predictive biomarkers would help identify the best candidates for the treatment. Two sets of parameters—neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR)—have already demonstrated their prognostic prowess in many malignancies, but how well will they do in platinum-treated mTNBC patients? Researchers from Fondazione IRCCS Istituto Nazionale dei Tumori, in Milan, Italy conducted a retrospective, single-center study to evaluate the association between baseline NLR or PLR and progression-free survival (PFS) in 57 mTNBC patients treated with carboplatin-paclitaxel or carboplatin-gemcitabine between 2007 and 2017, compared with 148 patients with hormone receptor-positive HER2-negative metastatic breast cancer.

Response was assessed every 3 chemotherapy cycles. Among platinum-treated patients, high NLR and PLR were associated with significantly lower PFS. Median PFS was 304 days in patients with NLR < 2.5, and 158 days in those with NLR ≥ 2.5. Progression-free survival was longer in patients with baseline PLR < 200, compared with PLR ≥ 200. The researchers found no significant association between NLR or PLR and the PFS of control patients.

When the same parameters were evaluated before the administration of the third treatment cycle, NLR < 2.5 was still associated with reduced risk of disease progression, although PLR < 200 was not.

In patients with mTNBC, median overall survival was significantly longer in patients with NLR < 2.5 compared with NLR ≥ 2.5. Platelet-to-lymphocyte ratio values were not associated with overall survival. The ratios also appeared to have a generally prognostic role independently from tumor biology.

The hormone receptors for NLR and PLR in multivariable analysis for PFS were similar, and the parameters correlated with each other, the researchers say, suggesting that both NLR and PLR “well reflect the inflammatory/immune contexture in mTNBC, and may be redundant as predictive biomarkers.”

Source:
Vernieri C, Mennitto A, Prisciandaro M, et al. Sci Rep. 2018;8(1):8703.

CHICAGO – For women with estrogen receptor–positive breast cancer resistant to endocrine therapy, the combination of everolimus and exemestane had better efficacy than did everolimus alone, but single-agent capecitabine appeared to offer benefit comparable to that of the combination therapy, results of the BOLERO-6 trial suggest.

Among 309 postmenopausal women with ER-positive, HER2-negative advanced breast cancer, the combination of everolimus (Afinitor) and exemestane (Aromasin and generics) was associated with a 26% improvement in progression-free survival (PFS) compared with everolimus alone, reported Guy Jerusalem, MD, PhD, of Liege University, Belgium.

There was also, however, a numerical but not statistically significant difference in PFS favoring capecitabine (Xeloda and generics) “which may be attributed to various baseline characteristics favoring capecitabine, and potential informative censoring,” he said at the annual meeting of the American Society of Clinical Oncology.

“We have noted in BOLERO-6 a better-than-expected outcome in median progression-free survival of capecitabine compared with the previously reported 4.1 to 7.9 months median progression-free survival,” he said.

BOLERO-6, results of which were published online June 3 in JAMA Oncology, was a postmarketing study by the sponsors to fulfill commitments to both the Food and Drug Administration and the European Medicines Agency to estimate the treatment benefit with combined everolimus and exemestane vs. monotherapy with everolimus or capecitabine in patients with ER-positive, HER2-negative breast cancer that progressed during nonsteroidal aromatase inhibitor therapy.

Patients from 83 centers in 18 countries were enrolled in the open label, phase 2 study and randomly assigned to receive oral everolimus 10 mg daily with oral exemestane 25 mg daily, everolimus at the same dose alone, or oral capecitabine 1,250 mg/m² twice daily for 2 weeks on, 1 week off.

The trial was not powered for statistical comparisons between arms, but was instead designed with the primary objective of estimated investigator-assessed PFS for the combination vs. everolimus alone.

At baseline, more patients assigned to capecitabine vs. everolimus-containing regimens were younger than 65, white, had an Eastern Cooperative Oncology Group status of 0 (fully active), and had bone-only metastases. In addition, fewer patients in the capecitabine arm had three or more metastatic sites, Dr. Jerusalem noted,

For the primary analysis, the median PFS with everolimus/exemestane was 8.4 months, compared with 6.8 months for everolimus alone. The estimated hazard ratio (HR) for PFS with everolimus/exemestane vs. everolimus alone was 0.74 (90% confidence interval [CI], 0.57-0.97)

In contrast, median PFS with capecitabine was 9.6 months, with a nonsignificant hazard ratio of 1.26 for the combination (90% CI, 0.96-1.66).

A stratified multivariate Cox regression model controlling for baseline difference and known prognostic factor yielded an HR for PFS of 1.15 (90% CI, 0.86-1.52) for the combination.

Censoring of patients was more frequent in the capecitabine arm (33% vs. 23% in the combination arm), which included 20% of patients on capecitabine who were censored for starting on a new antineoplastic therapy vs. 9% of patients on everolimus/exemestane.

The median time to treatment failure was 5.8 months with the combination, vs. 4.2 months with everolimus alone (HR, 0.66, 90% CI, 0.52-0.4), and 6.2 months with capecitabine alone (HR, 1.03, 90% CI, 0.81-1.31).

Median overall survival was 23.1 months in the combination arm, 29.3 months in the everolimus arm, and 25.6 months in the capecitabine arm. There were no statistically significant differences in overall survival among the groups.

Grade 3 or greater adverse events were more frequent in the combination vs. everolimus arms, and comparable between the combination and capecitabine arms, Dr. Jerusalem said.

Serious adverse events of any grade were more frequent in the combination arm than in the other two arms, but there were no significant differences in discontinuations due to adverse events

“The results of the present study suggest that mTOR inhibitor and endocrine therapy combinations remain important for aromatase inhibitor–refractory disease. Safety and PFS with everolimus plus exemestane in this study were consistent with BOLERO-2 and are now supported by real-world evidence,” the investigators wrote.

“The take home from the BOLERO-6 trial is that the progression-free survival for the combination of everolimus and exemestane is superior to everolimus alone, and is in line with data from the BOLERO-2 trial, and also the PrE0102 study, demonstrating the consistent activity of mTOR inhibition in combination with endocrine therapy in the aromatase inhibitor resistance setting, and this supports our use of the combination in the endocrine resistant patients,” said Cynthia X. Ma, MD, PhD, of Washington University, St. Louis, the invited discussant.

Novartis funded the study. Dr Jerusalem received research funding from Novartis and Roche; honoraria from Novartis, Roche, Pfizer, Lilly, Celgene, Amgen, BMS, and Puma Technology; and nonfinancial support from Novartis, Roche, Pfizer, Lilly, Amgen, and BMS. Dr. Ma reported consulting/advising, travel expenses, and institutional research funding from Novartis and others.

SOURCE: Jerusalem G et al. ASCO 2018 Abstract 1005

CHICAGO – For women with estrogen receptor–positive breast cancer resistant to endocrine therapy, the combination of everolimus and exemestane had better efficacy than did everolimus alone, but single-agent capecitabine appeared to offer benefit comparable to that of the combination therapy, results of the BOLERO-6 trial suggest.

Among 309 postmenopausal women with ER-positive, HER2-negative advanced breast cancer, the combination of everolimus (Afinitor) and exemestane (Aromasin and generics) was associated with a 26% improvement in progression-free survival (PFS) compared with everolimus alone, reported Guy Jerusalem, MD, PhD, of Liege University, Belgium.

There was also, however, a numerical but not statistically significant difference in PFS favoring capecitabine (Xeloda and generics) “which may be attributed to various baseline characteristics favoring capecitabine, and potential informative censoring,” he said at the annual meeting of the American Society of Clinical Oncology.

“We have noted in BOLERO-6 a better-than-expected outcome in median progression-free survival of capecitabine compared with the previously reported 4.1 to 7.9 months median progression-free survival,” he said.

BOLERO-6, results of which were published online June 3 in JAMA Oncology, was a postmarketing study by the sponsors to fulfill commitments to both the Food and Drug Administration and the European Medicines Agency to estimate the treatment benefit with combined everolimus and exemestane vs. monotherapy with everolimus or capecitabine in patients with ER-positive, HER2-negative breast cancer that progressed during nonsteroidal aromatase inhibitor therapy.

Patients from 83 centers in 18 countries were enrolled in the open label, phase 2 study and randomly assigned to receive oral everolimus 10 mg daily with oral exemestane 25 mg daily, everolimus at the same dose alone, or oral capecitabine 1,250 mg/m² twice daily for 2 weeks on, 1 week off.

The trial was not powered for statistical comparisons between arms, but was instead designed with the primary objective of estimated investigator-assessed PFS for the combination vs. everolimus alone.

At baseline, more patients assigned to capecitabine vs. everolimus-containing regimens were younger than 65, white, had an Eastern Cooperative Oncology Group status of 0 (fully active), and had bone-only metastases. In addition, fewer patients in the capecitabine arm had three or more metastatic sites, Dr. Jerusalem noted,

For the primary analysis, the median PFS with everolimus/exemestane was 8.4 months, compared with 6.8 months for everolimus alone. The estimated hazard ratio (HR) for PFS with everolimus/exemestane vs. everolimus alone was 0.74 (90% confidence interval [CI], 0.57-0.97)

In contrast, median PFS with capecitabine was 9.6 months, with a nonsignificant hazard ratio of 1.26 for the combination (90% CI, 0.96-1.66).

A stratified multivariate Cox regression model controlling for baseline difference and known prognostic factor yielded an HR for PFS of 1.15 (90% CI, 0.86-1.52) for the combination.

Censoring of patients was more frequent in the capecitabine arm (33% vs. 23% in the combination arm), which included 20% of patients on capecitabine who were censored for starting on a new antineoplastic therapy vs. 9% of patients on everolimus/exemestane.

The median time to treatment failure was 5.8 months with the combination, vs. 4.2 months with everolimus alone (HR, 0.66, 90% CI, 0.52-0.4), and 6.2 months with capecitabine alone (HR, 1.03, 90% CI, 0.81-1.31).

Median overall survival was 23.1 months in the combination arm, 29.3 months in the everolimus arm, and 25.6 months in the capecitabine arm. There were no statistically significant differences in overall survival among the groups.

Grade 3 or greater adverse events were more frequent in the combination vs. everolimus arms, and comparable between the combination and capecitabine arms, Dr. Jerusalem said.

Serious adverse events of any grade were more frequent in the combination arm than in the other two arms, but there were no significant differences in discontinuations due to adverse events

“The results of the present study suggest that mTOR inhibitor and endocrine therapy combinations remain important for aromatase inhibitor–refractory disease. Safety and PFS with everolimus plus exemestane in this study were consistent with BOLERO-2 and are now supported by real-world evidence,” the investigators wrote.

“The take home from the BOLERO-6 trial is that the progression-free survival for the combination of everolimus and exemestane is superior to everolimus alone, and is in line with data from the BOLERO-2 trial, and also the PrE0102 study, demonstrating the consistent activity of mTOR inhibition in combination with endocrine therapy in the aromatase inhibitor resistance setting, and this supports our use of the combination in the endocrine resistant patients,” said Cynthia X. Ma, MD, PhD, of Washington University, St. Louis, the invited discussant.

Novartis funded the study. Dr Jerusalem received research funding from Novartis and Roche; honoraria from Novartis, Roche, Pfizer, Lilly, Celgene, Amgen, BMS, and Puma Technology; and nonfinancial support from Novartis, Roche, Pfizer, Lilly, Amgen, and BMS. Dr. Ma reported consulting/advising, travel expenses, and institutional research funding from Novartis and others.

SOURCE: Jerusalem G et al. ASCO 2018 Abstract 1005

CHICAGO – For women with estrogen receptor–positive breast cancer resistant to endocrine therapy, the combination of everolimus and exemestane had better efficacy than did everolimus alone, but single-agent capecitabine appeared to offer benefit comparable to that of the combination therapy, results of the BOLERO-6 trial suggest.

Among 309 postmenopausal women with ER-positive, HER2-negative advanced breast cancer, the combination of everolimus (Afinitor) and exemestane (Aromasin and generics) was associated with a 26% improvement in progression-free survival (PFS) compared with everolimus alone, reported Guy Jerusalem, MD, PhD, of Liege University, Belgium.

There was also, however, a numerical but not statistically significant difference in PFS favoring capecitabine (Xeloda and generics) “which may be attributed to various baseline characteristics favoring capecitabine, and potential informative censoring,” he said at the annual meeting of the American Society of Clinical Oncology.

“We have noted in BOLERO-6 a better-than-expected outcome in median progression-free survival of capecitabine compared with the previously reported 4.1 to 7.9 months median progression-free survival,” he said.

BOLERO-6, results of which were published online June 3 in JAMA Oncology, was a postmarketing study by the sponsors to fulfill commitments to both the Food and Drug Administration and the European Medicines Agency to estimate the treatment benefit with combined everolimus and exemestane vs. monotherapy with everolimus or capecitabine in patients with ER-positive, HER2-negative breast cancer that progressed during nonsteroidal aromatase inhibitor therapy.

Patients from 83 centers in 18 countries were enrolled in the open label, phase 2 study and randomly assigned to receive oral everolimus 10 mg daily with oral exemestane 25 mg daily, everolimus at the same dose alone, or oral capecitabine 1,250 mg/m² twice daily for 2 weeks on, 1 week off.

The trial was not powered for statistical comparisons between arms, but was instead designed with the primary objective of estimated investigator-assessed PFS for the combination vs. everolimus alone.

At baseline, more patients assigned to capecitabine vs. everolimus-containing regimens were younger than 65, white, had an Eastern Cooperative Oncology Group status of 0 (fully active), and had bone-only metastases. In addition, fewer patients in the capecitabine arm had three or more metastatic sites, Dr. Jerusalem noted,

For the primary analysis, the median PFS with everolimus/exemestane was 8.4 months, compared with 6.8 months for everolimus alone. The estimated hazard ratio (HR) for PFS with everolimus/exemestane vs. everolimus alone was 0.74 (90% confidence interval [CI], 0.57-0.97)

In contrast, median PFS with capecitabine was 9.6 months, with a nonsignificant hazard ratio of 1.26 for the combination (90% CI, 0.96-1.66).

A stratified multivariate Cox regression model controlling for baseline difference and known prognostic factor yielded an HR for PFS of 1.15 (90% CI, 0.86-1.52) for the combination.

Censoring of patients was more frequent in the capecitabine arm (33% vs. 23% in the combination arm), which included 20% of patients on capecitabine who were censored for starting on a new antineoplastic therapy vs. 9% of patients on everolimus/exemestane.

The median time to treatment failure was 5.8 months with the combination, vs. 4.2 months with everolimus alone (HR, 0.66, 90% CI, 0.52-0.4), and 6.2 months with capecitabine alone (HR, 1.03, 90% CI, 0.81-1.31).

Median overall survival was 23.1 months in the combination arm, 29.3 months in the everolimus arm, and 25.6 months in the capecitabine arm. There were no statistically significant differences in overall survival among the groups.

Grade 3 or greater adverse events were more frequent in the combination vs. everolimus arms, and comparable between the combination and capecitabine arms, Dr. Jerusalem said.

Serious adverse events of any grade were more frequent in the combination arm than in the other two arms, but there were no significant differences in discontinuations due to adverse events

“The results of the present study suggest that mTOR inhibitor and endocrine therapy combinations remain important for aromatase inhibitor–refractory disease. Safety and PFS with everolimus plus exemestane in this study were consistent with BOLERO-2 and are now supported by real-world evidence,” the investigators wrote.

“The take home from the BOLERO-6 trial is that the progression-free survival for the combination of everolimus and exemestane is superior to everolimus alone, and is in line with data from the BOLERO-2 trial, and also the PrE0102 study, demonstrating the consistent activity of mTOR inhibition in combination with endocrine therapy in the aromatase inhibitor resistance setting, and this supports our use of the combination in the endocrine resistant patients,” said Cynthia X. Ma, MD, PhD, of Washington University, St. Louis, the invited discussant.

Novartis funded the study. Dr Jerusalem received research funding from Novartis and Roche; honoraria from Novartis, Roche, Pfizer, Lilly, Celgene, Amgen, BMS, and Puma Technology; and nonfinancial support from Novartis, Roche, Pfizer, Lilly, Amgen, and BMS. Dr. Ma reported consulting/advising, travel expenses, and institutional research funding from Novartis and others.

SOURCE: Jerusalem G et al. ASCO 2018 Abstract 1005

CHICAGO – Use of the 21–tumor gene expression assay (Oncotype DX Recurrence Score) allows nearly 70% of women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer to safely forgo adjuvant chemotherapy, sparing them adverse effects and preventing overtreatment, TAILORx trial results show.

The findings, which were reported in the plenary session at the annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine, mark a major advance in precision medicine.

Susan London/MDedge News

Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger having a recurrence score of 16-25 did fare better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” he maintained. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”

In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes among women with a low recurrence score (defined as 0-10) given endocrine therapy alone, and at the other end of the spectrum, need for a more aggressive approach, including chemotherapy, among women with a high recurrence score (defined as 26-100).

Ultimately, application of the recurrence score allowed 69% of the entire trial population to skip chemotherapy: all of those women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).

“Although this trial was designed in 2003, it was designed with the goal of addressing one of the themes at this 2018 meeting, expanding the reach of precision medicine,” Dr. Sparano pointed out. “It also embodies the core values of ASCO: By providing the highest level of evidence, it can have a direct and immediate impact on the care of our patients.”

An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but instead have node-positive disease.

Tailoring treatment: ‘not too much and not too little’

“These are very important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” said ASCO Expert Harold Burstein, MD, PhD, FASCO. “The data provided here today from this massive NCI-sponsored trial show that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”

Susan London/MDedge News

“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing extraordinarily well, and this test shows us how to tailor that management so they get exactly the right amount of treatment – not too much and not too little.”

Study details

All of the women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy.

Roughly 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% having a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.

Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr. Sparano explained. “I think you will see changes in the near future as to how Genomic Health reports their results.”

Among the women with midrange scores who were randomized, the hazard ratio for invasive disease-free survival with endocrine therapy alone compared with chemotherapy plus endocrine therapy (1.08) fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.

The groups had similar rates of freedom from distant recurrence (94.5% vs. 95.0%; hazard ratio, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs. 92.9%; hazard ratio, 1.11; P = .33), and similar overall survival (93.9% vs. 93.8%; hazard ratio for death, 0.99; P = .89).

In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive disease–free survival events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive disease–free survival events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr. Sparano said.

The 9-year rate of distant recurrence averaged 5% among the women with midrange scores overall. It was just 3% among the women with a low recurrence score given endocrine therapy alone, but it was still 13% among the women with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The last finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.

Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with Metastat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.

SOURCE: Sparano et al. ASCO 2018 Abstract LBA1

CHICAGO – Use of the 21–tumor gene expression assay (Oncotype DX Recurrence Score) allows nearly 70% of women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer to safely forgo adjuvant chemotherapy, sparing them adverse effects and preventing overtreatment, TAILORx trial results show.

The findings, which were reported in the plenary session at the annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine, mark a major advance in precision medicine.

Susan London/MDedge News

Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger having a recurrence score of 16-25 did fare better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” he maintained. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”

In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes among women with a low recurrence score (defined as 0-10) given endocrine therapy alone, and at the other end of the spectrum, need for a more aggressive approach, including chemotherapy, among women with a high recurrence score (defined as 26-100).

Ultimately, application of the recurrence score allowed 69% of the entire trial population to skip chemotherapy: all of those women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).

“Although this trial was designed in 2003, it was designed with the goal of addressing one of the themes at this 2018 meeting, expanding the reach of precision medicine,” Dr. Sparano pointed out. “It also embodies the core values of ASCO: By providing the highest level of evidence, it can have a direct and immediate impact on the care of our patients.”

An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but instead have node-positive disease.

Tailoring treatment: ‘not too much and not too little’

“These are very important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” said ASCO Expert Harold Burstein, MD, PhD, FASCO. “The data provided here today from this massive NCI-sponsored trial show that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”

Susan London/MDedge News

“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing extraordinarily well, and this test shows us how to tailor that management so they get exactly the right amount of treatment – not too much and not too little.”

Study details

All of the women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy.

Roughly 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% having a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.

Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr. Sparano explained. “I think you will see changes in the near future as to how Genomic Health reports their results.”

Among the women with midrange scores who were randomized, the hazard ratio for invasive disease-free survival with endocrine therapy alone compared with chemotherapy plus endocrine therapy (1.08) fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.

The groups had similar rates of freedom from distant recurrence (94.5% vs. 95.0%; hazard ratio, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs. 92.9%; hazard ratio, 1.11; P = .33), and similar overall survival (93.9% vs. 93.8%; hazard ratio for death, 0.99; P = .89).

In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive disease–free survival events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive disease–free survival events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr. Sparano said.

The 9-year rate of distant recurrence averaged 5% among the women with midrange scores overall. It was just 3% among the women with a low recurrence score given endocrine therapy alone, but it was still 13% among the women with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The last finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.

Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with Metastat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.

SOURCE: Sparano et al. ASCO 2018 Abstract LBA1

CHICAGO – Use of the 21–tumor gene expression assay (Oncotype DX Recurrence Score) allows nearly 70% of women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer to safely forgo adjuvant chemotherapy, sparing them adverse effects and preventing overtreatment, TAILORx trial results show.

The findings, which were reported in the plenary session at the annual meeting of the American Society of Clinical Oncology and simultaneously published in the New England Journal of Medicine, mark a major advance in precision medicine.

Susan London/MDedge News

Findings were similar across most subgroups. But analyses suggested that women aged 50 years and younger having a recurrence score of 16-25 did fare better when they received chemotherapy. “Though exploratory from a statistical perspective, this is a highly clinically relevant observation,” he maintained. “It suggests ... that chemotherapy should be spared with caution in this subgroup, after a careful discussion of potential benefits and risks in a shared decision process.”

In other findings, analyses of the trial’s nonrandomized groups confirmed excellent outcomes among women with a low recurrence score (defined as 0-10) given endocrine therapy alone, and at the other end of the spectrum, need for a more aggressive approach, including chemotherapy, among women with a high recurrence score (defined as 26-100).

Ultimately, application of the recurrence score allowed 69% of the entire trial population to skip chemotherapy: all of those women with a score of 0-10 (16% of the trial population), those older than 50 years with a score of 11-25 (45%), and those aged 50 years or younger with a score of 11-15 (8%).

“Although this trial was designed in 2003, it was designed with the goal of addressing one of the themes at this 2018 meeting, expanding the reach of precision medicine,” Dr. Sparano pointed out. “It also embodies the core values of ASCO: By providing the highest level of evidence, it can have a direct and immediate impact on the care of our patients.”

An ongoing companion phase 3 trial, RxPONDER, is assessing the benefit of applying the recurrence score in women who are similar but instead have node-positive disease.

Tailoring treatment: ‘not too much and not too little’

“These are very important data because this is the most common form of breast cancer in the United States and other developed countries, and the most challenging decision we make with these patients is whether or not to recommend adjuvant chemotherapy with all of its side effects and with its potential benefits,” said ASCO Expert Harold Burstein, MD, PhD, FASCO. “The data provided here today from this massive NCI-sponsored trial show that the vast majority of women who have this test performed on their tumor can be told that they don’t need chemotherapy, and that can be said with tremendous confidence and reassurance.”

Susan London/MDedge News

“This is extraordinary data for breast cancer doctors and women who have breast cancer. It allows you to individualize treatment based on extraordinary science, which now has tremendous prospective validation,” he said. Overall, “women with breast cancer who are getting modern therapy are doing extraordinarily well, and this test shows us how to tailor that management so they get exactly the right amount of treatment – not too much and not too little.”

Study details

All of the women with hormone receptor–positive, HER2-negative, node-negative early-stage breast cancer enrolled in TAILORx met National Comprehensive Cancer Network guidelines for receiving adjuvant chemotherapy.

Roughly 69% had an intermediate recurrence score (11-25) and were randomized. All of the 17% having a low recurrence score (0-10) were given only endocrine therapy, and all of the 14% with a high recurrence score (26-100) were given both adjuvant chemotherapy and endocrine therapy.

Of note, the recurrence scores used to define midrange were adjusted downward from those conventionally used to account for exclusion of patients with higher-risk HER2-positive disease and to minimize potential for undertreatment, Dr. Sparano explained. “I think you will see changes in the near future as to how Genomic Health reports their results.”

Among the women with midrange scores who were randomized, the hazard ratio for invasive disease-free survival with endocrine therapy alone compared with chemotherapy plus endocrine therapy (1.08) fell well within the predefined hazard ratio for noninferiority (1.322). The 9-year rate of invasive disease–free survival was 83.3% with endocrine therapy and 84.3% with chemotherapy plus endocrine therapy.

The groups had similar rates of freedom from distant recurrence (94.5% vs. 95.0%; hazard ratio, 1.10; P = .48) and distant or locoregional recurrence (92.2% vs. 92.9%; hazard ratio, 1.11; P = .33), and similar overall survival (93.9% vs. 93.8%; hazard ratio for death, 0.99; P = .89).

In exploratory analyses, there was an interaction of age and recurrence score (P = .004) whereby women aged 50 or younger derived some benefit from chemotherapy if they had a recurrence score of 16-20 (9% fewer invasive disease–free survival events, including 2% fewer distant recurrences) or a recurrence score 21-25 (6% fewer invasive disease–free survival events, mainly distant recurrences). “This is information that could drive some younger women who have a recurrence score in this range to accept chemotherapy,” Dr. Sparano said.

The 9-year rate of distant recurrence averaged 5% among the women with midrange scores overall. It was just 3% among the women with a low recurrence score given endocrine therapy alone, but it was still 13% among the women with a high recurrence score despite receiving both endocrine therapy and chemotherapy. The last finding may “indicate the need to explore potentially more effective therapies in this setting,” he proposed.

Dr. Sparano disclosed that he has a consulting or advisory role with Genentech/Roche, Novartis, AstraZeneca, Celgene, Lilly, Celldex, Pfizer, Prescient Therapeutics, Juno Therapeutics, and Merrimack; has stock or other ownership interests with Metastat; and receives research funding (institutional) from Prescient Therapeutics, Deciphera, Genentech/Roche, Merck, Novartis, and Merrimack. This study received funding primarily from the National Cancer Institute, National Institutes of Health. Additional support was provided by the Breast Cancer Research Foundation, Komen Foundation, and U.S. Postal Service Breast Cancer Stamp.

SOURCE: Sparano et al. ASCO 2018 Abstract LBA1

CHICAGO – William J. Gradishar, MD, discussed the clinical impact of breast cancer research presented at the annual meeting of the American Society of Clinical Oncology.

In a video interview, Dr. Gradishar, the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago, said TAILORx was a “big win” in that it has no doubt diminished the number of women with early-stage breast cancer who will require chemotherapy. However, although the trial has provided some clarity, it also has left some questions open, particularly for patients under 50 years of age, he said.

Dr. Gradishar also discussed the results of combination trials of targeted therapy with either endocrine therapy or chemotherapy. In discussing SANDPIPER, which evaluated whether a phosphoinositide 3-kinase inhibitor could enhance the effect of anti-hormonal therapy, he said that although it was a positive trial, “from a clinician’s standpoint, it’s probably not sufficient in my mind to get really excited about.”

[email protected]

CHICAGO – William J. Gradishar, MD, discussed the clinical impact of breast cancer research presented at the annual meeting of the American Society of Clinical Oncology.

In a video interview, Dr. Gradishar, the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago, said TAILORx was a “big win” in that it has no doubt diminished the number of women with early-stage breast cancer who will require chemotherapy. However, although the trial has provided some clarity, it also has left some questions open, particularly for patients under 50 years of age, he said.

Dr. Gradishar also discussed the results of combination trials of targeted therapy with either endocrine therapy or chemotherapy. In discussing SANDPIPER, which evaluated whether a phosphoinositide 3-kinase inhibitor could enhance the effect of anti-hormonal therapy, he said that although it was a positive trial, “from a clinician’s standpoint, it’s probably not sufficient in my mind to get really excited about.”

[email protected]

CHICAGO – William J. Gradishar, MD, discussed the clinical impact of breast cancer research presented at the annual meeting of the American Society of Clinical Oncology.

In a video interview, Dr. Gradishar, the Betsy Bramsen Professor of Breast Oncology at Northwestern University, Chicago, said TAILORx was a “big win” in that it has no doubt diminished the number of women with early-stage breast cancer who will require chemotherapy. However, although the trial has provided some clarity, it also has left some questions open, particularly for patients under 50 years of age, he said.

Dr. Gradishar also discussed the results of combination trials of targeted therapy with either endocrine therapy or chemotherapy. In discussing SANDPIPER, which evaluated whether a phosphoinositide 3-kinase inhibitor could enhance the effect of anti-hormonal therapy, he said that although it was a positive trial, “from a clinician’s standpoint, it’s probably not sufficient in my mind to get really excited about.”

[email protected]

CHICAGO – Matched targeted therapy improved long-term survival in patients with advanced cancer, according to findings from a retrospective analysis of molecularly profiled patients.

Of 3,743 patients tested as part of IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy), 1,307 (34.9%) had at least one targetable molecular alteration. Of those, 711 (54.4%) received either matched targeted therapy that was being tested in a clinical trial or – in a small number of cases – therapy with an approved treatment used off label, and 596 (45.6%) received nonmatched therapy, Apostolia-Maria Tsimberidou, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

The objective response rates in 697 evaluable matched therapy patients was 16.2% versus 5.4% in 571 evaluable nonmatched patients, and stable disease for at least 6 months occurred in 18.7% and 14.7% of patients, respectively, for an overall disease control rate of 34.9% versus 20.1%, said Dr. Tsimberidou, a professor at the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival in those who received matched versus nonmatched therapy was 4.0 months and 2.8 months, respectively (hazard ratio, 0.67), and median overall survival was 9.3 and 7.3 months, respectively (HR, 0.72), she said.

The 3-year overall survival rate was 15% versus 7%, respectively, and 10-year survival was 6% and 1%, respectively.

Patients included in IMPACT had a mean age of 57 years, and 39% were men. They were heavily pretreated (mean number of prior therapies was 4); only 2.8% of patients had no prior treatment. Cancers included gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%) and lung (8.7%).

In this video interview, Dr. Tsimberidou describes the rationale, methodology, and findings of IMPACT, including the use of a prognostic scoring system developed as part of the study to predict overall survival based on baseline characteristics, such as baseline p13K/AKT/mTOR pathway molecular alterations, which were shown on multivariate analysis in IMPACT to predict shorter overall survival versus other alterations. Other predictors of shorter survival included liver metastases, elevated lactate dehydrogenase levels, poor functional status, low albumin levels, elevated platelet counts, and age of 60 years or older.

SOURCE: Tsimberidou AM et al. ASCO 2018, Abstract LBA 2553.

CHICAGO – Matched targeted therapy improved long-term survival in patients with advanced cancer, according to findings from a retrospective analysis of molecularly profiled patients.

Of 3,743 patients tested as part of IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy), 1,307 (34.9%) had at least one targetable molecular alteration. Of those, 711 (54.4%) received either matched targeted therapy that was being tested in a clinical trial or – in a small number of cases – therapy with an approved treatment used off label, and 596 (45.6%) received nonmatched therapy, Apostolia-Maria Tsimberidou, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

The objective response rates in 697 evaluable matched therapy patients was 16.2% versus 5.4% in 571 evaluable nonmatched patients, and stable disease for at least 6 months occurred in 18.7% and 14.7% of patients, respectively, for an overall disease control rate of 34.9% versus 20.1%, said Dr. Tsimberidou, a professor at the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival in those who received matched versus nonmatched therapy was 4.0 months and 2.8 months, respectively (hazard ratio, 0.67), and median overall survival was 9.3 and 7.3 months, respectively (HR, 0.72), she said.

The 3-year overall survival rate was 15% versus 7%, respectively, and 10-year survival was 6% and 1%, respectively.

Patients included in IMPACT had a mean age of 57 years, and 39% were men. They were heavily pretreated (mean number of prior therapies was 4); only 2.8% of patients had no prior treatment. Cancers included gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%) and lung (8.7%).

In this video interview, Dr. Tsimberidou describes the rationale, methodology, and findings of IMPACT, including the use of a prognostic scoring system developed as part of the study to predict overall survival based on baseline characteristics, such as baseline p13K/AKT/mTOR pathway molecular alterations, which were shown on multivariate analysis in IMPACT to predict shorter overall survival versus other alterations. Other predictors of shorter survival included liver metastases, elevated lactate dehydrogenase levels, poor functional status, low albumin levels, elevated platelet counts, and age of 60 years or older.

SOURCE: Tsimberidou AM et al. ASCO 2018, Abstract LBA 2553.

CHICAGO – Matched targeted therapy improved long-term survival in patients with advanced cancer, according to findings from a retrospective analysis of molecularly profiled patients.

Of 3,743 patients tested as part of IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy), 1,307 (34.9%) had at least one targetable molecular alteration. Of those, 711 (54.4%) received either matched targeted therapy that was being tested in a clinical trial or – in a small number of cases – therapy with an approved treatment used off label, and 596 (45.6%) received nonmatched therapy, Apostolia-Maria Tsimberidou, MD, reported during a press briefing at the annual meeting of the American Society of Clinical Oncology.

The objective response rates in 697 evaluable matched therapy patients was 16.2% versus 5.4% in 571 evaluable nonmatched patients, and stable disease for at least 6 months occurred in 18.7% and 14.7% of patients, respectively, for an overall disease control rate of 34.9% versus 20.1%, said Dr. Tsimberidou, a professor at the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival in those who received matched versus nonmatched therapy was 4.0 months and 2.8 months, respectively (hazard ratio, 0.67), and median overall survival was 9.3 and 7.3 months, respectively (HR, 0.72), she said.

The 3-year overall survival rate was 15% versus 7%, respectively, and 10-year survival was 6% and 1%, respectively.

Patients included in IMPACT had a mean age of 57 years, and 39% were men. They were heavily pretreated (mean number of prior therapies was 4); only 2.8% of patients had no prior treatment. Cancers included gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%) and lung (8.7%).

In this video interview, Dr. Tsimberidou describes the rationale, methodology, and findings of IMPACT, including the use of a prognostic scoring system developed as part of the study to predict overall survival based on baseline characteristics, such as baseline p13K/AKT/mTOR pathway molecular alterations, which were shown on multivariate analysis in IMPACT to predict shorter overall survival versus other alterations. Other predictors of shorter survival included liver metastases, elevated lactate dehydrogenase levels, poor functional status, low albumin levels, elevated platelet counts, and age of 60 years or older.

SOURCE: Tsimberidou AM et al. ASCO 2018, Abstract LBA 2553.

Introduction

Breast cancer is the second leading cause of cancer deaths among women in the United States, according to the SEER database. It is estimated that 1 in 8 women will be diagnosed with breast cancer at some point during their lifetime (12.4% lifetime risk).^1,2 Because breast tumors are clinically and histopathologically heterogeneous, different diagnostic and therapeutic approaches are required for each subtype. Among the subtypes, tumors that are positive for human epidermal growth factor receptor 2 (HER2) account for approximately 15% to 20% of all newly diagnosed localized and metastatic invasive breast tumors.^3,4 Historically, this subset of tumors has been considered the most aggressive due to a higher propensity to relapse and metastasize, translating into poorer prognosis compared with other subtypes.^5–7 However, with the advent of HER2-targeted therapy in the late 1990s, prognosis has significantly improved for both early- and late-stage HER2-positive tumors.⁸

Pathogenesis

The HER2 proto-oncogene belongs to a family of human epidermal growth factor receptors that includes 4 transmembrane tyrosine kinase receptors: HER1 (also commonly known as epidermal growth factor receptor, EGFR), HER2, HER3, and HER4. Another commonly used nomenclature for this family of receptors is ERBB1 to ERBB4. Each of the receptors has a similar structure consisting of a growth factor–binding extracellular domain, a single transmembrane segment, an intracellular protein-tyrosine kinase catalytic domain, and a tyrosine-containing cytoplasmic tail. Activation of the extracellular domain leads to conformational changes that initiate a cascade of reactions resulting in protein kinase activation. ERBB tyrosine receptor kinases subsequently activate several intracellular pathways that are critical for cellular function and survival, including the PI3K-AKT, RAS-MAPK, and mTOR pathways. Hyperactivation or overexpression of these receptors leads to uncontrolled cell growth and proliferation, and eventually cancerogenesis.^9,10

HER2 gene amplification can cause activation of the receptor’s extramembranous domain by way of either dimerization of two HER2 receptors or heterodimerization with other ERBB family receptors, leading to ligand-independent activation of cell signaling (ie, activation in the absence of external growth factors). Besides breast cancer, HER2 protein is overexpressed in several other tumor types, including esophageal and gastric adenocarcinomas, colon and gynecological malignancies, and to a lesser extent in other malignancies.

Biomarker Testing

All patients with newly diagnosed breast cancer should have their tumor tissue submitted for biomarker testing for estrogen receptors (ER), progesterone receptors (PR), and HER2 overexpression, as the result this testing dictates therapy choices. The purpose of HER2 testing is to investigate whether the HER2 gene, located on chromosome 17, is overexpressed or amplified. HER2 status provides the basis for treatment selection, which impacts long-term outcome measures such as recurrence and survival. Routine testing of carcinoma in situ for HER2 expression/amplification is not recommended and has no implication on choice of therapy at this time.

In 2013, the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) updated their clinical guideline recommendations for HER2 testing in breast cancer to improve its accuracy and its utility as a predictive marker.¹¹ There are currently 2 approved modalities for HER2 testing: detection of HER2 protein overexpression by immunohistochemical staining (IHC), and detection of HER2 gene amplification using in-situ hybridization. The results of each type of testing are reported as positive, equivocal, or negative (Table 1).¹¹  IHC uses antibodies against HER2 protein to assess the level of protein expression at the membrane of invasive tumor cells; overexpression of HER2 is established based upon the intensity of cell membrane staining and the number of stained cells. Results are reported as positive for HER2 expression (3+ staining), negative for HER2 expression (0 or 1+ staining), or equivocal for HER2 expression (2+ staining).

Fluorescence in-situ hybridization (FISH) testing assesses for HER2 amplification by determining the number of HER2 signals and chromosome 17 centromere (CEP17) signals, respectively, in a tissue sample. HER2 status is based on the ratio of average HER2 signals to CEP17 signals and the average HER2 signal count per cell. FISH testing is considered positive when there are ≥ 6 copies of HER2 signals per cell or when the HER2/CEP17 ratio is ≥ 2. FISH testing is reported as negative when there are fewer than 4 copies of HER2 per cell and the HER2/CEP17 ratio is < 2. 

Neoadjuvant and Adjuvant Therapy for Locoregional Disease

Case Patient 1

A 56-year-old woman undergoes ultrasound-guided biopsy of a self-palpated breast lump. Pathology shows invasive ductal carcinoma that is ER-positive, PR-negative, and HER2 equivocal by IHC (2+ staining). Follow-up FISH testing shows a HER2/CEP17 ratio of 2.5. The tumor is estimated to be 2 cm in diameter by imaging and exam with no clinically palpable axillary lymphadenopathy. The patient exhibits no constitutional or localized symptoms concerning for metastases.

• What is the recommended management approach for this patient?

According to the ASCO/CAP guidelines, this patient’s tumor qualifies as HER2-positive based upon testing results showing amplification of the gene. This result has important implications for management since nearly all patients with macroscopically invasive HER2-positive tumors should be considered for adjuvant chemotherapy in combination with anti-HER2 therapy. The patient should proceed with upfront tumor resection and sentinel lymph node biopsy. Systemic staging imaging (ie, computed tomography [CT] or bone scan) is not indicated in early stage breast cancer.^12,13 Systemic staging scans are indicated when (1) any anatomical stage III disease is suspected (eg, with involvement of the skin or chest wall, the presence of enlarged matted or fixed axillary lymph nodes, and involvement of nodal stations other than in the axilla), and (2) when symptoms or abnormal laboratory values raise suspicion for distant metastases (eg, unexplained bone pain, unintentional weight loss, elevated serum alkaline phosphatase, and transaminitis).

Case 1 Continued

The patient presents to discuss treatment options after undergoing a lumpectomy and sentinel node biopsy procedure. The pathology report notes a single focus of carcinoma measuring 2 cm with negative sentinel lymph nodes.

• What agents are used for adjuvant therapy in HER2-postive breast cancer?

Nearly all patients with macroscopically invasive (> 1 mm) breast carcinoma should be considered for adjuvant therapy using a regimen that contains a taxane and trastuzumab. However, the benefit may be small for patients with tumors ≤ 5 mm (T1a, N0), so it is important to carefully weigh the risk against the benefit. Among the agents that targeting HER2, only trastuzumab has been shown to improve overall survival (OS) in the adjuvant setting; long-term follow-up data are awaited for other agents.⁸ A trastuzumab biosimilar, trastuzumab-dkst, was recently approved by the US Food and Drug Administration (FDA) for the same indications as trastuzumab.¹⁴ The regimens most commonly used in the adjuvant and neoadjuvant settings for nonmetastatic breast cancer are summarized in Table 2.

Patients with small (≤ 3 cm), node-negative tumors can generally be considered for a reduced-intensity regimen that includes weekly paclitaxel plus trastuzumab. This combination proved efficacious in a single-group, multicenter study that enrolled 406 patients.¹⁵ Paclitaxel and trastuzumab were given once weekly for 12 weeks, followed by trastuzumab, either weekly or every 3 weeks, to complete 1 year of therapy.After a median follow-up of more than 6 years, the rates of distant and locoregional recurrence were 1% and 1.2%, respectively.¹⁶

A combination of docetaxel, carboplatin, and trastuzumab is a nonanthracycline regimen that is also appropriate in this setting, based on the results of the Breast Cancer International Research Group 006 (BCIRG-006) trial.¹⁷ This phase 3 randomized trial enrolled 3222 women with HER2-positive, invasive, high-risk adenocarcinoma. Eligible patients had a T1–3 tumor and either lymph node–negative or –positive disease and were randomly assigned to receive 1 of 3 regimens: group 1 received doxorubicin and cyclophosphamide every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for 4 cycles (AC-T); group 2 received the AC-T regimen in combination with trastuzumab; and group 3 received docetaxel, carboplatin, and trastuzumab once every 3 weeks for 6 cycles (TCH). Groups 2 and 3 also received trastuzumab for an additional 34 weeks to complete 1 year of therapy. Trastuzumab-containing regimens were found to offer superior disease-free survival (DFS) and OS. When comparing the 2 trastuzumab arms after more than 10 years of follow-up, no statistically significant advantage of an anthracycline regimen over a nonanthracycline regimen was found.¹⁸ Furthermore, the anthracycline arm had a fivefold higher incidence of symptomatic congestive heart failure (grades 3 and 4), and the nonanthracycline regimen was associated with a lower incidence of treatment-related leukemia, a clinically significant finding despite not reaching statistical significance due to low overall numbers.

BCIRG-006, NSABP B-31, NCCTG N9831, and HERA are all large randomized trials with consistent results confirming trastuzumab’s role in reducing recurrence and improving survival in HER2-positive breast cancer in the adjuvant settings. The estimated overall benefit from addition of this agent was a 34% to 41% improvement in survival and a 33% to 52% improvement in DFS.^8,17–20

Dual anti-HER2 therapy containing both trastuzumab and pertuzumab should be strongly considered for patients with macroscopic lymph node involvement based on the results of the APHINITY trial.²¹ In this study, the addition of pertuzumab to standard trastuzumab-based therapy led to a significant improvement in invasive-disease-free survival at 3 years. In subgroup analysis, the benefit was restricted to the node-positive group (3-year invasive-disease-free survival rates of 92% in the pertuzumab group versus 90.2% in the placebo group, P = 0.02). Patients with hormone receptor–negative disease derived greater benefit from the addition of pertuzumab. Regimens used in the APHINITY trial included the anti-HER2 agents trastuzumab and pertuzumab in combination with 1 of the following chemotherapy regimens: sequential cyclophosphamide plus either doxorubicin or epirubicin, followed by either 4 cycles of docetaxel or 12 weekly doses of paclitaxel; sequential fluorouracil plus either epirubicin or doxorubicin plus cyclophosphamide (3 or 4 cycles), followed by 3 or 4 cycles of docetaxel or 12 weekly cycles of paclitaxel; or 6 cycles of concurrent docetaxel plus carboplatin.

One-year therapy with neratinib, an oral tyrosine kinase inhibitor of HER2, is now approved by the FDA after completion of trastuzumab in the adjuvant setting, based on the results of the ExteNET trial.²² In this study, patients who had completed trastuzumab within the preceding 12 months, without evidence of recurrence, were randomly assigned to receive either oral neratinib or placebo daily for 1 year. The 2-year DFS rate was 93.9% and 91.6% for the neratinib and placebo groups, respectively. The most common adverse effect of neratinib was diarrhea, with approximately 40% of patients experiencing grade 3 diarrhea. In subgroup analyses, hormone receptor–positive patients derived the most benefit, while hormone receptor–negative patients derived no or marginal benefit.²² OS benefit has not yet been established.²³

Trastuzumab therapy (with pertuzumab if indicated) should be offered for an optimal duration of 12 months (17 cycles, including those given with chemotherapy backbone). A shorter duration of therapy, 6 months, has been shown to be inferior,²⁴ while a longer duration, 24 months, has been shown to provide no additional benefit.²⁵

Finally, sequential addition of anti-estrogen endocrine therapy is indicated for hormone-positive tumors. Endocrine therapy is usually added after completion of the chemotherapy backbone of the regimen, but may be given concurrently with anti-HER2 therapy. If radiation is being administered, endocrine therapy can be given concurrently or started after radiation therapy is completed.

Case 1 Conclusion

The patient can be offered 1 of 2 adjuvant treatment regimens, either TH or TCH (Table 2). Since the patient had lumpectomy, she is an appropriate candidate for adjuvant radiation, which would be started after completion of the chemotherapy backbone (taxane/platinum). Endocrine therapy for at least 5 years should be offered sequentially or concurrently with radiation. Her long-term prognosis is very favorable.

Case Patient 2

A 43-year-old woman presents with a 4-cm breast mass, a separate skin nodule, and palpable matted axillary lymphadenopathy. Biopsies of the breast mass and subcutaneous nodule reveal invasive ductal carcinoma that is ER-negative, PR-negative, and HER2-positive by IHC (3+ staining). Based on clinical findings, the patient is staged as T4b (separate tumor nodule), N2 (matted axillary lymph nodes). Systemic staging with CT scan of the chest, abdomen, and pelvis shows no evidence of distant metastases.

• What is the recommended approach to management for this patient?

Recommendations for neoadjuvant therapy, given before definitive surgery, follow the same path as with other subtypes of breast cancer. Patients with suspected anatomical stage III disease are strongly encouraged to undergo upfront (neoadjuvant) chemotherapy in combination with HER2-targeted agents. In addition, all HER2-positive patients with clinically node-positive disease can be offered neoadjuvant therapy using chemotherapy plus dual anti-HER2 therapy (trastuzumab and pertuzumab), with complete pathological response expected in more than 60% of patients.^26,27 Because this patient has locally advanced disease, especially skin involvement and matted axillary nodes, she should undergo neoadjuvant therapy. Preferred regimens contain both trastuzumab and pertuzumab in combination with cytotoxic chemotherapy. The latter may be given concurrently (nonanthracycline regimens, such as docetaxel plus carboplatin) or sequentially (anthracycline-based regimens), as outlined in Table 2. Administration of anthracyclines and trastuzumab simultaneously is contraindicated due to increased risk of cardiomyopathy.²⁸

Endocrine therapy is not indicated for this patient per the current standard of care because the tumor was ER- and PR-negative. Had the tumor been hormone receptor–positive, endocrine therapy for a minimum of 5 years would have been indicated. Likewise, in the case of hormone receptor–positive disease, 12 months of neratinib therapy after completion of trastuzumab may add further benefit, as shown in the ExteNET trial.^22,23 Neratinib seems to have a propensity to prevent or delay trastuzumab-induced overexpression of estrogen receptors. This is mainly due to hormone receptor/HER2 crosstalk, a potential mechanism of resistance to trastuzumab.^29,30

In addition to the medical therapy options discussed here, this patient would be expected to benefit from adjuvant radiation to the breast and regional lymph nodes, given the presence of T4 disease and bulky adenopathy in the axilla.³¹

Case 2 Conclusion

The patient undergoes neoadjuvant treatment (docetaxel, carboplatin, trastuzumab, and pertuzumab every 21 days for a total of 6 cycles), followed by surgical resection (modified radical mastectomy) that reveals complete pathological response (no residual invasive carcinoma). Subsequently, she receives radiation therapy to the primary tumor site and regional lymph nodes while continuing trastuzumab and pertuzumab for 11 more cycles (17 total). Despite presenting with locally advanced disease, the patient has a favorable overall prognosis due to an excellent pathological response.

• What is the approach to follow-up after completion of primary therapy?

Patients may follow up every 3 to 6 months for clinical evaluation in the first 5 years after completing primary adjuvant therapy. An annual screening mammogram is recommended as well. Body imaging can be done if dictated by symptoms. However, routine CT, positron emission tomography, or bone scans are not recommended as part of follow-up in the absence of symptoms, mainly because of a lack of evidence that such surveillance improves survival.³²

Metastatic HER2-Positive Breast Cancer

Metastatic breast cancer most commonly presents as a distant recurrence of previously treated local disease. However, 6% to 18% of patients have no prior history of breast cancer and present with de novo metastatic disease.^33,34 The most commonly involved distant organs are the skeletal bones, liver, lung, distant lymph node stations, and brain. Compared to other subtypes, HER2-positive tumors have an increased tendency to involve the central nervous system.^35–38 Although metastatic HER2-positive breast cancer is not considered curable, significant improvement in survival has been achieved, and patients with metastatic disease have median survival approaching 5 years.³⁹

Case Presentation 3

A 69-year-old woman with a history of breast cancer 4 years ago presents with new-onset back pain and unintentional weight loss. On exam, she is found to have palpable axillary adenopathy on the same side as her previous cancer. Her initial disease was stage IIB ER-positive and HER2-positive and was treated with chemotherapy, mastectomy, and anastrozole, which the patient is still taking. She undergoes CT scan of the chest, abdomen, and pelvis and radionucleotide bone scan, which show multiple liver and bony lesions suspicious for metastatic disease. Axillary lymph node biopsy confirms recurrent invasive carcinoma that is ER-positive and HER2-positive by IHC (3+).

• What is the approach to management of a patient who presents with symptoms of recurrent HER2-positive disease?

This patient likely has metastatic breast cancer based on the imaging findings. In such cases, a biopsy of the recurrent disease should always be considered, if feasible, to confirm the diagnosis and rule out other etiologies such as different malignances and benign conditions. Hormone-receptor and HER2 testing should also be performed on recurrent disease, since a change in HER2 status can be seen in 15% to 33% of cases.^40–42

Based on data from the phase 3 CLEOPATRA trial, first-line systemic regimens for patients with metastatic breast cancer that is positive for HER2 should consist of a combination of docetaxel, trastuzumab, and pertuzumab.  Compared to placebo, adding pertuzumab yielded superior progression-free survival of 18.4 months (versus 12.4 months for placebo) and an unprecedented OS of 56.5 months (versus 40.8 for placebo).³⁹ Weekly paclitaxel can replace docetaxel with comparable efficacy (Table 3).⁴³

Patients can develop significant neuropathy as well as skin and nail changes after multiple cycles of taxane-based chemotherapy. Therefore, the taxane backbone may be dropped after 6 to 8 cycles, while patients continue the trastuzumab and pertuzumab combination until disease progression or unacceptable toxicity. Some patients may enjoy remarkable long-term survival on “maintenance” anti-HER2 therapy.⁴⁴ Despite lack of high-level evidence, such as from large randomized trials, some experts recommend the addition of a hormone blocker after discontinuation of the taxane in ER-positive tumors.⁴⁵

Premenopausal and perimenopausal women with hormone receptor–positive metastatic disease should be considered for simultaneous ovarian suppression. Ovarian suppression can be accomplished medically using a gonadotropin-releasing hormone agonist (goserelin) or surgically via salpingo-oophorectomy.^46–48

Case 3 Conclusion

The patient receives 6 cycles of docetaxel, trastuzumab, and pertuzumab, after which the docetaxel is discontinued due to neuropathy while she continues the other 2 agents. After 26 months of disease control, the patient is found to have new liver metastatic lesions, indicating progression of disease.

• What therapeutic options are available for this patient?

Patients whose disease progresses after receiving taxane- and trastuzumab-containing regimens are candidates to receive the novel antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). Early progressors (ie, patients with early stage disease who have progression of disease while receiving adjuvant trastuzumab or within 6 months of completion of adjuvant trastuzumab) are also candidates for T-DM1. Treatment usually fits in the second line or beyond based on data from the EMILIA trial, which randomly assigned patients to receive either capecitabine plus lapatinib or T-DM1.^49,50 Progression-free survival in the T-DM1 group was 9.6 months versus 6.4 months for the comparator. Improvement of 4 months in OS persisted with longer follow-up despite a crossover rate of 27%. Furthermore, a significantly higher objective response rate and fewer adverse effects were reported in the T-DM1 patients. Most patients included in the EMILIA trial were pertuzumab-naive. However, the benefit of T-DM1 appears to persist, albeit to a lesser extent, for pertuzumab-pretreated patients.^51,52

Patients in whom treatment fails with 2 or more lines of therapy containing taxane-trastuzumab (with or without pertuzumab) and T-DM1 are candidates to receive a combination of capecitabine and lapatinib, a TKI, in the third line and beyond. Similarly, the combination of capecitabine with trastuzumab in the same settings appears to have equal efficacy.^53,54 Trastuzumab may be continued beyond progression while changing the single-agent chemotherapy drug for subsequent lines of therapy, per ASCO guidelines,⁵⁵ although improvement in OS has not been demonstrated beyond the third line in a large randomized trial (Table 3).

Approved HER2-Targeted Drugs

HER2-directed therapy is implemented in the management of nearly all stages of HER2-positive invasive breast cancer, including early and late stages (Table 4).

Trastuzumab

Trastuzumab was the first anti-HER2 agent to be approved by the FDA in 1998. It is a humanized monoclonal antibody directed against the extracellular domain of the HER2 receptor (domain IV).  Trastuzumab functions by interrupting HER2 signal transduction and by flagging tumor cells for immune destruction.⁵⁶ Cardiotoxicity, usually manifested as left ventricular systolic dysfunction, is the most noteworthy adverse effect of trastuzumab. The most prominent risk factors for cardiomyopathy in patients receiving trastuzumab are low baseline ejection fraction (< 55%), age > 50 years, co-administration and higher cumulative dose of anthracyclines, and increased body mass index and obesity.^57–59 Whether patients receive therapy in the neoadjuvant, adjuvant, or metastatic settings, baseline cardiac function assessment with echocardiogram or multiple-gated acquisition scan is required. While well-designed randomized trials validating the value and frequency of monitoring are lacking, repeated cardiac testing every 3 months is generally recommended for patients undergoing adjuvant therapy. Patients with metastatic disease who are receiving treatment with palliative intent may be monitored less frequently.^60,61

An asymptomatic drop in ejection fraction is the most common manifestation of cardiac toxicity. Other cardiac manifestations have also been reported with much less frequency, including arrhythmias, severe congestive heart failure, ventricular thrombus formation, and even cardiac death. Until monitoring and dose-adjustment guidelines are issued, the guidance provided in the FDA-approved prescribing information should be followed, which recommends holding trastuzumab when there is ≥ 16% absolute reduction in left ventricular ejection fraction (LVEF) from the baseline value; or if the LVEF value is below the institutional lower limit of normal and the drop is ≥ 10%. After holding the drug, cardiac function can be re-evaluated every 4 weeks. In most patients, trastuzumab-induced cardiotoxicity can be reversed by withholding trastuzumab and initiating cardioprotective therapy, although the latter remains controversial. Re-challenging after recovery of ejection fraction is possible and toxicity does not appear to be proportional to cumulative dose. Cardiomyopathy due to trastuzumab therapy is potentially reversible within 6 months in more than 80% of cases.^{28,57,60–63}

Other notable adverse effects of trastuzumab include pulmonary toxicity (such as interstitial lung disease) and infusion reactions (usually during or within 24 hours of first dose).

Pertuzumab

Pertuzumab is another humanized monoclonal antibody directed to a different extracellular domain of the HER2 receptor, the dimerization domain (domain II), which is responsible for heterodimerization of HER2 with other HER receptors, especially HER3. This agent should always be co-administered with trastuzumab as the 2 drugs produce synergistic anti-tumor effect, without competition for the receptor. Activation of HER3, via dimerization with HER2, produces an alternative mechanism of downstream signaling, even in the presence of trastuzumab and in the absence of growth factors (Figure 2). 

Ado-Trastuzumab Emtansine

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the monoclonal antibody trastuzumab with the cytotoxic agent DM1 (emtansine), a potent microtubule inhibitor and a derivative of maytansine, in a single structure (Figure 3). 

Lapatinib

Lapatinib is an oral small-molecule tyrosine kinase inhibitor of EGFR (HER1) and HER2 receptors. It is approved in combination with capecitabine for patients with HER2-expressing metastatic breast cancer who previously received trastuzumab, an anthracycline, and a taxane chemotherapy or T-DM1. Lapatinib is also approved in combination with letrozole in postmenopausal women with HER2-positive, hormone receptor–positive metastatic disease, although it is unclear where this regimen would fit in the current schema. It may be considered for patients with hormone receptor–positive disease who are not candidates for therapy with taxane-trastuzumab and T-DM1 or who decline this therapy. Diarrhea is seen in most patients treated with lapatinib and may be severe in 20% of cases when lapatinib is combined with capecitabine. Decreases in LVEF have been reported and cardiac function monitoring at baseline and periodically may be considered.^69,70 Lapatinib is not approved for use in adjuvant settings.

Neratinib

Neratinib is an oral small-molecule irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4. It is currently approved only for extended adjuvant therapy after completion of 1 year of standard trastuzumab therapy. It is given orally every day for 1 year. The main side effect, expected in nearly all patients, is diarrhea, which can be severe in up to 40% of patients and may lead to dehydration and electrolyte imbalance. Diarrhea usually starts early in the course of therapy and can be most intense during the first cycle. Therefore, prophylactic antidiarrheal therapy is recommended to reduce the intensity of diarrhea. Loperamide prophylaxis may be initiated simultaneously for all patients using a tapering schedule. Drug interruption or dose reduction may be required if diarrhea is severe or refractory.^21,71 Neratinib is not FDA-approved in the metastatic settings.

Conclusion

HER2-positive tumors represent a distinct subset(s) of breast tumors with unique pathological and clinical characteristics. Treatment with a combination of cytotoxic chemotherapy and HER2-targeted agents has led to a dramatic improvement in survival for patients with locoregional and advanced disease. Trastuzumab is an integral part of adjuvant therapy for HER2-positive invasive disease. Pertuzumab should be added to trastuzumab in node-positive disease. Neratinib may be considered after completion of trastuzumab therapy in patients with hormone receptor–positive disease. For metastatic HER2-positive breast cancer, a regimen consisting of docetaxel plus trastuzumab and pertuzumab is the standard first-line therapy. Ado-trastuzumab is an ideal next line option for patients whose disease progresses on trastuzumab and taxanes.

Introduction

Breast cancer is the second leading cause of cancer deaths among women in the United States, according to the SEER database. It is estimated that 1 in 8 women will be diagnosed with breast cancer at some point during their lifetime (12.4% lifetime risk).^1,2 Because breast tumors are clinically and histopathologically heterogeneous, different diagnostic and therapeutic approaches are required for each subtype. Among the subtypes, tumors that are positive for human epidermal growth factor receptor 2 (HER2) account for approximately 15% to 20% of all newly diagnosed localized and metastatic invasive breast tumors.^3,4 Historically, this subset of tumors has been considered the most aggressive due to a higher propensity to relapse and metastasize, translating into poorer prognosis compared with other subtypes.^5–7 However, with the advent of HER2-targeted therapy in the late 1990s, prognosis has significantly improved for both early- and late-stage HER2-positive tumors.⁸

Pathogenesis

The HER2 proto-oncogene belongs to a family of human epidermal growth factor receptors that includes 4 transmembrane tyrosine kinase receptors: HER1 (also commonly known as epidermal growth factor receptor, EGFR), HER2, HER3, and HER4. Another commonly used nomenclature for this family of receptors is ERBB1 to ERBB4. Each of the receptors has a similar structure consisting of a growth factor–binding extracellular domain, a single transmembrane segment, an intracellular protein-tyrosine kinase catalytic domain, and a tyrosine-containing cytoplasmic tail. Activation of the extracellular domain leads to conformational changes that initiate a cascade of reactions resulting in protein kinase activation. ERBB tyrosine receptor kinases subsequently activate several intracellular pathways that are critical for cellular function and survival, including the PI3K-AKT, RAS-MAPK, and mTOR pathways. Hyperactivation or overexpression of these receptors leads to uncontrolled cell growth and proliferation, and eventually cancerogenesis.^9,10

HER2 gene amplification can cause activation of the receptor’s extramembranous domain by way of either dimerization of two HER2 receptors or heterodimerization with other ERBB family receptors, leading to ligand-independent activation of cell signaling (ie, activation in the absence of external growth factors). Besides breast cancer, HER2 protein is overexpressed in several other tumor types, including esophageal and gastric adenocarcinomas, colon and gynecological malignancies, and to a lesser extent in other malignancies.

Biomarker Testing

All patients with newly diagnosed breast cancer should have their tumor tissue submitted for biomarker testing for estrogen receptors (ER), progesterone receptors (PR), and HER2 overexpression, as the result this testing dictates therapy choices. The purpose of HER2 testing is to investigate whether the HER2 gene, located on chromosome 17, is overexpressed or amplified. HER2 status provides the basis for treatment selection, which impacts long-term outcome measures such as recurrence and survival. Routine testing of carcinoma in situ for HER2 expression/amplification is not recommended and has no implication on choice of therapy at this time.

In 2013, the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) updated their clinical guideline recommendations for HER2 testing in breast cancer to improve its accuracy and its utility as a predictive marker.¹¹ There are currently 2 approved modalities for HER2 testing: detection of HER2 protein overexpression by immunohistochemical staining (IHC), and detection of HER2 gene amplification using in-situ hybridization. The results of each type of testing are reported as positive, equivocal, or negative (Table 1).¹¹  IHC uses antibodies against HER2 protein to assess the level of protein expression at the membrane of invasive tumor cells; overexpression of HER2 is established based upon the intensity of cell membrane staining and the number of stained cells. Results are reported as positive for HER2 expression (3+ staining), negative for HER2 expression (0 or 1+ staining), or equivocal for HER2 expression (2+ staining).

Fluorescence in-situ hybridization (FISH) testing assesses for HER2 amplification by determining the number of HER2 signals and chromosome 17 centromere (CEP17) signals, respectively, in a tissue sample. HER2 status is based on the ratio of average HER2 signals to CEP17 signals and the average HER2 signal count per cell. FISH testing is considered positive when there are ≥ 6 copies of HER2 signals per cell or when the HER2/CEP17 ratio is ≥ 2. FISH testing is reported as negative when there are fewer than 4 copies of HER2 per cell and the HER2/CEP17 ratio is < 2. 

Neoadjuvant and Adjuvant Therapy for Locoregional Disease

Case Patient 1

A 56-year-old woman undergoes ultrasound-guided biopsy of a self-palpated breast lump. Pathology shows invasive ductal carcinoma that is ER-positive, PR-negative, and HER2 equivocal by IHC (2+ staining). Follow-up FISH testing shows a HER2/CEP17 ratio of 2.5. The tumor is estimated to be 2 cm in diameter by imaging and exam with no clinically palpable axillary lymphadenopathy. The patient exhibits no constitutional or localized symptoms concerning for metastases.

• What is the recommended management approach for this patient?

According to the ASCO/CAP guidelines, this patient’s tumor qualifies as HER2-positive based upon testing results showing amplification of the gene. This result has important implications for management since nearly all patients with macroscopically invasive HER2-positive tumors should be considered for adjuvant chemotherapy in combination with anti-HER2 therapy. The patient should proceed with upfront tumor resection and sentinel lymph node biopsy. Systemic staging imaging (ie, computed tomography [CT] or bone scan) is not indicated in early stage breast cancer.^12,13 Systemic staging scans are indicated when (1) any anatomical stage III disease is suspected (eg, with involvement of the skin or chest wall, the presence of enlarged matted or fixed axillary lymph nodes, and involvement of nodal stations other than in the axilla), and (2) when symptoms or abnormal laboratory values raise suspicion for distant metastases (eg, unexplained bone pain, unintentional weight loss, elevated serum alkaline phosphatase, and transaminitis).

Case 1 Continued

The patient presents to discuss treatment options after undergoing a lumpectomy and sentinel node biopsy procedure. The pathology report notes a single focus of carcinoma measuring 2 cm with negative sentinel lymph nodes.

• What agents are used for adjuvant therapy in HER2-postive breast cancer?

Nearly all patients with macroscopically invasive (> 1 mm) breast carcinoma should be considered for adjuvant therapy using a regimen that contains a taxane and trastuzumab. However, the benefit may be small for patients with tumors ≤ 5 mm (T1a, N0), so it is important to carefully weigh the risk against the benefit. Among the agents that targeting HER2, only trastuzumab has been shown to improve overall survival (OS) in the adjuvant setting; long-term follow-up data are awaited for other agents.⁸ A trastuzumab biosimilar, trastuzumab-dkst, was recently approved by the US Food and Drug Administration (FDA) for the same indications as trastuzumab.¹⁴ The regimens most commonly used in the adjuvant and neoadjuvant settings for nonmetastatic breast cancer are summarized in Table 2.

Patients with small (≤ 3 cm), node-negative tumors can generally be considered for a reduced-intensity regimen that includes weekly paclitaxel plus trastuzumab. This combination proved efficacious in a single-group, multicenter study that enrolled 406 patients.¹⁵ Paclitaxel and trastuzumab were given once weekly for 12 weeks, followed by trastuzumab, either weekly or every 3 weeks, to complete 1 year of therapy.After a median follow-up of more than 6 years, the rates of distant and locoregional recurrence were 1% and 1.2%, respectively.¹⁶

A combination of docetaxel, carboplatin, and trastuzumab is a nonanthracycline regimen that is also appropriate in this setting, based on the results of the Breast Cancer International Research Group 006 (BCIRG-006) trial.¹⁷ This phase 3 randomized trial enrolled 3222 women with HER2-positive, invasive, high-risk adenocarcinoma. Eligible patients had a T1–3 tumor and either lymph node–negative or –positive disease and were randomly assigned to receive 1 of 3 regimens: group 1 received doxorubicin and cyclophosphamide every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for 4 cycles (AC-T); group 2 received the AC-T regimen in combination with trastuzumab; and group 3 received docetaxel, carboplatin, and trastuzumab once every 3 weeks for 6 cycles (TCH). Groups 2 and 3 also received trastuzumab for an additional 34 weeks to complete 1 year of therapy. Trastuzumab-containing regimens were found to offer superior disease-free survival (DFS) and OS. When comparing the 2 trastuzumab arms after more than 10 years of follow-up, no statistically significant advantage of an anthracycline regimen over a nonanthracycline regimen was found.¹⁸ Furthermore, the anthracycline arm had a fivefold higher incidence of symptomatic congestive heart failure (grades 3 and 4), and the nonanthracycline regimen was associated with a lower incidence of treatment-related leukemia, a clinically significant finding despite not reaching statistical significance due to low overall numbers.

BCIRG-006, NSABP B-31, NCCTG N9831, and HERA are all large randomized trials with consistent results confirming trastuzumab’s role in reducing recurrence and improving survival in HER2-positive breast cancer in the adjuvant settings. The estimated overall benefit from addition of this agent was a 34% to 41% improvement in survival and a 33% to 52% improvement in DFS.^8,17–20

Dual anti-HER2 therapy containing both trastuzumab and pertuzumab should be strongly considered for patients with macroscopic lymph node involvement based on the results of the APHINITY trial.²¹ In this study, the addition of pertuzumab to standard trastuzumab-based therapy led to a significant improvement in invasive-disease-free survival at 3 years. In subgroup analysis, the benefit was restricted to the node-positive group (3-year invasive-disease-free survival rates of 92% in the pertuzumab group versus 90.2% in the placebo group, P = 0.02). Patients with hormone receptor–negative disease derived greater benefit from the addition of pertuzumab. Regimens used in the APHINITY trial included the anti-HER2 agents trastuzumab and pertuzumab in combination with 1 of the following chemotherapy regimens: sequential cyclophosphamide plus either doxorubicin or epirubicin, followed by either 4 cycles of docetaxel or 12 weekly doses of paclitaxel; sequential fluorouracil plus either epirubicin or doxorubicin plus cyclophosphamide (3 or 4 cycles), followed by 3 or 4 cycles of docetaxel or 12 weekly cycles of paclitaxel; or 6 cycles of concurrent docetaxel plus carboplatin.

One-year therapy with neratinib, an oral tyrosine kinase inhibitor of HER2, is now approved by the FDA after completion of trastuzumab in the adjuvant setting, based on the results of the ExteNET trial.²² In this study, patients who had completed trastuzumab within the preceding 12 months, without evidence of recurrence, were randomly assigned to receive either oral neratinib or placebo daily for 1 year. The 2-year DFS rate was 93.9% and 91.6% for the neratinib and placebo groups, respectively. The most common adverse effect of neratinib was diarrhea, with approximately 40% of patients experiencing grade 3 diarrhea. In subgroup analyses, hormone receptor–positive patients derived the most benefit, while hormone receptor–negative patients derived no or marginal benefit.²² OS benefit has not yet been established.²³

Trastuzumab therapy (with pertuzumab if indicated) should be offered for an optimal duration of 12 months (17 cycles, including those given with chemotherapy backbone). A shorter duration of therapy, 6 months, has been shown to be inferior,²⁴ while a longer duration, 24 months, has been shown to provide no additional benefit.²⁵

Finally, sequential addition of anti-estrogen endocrine therapy is indicated for hormone-positive tumors. Endocrine therapy is usually added after completion of the chemotherapy backbone of the regimen, but may be given concurrently with anti-HER2 therapy. If radiation is being administered, endocrine therapy can be given concurrently or started after radiation therapy is completed.

Case 1 Conclusion

The patient can be offered 1 of 2 adjuvant treatment regimens, either TH or TCH (Table 2). Since the patient had lumpectomy, she is an appropriate candidate for adjuvant radiation, which would be started after completion of the chemotherapy backbone (taxane/platinum). Endocrine therapy for at least 5 years should be offered sequentially or concurrently with radiation. Her long-term prognosis is very favorable.

Case Patient 2

A 43-year-old woman presents with a 4-cm breast mass, a separate skin nodule, and palpable matted axillary lymphadenopathy. Biopsies of the breast mass and subcutaneous nodule reveal invasive ductal carcinoma that is ER-negative, PR-negative, and HER2-positive by IHC (3+ staining). Based on clinical findings, the patient is staged as T4b (separate tumor nodule), N2 (matted axillary lymph nodes). Systemic staging with CT scan of the chest, abdomen, and pelvis shows no evidence of distant metastases.

• What is the recommended approach to management for this patient?

Recommendations for neoadjuvant therapy, given before definitive surgery, follow the same path as with other subtypes of breast cancer. Patients with suspected anatomical stage III disease are strongly encouraged to undergo upfront (neoadjuvant) chemotherapy in combination with HER2-targeted agents. In addition, all HER2-positive patients with clinically node-positive disease can be offered neoadjuvant therapy using chemotherapy plus dual anti-HER2 therapy (trastuzumab and pertuzumab), with complete pathological response expected in more than 60% of patients.^26,27 Because this patient has locally advanced disease, especially skin involvement and matted axillary nodes, she should undergo neoadjuvant therapy. Preferred regimens contain both trastuzumab and pertuzumab in combination with cytotoxic chemotherapy. The latter may be given concurrently (nonanthracycline regimens, such as docetaxel plus carboplatin) or sequentially (anthracycline-based regimens), as outlined in Table 2. Administration of anthracyclines and trastuzumab simultaneously is contraindicated due to increased risk of cardiomyopathy.²⁸

Endocrine therapy is not indicated for this patient per the current standard of care because the tumor was ER- and PR-negative. Had the tumor been hormone receptor–positive, endocrine therapy for a minimum of 5 years would have been indicated. Likewise, in the case of hormone receptor–positive disease, 12 months of neratinib therapy after completion of trastuzumab may add further benefit, as shown in the ExteNET trial.^22,23 Neratinib seems to have a propensity to prevent or delay trastuzumab-induced overexpression of estrogen receptors. This is mainly due to hormone receptor/HER2 crosstalk, a potential mechanism of resistance to trastuzumab.^29,30

In addition to the medical therapy options discussed here, this patient would be expected to benefit from adjuvant radiation to the breast and regional lymph nodes, given the presence of T4 disease and bulky adenopathy in the axilla.³¹

Case 2 Conclusion

The patient undergoes neoadjuvant treatment (docetaxel, carboplatin, trastuzumab, and pertuzumab every 21 days for a total of 6 cycles), followed by surgical resection (modified radical mastectomy) that reveals complete pathological response (no residual invasive carcinoma). Subsequently, she receives radiation therapy to the primary tumor site and regional lymph nodes while continuing trastuzumab and pertuzumab for 11 more cycles (17 total). Despite presenting with locally advanced disease, the patient has a favorable overall prognosis due to an excellent pathological response.

• What is the approach to follow-up after completion of primary therapy?

Patients may follow up every 3 to 6 months for clinical evaluation in the first 5 years after completing primary adjuvant therapy. An annual screening mammogram is recommended as well. Body imaging can be done if dictated by symptoms. However, routine CT, positron emission tomography, or bone scans are not recommended as part of follow-up in the absence of symptoms, mainly because of a lack of evidence that such surveillance improves survival.³²

Metastatic HER2-Positive Breast Cancer

Metastatic breast cancer most commonly presents as a distant recurrence of previously treated local disease. However, 6% to 18% of patients have no prior history of breast cancer and present with de novo metastatic disease.^33,34 The most commonly involved distant organs are the skeletal bones, liver, lung, distant lymph node stations, and brain. Compared to other subtypes, HER2-positive tumors have an increased tendency to involve the central nervous system.^35–38 Although metastatic HER2-positive breast cancer is not considered curable, significant improvement in survival has been achieved, and patients with metastatic disease have median survival approaching 5 years.³⁹

Case Presentation 3

A 69-year-old woman with a history of breast cancer 4 years ago presents with new-onset back pain and unintentional weight loss. On exam, she is found to have palpable axillary adenopathy on the same side as her previous cancer. Her initial disease was stage IIB ER-positive and HER2-positive and was treated with chemotherapy, mastectomy, and anastrozole, which the patient is still taking. She undergoes CT scan of the chest, abdomen, and pelvis and radionucleotide bone scan, which show multiple liver and bony lesions suspicious for metastatic disease. Axillary lymph node biopsy confirms recurrent invasive carcinoma that is ER-positive and HER2-positive by IHC (3+).

• What is the approach to management of a patient who presents with symptoms of recurrent HER2-positive disease?

This patient likely has metastatic breast cancer based on the imaging findings. In such cases, a biopsy of the recurrent disease should always be considered, if feasible, to confirm the diagnosis and rule out other etiologies such as different malignances and benign conditions. Hormone-receptor and HER2 testing should also be performed on recurrent disease, since a change in HER2 status can be seen in 15% to 33% of cases.^40–42

Based on data from the phase 3 CLEOPATRA trial, first-line systemic regimens for patients with metastatic breast cancer that is positive for HER2 should consist of a combination of docetaxel, trastuzumab, and pertuzumab.  Compared to placebo, adding pertuzumab yielded superior progression-free survival of 18.4 months (versus 12.4 months for placebo) and an unprecedented OS of 56.5 months (versus 40.8 for placebo).³⁹ Weekly paclitaxel can replace docetaxel with comparable efficacy (Table 3).⁴³

Patients can develop significant neuropathy as well as skin and nail changes after multiple cycles of taxane-based chemotherapy. Therefore, the taxane backbone may be dropped after 6 to 8 cycles, while patients continue the trastuzumab and pertuzumab combination until disease progression or unacceptable toxicity. Some patients may enjoy remarkable long-term survival on “maintenance” anti-HER2 therapy.⁴⁴ Despite lack of high-level evidence, such as from large randomized trials, some experts recommend the addition of a hormone blocker after discontinuation of the taxane in ER-positive tumors.⁴⁵

Premenopausal and perimenopausal women with hormone receptor–positive metastatic disease should be considered for simultaneous ovarian suppression. Ovarian suppression can be accomplished medically using a gonadotropin-releasing hormone agonist (goserelin) or surgically via salpingo-oophorectomy.^46–48

Case 3 Conclusion

The patient receives 6 cycles of docetaxel, trastuzumab, and pertuzumab, after which the docetaxel is discontinued due to neuropathy while she continues the other 2 agents. After 26 months of disease control, the patient is found to have new liver metastatic lesions, indicating progression of disease.

• What therapeutic options are available for this patient?

Patients whose disease progresses after receiving taxane- and trastuzumab-containing regimens are candidates to receive the novel antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). Early progressors (ie, patients with early stage disease who have progression of disease while receiving adjuvant trastuzumab or within 6 months of completion of adjuvant trastuzumab) are also candidates for T-DM1. Treatment usually fits in the second line or beyond based on data from the EMILIA trial, which randomly assigned patients to receive either capecitabine plus lapatinib or T-DM1.^49,50 Progression-free survival in the T-DM1 group was 9.6 months versus 6.4 months for the comparator. Improvement of 4 months in OS persisted with longer follow-up despite a crossover rate of 27%. Furthermore, a significantly higher objective response rate and fewer adverse effects were reported in the T-DM1 patients. Most patients included in the EMILIA trial were pertuzumab-naive. However, the benefit of T-DM1 appears to persist, albeit to a lesser extent, for pertuzumab-pretreated patients.^51,52

Patients in whom treatment fails with 2 or more lines of therapy containing taxane-trastuzumab (with or without pertuzumab) and T-DM1 are candidates to receive a combination of capecitabine and lapatinib, a TKI, in the third line and beyond. Similarly, the combination of capecitabine with trastuzumab in the same settings appears to have equal efficacy.^53,54 Trastuzumab may be continued beyond progression while changing the single-agent chemotherapy drug for subsequent lines of therapy, per ASCO guidelines,⁵⁵ although improvement in OS has not been demonstrated beyond the third line in a large randomized trial (Table 3).

Approved HER2-Targeted Drugs

HER2-directed therapy is implemented in the management of nearly all stages of HER2-positive invasive breast cancer, including early and late stages (Table 4).

Trastuzumab

Trastuzumab was the first anti-HER2 agent to be approved by the FDA in 1998. It is a humanized monoclonal antibody directed against the extracellular domain of the HER2 receptor (domain IV).  Trastuzumab functions by interrupting HER2 signal transduction and by flagging tumor cells for immune destruction.⁵⁶ Cardiotoxicity, usually manifested as left ventricular systolic dysfunction, is the most noteworthy adverse effect of trastuzumab. The most prominent risk factors for cardiomyopathy in patients receiving trastuzumab are low baseline ejection fraction (< 55%), age > 50 years, co-administration and higher cumulative dose of anthracyclines, and increased body mass index and obesity.^57–59 Whether patients receive therapy in the neoadjuvant, adjuvant, or metastatic settings, baseline cardiac function assessment with echocardiogram or multiple-gated acquisition scan is required. While well-designed randomized trials validating the value and frequency of monitoring are lacking, repeated cardiac testing every 3 months is generally recommended for patients undergoing adjuvant therapy. Patients with metastatic disease who are receiving treatment with palliative intent may be monitored less frequently.^60,61

An asymptomatic drop in ejection fraction is the most common manifestation of cardiac toxicity. Other cardiac manifestations have also been reported with much less frequency, including arrhythmias, severe congestive heart failure, ventricular thrombus formation, and even cardiac death. Until monitoring and dose-adjustment guidelines are issued, the guidance provided in the FDA-approved prescribing information should be followed, which recommends holding trastuzumab when there is ≥ 16% absolute reduction in left ventricular ejection fraction (LVEF) from the baseline value; or if the LVEF value is below the institutional lower limit of normal and the drop is ≥ 10%. After holding the drug, cardiac function can be re-evaluated every 4 weeks. In most patients, trastuzumab-induced cardiotoxicity can be reversed by withholding trastuzumab and initiating cardioprotective therapy, although the latter remains controversial. Re-challenging after recovery of ejection fraction is possible and toxicity does not appear to be proportional to cumulative dose. Cardiomyopathy due to trastuzumab therapy is potentially reversible within 6 months in more than 80% of cases.^{28,57,60–63}

Other notable adverse effects of trastuzumab include pulmonary toxicity (such as interstitial lung disease) and infusion reactions (usually during or within 24 hours of first dose).

Pertuzumab

Pertuzumab is another humanized monoclonal antibody directed to a different extracellular domain of the HER2 receptor, the dimerization domain (domain II), which is responsible for heterodimerization of HER2 with other HER receptors, especially HER3. This agent should always be co-administered with trastuzumab as the 2 drugs produce synergistic anti-tumor effect, without competition for the receptor. Activation of HER3, via dimerization with HER2, produces an alternative mechanism of downstream signaling, even in the presence of trastuzumab and in the absence of growth factors (Figure 2). 

Ado-Trastuzumab Emtansine

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the monoclonal antibody trastuzumab with the cytotoxic agent DM1 (emtansine), a potent microtubule inhibitor and a derivative of maytansine, in a single structure (Figure 3). 

Lapatinib

Lapatinib is an oral small-molecule tyrosine kinase inhibitor of EGFR (HER1) and HER2 receptors. It is approved in combination with capecitabine for patients with HER2-expressing metastatic breast cancer who previously received trastuzumab, an anthracycline, and a taxane chemotherapy or T-DM1. Lapatinib is also approved in combination with letrozole in postmenopausal women with HER2-positive, hormone receptor–positive metastatic disease, although it is unclear where this regimen would fit in the current schema. It may be considered for patients with hormone receptor–positive disease who are not candidates for therapy with taxane-trastuzumab and T-DM1 or who decline this therapy. Diarrhea is seen in most patients treated with lapatinib and may be severe in 20% of cases when lapatinib is combined with capecitabine. Decreases in LVEF have been reported and cardiac function monitoring at baseline and periodically may be considered.^69,70 Lapatinib is not approved for use in adjuvant settings.

Neratinib

Neratinib is an oral small-molecule irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4. It is currently approved only for extended adjuvant therapy after completion of 1 year of standard trastuzumab therapy. It is given orally every day for 1 year. The main side effect, expected in nearly all patients, is diarrhea, which can be severe in up to 40% of patients and may lead to dehydration and electrolyte imbalance. Diarrhea usually starts early in the course of therapy and can be most intense during the first cycle. Therefore, prophylactic antidiarrheal therapy is recommended to reduce the intensity of diarrhea. Loperamide prophylaxis may be initiated simultaneously for all patients using a tapering schedule. Drug interruption or dose reduction may be required if diarrhea is severe or refractory.^21,71 Neratinib is not FDA-approved in the metastatic settings.

Conclusion

HER2-positive tumors represent a distinct subset(s) of breast tumors with unique pathological and clinical characteristics. Treatment with a combination of cytotoxic chemotherapy and HER2-targeted agents has led to a dramatic improvement in survival for patients with locoregional and advanced disease. Trastuzumab is an integral part of adjuvant therapy for HER2-positive invasive disease. Pertuzumab should be added to trastuzumab in node-positive disease. Neratinib may be considered after completion of trastuzumab therapy in patients with hormone receptor–positive disease. For metastatic HER2-positive breast cancer, a regimen consisting of docetaxel plus trastuzumab and pertuzumab is the standard first-line therapy. Ado-trastuzumab is an ideal next line option for patients whose disease progresses on trastuzumab and taxanes.

Introduction

Breast cancer is the second leading cause of cancer deaths among women in the United States, according to the SEER database. It is estimated that 1 in 8 women will be diagnosed with breast cancer at some point during their lifetime (12.4% lifetime risk).^1,2 Because breast tumors are clinically and histopathologically heterogeneous, different diagnostic and therapeutic approaches are required for each subtype. Among the subtypes, tumors that are positive for human epidermal growth factor receptor 2 (HER2) account for approximately 15% to 20% of all newly diagnosed localized and metastatic invasive breast tumors.^3,4 Historically, this subset of tumors has been considered the most aggressive due to a higher propensity to relapse and metastasize, translating into poorer prognosis compared with other subtypes.^5–7 However, with the advent of HER2-targeted therapy in the late 1990s, prognosis has significantly improved for both early- and late-stage HER2-positive tumors.⁸

Pathogenesis

The HER2 proto-oncogene belongs to a family of human epidermal growth factor receptors that includes 4 transmembrane tyrosine kinase receptors: HER1 (also commonly known as epidermal growth factor receptor, EGFR), HER2, HER3, and HER4. Another commonly used nomenclature for this family of receptors is ERBB1 to ERBB4. Each of the receptors has a similar structure consisting of a growth factor–binding extracellular domain, a single transmembrane segment, an intracellular protein-tyrosine kinase catalytic domain, and a tyrosine-containing cytoplasmic tail. Activation of the extracellular domain leads to conformational changes that initiate a cascade of reactions resulting in protein kinase activation. ERBB tyrosine receptor kinases subsequently activate several intracellular pathways that are critical for cellular function and survival, including the PI3K-AKT, RAS-MAPK, and mTOR pathways. Hyperactivation or overexpression of these receptors leads to uncontrolled cell growth and proliferation, and eventually cancerogenesis.^9,10

HER2 gene amplification can cause activation of the receptor’s extramembranous domain by way of either dimerization of two HER2 receptors or heterodimerization with other ERBB family receptors, leading to ligand-independent activation of cell signaling (ie, activation in the absence of external growth factors). Besides breast cancer, HER2 protein is overexpressed in several other tumor types, including esophageal and gastric adenocarcinomas, colon and gynecological malignancies, and to a lesser extent in other malignancies.

Biomarker Testing

All patients with newly diagnosed breast cancer should have their tumor tissue submitted for biomarker testing for estrogen receptors (ER), progesterone receptors (PR), and HER2 overexpression, as the result this testing dictates therapy choices. The purpose of HER2 testing is to investigate whether the HER2 gene, located on chromosome 17, is overexpressed or amplified. HER2 status provides the basis for treatment selection, which impacts long-term outcome measures such as recurrence and survival. Routine testing of carcinoma in situ for HER2 expression/amplification is not recommended and has no implication on choice of therapy at this time.

In 2013, the American Society of Clinical Oncology and the College of American Pathologists (ASCO/CAP) updated their clinical guideline recommendations for HER2 testing in breast cancer to improve its accuracy and its utility as a predictive marker.¹¹ There are currently 2 approved modalities for HER2 testing: detection of HER2 protein overexpression by immunohistochemical staining (IHC), and detection of HER2 gene amplification using in-situ hybridization. The results of each type of testing are reported as positive, equivocal, or negative (Table 1).¹¹  IHC uses antibodies against HER2 protein to assess the level of protein expression at the membrane of invasive tumor cells; overexpression of HER2 is established based upon the intensity of cell membrane staining and the number of stained cells. Results are reported as positive for HER2 expression (3+ staining), negative for HER2 expression (0 or 1+ staining), or equivocal for HER2 expression (2+ staining).

Fluorescence in-situ hybridization (FISH) testing assesses for HER2 amplification by determining the number of HER2 signals and chromosome 17 centromere (CEP17) signals, respectively, in a tissue sample. HER2 status is based on the ratio of average HER2 signals to CEP17 signals and the average HER2 signal count per cell. FISH testing is considered positive when there are ≥ 6 copies of HER2 signals per cell or when the HER2/CEP17 ratio is ≥ 2. FISH testing is reported as negative when there are fewer than 4 copies of HER2 per cell and the HER2/CEP17 ratio is < 2. 

Neoadjuvant and Adjuvant Therapy for Locoregional Disease

Case Patient 1

A 56-year-old woman undergoes ultrasound-guided biopsy of a self-palpated breast lump. Pathology shows invasive ductal carcinoma that is ER-positive, PR-negative, and HER2 equivocal by IHC (2+ staining). Follow-up FISH testing shows a HER2/CEP17 ratio of 2.5. The tumor is estimated to be 2 cm in diameter by imaging and exam with no clinically palpable axillary lymphadenopathy. The patient exhibits no constitutional or localized symptoms concerning for metastases.

• What is the recommended management approach for this patient?

According to the ASCO/CAP guidelines, this patient’s tumor qualifies as HER2-positive based upon testing results showing amplification of the gene. This result has important implications for management since nearly all patients with macroscopically invasive HER2-positive tumors should be considered for adjuvant chemotherapy in combination with anti-HER2 therapy. The patient should proceed with upfront tumor resection and sentinel lymph node biopsy. Systemic staging imaging (ie, computed tomography [CT] or bone scan) is not indicated in early stage breast cancer.^12,13 Systemic staging scans are indicated when (1) any anatomical stage III disease is suspected (eg, with involvement of the skin or chest wall, the presence of enlarged matted or fixed axillary lymph nodes, and involvement of nodal stations other than in the axilla), and (2) when symptoms or abnormal laboratory values raise suspicion for distant metastases (eg, unexplained bone pain, unintentional weight loss, elevated serum alkaline phosphatase, and transaminitis).

Case 1 Continued

The patient presents to discuss treatment options after undergoing a lumpectomy and sentinel node biopsy procedure. The pathology report notes a single focus of carcinoma measuring 2 cm with negative sentinel lymph nodes.

• What agents are used for adjuvant therapy in HER2-postive breast cancer?

Nearly all patients with macroscopically invasive (> 1 mm) breast carcinoma should be considered for adjuvant therapy using a regimen that contains a taxane and trastuzumab. However, the benefit may be small for patients with tumors ≤ 5 mm (T1a, N0), so it is important to carefully weigh the risk against the benefit. Among the agents that targeting HER2, only trastuzumab has been shown to improve overall survival (OS) in the adjuvant setting; long-term follow-up data are awaited for other agents.⁸ A trastuzumab biosimilar, trastuzumab-dkst, was recently approved by the US Food and Drug Administration (FDA) for the same indications as trastuzumab.¹⁴ The regimens most commonly used in the adjuvant and neoadjuvant settings for nonmetastatic breast cancer are summarized in Table 2.

Patients with small (≤ 3 cm), node-negative tumors can generally be considered for a reduced-intensity regimen that includes weekly paclitaxel plus trastuzumab. This combination proved efficacious in a single-group, multicenter study that enrolled 406 patients.¹⁵ Paclitaxel and trastuzumab were given once weekly for 12 weeks, followed by trastuzumab, either weekly or every 3 weeks, to complete 1 year of therapy.After a median follow-up of more than 6 years, the rates of distant and locoregional recurrence were 1% and 1.2%, respectively.¹⁶

A combination of docetaxel, carboplatin, and trastuzumab is a nonanthracycline regimen that is also appropriate in this setting, based on the results of the Breast Cancer International Research Group 006 (BCIRG-006) trial.¹⁷ This phase 3 randomized trial enrolled 3222 women with HER2-positive, invasive, high-risk adenocarcinoma. Eligible patients had a T1–3 tumor and either lymph node–negative or –positive disease and were randomly assigned to receive 1 of 3 regimens: group 1 received doxorubicin and cyclophosphamide every 3 weeks for 4 cycles followed by docetaxel every 3 weeks for 4 cycles (AC-T); group 2 received the AC-T regimen in combination with trastuzumab; and group 3 received docetaxel, carboplatin, and trastuzumab once every 3 weeks for 6 cycles (TCH). Groups 2 and 3 also received trastuzumab for an additional 34 weeks to complete 1 year of therapy. Trastuzumab-containing regimens were found to offer superior disease-free survival (DFS) and OS. When comparing the 2 trastuzumab arms after more than 10 years of follow-up, no statistically significant advantage of an anthracycline regimen over a nonanthracycline regimen was found.¹⁸ Furthermore, the anthracycline arm had a fivefold higher incidence of symptomatic congestive heart failure (grades 3 and 4), and the nonanthracycline regimen was associated with a lower incidence of treatment-related leukemia, a clinically significant finding despite not reaching statistical significance due to low overall numbers.

BCIRG-006, NSABP B-31, NCCTG N9831, and HERA are all large randomized trials with consistent results confirming trastuzumab’s role in reducing recurrence and improving survival in HER2-positive breast cancer in the adjuvant settings. The estimated overall benefit from addition of this agent was a 34% to 41% improvement in survival and a 33% to 52% improvement in DFS.^8,17–20

Dual anti-HER2 therapy containing both trastuzumab and pertuzumab should be strongly considered for patients with macroscopic lymph node involvement based on the results of the APHINITY trial.²¹ In this study, the addition of pertuzumab to standard trastuzumab-based therapy led to a significant improvement in invasive-disease-free survival at 3 years. In subgroup analysis, the benefit was restricted to the node-positive group (3-year invasive-disease-free survival rates of 92% in the pertuzumab group versus 90.2% in the placebo group, P = 0.02). Patients with hormone receptor–negative disease derived greater benefit from the addition of pertuzumab. Regimens used in the APHINITY trial included the anti-HER2 agents trastuzumab and pertuzumab in combination with 1 of the following chemotherapy regimens: sequential cyclophosphamide plus either doxorubicin or epirubicin, followed by either 4 cycles of docetaxel or 12 weekly doses of paclitaxel; sequential fluorouracil plus either epirubicin or doxorubicin plus cyclophosphamide (3 or 4 cycles), followed by 3 or 4 cycles of docetaxel or 12 weekly cycles of paclitaxel; or 6 cycles of concurrent docetaxel plus carboplatin.

One-year therapy with neratinib, an oral tyrosine kinase inhibitor of HER2, is now approved by the FDA after completion of trastuzumab in the adjuvant setting, based on the results of the ExteNET trial.²² In this study, patients who had completed trastuzumab within the preceding 12 months, without evidence of recurrence, were randomly assigned to receive either oral neratinib or placebo daily for 1 year. The 2-year DFS rate was 93.9% and 91.6% for the neratinib and placebo groups, respectively. The most common adverse effect of neratinib was diarrhea, with approximately 40% of patients experiencing grade 3 diarrhea. In subgroup analyses, hormone receptor–positive patients derived the most benefit, while hormone receptor–negative patients derived no or marginal benefit.²² OS benefit has not yet been established.²³

Trastuzumab therapy (with pertuzumab if indicated) should be offered for an optimal duration of 12 months (17 cycles, including those given with chemotherapy backbone). A shorter duration of therapy, 6 months, has been shown to be inferior,²⁴ while a longer duration, 24 months, has been shown to provide no additional benefit.²⁵

Finally, sequential addition of anti-estrogen endocrine therapy is indicated for hormone-positive tumors. Endocrine therapy is usually added after completion of the chemotherapy backbone of the regimen, but may be given concurrently with anti-HER2 therapy. If radiation is being administered, endocrine therapy can be given concurrently or started after radiation therapy is completed.

Case 1 Conclusion

The patient can be offered 1 of 2 adjuvant treatment regimens, either TH or TCH (Table 2). Since the patient had lumpectomy, she is an appropriate candidate for adjuvant radiation, which would be started after completion of the chemotherapy backbone (taxane/platinum). Endocrine therapy for at least 5 years should be offered sequentially or concurrently with radiation. Her long-term prognosis is very favorable.

Case Patient 2

A 43-year-old woman presents with a 4-cm breast mass, a separate skin nodule, and palpable matted axillary lymphadenopathy. Biopsies of the breast mass and subcutaneous nodule reveal invasive ductal carcinoma that is ER-negative, PR-negative, and HER2-positive by IHC (3+ staining). Based on clinical findings, the patient is staged as T4b (separate tumor nodule), N2 (matted axillary lymph nodes). Systemic staging with CT scan of the chest, abdomen, and pelvis shows no evidence of distant metastases.

• What is the recommended approach to management for this patient?

Recommendations for neoadjuvant therapy, given before definitive surgery, follow the same path as with other subtypes of breast cancer. Patients with suspected anatomical stage III disease are strongly encouraged to undergo upfront (neoadjuvant) chemotherapy in combination with HER2-targeted agents. In addition, all HER2-positive patients with clinically node-positive disease can be offered neoadjuvant therapy using chemotherapy plus dual anti-HER2 therapy (trastuzumab and pertuzumab), with complete pathological response expected in more than 60% of patients.^26,27 Because this patient has locally advanced disease, especially skin involvement and matted axillary nodes, she should undergo neoadjuvant therapy. Preferred regimens contain both trastuzumab and pertuzumab in combination with cytotoxic chemotherapy. The latter may be given concurrently (nonanthracycline regimens, such as docetaxel plus carboplatin) or sequentially (anthracycline-based regimens), as outlined in Table 2. Administration of anthracyclines and trastuzumab simultaneously is contraindicated due to increased risk of cardiomyopathy.²⁸

Endocrine therapy is not indicated for this patient per the current standard of care because the tumor was ER- and PR-negative. Had the tumor been hormone receptor–positive, endocrine therapy for a minimum of 5 years would have been indicated. Likewise, in the case of hormone receptor–positive disease, 12 months of neratinib therapy after completion of trastuzumab may add further benefit, as shown in the ExteNET trial.^22,23 Neratinib seems to have a propensity to prevent or delay trastuzumab-induced overexpression of estrogen receptors. This is mainly due to hormone receptor/HER2 crosstalk, a potential mechanism of resistance to trastuzumab.^29,30

In addition to the medical therapy options discussed here, this patient would be expected to benefit from adjuvant radiation to the breast and regional lymph nodes, given the presence of T4 disease and bulky adenopathy in the axilla.³¹

Case 2 Conclusion

The patient undergoes neoadjuvant treatment (docetaxel, carboplatin, trastuzumab, and pertuzumab every 21 days for a total of 6 cycles), followed by surgical resection (modified radical mastectomy) that reveals complete pathological response (no residual invasive carcinoma). Subsequently, she receives radiation therapy to the primary tumor site and regional lymph nodes while continuing trastuzumab and pertuzumab for 11 more cycles (17 total). Despite presenting with locally advanced disease, the patient has a favorable overall prognosis due to an excellent pathological response.

• What is the approach to follow-up after completion of primary therapy?

Patients may follow up every 3 to 6 months for clinical evaluation in the first 5 years after completing primary adjuvant therapy. An annual screening mammogram is recommended as well. Body imaging can be done if dictated by symptoms. However, routine CT, positron emission tomography, or bone scans are not recommended as part of follow-up in the absence of symptoms, mainly because of a lack of evidence that such surveillance improves survival.³²

Metastatic HER2-Positive Breast Cancer

Metastatic breast cancer most commonly presents as a distant recurrence of previously treated local disease. However, 6% to 18% of patients have no prior history of breast cancer and present with de novo metastatic disease.^33,34 The most commonly involved distant organs are the skeletal bones, liver, lung, distant lymph node stations, and brain. Compared to other subtypes, HER2-positive tumors have an increased tendency to involve the central nervous system.^35–38 Although metastatic HER2-positive breast cancer is not considered curable, significant improvement in survival has been achieved, and patients with metastatic disease have median survival approaching 5 years.³⁹

Case Presentation 3

A 69-year-old woman with a history of breast cancer 4 years ago presents with new-onset back pain and unintentional weight loss. On exam, she is found to have palpable axillary adenopathy on the same side as her previous cancer. Her initial disease was stage IIB ER-positive and HER2-positive and was treated with chemotherapy, mastectomy, and anastrozole, which the patient is still taking. She undergoes CT scan of the chest, abdomen, and pelvis and radionucleotide bone scan, which show multiple liver and bony lesions suspicious for metastatic disease. Axillary lymph node biopsy confirms recurrent invasive carcinoma that is ER-positive and HER2-positive by IHC (3+).

• What is the approach to management of a patient who presents with symptoms of recurrent HER2-positive disease?

This patient likely has metastatic breast cancer based on the imaging findings. In such cases, a biopsy of the recurrent disease should always be considered, if feasible, to confirm the diagnosis and rule out other etiologies such as different malignances and benign conditions. Hormone-receptor and HER2 testing should also be performed on recurrent disease, since a change in HER2 status can be seen in 15% to 33% of cases.^40–42

Based on data from the phase 3 CLEOPATRA trial, first-line systemic regimens for patients with metastatic breast cancer that is positive for HER2 should consist of a combination of docetaxel, trastuzumab, and pertuzumab.  Compared to placebo, adding pertuzumab yielded superior progression-free survival of 18.4 months (versus 12.4 months for placebo) and an unprecedented OS of 56.5 months (versus 40.8 for placebo).³⁹ Weekly paclitaxel can replace docetaxel with comparable efficacy (Table 3).⁴³

Patients can develop significant neuropathy as well as skin and nail changes after multiple cycles of taxane-based chemotherapy. Therefore, the taxane backbone may be dropped after 6 to 8 cycles, while patients continue the trastuzumab and pertuzumab combination until disease progression or unacceptable toxicity. Some patients may enjoy remarkable long-term survival on “maintenance” anti-HER2 therapy.⁴⁴ Despite lack of high-level evidence, such as from large randomized trials, some experts recommend the addition of a hormone blocker after discontinuation of the taxane in ER-positive tumors.⁴⁵

Premenopausal and perimenopausal women with hormone receptor–positive metastatic disease should be considered for simultaneous ovarian suppression. Ovarian suppression can be accomplished medically using a gonadotropin-releasing hormone agonist (goserelin) or surgically via salpingo-oophorectomy.^46–48

Case 3 Conclusion

The patient receives 6 cycles of docetaxel, trastuzumab, and pertuzumab, after which the docetaxel is discontinued due to neuropathy while she continues the other 2 agents. After 26 months of disease control, the patient is found to have new liver metastatic lesions, indicating progression of disease.

• What therapeutic options are available for this patient?

Patients whose disease progresses after receiving taxane- and trastuzumab-containing regimens are candidates to receive the novel antibody-drug conjugate ado-trastuzumab emtansine (T-DM1). Early progressors (ie, patients with early stage disease who have progression of disease while receiving adjuvant trastuzumab or within 6 months of completion of adjuvant trastuzumab) are also candidates for T-DM1. Treatment usually fits in the second line or beyond based on data from the EMILIA trial, which randomly assigned patients to receive either capecitabine plus lapatinib or T-DM1.^49,50 Progression-free survival in the T-DM1 group was 9.6 months versus 6.4 months for the comparator. Improvement of 4 months in OS persisted with longer follow-up despite a crossover rate of 27%. Furthermore, a significantly higher objective response rate and fewer adverse effects were reported in the T-DM1 patients. Most patients included in the EMILIA trial were pertuzumab-naive. However, the benefit of T-DM1 appears to persist, albeit to a lesser extent, for pertuzumab-pretreated patients.^51,52

Patients in whom treatment fails with 2 or more lines of therapy containing taxane-trastuzumab (with or without pertuzumab) and T-DM1 are candidates to receive a combination of capecitabine and lapatinib, a TKI, in the third line and beyond. Similarly, the combination of capecitabine with trastuzumab in the same settings appears to have equal efficacy.^53,54 Trastuzumab may be continued beyond progression while changing the single-agent chemotherapy drug for subsequent lines of therapy, per ASCO guidelines,⁵⁵ although improvement in OS has not been demonstrated beyond the third line in a large randomized trial (Table 3).

Approved HER2-Targeted Drugs

HER2-directed therapy is implemented in the management of nearly all stages of HER2-positive invasive breast cancer, including early and late stages (Table 4).

Trastuzumab

Trastuzumab was the first anti-HER2 agent to be approved by the FDA in 1998. It is a humanized monoclonal antibody directed against the extracellular domain of the HER2 receptor (domain IV).  Trastuzumab functions by interrupting HER2 signal transduction and by flagging tumor cells for immune destruction.⁵⁶ Cardiotoxicity, usually manifested as left ventricular systolic dysfunction, is the most noteworthy adverse effect of trastuzumab. The most prominent risk factors for cardiomyopathy in patients receiving trastuzumab are low baseline ejection fraction (< 55%), age > 50 years, co-administration and higher cumulative dose of anthracyclines, and increased body mass index and obesity.^57–59 Whether patients receive therapy in the neoadjuvant, adjuvant, or metastatic settings, baseline cardiac function assessment with echocardiogram or multiple-gated acquisition scan is required. While well-designed randomized trials validating the value and frequency of monitoring are lacking, repeated cardiac testing every 3 months is generally recommended for patients undergoing adjuvant therapy. Patients with metastatic disease who are receiving treatment with palliative intent may be monitored less frequently.^60,61

An asymptomatic drop in ejection fraction is the most common manifestation of cardiac toxicity. Other cardiac manifestations have also been reported with much less frequency, including arrhythmias, severe congestive heart failure, ventricular thrombus formation, and even cardiac death. Until monitoring and dose-adjustment guidelines are issued, the guidance provided in the FDA-approved prescribing information should be followed, which recommends holding trastuzumab when there is ≥ 16% absolute reduction in left ventricular ejection fraction (LVEF) from the baseline value; or if the LVEF value is below the institutional lower limit of normal and the drop is ≥ 10%. After holding the drug, cardiac function can be re-evaluated every 4 weeks. In most patients, trastuzumab-induced cardiotoxicity can be reversed by withholding trastuzumab and initiating cardioprotective therapy, although the latter remains controversial. Re-challenging after recovery of ejection fraction is possible and toxicity does not appear to be proportional to cumulative dose. Cardiomyopathy due to trastuzumab therapy is potentially reversible within 6 months in more than 80% of cases.^{28,57,60–63}

Other notable adverse effects of trastuzumab include pulmonary toxicity (such as interstitial lung disease) and infusion reactions (usually during or within 24 hours of first dose).

Pertuzumab

Pertuzumab is another humanized monoclonal antibody directed to a different extracellular domain of the HER2 receptor, the dimerization domain (domain II), which is responsible for heterodimerization of HER2 with other HER receptors, especially HER3. This agent should always be co-administered with trastuzumab as the 2 drugs produce synergistic anti-tumor effect, without competition for the receptor. Activation of HER3, via dimerization with HER2, produces an alternative mechanism of downstream signaling, even in the presence of trastuzumab and in the absence of growth factors (Figure 2). 

Ado-Trastuzumab Emtansine

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that combines the monoclonal antibody trastuzumab with the cytotoxic agent DM1 (emtansine), a potent microtubule inhibitor and a derivative of maytansine, in a single structure (Figure 3). 

Lapatinib

Lapatinib is an oral small-molecule tyrosine kinase inhibitor of EGFR (HER1) and HER2 receptors. It is approved in combination with capecitabine for patients with HER2-expressing metastatic breast cancer who previously received trastuzumab, an anthracycline, and a taxane chemotherapy or T-DM1. Lapatinib is also approved in combination with letrozole in postmenopausal women with HER2-positive, hormone receptor–positive metastatic disease, although it is unclear where this regimen would fit in the current schema. It may be considered for patients with hormone receptor–positive disease who are not candidates for therapy with taxane-trastuzumab and T-DM1 or who decline this therapy. Diarrhea is seen in most patients treated with lapatinib and may be severe in 20% of cases when lapatinib is combined with capecitabine. Decreases in LVEF have been reported and cardiac function monitoring at baseline and periodically may be considered.^69,70 Lapatinib is not approved for use in adjuvant settings.

Neratinib

Neratinib is an oral small-molecule irreversible tyrosine kinase inhibitor of HER1, HER2, and HER4. It is currently approved only for extended adjuvant therapy after completion of 1 year of standard trastuzumab therapy. It is given orally every day for 1 year. The main side effect, expected in nearly all patients, is diarrhea, which can be severe in up to 40% of patients and may lead to dehydration and electrolyte imbalance. Diarrhea usually starts early in the course of therapy and can be most intense during the first cycle. Therefore, prophylactic antidiarrheal therapy is recommended to reduce the intensity of diarrhea. Loperamide prophylaxis may be initiated simultaneously for all patients using a tapering schedule. Drug interruption or dose reduction may be required if diarrhea is severe or refractory.^21,71 Neratinib is not FDA-approved in the metastatic settings.

Conclusion

HER2-positive tumors represent a distinct subset(s) of breast tumors with unique pathological and clinical characteristics. Treatment with a combination of cytotoxic chemotherapy and HER2-targeted agents has led to a dramatic improvement in survival for patients with locoregional and advanced disease. Trastuzumab is an integral part of adjuvant therapy for HER2-positive invasive disease. Pertuzumab should be added to trastuzumab in node-positive disease. Neratinib may be considered after completion of trastuzumab therapy in patients with hormone receptor–positive disease. For metastatic HER2-positive breast cancer, a regimen consisting of docetaxel plus trastuzumab and pertuzumab is the standard first-line therapy. Ado-trastuzumab is an ideal next line option for patients whose disease progresses on trastuzumab and taxanes.

CHICAGO – Is two months of progression-free survival worth it if those months mean living with serious side effects?

Neil Osterweil/ MDedge News

For women with advanced estrogen receptor-positive, HER2-negative breast cancer, the combination of the PI3K inhibitor taselisib and the selective estrogen receptor modifier fulvestrant (Faslodex) bought two additional months of PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half the patients treated with the combination, results of the SANDPIPER trial show.

“These results are positive, but I think we all agree they are modest,” lead investigator José Baselga, MD, PhD from Memorial Sloan Kettering Cancer Center in New York, said at a briefing at the annual meeting of the American Society of Clinical Oncology.

The “challenging tolerability” of the combination led to frequent treatment discontinuations, and may have limited the clinical benefit of the combination, he said, but added that the study serves as proof of principle that PI3K may be a bona fide target in advanced breast cancer.

ASCO expert Harold Burstein, MD, from the Dana-Farber Cancer Institute in Boston agreed that PI3K “is a very appealing target. It’s a mutation that probably is the most common in breast cancer when you do genomic sequencing, and it arises in other tumors as well.”

He likened the study findings, however, to a key opening a locked door, only to find that there is a chain latch on the other side preventing entry.

In an interview, Dr. Burstein said that despite the best efforts of Dr. Baselga and others to find a suitable approach to targeting the PI3K pathway, the evidence to date suggests that it may not be an important driver of breast cancer.

Neil Osterweill/ MDedge News

“The side effects that we see that are limiting patients staying on [taselisib] are mostly delta and gamma. So I do think that in the case of breast cancer, what we need to do is to work on more specific alpha inhibitors that will be safer,” he said.

SOURCE: : Baselga J et al. ASCO 2018 Abstract LBA1006 .

CHICAGO – Is two months of progression-free survival worth it if those months mean living with serious side effects?

Neil Osterweil/ MDedge News

For women with advanced estrogen receptor-positive, HER2-negative breast cancer, the combination of the PI3K inhibitor taselisib and the selective estrogen receptor modifier fulvestrant (Faslodex) bought two additional months of PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half the patients treated with the combination, results of the SANDPIPER trial show.

“These results are positive, but I think we all agree they are modest,” lead investigator José Baselga, MD, PhD from Memorial Sloan Kettering Cancer Center in New York, said at a briefing at the annual meeting of the American Society of Clinical Oncology.

The “challenging tolerability” of the combination led to frequent treatment discontinuations, and may have limited the clinical benefit of the combination, he said, but added that the study serves as proof of principle that PI3K may be a bona fide target in advanced breast cancer.

ASCO expert Harold Burstein, MD, from the Dana-Farber Cancer Institute in Boston agreed that PI3K “is a very appealing target. It’s a mutation that probably is the most common in breast cancer when you do genomic sequencing, and it arises in other tumors as well.”

He likened the study findings, however, to a key opening a locked door, only to find that there is a chain latch on the other side preventing entry.

In an interview, Dr. Burstein said that despite the best efforts of Dr. Baselga and others to find a suitable approach to targeting the PI3K pathway, the evidence to date suggests that it may not be an important driver of breast cancer.

Neil Osterweill/ MDedge News

“The side effects that we see that are limiting patients staying on [taselisib] are mostly delta and gamma. So I do think that in the case of breast cancer, what we need to do is to work on more specific alpha inhibitors that will be safer,” he said.

SOURCE: : Baselga J et al. ASCO 2018 Abstract LBA1006 .

CHICAGO – Is two months of progression-free survival worth it if those months mean living with serious side effects?

Neil Osterweil/ MDedge News

For women with advanced estrogen receptor-positive, HER2-negative breast cancer, the combination of the PI3K inhibitor taselisib and the selective estrogen receptor modifier fulvestrant (Faslodex) bought two additional months of PFS, compared with fulvestrant alone, but at the cost of serious toxicities in half the patients treated with the combination, results of the SANDPIPER trial show.

“These results are positive, but I think we all agree they are modest,” lead investigator José Baselga, MD, PhD from Memorial Sloan Kettering Cancer Center in New York, said at a briefing at the annual meeting of the American Society of Clinical Oncology.

The “challenging tolerability” of the combination led to frequent treatment discontinuations, and may have limited the clinical benefit of the combination, he said, but added that the study serves as proof of principle that PI3K may be a bona fide target in advanced breast cancer.

ASCO expert Harold Burstein, MD, from the Dana-Farber Cancer Institute in Boston agreed that PI3K “is a very appealing target. It’s a mutation that probably is the most common in breast cancer when you do genomic sequencing, and it arises in other tumors as well.”

He likened the study findings, however, to a key opening a locked door, only to find that there is a chain latch on the other side preventing entry.

In an interview, Dr. Burstein said that despite the best efforts of Dr. Baselga and others to find a suitable approach to targeting the PI3K pathway, the evidence to date suggests that it may not be an important driver of breast cancer.

Neil Osterweill/ MDedge News

“The side effects that we see that are limiting patients staying on [taselisib] are mostly delta and gamma. So I do think that in the case of breast cancer, what we need to do is to work on more specific alpha inhibitors that will be safer,” he said.

SOURCE: : Baselga J et al. ASCO 2018 Abstract LBA1006 .