GeparTrio was an innovative phase III trial conducted by the German Breast Group, enrolling over 2,000 women with early breast cancer who were candidates for neoadjuvant chemotherapy. Patients with evidence of early response, defined as reduction in clinical tumor size by 50% or more, following two cycles of docetaxel, doxorubicin, and cyclophosphamide (TAC) were randomized to conventional vs intensification arms for a total of six or eight cycles of the combination (TAC × 6 and TAC × 8, respectively). The response-guided treatment intensification did not lead to improvement in pathologic complete response rates, the primary endpoint of the study (21% and 23.5% for TAC × 6 and TAC × 8, respectively). Moreover, the longer duration of chemotherapy was associated with a higher degree of toxicity.1,2
Patients without an early response after two cycles of TAC were randomized to conventional four additional cycles of TAC or to an investigational arm consisting of vinorelbine and capecitabine (NX). Pathologic complete response rates in early nonresponders was low in both arms (approximately 6%).
Role of Pathologic Complete Response
Pathologic complete response following neoadjuvant chemotherapy is an accepted primary endpoint in clinical trials, as it is associated with improved disease-free survival and overall survival.3,4 It is intriguing, therefore, that the exploratory analysis of long-term survival of the GeparTrio trial indicated that disease-free survival was significantly longer in early responders receiving TAC × 8 than in those receiving TAC × 6, and in early nonresponders receiving TAC-NX than in those receiving TAC × 6.
Compared to the conventional groups combined, response-guided therapy was associated with a significantly longer disease-free survival and with a significant but marginal overall survival benefit. This observation may relate, in part, to inadequate follow-up for the predominantly hormone receptor–positive population enrolled in the study. In an exploratory post hoc subgroup analysis, response-guided therapy was most effective in patients with hormone receptor–positive disease.
It has been recognized that pathologic complete response is not an appropriate surrogate for survival in all breast cancer subtypes. Indeed, the U.S. Food and Drug Administration (FDA) released a Draft Guidance to Industry in 2012 outlining a pathway to accelerated approval for neoadjuvant breast cancer therapies.5 This guidance supports the use of pathologic complete response as a regulatory endpoint for new drug development in HER2-positive and triple-negative but not hormone receptor–positive breast cancer. Furthermore, final approval of an agent or a combination based on a neoadjuvant treatment strategy is dependent on the provision of additional supportive data, including the results of adjuvant studies that are ongoing or planned at the time of accelerated approval.
Other Clinical Trial Designs
While results from GeparTrio support the hypothesis that response-guided treatment strategies may be beneficial for early breast cancer patients receiving neoadjuvant chemotherapy, this approach is “not ready for prime time” for a number of reasons, including the exploratory nature of the analysis, which was not powered to show differences in survival. In addition, the subgroup analysis that suggested a benefit to response-guided treatment in hormone receptor–positive patients was not preplanned. Other limitations include lack of anti-HER2 therapy in patients with HER2-positive tumors and subtype designation based on immunohistochemical analysis and histologic grading. Dr. von Minckwitz and colleagues correctly conclude that a prospective validation of the results is required prior to adopting the approach, and that the results may guide the design of future studies.
In addition to response-guided strategies, other clinical trial designs in the neoadjuvant setting have been used in order to improve both short- and long-term outcomes for breast cancer patients. For example, in GeparSixto, higher pathologic complete response rates were observed when carboplatin was added to an anthracycline/taxane–based backbone compared to anthracycline/taxane alone, although the more-intensive regimen was also associated with increased toxicity.6
Cancer and Leukemia Group B (CALGB) 40603 investigators are also evaluating the value of adding platinum agents to an anthracycline/taxane approach in a similar patient population, and results are eagerly awaited. Novel agents may also be added to the standard anthracycline/taxane–based backbone in an effort to improve outcomes for high-risk patients.
Personalizing Therapy
Most of the studies conducted to date in the neoadjuvant setting involve intensifying therapy in order to improve outcomes in patients with high-risk early breast cancer. However, it is clear that there are many patients who do not require or will not benefit from this aggressive approach. The challenge is how to reduce the number of agents or duration of treatment administered to some women with stage II/III breast cancer.
Advances have been made in personalizing therapy for breast cancer over the past several years, with prospective/retrospective studies suggesting a role for gene-expression signatures such as Oncotype DX as a prognostic marker in patients with hormone receptor–positive disease who have been treated with endocrine agents.7 Patients with a high recurrence score appear to be the ones most likely to derive benefit from the addition of chemotherapy, and those with a low score may be better served by entering into clinical trials attempting to overcome resistance to endocrine-based strategies. Similar prognostic and predictive tools are needed for women with hormone receptor–negative or HER2-positive disease.
Clinical trials in patients with hormone receptor–positive and HER2-positive disease should also aim to identify subpopulations of patients who may be treated with targeted therapy alone, avoiding chemotherapy, through innovative study designs. Prior to initiating large-scale studies, investigators should also consider smaller neoadjuvant studies using surrogate biomarkers of response to assess magnitude of effects in specific populations. Early biomarkers (for example functional imaging or blood- or tissue-based biomarkers as early as 1 or 2 weeks following treatment initiation) have the potential to identify a group of women who can be spared additional futile, toxic, and costly therapies, and who can be transitioned to an alternative regimen or proceed with local therapy.
Conclusions
In summary, studies in the neoadjuvant setting should be specific to tumor subtype and may include standard and/or novel targeted therapies. For patients with triple-negative and HER2-positive breast cancer, pathologic complete response is an acceptable primary endpoint and surrogate for long-term outcomes. The neoadjuvant approach is more challenging for patients with hormone receptor–positive disease, due to the lack of correlation with pathologic complete response and long-term outcome. Predictors of pathologic complete response at baseline and early in the treatment course may be most valuable in limiting the administration of unnecessary and aggressive therapies to breast cancer patients. Until additional data are available, investigators should continue to follow practice guidelines clinically and FDA guidance as they design new trials. ■
Dr. Connolly is Assistant Professor of Oncology, and Dr. Stearns is Professor of Oncology, Breast Cancer Research Chair in Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore.
Disclosure: Dr. Connolly has received grants for clinical trial conduct from Novartis and Puma Biotechnology. Dr. Stearns has received grants for clinical trial conduct from Abbott, Abraxis (Celegene), Medimmune, Merck, Novartis, and Pfizer.
References
1. von Minckwitz G, Kummel S, Vogel P, et al: J Natl Cancer Inst 100:542-551, 2008.
2. von Minckwitz G, Kummel S, Vogel P, et al: J Natl Cancer Inst 100:552-562, 2008.
3. Wolmark N, Wang J, Mamounas E, et al: J Natl Cancer Inst Monogr 30:96-102, 2001.
4. Kong X, Moran MS, Zhang N, et al: Eur J Cancer 47:2084-2090, 2011.
5. U.S. Food and Drug Administration: Guidance for Industry. Available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM305501.pdf. Accessed November 4, 2013.
6. von Minckwitz G, Schneeweiss A, Salat C, et al: ASCO Annual Meeting. Abstract 1004. Presented June 3, 2013.
7. Dowsett M, Cuzick J, Wale C, et al: J Clin Oncol 28:1829-1834, 2010.
