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JOURNAL OF CLINICAL ONCOLOGY
A S C O 50TH A N N I V E R S A R Y
Past, Present, and Future Challenges in Breast Cancer Treatment George W. Sledge, Stanford University School of Medicine, Stanford, CA Eleftherios P. Mamounas, University of Florida Health Cancer Center, Orlando, FL Gabriel N. Hortobagyi, MD Anderson Cancer Center, Houston, TX Harold J. Burstein, Dana-Farber Cancer Institute, Boston, MA Pamela J. Goodwin, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, and Antonio C. Wolff, Johns Hopkins Cancer Center, Baltimore, MD
The past half century—the lifetime of the American Society of Clinical Oncology—represents a historical watershed in the management of breast cancer, a period in which old dogmas were overthrown, to be replaced by biology-driven therapeutic approaches. These approaches transformed the disease from one where mutilating local therapy was followed by distant recurrence and death, to one where patients regularly choose local (and often minimal) therapy, then receive systemic therapies that are increasingly effective and progressively more targeted. Breast cancer, perhaps more than any other solid tumor, was transformed by the progressive application of clinical hypothesis testing of basic biologic concepts. The revolutionary overthrow of the Halstedian hypothesis, with its emphasis on the primacy of locoregional control through extensive surgery, led to changes both in locoregional therapy as well as providing the intellectual basis for adjuvant systemic therapies. And, at a time when systemic therapies were dominated by rank empiricism, breast cancer led the way in the application of targeted biologic therapy, long before targeted therapy became an oncologic mantra. This article will review a half-century of progress, focusing on the areas in which the greatest progress has been seen: the revolution in locoregional therapy; the application of cytotoxic chemotherapy in both local and advanced disease; the discovery and therapeutic exploitation of estrogen receptor biology; the use of estrogen receptor biology for breast cancer prevention; and the targeting of the human epidermal growth factor receptor complex. Collectively, these constitute a revolution in breast cancer therapeutics that has occurred within the lifetime of an organization. Finally, we will touch on the remaining therapeutic challenges for this disease. Locoregional Therapy The locoregional treatment of breast cancer has been transformed through changes in both the biologic understanding and the clinical presentation of the disease. Starting with the pivotal randomized clinical trials from the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Milan group, radical mastectomy was replaced by modified radical mastectomy and eventually breastconserving surgery, with breast radiation becoming the preferred method of locoregional management in appropriate candidates.1 InJournal of Clinical Oncology, Vol 32, No 19 (July 1), 2014: pp 1979-1986
Although the initial impetus for neoadjuvant therapy was provided by the desire to convert patients with inoperable tumors to operable mastectomy candidates, and those who were mastectomy candidates to candidates for breast-conserving surgery, more recently the focus has been in the potential downstaging of axillary nodes with resulting reduction in the extent of axillary surgery and in the potential tailoring of postoperative radiotherapy. Accurate assessment of the location and extent of the primary breast tumor and axillary nodes before, during, and after neoadjuvant chemotherapy remain important challenges. In coming years, the development of more active neoadjuvant chemotherapy regimens and novel molecular and imaging techniques will undoubtedly lead to additional individualization of locoregional management, including the real possibility of avoiding formal surgical resection of the primary tumor and axillary nodes in patients who have high likelihood to have achieved a pathologic complete response. Recently, the Food and Drug Administration accepted the use of pathologic complete response in the neoadjuvant setting as a biomarker for therapeutic benefit and accelerated drug approval, a policy shift with major implications for new drug development. The demonstration of an association between genomic profiling/ molecular subtyping and locoregional recurrence is an exciting development, and several seminal papers on the subject have been published in Journal of Clinical Oncology.20-25 This is a promising approach for further individualizing locoregional management. Chemotherapy and Triple-Negative Breast Cancer By the 1960s, several combinations of cytotoxic agents had been proposed and tested.26 The five-drug Cooper regimen became quite popular because of its high response rate.27 Doxorubicin was introduced into clinical trials in 1967 and by the early 1970s was considered the most effective agent against breast cancer.19,28 Anthracyclinebased combinations with cyclophosphamide followed (doxorubicin plus cyclophosphamide, as well as fluorouracil, doxorubicin, and cyclophosphamide), and combination chemotherapy became the standard of care in both the metastatic and adjuvant setting.29 Sporadic reports of the significant activity of platinum salts in previously untreated metastatic breast cancer were largely ignored.30,31 Many new cytotoxic agents were developed and tested during the 1970s and 1980s, but none had a satisfactory therapeutic index. The development of the taxanes represented a major milestone in the systemic therapy of breast cancer, with both paclitaxel and docetaxel showing activity similar to and sometimes exceeding that of the anthracyclines.32 Randomized trials demonstrated at this stage that anthracycline-containing regimens were somewhat superior to regimens not containing an anthracycline.33 Simultaneously, the routine use of combination chemotherapy for patients with metastatic breast cancer began to be questioned.34 A large randomized trial comparing single-agent doxorubicin to singleagent paclitaxel and to the combination of both agents indicated that the combination produced higher response rate and longer time to treatment failure, but no difference in overall survival.35 This study and meta-analysis of other controlled trials turned the tide, and the standard of care became again sequential single-agent chemotherapy.36 The exceptions to this rule are patients with rapidly progressive or extensive visceral disease in whom a rapid response is needed or patients with oligometastases treated with multimodality strategies with curative intent. 1980
Following the introduction of the taxanes, other cytotoxic agents were developed: vinorelbine37 and other vinca alkaloids, gemcitabine,38 capecitabine,39 ixabepilone,40 and eribulin.41 These agents have been incorporated into the management of metastatic breast cancer, with capecitabine playing a particularly major role on the basis of its excellent therapeutic index once the appropriate dose for each patient is determined. Clinical trials of combination and sequential therapy continued and informed the development of third-generation adjuvant chemotherapy trials. Much of the progress in breast cancer was the result of the development of adjuvant chemotherapy. Fisher and Bonadonna showed in the mid-1970s that the addition of adjuvant chemotherapy to definitive surgery improved disease-free and overall survival in primary breast cancer.41a,41b The results of these seminal trials were presented at the respective annual meetings of ASCO. Subsequently, multiple confirmatory trials were summarized by the Early Breast Cancer Trialists Collaborative Group.41c Additional publications from this group demonstrated that in the adjuvant setting, combination chemotherapy was superior to single-agent chemotherapy; that anthracycline-based regimens were superior to nonanthracyclinebased regimens; and that about 6 months of chemotherapy were sufficient, with longer treatments not resulting in additional benefit.41d,41e Clinical trials and the meta-analysis also showed the incremental benefit of combining chemotherapy and endocrine therapy in sequential schedules for women with hormone receptor– positive breast cancer. Another major step forward came with the introduction of taxanes into adjuvant therapy.41f,41g In 1992, the efficacy of adjuvant chemotherapy and endocrine therapy was established in lymph node–negative breast cancer, and exploratory analyses indicated that such treatments had a positive therapeutic ratio in older patients with breast cancer.41h Randomized trials provided evidence for the incremental benefit of dose-dense administration of chemotherapy.41i Additional trials and the meta-analysis demonstrated no significant benefit from the use of high-dose chemotherapy with hematopoietic stem cell rescue for breast cancer.41j Such incremental progress now provides a greater than 50% reduction in the odds of recurrence and a similar reduction in odds of death for patients with primary breast cancer. With the completion of the Human Genome Project, gene expression technology led to the identification of various molecular subtypes of breast cancer, subtypes that today are considered separate entities, with different clinical courses, patterns of metastases, and sensitivity to existing therapeutic agents.42 Although gene expression technology has become much less expensive, the great majority of patients have no easy access to such assays. Thus, the genomic classification has been superseded by a clinical-pathological classification on the basis of expression of estrogen receptor, progesterone receptor, HER2, and Ki-67 of grade.43,44 It should be understood that the two classifications differ, and the overlap between similar subtypes is only approximately 75%. However, this represents a practical compromise. Gene expression profiling identified the basal-like subtype as being arguably one of the most aggressive types of breast cancer, with a higher probability of metastasis and death from progressive disease.45 In clinical practice, the term triple-negative breast cancer, indicating the absence of expression of estrogen receptor (ER) and progesterone receptor (PR) and normal expression of HER, has acted as a ready clinical surrogate for the basal-like subtype.45,46 Although responsive to chemotherapy, many responses in the metastatic setting JOURNAL OF CLINICAL ONCOLOGY
are short, with median overall survival remaining less than 2 years. Although standard chemotherapy includes all the agents listed earlier, there is increasing interest in incorporating platinum salts into systemic regimens.47 Triple-negative breast cancer also includes most of the BRCA1 mutated tumors, which appear quite responsive to PARP inhibitors,48 so there is much interest in pivotal trials of these agents. Several signaling pathways are under intense scrutiny, and signaling inhibitors alone or in combination are being tested. ER: The First Targeted Therapy The development of therapeutics for ER-expressing breast cancers has been one of the great clinical advances of the past 50 years and has served as a paradigm for the development of targeted therapies in oncology. It had been known for more than a century that hormonal ablation of ovarian, pituitary, or adrenal function could cause tumor responses among some patients with advanced breast cancer. In the late 1960s and early 1970s, tumor expression of steroid hormone receptors (ER and PR) was identified as both a critical prognostic marker and the seminal biomarker predicting benefit from antiestrogen treatments.49 Randomized clinical trials subsequently proved that, across the full spectrum of breast disease ranging from cancer prevention50 to management of ductal carcinoma in situ22 to treatment of early51 and advanced stage breast cancer, anti-estrogen therapies have powerful impact on the natural history of ER-expressing breast cancers, and that ER expression is the sine qua non for clinical benefit. ER expression correlates closely with other important clinical and pathological features of breast cancer, including tumor grade, HER2 expression, recurrence risk, and benefit from adjuvant chemotherapy,52 and helps define the clinically important subtypes of breast cancers. Recognition of the relationship between tumor ER expression and clinical outcomes served as the model for biomarker/targetedagent clinical translational research, heralding a new era for detailed clinicopathological correlations and subset analyses now found widely throughout oncology. Presently, anti-estrogen therapies are a mainstay of treatment of ER-positive breast cancers. As most breast cancers are ER positive, and given the worldwide prevalence of the disease, it is arguable that anti-estrogen treatments have had greater global impact that any other treatment intervention in cancer medicine. The innumerable randomized trials of adjuvant endocrine therapy engendered innovative biostatistical meta-analyses and investigator collaborations, now the norm in international oncology, and helped establish the paradigm of adjuvant drug treatment for solid tumors. Five years of therapy with the selective estrogen receptor modulator tamoxifen or aromatase inhibitors (AIs, which cause estrogen depletion) reduces breast cancer recurrence and improves overall survival in women with ER-positive early-stage breast cancer and has been the worldwide standard of care.1 Despite adjuvant therapy with 5 years of endocrine agents, there remains persistent risk of tumor recurrence beyond 5 years of treatment. Recent data suggest that longer durations of adjuvant endocrine therapy— out to 10 years—lower the risk of tumor recurrence and improve survival53 These findings underscore the chronic nature of ER-positive breast cancer, and the innovation of long durations of therapy to prevent late recurrence is the new frontier in adjuvant endocrine treatment. Additional studies are needed to clarify which tumors pose persistent jeopardy for recurrence. www.jco.org
Table 1. Randomized Breast Cancer Prevention Trials of Hormonal Interventions
Trial and Year NSABP-P1,
Veronesi et al,57 2007
Tamoxifen 20 mg per day v placebo for 5 years Tamoxifen 20 mg per day v placebo for 5 years Tamoxifen 20 mg per day v placebo for 8 years Tamoxifen 20 mg per day v placebo for 5 years
No. Randomly Assigned
Eligibility Criteria Gail 5-year risk score ⬎ 1.66% Relative risk ⱖ 2 ⫻ general population (on basis of family history, results of previous benign breast biopsies) Family history of breast cancer
Average breast cancer risk, prior hysterectomy
Reduced invasive, noninvasive breast cancer (HR, 0.51) Effect on ER⫹ but not ER⫺ cancers
Reduced invasive, noninvasive breast cancer (HR, 0.73; 95% CI, 0.58 to 0.91) Effect on ER⫹ but not ER⫺ cancers Nonsignificantly lower invasive breast cancer (HR, 0.78; 95% CI, 0.58 to 1.04) Effect on ER⫹ but not ER⫺ cancers Nonsignificantly lower invasive, noninvasive breast cancer (HR, 0.84; 95% CI, 0.60 to 1.17) Significantly reduced breast cancer in high-risk women (HR, 0.24; 95% CI, 0.10 to 0.59) Significantly reduced breast cancer in women receiving estrogen replacement (HR, 0.43; 95% CI, 0.20 to 0.95) Comparable invasive breast cancer risk at 47 months (HR, 1.03; 95% CI, 0.82 to 1.28) Increased invasive breast cancer risk with raloxifene at 81 months (HR, 1.24; 95% CI, 1.05 to 1.47) More noninvasive breast cancers with raloxifene Reduced invasive breast cancer (HR, 0.35; 95% CI, 0.18 to 0.70) Reduced invasive and noninvasive breast cancer (HR, 0.47; 95% CI, 0.27 to 0.79) Reduced ER⫹ but not ER⫺ cancers
NSABP (STAR),58,59 2006, 2010
Raloxifene 60 mg per day v tamoxifen 20 mg per day for 5 years
Gail 5-year risk score ⬎ 1.6% (postmenopausal)
Exemestane 25 mg per day v placebo for 5 years (analysis at 35 months median follow-up) Anastrozole 1 mg per day v placebo for 5 years
Gail 5-year risk score ⬎ 1.66% (postmenopausal)
Relative risk ⱖ 2 ⫻ general population (family history, benign breast disease; postmenopausal)
Effect on Breast Cancer
Reduced invasive, noninvasive breast cancer (HR, 0.47; 95% CI, 0.32 to 0.68) Reduced ER⫹ but not ER⫺ cancers
Abbreviations: ER, estrogen receptor; HR, hazard ratio; IBIS-I, International Breast Cancer Intervention Study I; IBIS-II, International Breast Cancer Intervention Study II; MAP.3, Mammary Prevention 3; NSABP-P1, National Surgical Adjuvant Breast and Bowel Project trial P1; STAR, Study of Tamoxifen and Raloxifene.
more favorable adverse effect profile of raloxifene (lower risk of endometrial cancer, cataracts, and thromboembolic events), this agent has not been widely embraced as a substitute for tamoxifen in breast cancer prevention. Two recent trials compared the preventive effects of an AI (exemestane, anastrozole) versus placebo (Table 1).60,61 Both identified a marked reduction in invasive breast cancer risk of about one half to two thirds. Toxicities were lower than expected from the use of these agents in the adjuvant setting, with no evidence of increased fracture risk and minimal impact on quality of life. Both trials used placebo (rather than tamoxifen) in their comparison arm; as a result, it is difficult to ascertain the relative benefits of these agents versus tamoxifen. However, the favorable adverse effect profile of AIs that has been reported in the prevention setting may lead to greater use of these agents. Tamoxifen is the only agent with demonstrated preventive efficacy in premenopausal women. In postmenopausal women, raloxifene and the AIs are potential options. Individual patient characteristics (including prior hysterectomy) and preferences should guide agent selection in postmenopausal women; modeling benefits and harms may facilitate this selection.62 Unfortunately, no survival benefits have been identified in any of these prevention trials; short follow-up and early stopping (with unblinding and cross-over of control subjects to the active agent) have made it difficult to identify any survival benefits that may exist. None of these endocrine agents has lowered risk of ER-negative breast can1982
cer. These factors, and the potential for serious toxicities, have also contributed to the continued low uptake of these agents. Prophylactic mastectomy has also been investigated as a means of lowering breast cancer risk. It has been associated with lower breast cancer incidence in selected high or higher risk populations,63 and its use may be associated with reduced breast cancer mortality in BRCA mutation carriers. However, it can adversely affect body image and quality of life, even when combined with reconstruction. There is growing acceptance of its role in selected high-risk women, notably BRCA mutation carriers. Lifestyle change (physical activity,64 avoidance of postmenopausal obesity,65 dietary change, vitamin supplementation) has also been advocated as a means of preventing breast cancer, based largely on associations of these factors with lower risk. The feasibility of long-term lifestyle change is controversial, but modest change is likely feasible in motivated women. A Women’s Health Initiative randomized trial of dietary fat reduction identified a small (9%) reduction in breast cancer risk that was of borderline statistical significance; a greater benefit was seen in more adherent women.66 Randomized trials of vitamin D supplementation identified no evidence of reduction in breast cancer incidence. An effective and broadly accepted approach to breast cancer prevention remains elusive. Healthy women have less tolerance for toxicity, particularly serious events such as cancer and thromboembolism. The continuing challenge will be to find approaches that are effective and have an acceptable risk-benefit ratio. JOURNAL OF CLINICAL ONCOLOGY
HER2-Positive Disease In the late 1980s, HER2 gene amplification was recognized as a prognostic marker for poor clinical outcome in early-stage breast cancer.67,68 While retrospective studies suggested a preferential benefit with adjuvant anthracycline regimens,69 the true revolution in therapy for HER2-positive patients awaited the development of the targeted monoclonal anti-HER2 antibody trastuzumab. In 1998, a randomized clinical trial showed an unprecedented improvement in survival when trastuzumab was added to standard chemotherapy in metastatic disease,70 and by 2005, the use of adjuvant trastuzumab transformed the face of HER2-positive disease, substantially improving disease-free and overall survival.13,71-73 Trastuzumab resistance occurs in both the metastatic and adjuvant settings. Starting in 2007, several new drugs became available, including the small molecule tyrosine kinase inhibitor lapatinib, the anti HER2-HER3 dimerization antibody pertuzumab, and the antibody drug conjugate ado-trastuzumab emtansine or T-DM1 in 2013. These approvals were based on improvement in survival outcomes in metastatic patients with mostly trastuzumab-naive (pertuzumab74) or trastuzumab-exposed (lapatinib18 and T-DM175) breast cancer, and all these agents are now being tested in ongoing adjuvant trials. In 2014, the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) trial will be the first trial to report on whether dual anti-HER2 therapy with trastuzumab and lapatinib (in sequence or in combination) improves outcomes compared to single agent trastuzumab. The Addition to Chemotherapy and Herceptin (Trastuzumab) As Adjuvant Therapy in Patients With HER2-Positive Primary Breast Cancer (APHINITY) trial is testing the addition of pertuzumab to standard nonanthracycline or anthracycline-based chemotherapy plus trastuzumab. In addition, A Study of Trastuzumab Emtansine Versus Trastuzumab as Adjuvant Therapy in Patients With HER2-Positive Breast Cancer Who Have Residual Tumor in the Breast or Axillary Lymph Nodes Following Preoperative Therapy (KATHERINE) is examining the role of postoperative T-DM1 versus trastuzumab in patients with HER2-positive disease and less than a pathologic complete response after preoperative therapy with a trastuzumab-based regimen. The remarkable switch from a prognostic marker for worse survival in the absence of treatment to a predictive marker for improved outcome cemented the clinical utility of HER2 overexpression. HER2 amplification occurs in approximately 15% of all newly diagnosed patients.76 Findings from the first generation of adjuvant HER2targeted trials also led the American Society of Clinical Oncology and the College of American Pathologists to provide guidance on HER2 testing.77 Earlier concerns about the high frequency of false-positive HER2 test results have diminished as a result of greater standardization of tissue handling, improved laboratory performance of HER2 testing, and more careful reporting of test results. Current guidelines examine less common clinical scenarios and expand the focus beyond specificity (false-positive results) to also address concerns about sensitivity (false-negative results).77 NSABP B-47 is now attempting to confirm retrospective, hypothesis-generating exploratory data from two of the adjuvant trastuzumab trials regarding a possible benefit in patients confirmed on central testing to have HER2-negative disease but whose tumors had initially tested positive in a local laboratory.78,79 HER2-targeted therapy combined with radiation therapy is also the subject of another www.jco.org
therapy, to be effective, must be accessible to all who suffer from the disease. These are important challenges. But as the American Society of Clinical Oncology faces its second half-century, there is no question but that our community, the front-line of clinical research and practice, is up for the challenge. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: George W. Sledge, Syndax Pharmaceuticals (C) Consultant or Advisory Role: George W. Sledge, Seattle Genetics (C); Eleftherios P. Mamounas, Genomic Health (C), Pfizer (C), Celgene (C), Eisai (C); Gabriel N. Hortobagyi, Allergan (C), Antigen Express (C), Galena (C), Genentech (C), Novartis (C), sanofi-aventis (C) Stock Ownership: None Honoraria: George W. Sledge, Genentech; Eleftherios P. Mamounas, Genomic Health Research Funding: Gabriel N. Hortobagyi, Novartis; Antonio C. Wolff, Genentech, AstraZeneca Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None AUTHOR CONTRIBUTIONS
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DOI: 10.1200/JCO.2014.55.4139; published online ahead of print at www.jco.org on June 2, 2014
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