Volume 11, Issue 10, Supplement 16 October 2013
New Developments in Metastatic Breast Cancer: Integrating Recent Data into Clinical Practice
Moderator
Edith A. Perez, MD
Deputy Director at Large, Mayo Clinic Cancer Center
Director, Breast Cancer Translational Genomics Program
Serene M. and Frances C. Durling Professor of Medicine
Mayo Clinic
Jacksonville, Florida
Discussants
Hope S. Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trial Education
University of California San Francisco
Helen Diller Family Comprehensive Cancer Center
San Francisco, California
Linda T. Vahdat, MD
Professor of Medicine
Director, Breast Cancer Research Program Head, Solid Tumor Service
Weill Cornell Medical College
New York, New York
A CME Activity
Approved for 1.25 AMA PRA Category 1 Credit(s)-TM
Release Date: October 2013
Expiration Date: October 31, 2014
Estimated time to complete activity: 1.25 hours
Project ID: 9285
Abstract: The treatment of metastatic breast cancer continues to be a challenging area for medical oncologists. Breast tumors are classified into several groups based on immunohistochemistry: those that are estrogen-receptor–positive and human epidermal growth factor receptor 2 (HER2)-negative; those that are HER2-positive and either estrogen-receptor–positive or estrogen-receptor–negative; and those that are negative for the estrogen receptor, progesterone receptor, and HER2 (known as triple-negative). These biologic factors are an important component of the risk assessment and treatment strategy. Management goals for advanced disease are to target treatment to the specific biology in a more effective way, and to add in targeted agents that may improve the effectiveness of standard therapies, such as hormone therapy and chemotherapy. There are several new therapies that are changing outcome for patients with metastatic disease, such as eribulin, pertuzumab, and ado-trastuzumab emtansine. It is critical to understand the appropriate dosing schedules of novel agents and how best to combine them with standard therapy. Ongoing clinical trials are evaluating new treatment approaches, as well as ways to identify biologic subsets that might benefit from particular therapies. Investigational agents include glembatumumab vedotin, neratinib, and margetuximab.
Supported through an educational grant from Eisai Inc.
Sponsored by the Postgraduate Institute for Medicine
Disclaimer
Funding for this clinical roundtable monograph has been provided through an educational grant from Eisai Inc. Support of this monograph does not imply the supporter’s agreement with the views expressed herein. Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc., the supporter, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation.
©2013 Millennium Medical Publishing, Inc., 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.
New Developments in Metastatic Breast Cancer: Introduction
Hope S. Rugo, MD
Breast cancer is the most common malignancy among women worldwide.1 In the United States, it is diagnosed in approximately 200,000 women each year.2 There have been significant improvements in understanding the biology of the disease, as well as in treatment and supportive care. The majority of women who are diagnosed with early-stage breast cancer enjoy long-term survival, usually with tolerable treatment. The prognosis for women with metastatic disease is more limited. Each year, approximately 40,000 women die of metastatic breast cancer.3 Approximately 5% to 10% of women with breast cancer are diagnosed with metastatic disease,4 and 15% to 20% of women with breast cancer will develop recurrent disease.5 Recurrent disease is usually considered either locoregional or distant. In medical oncology, the more important type of recurrence is distant disease because these patients have incurable cancer at the start. Patients with locoregional disease are at increased risk of developing distant disease, and they are often re-treated with systemic therapy.
Metastatic breast cancer can develop long after a patient is diagnosed with early-stage disease. The more aggressive proliferative cancers tend to recur within the first 5 years after diagnosis. Patients with hormone-receptor–positive disease have a longer duration of risk. Approximately 50% of recurrences in hormone receptor–disease occur more than 5 years after initial diagnosis.6 The subset of hormone receptor-positive–disease that is more proliferative has a higher risk of recurrence in the first 5 years.
Classically, breast tumors are classified into several groups based on immunohistochemistry: those that are estrogen-receptor–positive and human epidermal growth factor receptor 2 (HER2)-negative; those that are HER2-positive and either estrogen-receptor–positive or estrogen-receptor–negative; and those that are negative for the estrogen receptor, progesterone receptor, and HER2 (known as triple-negative). These biologic factors are an important component of the risk assessment and treatment strategy (Table 1).4
Prognosis
Evaluation of patients with recurrent breast cancer must include consideration of therapeutic goals and prognosis. The median overall survival for patients with HER2 normal disease starting chemotherapy for metastatic breast cancer is approximately 2 and a half years.7 Overall, this prognosis has not changed significantly in the past 10 years. However, additional therapy has changed the prognosis for patients with HER2-positive breast cancer, especially those who have not previously received HER2-targeted agents. In addition, patients who have hormone-receptor–positive, hormone-sensitive disease have a longer median survival of approximately 5 years. Approximately 5% of patients with metastatic breast cancer have a much longer survival. The disease biology of this small subset is poorly understood.
Treatment
It is important to address the goals of therapy when metastatic breast cancer is diagnosed and at every point when treatment decisions are made. For the majority of patients, the goals of therapy are to live as long as possible with the best quality of life. The patient should be an integral partner in the decision-making process regarding treatment, and her goals of therapy should be considered. For example, some patients may want to avoid drugs that cause hair loss until there are no other options. Other issues of importance to patients include treatment of brain metastases and the use of intravenous vs oral therapy.
The first treatment consideration is the disease biology (Figure 1). Treatment will be guided by the same markers used for early-stage disease, including estrogen receptor status and HER2/neu status. (In the future, we hope to incorporate additional markers—including mutations, activation of specific pathways, proteomics, and expression analyses—but current data do not support their use.) Comparison of a metastatic patient’s current markers with those present in early-stage disease appears to be extremely important. In most patients, diagnosis of metastatic disease should prompt an additional biopsy with assessment of markers to provide insight into the biology of their current disease. Metastatic breast cancer may be biologically heterogeneous, similar to the primary tumor. Therefore, tumors that express a specific clinical phenotype, but have markers that are discordant with this phenotype, should be reevaluated at every opportunity to ensure that a specific subset of breast cancer cells that might benefit from an alternative treatment has not been missed.
In addition, management choices will be based on clinical parameters such as disease-free interval and presence of visceral disease. In general, 1 year has been the disease-free interval used to assess the effectiveness of therapy. Based on recent data, however, it appears more reasonable to use a disease-free interval of approximately 2 years. Patients with a shorter disease-free interval after upfront therapy appeared to have a significantly worse prognosis and less durable responses to initial therapy.8 The second important clinical parameter is the extent of disease, which includes the number of visceral sites and symptoms related to disease. For patients with hormone-receptor–positive breast cancer, the presence of limited visceral disease does not appear to affect response to hormone therapy. These patients may therefore be treated with hormone therapy upfront. Patients receive more aggressive treatment if they have visceral crises, which refers to extensive visceral disease and symptoms related to visceral involvement, such as shortness of breath, abdominal pain, or laboratory findings of organ dysfunction (eg, abnormal liver function tests).
In general, treatment is divided into hormone therapy, chemotherapy, and HER2-targeted therapy. When possible, treatment begins with oral agents and those with the least toxicity. For metastatic patients, treatment is a modification of that used in early-stage therapy to reduce toxicity. Combination chemotherapy may be appropriate as a first-line approach in patients who have very short disease-free intervals, chemotherapy-resistant disease, or, in some cases, triple-negative disease.
Treatment with hormone therapy or single-agent chemotherapy is likely to be appropriate for patients who have more indolent disease with fewer symptoms or symptoms that are easily controlled, such as bone pain. Only a subset of patients require a more aggressive approach. Patients with HER2-positive disease are generally treated with HER2-targeted therapy upfront in combination with chemotherapy, with the chemotherapy usually discontinued after the patient achieves a reasonable radiographic and clinical response, usually after administration of 6 to 8 cycles.
Interestingly, in studies of HER2-positive disease, a complete response did not correlate with prolonged progression-free survival and, therefore, a partial response is considered adequate for discontinuation of chemotherapy.9 At that point, treatment with HER2-targeted therapies should continue.
Traditional management includes sequential treatment with chemotherapy, hormone therapy, and HER2-targeted agents as appropriate. If a patient has hormone-receptive–positive disease and is receiving chemotherapy, a chemotherapy holiday might be appropriate, particularly when hormone therapy can be used as a bridge. For triple-negative breast cancer, however, data have demonstrated that continuing chemotherapy results in improved survival compared to stopping chemotherapy after response and waiting for progression. For patients with HER2-positive disease, as mentioned earlier, the general approach is to treat with chemotherapy and HER2-targeted therapy and then allow a break from chemotherapy with continuation of HER2-targeted agents until disease progression. Some of these patients will have a very long progression-free survival on HER2-targeted therapy alone.
With traditional treatment approaches, patients generally experience progressively shorter progression-free survival and lower response rates until they exhaust all options or die from organ dysfunction. Management goals for advanced disease are to target treatment to the specific biology in a more effective way, and to add in targeted agents that may improve the effectiveness of standard therapies, such as hormone therapy and chemotherapy. There has already been much success in improving the response to chemotherapy and hormone therapy with HER2-targeted agents. Many of the new HER2-targeted agents have been associated with improved response, progression-free survival, and overall survival without increased toxicity. The goal moving forward is to be able to achieve this same degree of success in other subsets of breast cancer. Most excitingly, response to hormone therapy has been improved with an agent targeted to the phosphatidylinositol 3-kinase (PI3K) pathway, specifically the mammalian target of rapamycin (mTOR) inhibitor everolimus.10 There are multiple new agents targeting this pathway in clinical trials. In addition, there are new agents targeting the cyclin-dependent kinases 4 and 6 that appear to be very promising in their ability to increase responses and improve response duration in patients receiving hormone therapy for metastatic hormone receptor–positive breast cancer.
Biologic agents have toxicities that differ from those associated with chemotherapy. For example, few biologic agents, if any, cause complete alopecia. These agents may, however, have other noxious side effects that prevent their delivery in adequate doses over time. It is therefore critical to understand the appropriate doses of biologic agents and how best to combine them with standard therapy. It has been difficult to identify subsets of patients within broader biologic groups that might benefit from specific targeted therapies. For example, the new HER2-targeted therapies appear to be effective in patients with HER2-positive disease, but it has not yet been possible to identify specific subgroups that benefit more. The same is true for new agents that improve response and response duration to hormone therapy. There is a small group of patients with disease that responds very poorly. A larger group of patients appears to benefit regardless of whether the specific targeted pathway, such as PI3K, is activated. Future goals are to better understand whether new biologic techniques, or perhaps evaluation of metastatic tumor tissue vs archived tissue from the initial diagnosis, can help to identify specific tumor subsets that might benefit from newer targeted agents.
Unmet Needs
Traditional treatments leave several unmet needs. The least amount of progress has been seen in the management of triple-negative breast cancers, a heterogeneous group with different biologic subtypes. There is intense study, both in the clinic and in the laboratory, to find better agents that can eventually translate into longer survival for these patients, who have the shortest survival after diagnosis of all patients with metastatic disease (Figure 2).11 It has not yet been possible to identify a specific target that is expressed in the majority of these patients and that can be the focus of an effective targeted biologic agent. Some of the new chemotherapy agents are very effective in patients with triple-negative breast cancer. We are trying to understand the value of DNA-damaging agents and whether patients most likely to benefit from these agents can be identified through specific tests, such as the homologous recombination defect efficiency test. The study of PARP inhibitors is ongoing, particularly in patients with BRCA-mutated tumors.
Other unmet needs are to adequately control treatment toxicity and to provide appropriate supportive care for fatigue and peripheral neuropathy. A better understanding is needed to better identify which patients are at risk for peripheral neuropathy and to provide them with protective therapies or alternative therapies. In addition, agents are needed to prevent the development of brain metastases and to treat them more effectively to prevent continued progression.
Summary
The treatment of metastatic breast cancer continues to be a challenging area for medical oncologists. However, there are several exciting new therapies that have changed outcome for patients with this disease. In addition, ongoing clinical trials are evaluating new treatment approaches, as well as ways to identify biologic subsets that might benefit from particular therapies.
Acknowledgment
Dr Rugo receives funding for clinical trials through the University of California San Francisco from Genentech/Roche, Merck, Plexxikon, Novartis, Pfizer, and GSK, and she serves as an unpaid scientific advisory board member for Galena and OBI Pharmaceuticals.
References
1. Forouzanfar MH, Foreman KJ, Delossantos AM, et al. Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet. 2011;378(9801):1461-1484.
2. United States Cancer Statistics (USCS): 2009 Top Ten Cancers. Centers for Disease Control and Prevention. http://apps.nccd.cdc.gov/uscs/toptencancers.aspx. Accessed September 25, 2013.
3. Irvin W, Muss HY, Mayer DK. Symptom management in metastatic breast cancer. Oncologist. 2011;16(9):1203-1214.
4. Cardoso F, Harbeck N, Fallowfield L, et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2012;23(suppl 7):vii11-vii19.
5. Lichter AS, Lippman ME, Danforth DN Jr, et al. Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. J Clin Oncol. 1992;10(6):976-983.
6. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;365(9472):1687-1717.
7. Lück HJ, Du Bois A, Loibl S, et al. Capecitabine plus paclitaxel versus epirubicin plus paclitaxel as first-line treatment for metastatic breast cancer: efficacy and safety results of a randomized, phase III trial by the AGO Breast Cancer Study Group. Breast Cancer Res Treat. 2013;139(3):779-787.
8. Tevaarwerk AJ, Gray RJ, Schneider BP, et al. Survival in patients with metastatic recurrent breast cancer after adjuvant chemotherapy: little evidence of improvement over the past 30 years. Cancer. 2013;119(6):1140-1148.
9. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119.
10. Piccart M, Baselga J, Noguchi S, et al. Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer [SABCS abstract P6-04-02]. Cancer Res. 2012;72(suppl 3).
11. Dent R, Trudeau M, Pritchard KI, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429-4434.
Practice-Changing Data in Metastatic Breast Cancer
Edith A. Perez, MD
Many advances continue to be made in the field of metastatic breast cancer, especially in the context of managing patients according to a better understanding of the underlying biology of the disease. Results from a number of clinical studies have recently been reported, and the field eagerly awaits the findings of many ongoing trials. Some of these studies are attempting to correlate molecular signatures or abnormalities in the breast tumor with the way patients respond to particular interventions. Hopefully, these findings will guide clinicians in better management and treatment decisions.
In the interim, many of the findings reported by recent clinical trials are applicable to the care of patients with metastatic breast cancer. Clinical trials in metastatic breast cancer largely focus on treatment of the 3 main subtypes of the disease: hormone receptor–positive, HER2-positive, and triple negative (that is, negative for the estrogen receptor, progesterone receptor, and HER2; Table 2). When interpreting the results from these studies, it is important to recognize the significant and clinically meaningful heterogeneity that exists among even these 3 subtypes.
Agents Targeting HER2-Positive Metastatic Breast Cancer
HER2 overexpression is a frequent event in breast cancer, occurring in approximately 15% to 20% of all breast cancers.1,2 The treatment of HER2-positive metastatic breast cancer was revolutionized in 1998 with the US Food and Drug Administration (FDA) approval of trastuzumab, a HER2-directed recombinant humanized monoclonal antibody. Nearly a decade later, in 2007, the FDA approved use of the small-molecule tyrosine kinase inhibitor lapatinib (in combination with capecitabine) for patients with HER2-positive metastatic breast cancer previously treated with an anthracycline, a taxane, and trastuzumab. Subsequently, in 2010, lapatinib was approved in combination with letrozole for the treatment of postmenopausal women with hormone receptor–positive metastatic breast cancer overexpressing HER2. More recently, 2 other drugs were approved for this disease setting: pertuzumab (in 2012) and ado-trastuzumab emtansine (T-DM1; in 2013).
Like trastuzumab, pertuzumab is a (fully) humanized monoclonal antibody directed against HER2. However, slight but significant differences exist between the 2 antibodies.3 For example, although the mechanism of action of pertuzumab is complementary to trastuzumab, it is not identical. The primary mechanism of action of trastuzumab has been attributed to inhibition of HER2-dependent signal transduction, but pertuzumab is thought to act primarily by inhibiting ligand-induced dimerization between HER2 and other HER family members, such as HER3. This difference is attributed to the fact that pertuzumab recognizes and binds a different epitope on the HER2 receptor. A number of other mechanisms of action have been attributed to both antibodies, including antibody-dependent cell-mediated cytotoxicity (ADCC).
Pertuzumab is indicated for use in combination with trastuzumab and docetaxel for the treatment of HER2-positive metastatic breast cancer patients who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.4 Approval of pertuzumab was based primarily on the positive results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study, an international, randomized, double-blind, placebo-controlled phase 3 trial.5,6 A total of 808 metastatic breast cancer patients were enrolled and randomized in a 1:1 fashion to receive pertuzumab, trastuzumab, and docetaxel or placebo, trastuzumab, and docetaxel as first-line therapy. Treatment was continued until time of disease progression or development of unmanageable toxicity. The baseline demographic characteristics were well balanced between the treatment arms. In both arms, the median age was 54.0 years, and 99% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Other similar characteristics included hormone receptor–positive status (47.0% and 49.0% in the pertuzumab and placebo arms, respectively) and use of prior adjuvant or neoadjuvant therapy (45.8% and 47.3% in the pertuzumab and placebo arms, respectively). Notably, trastuzumab was a component of prior adjuvant or neoadjuvant therapy in 11.7% of patients in the pertuzumab arm and 10.1% of patients in the placebo arm. These rates are lower than those typically observed in most real-world clinical settings, in which a large majority of HER2-positive metastatic breast cancer patients have previously received adjuvant or neoadjuvant trastuzumab based on its high efficacy.
The primary study endpoint—progression-free survival—was significantly improved among patients in the pertuzumab group compared with the placebo group (median independently reviewed progression-free survival, 18.5 vs 12.4 months; hazard ratio for progression or death, 0.62; 95% CI, 0.51-0.75; P<.001).5,6 Importantly, this benefit in progression-free survival occurred across all patient subgroups, including age, race/ethnicity and geographic region, visceral vs nonvisceral disease, hormone receptor status, and use of prior adjuvant therapy. The objective response rate was also improved in the pertuzumab arm compared with the placebo arm (80.2% vs 69.3%; P=.001). This difference was caused primarily by an increase in the number of partial responses (74.6% vs 65.2%); the proportion of complete responses was similar between the 2 arms (5.5% vs 4.2%).
In a second interim analysis of overall survival, the median overall survival was 37.6 months in the placebo group and was not reached in the pertuzumab group (hazard ratio, 0.66; 95% CI, 0.52-0.84; P=.0008; Figure 3).7 Estimated overall survival rates were as follows for the pertuzumab and placebo arms, respectively: 94.4% vs 89.0% at 1 year, 80.7% vs 69.4% at 2 years, and 65.8% vs 50.4% at 3 years.
An exploratory analysis of biomarkers in CLEOPATRA did not identify any that were predictive of response to therapy or prognostic of outcome.6 The investigators concluded that HER2 was the only currently available biomarker suitable for selecting patients for HER2-directed therapy.
All-grade adverse events occurring at a greater frequency (by at least 5 percentage points) in the pertuzumab-treated arm included diarrhea, rash, mucosal inflammation, febrile neutropenia, and dry skin.5,6 Rates of grade 3 or higher febrile neutropenia and diarrhea were at least 2 percentage points higher in the pertuzumab arm. A higher incidence of any-grade left ventricular systolic dysfunction occurred in the placebo arm compared with the pertuzumab arm (8.3% vs 4.4%). In a follow-up analysis of cardiac tolerability, the overall incidence of all-grade cardiac adverse events was 14.5% in the pertuzumab arm and 16.4% in the placebo arm; most of these events were reversible.8 Importantly, it was concluded that the addition of a second HER2-directed monoclonal antibody to trastuzumab did not increase risk for cardiac toxicity.
To maintain or improve upon the efficacy—and minimize the toxicity—observed with the triple combination in CLEOPATRA, the pertuzumab plus trastuzumab combination is being evaluated with other chemotherapy backbones. For example, the VELVET (A Combination of Pertuzumab, Trastuzumab, and Vinorelbine for First-Line Treatment of Patients With HER2-Positive Metastatic Breast Cancer: An Open-Label, Two-Cohort, Phase II Study) trial is a phase 2 evaluation of pertuzumab and trastuzumab plus vinorelbine in 210 previously untreated HER2-positive metastatic breast cancer patients.9 Included in this study design is an evaluation of antibody administration that is sequential vs combined (in a single infusion bag), with the purpose of determining the feasibility of the latter approach to minimize the infusion time. The primary endpoint of this study is overall objective response, although tolerability and progression-free survival are also being evaluated. Future studies are needed in metastatic breast cancer to evaluate pertuzumab in combination with chemotherapy for treatment of HER2-positive tumors that are refractory to trastuzumab.
T-DM1 is an antibody-drug conjugate in which trastuzumab is conjugated to the potent tubulin-targeted cytotoxic agent maytansinoid DM1. The mechanism of T-DM1 is thought to rely upon targeted delivery of the T-DM1 molecule to HER2-overexpressing breast cancer cells via the trastuzumab antibody.10 Once bound, T-DM1 is internalized and the DM1 moiety is released, freeing it to bind to tubulin and disrupt microtubule dynamics.
In addition, T-DM1 has been shown to exhibit the mechanisms of action typically associated with trastuzumab, including inhibition of HER2 signal cascades and ADCC.
T-DM1 is now approved by the FDA, with an indication as a single agent for the treatment of HER2-positive metastatic breast cancer patients who previously received trastuzumab and a taxane separately or in combination.11 The approval was largely based on results from the EMILIA (An Open-Label Study of Trastuzumab Emtansine [T-DM1] vs Capecitabine Plus Lapatinib in Patients With HER2-Positive Locally Advanced or Metastatic Breast Cancer) study, an open-label, international, phase 3 trial that randomized 991 patients in a 1:1 ratio to receive either T-DM1 or the combination of lapatinib plus capecitabine.12 Eligible patients had received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. The HER2-positive metastatic breast cancer patients had previously received therapy with trastuzumab and a taxane, and the lapatinib plus capecitabine combination used in the control arm is a standard regimen for this patient population. Prior to randomization, patients were stratified according to world region, number of prior chemotherapy regimens, and extent of disease involvement. The baseline characteristics were balanced between the 2 treatment groups. They included median age (53 years in each arm), ECOG performance status of 0 or 1 (99% in the T-DM1 arm and 98% in the lapatinib plus capecitabine arm), hormone receptor–positive status (57% in the T-DM1 arm and 53% in the lapatinib plus capecitabine arm), and more than 1 prior chemotherapy regimen for locally advanced or metastatic disease (39% in each arm).
One of the primary study endpoints—progression-free survival—was significantly prolonged in patients who received T-DM1 compared with patients who received lapatinib plus capecitabine (median progression-free survival, 9.6 vs 6.4 months; hazard ratio, 0.65; 95% CI, 0.55-0.77; P<.001; Figure 4).12 The objective response rate was also increased in the T-DM1 group vs the lapatinib plus capecitabine group (43.6% vs 30.8%; P<.001). Responses with T-DM1 proved to be more durable, with a median duration of response of 12.6 months in the T-DM1 arm vs 6.5 months in the lapatinib plus capecitabine arm.
Overall survival was another primary study endpoint of the EMILIA trial.12 In a second interim analysis, the median overall survival was greater in the T-DM1 arm vs the lapatinib plus capecitabine arm, and crossed the stopping boundary for efficacy (30.9 vs 25.1 months; hazard ratio, 0.68; 95% CI, 0.55-0.85; P<.001).
More grade 3 or higher adverse events were reported in the lapatinib plus capecitabine arm (57.0%) compared with the T-DM1 arm (40.8%).12 The most frequently reported grade 3 or 4 adverse events among T-DM1–treated patients were thrombocytopenia (12.9%) and elevated levels of aspartate aminotransferase (4.3%) and alanine aminotransferase (2.9%).
With the approval of T-DM1 in the setting of previously treated metastatic breast cancer, effort has now turned to assessing this agent in the first-line treatment of metastatic disease. One recent phase 2 randomized trial compared single-agent T-DM1 with trastuzumab plus docetaxel for the first-line treatment of 137 patients with HER2-positive metastatic breast cancer (or locally advanced recurrent breast cancer).13 Median progression-free survival increased from 9.2 months with trastuzumab plus docetaxel to 14.2 months with T-DM1 (hazard ratio, 0.59; 95% CI, 0.36-0.97). The objective response rate with T-DM1 was also higher compared with trastuzumab plus docetaxel (64.2% vs 58.0%). These promising data have heightened the anticipation of results from the MARIANNE (A Study of Trastuzumab Emtansine [T-DM1] Plus Pertuzumab/Pertuzumab Placebo Versus Trastuzumab [Herceptin] Plus a Taxane in Patients With Metastatic Breast Cancer) study, an ongoing phase 3 trial comparing 3 regimens in first-line metastatic breast cancer treatment: T-DM1, T-DM1 plus pertuzumab, and a taxane plus trastuzumab.14,15
Together, the CLEOPATRA and EMILIA trials provide new data demonstrating significant and clinically meaningful improvements in both progression-free survival and overall survival for patients with HER2-positive metastatic breast cancer. These studies have changed the standard of care for management of patients with HER2-positive advanced breast cancer.
Novel Strategy for Targeting Microtubules in Metastatic Breast Cancer
Eribulin mesylate is a synthetic analogue of halichondrin B, an antineoplastic agent produced by marine sponges. Eribulin binds to tubulin, inhibiting tubulin polymerization and thus microtubule assembly. Eribulin has gained FDA approval for the treatment of metastatic breast cancer patients who have previously received an anthracycline and a taxane in either the adjuvant or metastatic setting and at least 2 chemotherapeutic regimens for the treatment of metastatic disease.16 This approval was based on results from the EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus Eribulin) trial, a phase 3, global, multicenter, open-label randomized trial that compared eribulin with a treatment of the physician’s choice in 762 women with heavily pretreated locally recurrent or metastatic breast cancer.17 The baseline patient characteristics were well balanced between the treatment arms. Most patients had an ECOG performance status of 0 or 1 (42% and 49%, respectively). A majority of the study population was HER2-negative (74%), and most patients were hormone receptor–positive (64%). A total of 19% of the patients had triple-negative disease. The median number of prior chemotherapy regimens was 4 (range, 1-7), with capecitabine the most common agent.
The EMBRACE study met its primary endpoint by demonstrating a significantly improved median overall survival in the eribulin arm compared with the treatment of physician’s choice arm (13.1 vs 10.6 months; hazard ratio, 0.81; 95% CI, 0.66-0.99; P=.041).17 The increase in median overall survival observed in the eribulin arm compared with the treatment of physician’s choice arm remained significant in an updated analysis (13.2 vs 10.5 months; hazard ratio, 0.81; 95% CI, 0.67-0.96; P=.014; Figure 5).16 The 1-year overall survival rate was 54.5% in the eribulin group and 42.8% in the treatment of physician’s choice group.
An independent review showed a trend toward improved median progression-free survival with eribulin compared with the treatment of physician’s choice; however, this difference did not reach statistical significance (3.7 vs 2.2 months; hazard ratio, 0.87; 95% CI, 0.71-1.05; P=0137).17 Statistical significance was achieved when an investigator review was conducted (hazard ratio, 0.76; 95% CI, 0.64-0.90; P=.002). The rate of objective response was significantly improved with eribulin vs treatment of physician’s choice (12% vs 5%; P=.002).
Most adverse events occurring in both arms were mild or moderate (grade 1/2).17 Grade 3 or 4 adverse events occurring more frequently in the eribulin arm vs the treatment of physician’s choice arm were neutropenia, leukopenia, and peripheral neuropathy. Grade 3 and 4 peripheral neuropathy occurred at a rate of 8% in the eribulin arm and less than 1% in the control arm.
A complementary trial, Study 301, was a global, open-label, randomized, multicenter, phase 3 study in 1,102 women with locally advanced or metastatic breast cancer.18 Patients were randomized 1:1 to receive either eribulin or capecitabine; prior to randomization, patients were stratified by geographic region and HER2 status. Enrolled patients had received 3 or fewer prior chemotherapy regimens, up to 2 of which for advanced disease. All patients had received a prior anthracycline and taxane, either in the adjuvant or neoadjuvant setting or for locally advanced or metastatic disease. Baseline demographics were well balanced between the treatment arms. The median age was 53 to 54 years, and most patients had an ECOG performance score of either 0 or 1 (97%-98%). Approximately half of patients (50%-53%) had received 1 prior chemotherapy regimen, and 27% to 28% had received 2 prior chemotherapy regimens. The majority of patients were HER2-negative (68%-69%), and 25% to 27% had triple-negative disease.
The primary study endpoints were overall survival and progression-free survival.18 There was not a statistically significant improvement in overall survival with eribulin vs capecitabine (15.9 vs 14.5 months; hazard ratio, 0.879; 95% CI, 0.770-1.003; P=.056). Interestingly, however, the yearly overall survival rates showed a consistent trend for benefit with eribulin vs capecitabine at 1 year (64.4% vs 58.0%; P=.035), 2 years (32.8% vs 29.8%; P=.324), and 3 years (17.8% vs 14.5%; P=.175). A subgroup analysis suggested that eribulin may increase survival over capecitabine in patients with certain tumor subtypes, such as triple-negative tumors (14.4 vs 9.4 months; hazard ratio, 0.702; 95% CI, 0.545-0.906; Figure 6).
Median progression-free survival was also not significantly different between the eribulin and capecitabine treatment groups (investigator review, 4.2 vs 4.1 months; hazard ratio, 0.977; 95% CI, 0.857-1.114; P=0.736; independent review, 4.1 vs 4.2 months; hazard ratio, 1.079; 95% CI, 0.932-1.250; P=.305).18 Objective response was also similar between the eribulin and capecitabine arms (11% vs 12%; P=.849).
Although Study 301 did not demonstrate a significant superiority with eribulin vs capecitabine in either overall survival or progression-free survival, it did show that both agents had similar activity.18 Notably, certain adverse events occurred with less frequency in the eribulin arm vs the capecitabine arm, including hand-foot syndrome and diarrhea. However, grade 3/4 neutropenia and leukopenia were more frequent with eribulin. The suggestion that eribulin may be more effective in certain patient subgroups—such as those with triple-negative metastatic breast cancer—should be explored in future clinical studies.
Etirinotecan Pegol
The novel agent etirinotecan pegol (NKTR-102) was examined in a randomized phase 2 study of patients with refractory metastatic breast cancer who had received prior therapy with anthracyclines and taxanes (capecitabine was allowed).19 The study evaluated 2 schedules. It showed a response rate of 29%, and disease stability in approximately 35% of patients at 6 months. The toxicity profile was fairly tolerable; the main issue was diarrhea, which occurred in approximately one-quarter of the patients, but it tended to occur later in the therapy (after a median of 3 months on therapy). This late occurrence reflects the fact that this toxicity was observed mainly in patients who were otherwise deriving clinical benefit from the treatment. This trial led to the ongoing BEACON (Breast Cancer Outcomes With NKTR-102) phase 3 trial, which recently completed accrual.20 BEACON is a global study evaluating NKTR-102 vs physician’s choice of single-agent chemotherapy in patients with metastatic breast cancer previously treated with anthracyclines, taxanes, and capecitabine. Results are expected in 2014 or 2015.
Acknowledgment
Dr Perez has no real or apparent conflicts of interest to report.
References
1. Perez EA, Roche PC, Jenkins RB, et al. HER2 testing in patients with breast cancer: poor correlation between weak positivity by immunohistochemistry and gene amplification by fluorescence in situ hybridization. Mayo Clin Proc. 2002;77:148-154.
2. Perez EA, Reinholz MM, Hillman DW, et al. HER2 and chromosome 17 effect on patient outcome in the N9831 adjuvant trastuzumab trial. J Clin Oncol. 2010;28(28):4307-4315.
3. Capelan M, Pugliano L, De Azambuja E, et al. Pertuzumab: new hope for patients with HER2-positive breast cancer. Ann Oncol. 2013;24(2):273-282.
4. Perjeta [package insert]. South San Francisco, CA: Genentech, Inc.; 2013.
5. Baselga J, Cortes J, Im SA, et al. Biomarker analyses in CLEOPATRA: a phase III, placebo-controlled study of pertuzumab in HER2-positive, first-line metastatic breast cancer (MBC) [abstract S5-1]. Cancer Res. 2012;72(suppl 3).
6. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119.
7. Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14(6):461-471.
8. Swain SM, Ewer MS, Cortés J, et al. Cardiac tolerability of pertuzumab plus trastuzumab plus docetaxel in patients with HER2-positive metastatic breast cancer in CLEOPATRA: a randomized, double-blind, placebo-controlled phase III study. Oncologist. 2013;18(3):257-264.
9. A study of pertuzumab in combination with Herceptin (trastuzumab) and vinorelbine in first line in patients with metastatic or locally advanced HER2-positive breast cancer. ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01565083?term=NCT01565083&rank=1. Identifier: NCT01565083. Accessed October 9, 2013.
10. LoRusso PM, Weiss D, Guardino E, et al. Trastuzumab emtansine: a unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res. 2011;17(20):6437-6447.
11. Kadcyla [package insert]. South San Francisco, CA: Genentech, Inc; 2013.
12. Verma S, Miles D, Gianni Let al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-1791.
13. Hurvitz SA, Dirix L, Kocsis J, et al. Phase II randomized study of trastuzumab emtansine versus trastuzumab plus docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2013;31(9):1157-1163.
14. A study of trastuzumab emtansine (T-DM1) plus pertuzumab/pertuzumab placebo versus trastuzumab [Herceptin] plus a taxane in patients with metastatic breast cancer (MARIANNE). ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01120184?term=NCT01120184&rank=1. Identifier: NCT01120184. Accessed October 9, 2013.
15. Barginear MF, John V, Budman DR. Trastuzumab-DM1: a clinical update of the novel antibody-drug conjugate for HER2-overexpressing breast cancer. Mol Med. 2013;18:1473-1479.
16. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2013.
17. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914-923.
18. Kaufman PA, Awada A, Twelves C, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes [SABCS abstract S6-6]. Cancer Res. 2012;72(suppl 3).
19. Awada A, Garcia AA, Chan S, et al. Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study. Lancet Oncol. 2013 Oct 3. pii: S1470-2045(13)70429-7. doi: 10.1016/S1470-2045(13)70429-7. [Epub ahead of print]
20. The BEACON study (Breast Cancer Outcomes With NKTR-102). ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT01492101?term=beacon&rank=2. Identifier: NCT01492101. Accessed October 9, 2013.
Novel Data in Metastatic Breast Cancer
Linda T. Vahdat, MD
Data from recent and ongoing clinical trials in metastatic breast cancer are providing insight into the use of existing agents and identifying novel agents with activity in this setting. Management of metastatic breast cancer will likely evolve over the next few years as these data are incorporated into clinical care.
New Data for Everolimus
Everolimus is an agent that targets the mTOR protein for inhibition. In 2012, it gained approval for use in combination with exemestane for the treatment of postmenopausal women with advanced hormone receptor–positive, HER2-negative breast cancer, following failure of treatment with either letrozole or anastrozole.1 Both the mTOR and the related PI3K pathways have been implicated in the development of resistance to endocrine therapy in patients with hormone receptor–positive disease, and therefore targeting 1 or both of these pathways is likely a reasonable strategy.2 This approach was successful in the phase 3 BOLERO-2 (Breast Cancer Trials of Oral Everolimus-2) trial, which randomized patients to receive either exemestane plus everolimus or exemestane plus placebo.3 The resulting median progression-free survival was 7.8 months for exemestane plus everolimus compared with 3.2 months for exemestane plus placebo (hazard ratio, 0.45; 95% CI, 0.38-0.54; P<.0001; Figure 7).4 The overall response rates were 12.6% for patients receiving exemestane plus everolimus vs only 1.7% in patients receiving exemestane plus placebo. In a planned interim analysis, overall survival was not significantly different between the treatment groups (hazard ratio, 0.77; 95% CI, 0.57-1.04).
In the BOLERO-3 follow-up study, 569 patients with HER2-positive trastuzumab-resistant locally advanced or metastatic breast cancer were randomized to receive vinorelbine plus trastuzumab, given with either everolimus or placebo.5 Although overall survival data were not yet available, a significant improvement in median progression-free survival was observed in the everolimus group compared with the placebo group (7.0 vs 5.78 months, hazard ratio, 0.78; 95% CI, 0.65-0.95; P=.0067).
Investigational Agents in Clinical Development
Glembatumumab Vedotin
Glembatumumab vedotin (CDX-011) is a novel antibody-drug conjugate consisting of a fully human monoclonal antibody directed against an extracellular domain of the glycoprotein non-metastatic melanoma protein B (GPNMB), and the potent microtubule inhibitor monomethyl auristatin E.6 GPNMB is a transmembrane glycoprotein important for cellular invasion and migration. Patients with tumors that express high amounts of GPNMB have shorter metastasis-free survival and overall survival (Figures 8 and 9).7 In a phase 1/2 trial that enrolled 42 patients, glembatumumab vedotin treatment resulted in an objective response rate of 17%. Interestingly, in a small subset of patients with triple-negative breast cancer, the objective response rate appeared to be slightly higher, at 25%. Dose-limiting toxicities were grade 3 peripheral neuropathy (in 10%) and rash (in 6%). An interesting observation in this study was that patients with GPNMB overexpression, as assessed by immunohistochemistry, appeared to derive a greater benefit from glembatumumab vedotin treatment.8
To build upon these data, the EMERGE (A Study of CDX-011 [CR011-vcMMAE] in Patients With Advanced GPNMB-Expressing Breast Cancer) study was conducted to further characterize the safety and efficacy of glembatumumab vedotin in 120 patients with locally advanced or metastatic breast cancer and GPNMB overexpression.9 Patients were randomized in a 2:1 fashion to treatment with either glembatumumab vedotin or treatment of the physician’s choice. All patients had received between 2 and 7 prior therapies, including an anthracycline, a taxane, and capecitabine. Crossover was allowed at the time of disease progression for patients randomized to the treatment of physician’s choice arm. Patients were confirmed to have GPNMB overexpression using a centralized immunohistochemistry method. GPNMB overexpression, which was required for eligibility, was defined as more than 5% expression in either the epithelial or stromal component of a tumor block specimen; as a result, enrolled patients had varying levels of GPNMB overexpression. Interestingly, it became clear in the study analysis that patients with triple-negative metastatic breast cancer tended to show greater levels of GPNMB overexpression.
At baseline, patients in both arms had received a median of 6 prior treatment regimens. In addition to anthracyclines, taxanes, and capecitabine (which were required for study enrollment), other prior therapies included gemcitabine, bevacizumab, and vinorelbine. Overall, these patients seemed to be fairly representative of a heavily pretreated metastatic breast cancer population.
The objective response rate achieved with glembatumumab vedotin was 19% vs 14% with treatment of physician’s choice. When the subgroup of patients with triple-negative disease was assessed separately, the objective response rates were 21% with glembatumumab vedotin and 0% with the control. Patients with triple-negative disease who had high levels of GPNMB overexpression achieved a 36% objective response rate with glembatumumab vedotin, compared with 0% with treatment of physician’s choice. In this subgroup of patients with high GPNMB overexpression and triple-negative breast cancer, the median progression-free survival was 3.5 months with glembatumumab vedotin vs 1 month with treatment of physician’s choice.
There were no new toxicities apparent with glembatumumab vedotin in the EMERGE trial. Overall, this agent was well tolerated. Adverse events included grade 3/4 neutropenia (in 24%), grade 3/4 rash (in 4%), and grade 3/4 peripheral neuropathy (in 3%).
Glembatumumab vedotin will be evaluated as an earlier line of treatment in a randomized phase 2 trial. This study is expected to focus especially on the subset of metastatic breast cancer patients with both high levels of GPNMB overexpression and triple-negative disease.
Neratinib
Neratinib (HKI-272) is a potent tyrosine kinase inhibitor active against HER1, HER2, and HER4.10,11 In an open-label, multicenter, phase 2 trial evaluating single-agent neratinib in patients with HER2-positive metastatic breast cancer, the 16-week progression-free survival rate was 59% among women with prior exposure to trastuzumab and 78% among women with no prior trastuzumab therapy.11 The respective median progression-free survival was 22.3 weeks and 39.6 weeks, respectively, and the objective response rates were 24% and 56%. Single-agent neratinib was compared against lapatinib plus capecitabine in a randomized phase 2 trial, which found that neither inferiority nor noninferiority could be established.12
Of particular interest is a phase 1/2 trial investigating the combination of the mTOR inhibitor temsirolimus with neratinib in trastuzumab-refractory HER2-positive metastatic breast cancer.13 At baseline, the median number of prior therapies was 3, and 52% of the 27 patients had hormone receptor–positive disease. The combination was associated with a 44% rate of partial responses, although no complete responses were reported. Patients who experienced a partial response with neratinib plus temsirolimus showed a maximum change in the size of their target lesions of between 33% and 83%. Median progression-free survival of the 27 evaluable patients was 18 weeks. The combination of neratinib and temsirolimus had acceptable tolerability. The most frequent severe adverse events were grade 3 diarrhea (22%), grade 3 mucositis (15%), grade 3 hyperglycemia (4%), grade 3 leukopenia (4%), and grade 3 fatigue (4%).
Margetuximab
Margetuximab (MGAH22) is an Fc-modified chimeric monoclonal antibody directed against the HER2 receptor. Unlike other HER2-targeted antibodies, the Fc region of margetuximab has been modified to enhance the ADCC activity of the molecule. A recent phase 1 trial of margetuximab in patients with advanced solid tumors showed promising activity.14 A phase 2 trial is now initiating, which will enroll HER2-positive metastatic breast cancer patients.
Hsp90 Inhibitors
Heat shock protein 90 (Hsp90) is a molecular chaperone protein required for the proper maturation and activation of numerous client proteins. Many of these Hsp90 client proteins play critical roles in cell growth, differentiation, and survival. Relative to normal cells, cancerous cells rely more heavily on Hsp90 activity. Inhibitors of Hsp90 are particularly interesting in HER2-positive metastatic breast cancer, as HER2 is known to be a client protein of Hsp90.15 Several ongoing clinical trials are evaluating these agents both as monotherapy and in combination with trastuzumab.
PARP Inhibitors
Inhibitors of the poly(ADP-ribose) polymerase (PARP) showed significant promise a few years ago. In a randomized phase 2 trial of patients with triple-negative metastatic breast cancer, the PARP inhibitor iniparib demonstrated improved outcomes (including response rate, progression-free survival, and overall survival) when combined with gemcitabine and carboplatin. These results failed to be reproduced in a similarly designed phase 3 trial.16,17 Despite these disappointing results, a number of recently published reports point to a potential for the use of PARP inhibitors in patients with BRCA mutations.18-20
Acknowledgment
Dr Vahdat is on the speaker’s board for Eisai, and she has received research support from Puma and Synta.
References
1. Afinitor [package insert]. East Hanover, NJ: Novartis; 2013.
2. Provenzano A, Kurian S, Abraham J. Overcoming endocrine resistance in breast cancer: role of the PI3K and the mTOR pathways. Expert Rev Anticancer Ther. 2013;13(2):143-147.
3. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520-529.
4. Piccart M, Baselga J, Noguchi S, et al. Final progression-free survival analysis of BOLERO-2: a phase III trial of everolimus for postmenopausal women with advanced breast cancer [SABCS abstract P6-04-02]. Cancer Res. 2012;72(suppl 3).
5. O’Regan R, Ozguroglu M, Andre F, et al. Phase III, randomized, double-blind, placebo-controlled multicenter trial of daily everolimus plus weekly trastuzumab and vinorelbine in trastuzumab-resistant, advanced breast cancer (BOLERO-3) [ASCO abstract 505]. J Clin Oncol. 2013;31(15 suppl).
6. Keir CH, Vahdat LT. The use of an antibody drug conjugate, glembatumumab vedotin (CDX-011), for the treatment of breast cancer. Expert Opin Biol Ther. 2012;12(2):259-263.
7. Rose AA, Grosset AA, Dong Z, et al. Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer. Clin Cancer Res. 2010;16(7):2147-2156.
8. Burris H, Burris H, Saleh M, et al. A phase (Ph) I/II study of CR011-VcMMAE, an antibody-drug conjugate, in patients (Pts) with locally advanced or metastatic breast cancer (MBC) [SABCS abstract 6096]. Cancer Res. 2009;69(24 suppl).
9. Yardley DA, Weaver R, Melisko ME, et al. A randomized phase 2 study of the antibody-drug conjugate CDX-011 in advanced GPNMB-overexpressing breast cancer: the EMERGE study [SABCS abstract P6-10-01]. Cancer Res. 2012;72;24(suppl 3).
10. Rabindran SK, Discafani CM, Rosfjord EC, et al. Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004;64(11):3958-3965.
11. Burstein HJ, Sun Y, Dirix LY, et al. Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010;28(8):1301-1307.
12. Martin M, Bonneterre J, Geyer CE Jr, et al. A phase two randomised trial of neratinib monotherapy versus lapatinib plus capecitabine combination therapy in patients with HER2+ advanced breast cancer. Eur J Cancer. 2013 Aug 14. [Epub ahead of print] PubMed PMID: 23953056.
13. Gajria D, King T, Pannu H, et al. Combined inhibition of mTORC1 with temsirolimus and HER2 with neratinib: a phase I/II study in patients with metastatic HER2-amplified or triple-negative breast cancer [SABCS abstract PD-09-08]. Cancer Res. 2011;71(suppl 3).
14. Burris HA, Giaccone G, Seock-Ah Im S, et al. Phase I study of margetuximab (MGAH22), an FC-modified chimeric monoclonal antibody (MAb), in
patients (pts) with advanced solid tumors expressing the HER2 oncoprotein [ASCO abstract 3004]. J Clin Oncol. 2013;31(15 suppl).
15. De Mattos-Arruda L, Cortes J. Breast cancer and HSP90 inhibitors: is there a role beyond the HER2-positive subtype? Breast. 2012;21(4):604-607.
16. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC) [ASCO abstract 1007]. J Clin Oncol. 2011;29(15 suppl).
17. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205-214.
18. Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germ-like BRCA1/2 mutation: an open-label phase II study [ASCO abstract 11024]. J Clin Oncol. 2013;31(15 suppl).
19. Somlo G, Frankel PH, Luu TH, et al. Efficacy of the combination of ABT-888 (veliparib) and carboplatin in patients with BRCA-associated breast cancer [ASCO abstract 1024]. J Clin Oncol. 2013;31(15 suppl).
20. Lee J-M, Annunziata CM, Hays JL, et al. Phase I/Ib study of the PARP inhibitor olaparib (O) with carboplatin (C) in BRCA1/2 mutation carriers with breast or ovarian cancer (Br/OvCa) (NCT00647062) [ASCO abstract 2514]. J Clin Oncol. 2013;31(15 suppl).
New Developments in Metastatic Breast Cancer: General Discussion
Edith A. Perez, MD What are some unmet needs in metastatic breast cancer?
Linda T. Vahdat, MD One issue that I think is particularly relevant for the metastatic breast cancer field is the need to increase the number of patients enrolled in clinical trials. That stated, there is also a need for better-designed clinical studies. New drugs must be moved through the clinical development process as quickly as possible, but it is also important to have better judgment in how these drugs are evaluated in the clinical trial setting. It would be very helpful if more of these new agents could be moved into the neoadjuvant and adjuvant setting. In addition, there is a great need to assess molecular targets of predictive or prognostic significance for these newer agents.
Hope S. Rugo, MD One issue with clinical trial development is collaboration between drug manufacturers to facilitate testing active combinations in the clinic as early as possible. Often studies are limited by a specific company’s drug portfolio, so that important potential combinations are lost or poorly studied. The neoadjuvant setting has emerged as a mechanism for studying agents at an early stage of development, using pathologic complete remission as a surrogate endpoint, and providing accessible tissue for biomarker development.
Linda T. Vahdat, MD An important question in the management of these patients is when to repeat biopsies. Many metastatic breast cancer patients actually want to be rebiopsied. Often they also request it after second-line or third-line therapy. In some cases I agree, but in others I do not.
Edith A. Perez, MD The issue of repeated biopsies is one that will be very important for research. The more trials we have to target these abnormalities, the better it will be for our patients. There has been an increasing reliance on the use of biopsies in the metastatic setting as part of the standard of care. In fact, I see this happening in our own practice. This is very different compared to a decade ago, when biopsies were almost never performed in metastatic breast cancer patients. Some clinicians are now recommending biopsies before they decide on a first-line treatment regimen, in order to assess if there has been a change in biomarkers that may lead to a better utilization of targeted therapies. More and more data are becoming available regarding changes in the 3 primary biomarkers in breast cancer—estrogen receptor, progesterone receptor, and HER2—that occur between the primary setting and the appearance of metastatic disease. Overall, these data support obtaining a biopsy when a patient presents with metastatic breast cancer, especially in cases where the biomarkers were initially negative, because a shift to positive would vastly increase the therapeutic options. We can also extend this discussion to the next level, whereby there may be a cause to evaluate biomarkers that may be of importance for novel agents in clinical development, especially if it is feasible that the patient could then participate in a trial depending on the results of her biopsy.
Technologies are becoming more readily commercially available, allowing physicians to send a patient’s biopsy specimens to be assayed for any number of genes. But one of the challenges we have is the growing number of technologies, coupled with the fact that the expression of the single gene itself may not be what is important. Even in the setting of HER2-positive breast cancer, the single-agent activity of trastuzumab is in the range of 20% to 25%. Therefore, just because a patient has the HER2 biomarker does not necessarily mean that she will automatically have a robust response to HER2-directed therapy.
One of my concerns is that the community will assume that if a biopsy reveals the presence of a particular biomarker of interest, such as a mutation in PI3K, it will result in an easy treatment decision for targeted therapy. As was shown in BOLERO-2, there was no correlation between the presence of PI3K mutations and benefit with everolimus. So although the field is complex, we at least have growing access to the technology that will eventually help us to better understand the clinical importance of patterns of gene expression.
Linda T. Vahdat, MD Yes, I completely agree with you. One strategy I have been relying upon recently, especially in difficult-to-treat metastatic breast cancers, is to use genomic studies to see if they can help suggest a particular direction for treatment. There is a great deal of technology available, but how best to use the information it provides in clinical practice is not yet known. Every so often, I come across an unsuspected BRCA mutation or a HER2-activating mutation, which can be used to drive treatment decisions.
Hope S. Rugo, MD I agree that we must be cautious applying genomic data to clinical practice. We do not have the data to demonstrate that mutations in specific genes correlates with response to an added or targeted agent. Indeed, patients whose tumors have either mutated or wild-type PI3K appear to have similar responses to agents targeting this pathway. One comment about obtaining multiple biopsies in metastatic disease is that this will be challenging in several ways. First is obtaining adequate tissue, which can be quite difficult depending on the source. The second is obtaining tissue that represents the majority of the tumor, given that significant heterogeneity may exist. Last is the discomfort, risk, and cost associated with these procedures.
Edith A. Perez, MD This technology will be particularly intriguing when it can be used in every patient. An important issue to be aware of is that biopsy samples may receive divergent results from different companies. Another area of interest in the area of biopsy gene profiling is the identification of novel transcripts in breast cancer. These transcripts need to be explored further to determine whether they can predict therapeutic benefit.
I would like to echo your comment on the importance of clinical trials, as this remains a major issue in the metastatic breast cancer field. Hopefully, as phase 2 trials are becoming more well designed, there will be a greater likelihood of having these studies approved more rapidly. This will greatly increase the opportunities available for our patients.
Linda T. Vahdat, MD Yes. For example, right now it is better to manage women with triple-negative metastatic disease in a clinical trial, as opposed to giving them standard cytotoxic chemotherapeutic options, because we know these drugs do not work in these patients. That said, there should be more studies available for these patients.
Hope S. Rugo, MD Indeed this is true, but trials may not be accessible or feasible for all patients. Certainly standard chemotherapy agents, either alone or in combination, have activity in a number of triple-negative tumors. However, clinical trials are an important option to consider if they are available, as each new option provides an additional opportunity for disease control.
Acknowledgments
Dr Vahdat is on the speaker’s board for Eisai, and she has received research support from Puma and Synta. Dr Perez has no real or apparent conflicts of interest to report. Dr Rugo receives funding for clinical trials through the University of California San Francisco from Genentech/Roche, Merck, Plexxikon, Novartis, Pfizer, and GSK, and she serves as an unpaid scientific advisory board member for Galena and OBI Pharmaceuticals.
Target Audience
This activity has been designed for all physicians, academicians, researchers, investigators, support staff, nurses, and program directors from the fields of oncology with a special interest in metastatic breast cancer.
Statement of Need/Program Overview
Patients with early-stage breast cancer are likely to achieve long-term survival, usually with tolerable treatments. Metastatic disease has been more intractable. Prognosis for these patients has recently improved with the approval of several new agents, including eribulin, lapatinib, pertuzumab, and ado-trastuzumab emtansine. Many more agents are in clinical development. Clinical trials in metastatic breast cancer largely focus on treatment of the 3 main subtypes of the disease: hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive, and triple negative (that is, negative for the estrogen receptor, progesterone receptor, and HER2). The patient’s tumor biology will help guide treatment decisions. Biologic agents have toxicities that differ from those associated with chemotherapy. It is critical to understand the appropriate dosing schedules of novel agents and how best to combine them with standard therapy. Quality of life should be an important consideration when discussing management goals with patients.
Educational Objectives
After completing this activity, the participant should be better able to:
• Discuss the latest efficacy and safety data from recently reported clinical trials on new and emerging metastatic breast cancer therapies
• Identify patients most likely to benefit from novel treatment approaches
• Integrate new and emerging agents into clinical practice
• Develop management goals based on tumor biology, treatment efficacy and safety, and quality of life concerns
Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Postgraduate Institute for Medicine (PIM) and Millennium Medical Publishing, Inc. PIM is accredited by the ACCME to provide continuing medical education for physicians.
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The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credit(s)TM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
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PIM assesses conflict of interest with its instructors, planners, managers, and other individuals who are in a position to control the content of continuing medical education (CME) activities. All relevant conflicts of interest that are identified are thoroughly vetted by PIM for fair balance, scientific objectivity of studies utilized in this activity, and patient care recommendations. PIM is committed to providing its learners with high-quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest or a commercial interest.
The contributing speakers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity:
Edith A. Perez, MD—No real or apparent conflicts of interest to report.
Hope S. Rugo, MD—Funding for clinical trials through the University of California San Francisco: Genentech/Roche, Merck, Plexxikon, Novartis, Pfizer, and GSK; Scientific advisory board member (unpaid): Galena and OBI Pharmaceuticals.
Linda T. Vahdat, MD—Speaker’s board: Eisai; Research support: Puma and Synta.
The following PIM planners and managers, Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; Jan Schultz, RN, MSN, CCMEP; and Patricia Staples, MSN, NP-C, CCRN hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Jacquelyn Matos: No real or apparent conflicts of interest to report. Lisa Cockrell, PhD: No real or apparent conflicts of interest to report.
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There are no fees for participating in and receiving CME credit for this activity. During the period October 2013 through October 31, 2014, participants must 1) read the learning objectives and faculty disclosures; 2) study the educational activity; 3) complete the post-test by recording the best answer to each question in the answer key on the evaluation form; 4) complete the evaluation form; and 5) mail or fax the evaluation form with answer key to Postgraduate Institute for Medicine. You may also complete the post-test online at www.cmeuniversity com. On the navigation menu, click on “Find Post-tests by Course” and search by project ID 9285. Upon successfully completing the post-test and evaluation, your certificate will be made available immediately.
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Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.