Insight or Confusion: Survival After Response-Guided Neoadjuvant Chemotherapy in Breast Cancer

Abstract

In current clinical practice, the use of neoadjuvant chemotherapy for the treatment of breast cancer is well established. Once reserved for the treatment of locally advanced inoperable tumors, the neoadjuvant treatment strategy has been increasingly employed in operable breast cancer with good reason. This strategy offers a number of advantages over adjuvant therapy, with in vivo assessment of tumor response ranking among the most important. The neoadjuvant strategy has shown great potential as a platform for drug development, and this has led the US Food and Drug Administration to recently strongly consider pathologic response to neoadjuvant therapy as an end point to support accelerated drug approval in high-risk early-stage breast cancer. 1 Historical results from a series of important neoadjuvant trials have shaped our current thinking. It has been clearly established that long-term outcomes are similar whether treatment is given preoperatively or postoperatively and that a pathologic complete response (pCR) at the time of surgery is associated with a favorable outcome in all patients who achieve it. 2-4 Failure to achieve a pCR is clearly associated with worse long-term outcomes in triple-negative and human epidermal growth factor receptor 2 (HER2) –positive breast cancer, though this negative prognostic association is not observed for the majority of hormone receptor–positive breast cancers. 5-7 Rates of pCR following neoadjuvant chemotherapy in hormone responsive breast cancer are uniformly low and because these patients arguably receive their most important therapy, endocrine therapy, after chemotherapy, the focus of current neoadjuvant chemotherapy trials has shifted away from this group of patients in large part. Instead, neoadjuvant endocrine therapy strategies have been increasingly investigated for these patients and the field has moved more generally toward strategies to omit chemotherapy in hormone receptor–positive patients unlikely to derive benefit based on results of multiplex gene expression assays. In the article that accompanies this editorial, von Minckwitz et al 8 report survival outcomes after response-guided neoadjuvant chemotherapy in the German Breast Group GeparTrio study. In the German Breast Group tradition, this phase III study represents an enormous effort that tests an interesting strategy of response-guided chemotherapy treatment. More than 2,000 patients with stage II/III breast cancer were treated with an initial two cycles of docetaxel 75 mg/m 2 , doxorubicin 50 mg/m 2 , and cyclophosphamide 500 mg/m 2 on day 1 every 21 days (TAC). Patients achieving clinical response were then randomly assigned to continuing the same therapy for four or six additional cycles and nonresponders were randomly assigned to continue the same therapy or sequence to an alternate chemotherapy combination of navelbine 25 mg/m 2 days 1 and 8 and capecitabine 1,000 mg/m 2 orally twice per day on days 1 through 14 of a 21-day cycle (NX) for four cycles. Patients were accrued from 2002 to 2005 and the patient characteristics and therapies are reflective of the times. Notably, HER2 status was unknown in approximately 20% and no patient received neoadjuvant or adjuvant trastuzumab. The primary end points of the study were to compare pCR rates in early responders and clinical response in early nonresponders. The previously reported primary results showed a nonstatistically significant difference in pCR among early responders treated with TAC 6 compared with TAC 8 (21% v 23.5%; P .27) 9 and similar clinical responses were observed among early nonresponders with TAC 6 compared with TAC NX (50.5% v 51.2%; P .008 for noninferiority). 10 In the article accompanying this editorial, von Minckwitz et al 8 report on the predefined secondary end points of disease-free survival (DFS) and overall survival (OS). At a median follow-up of 62 months, DFS was significantly longer in early responders treated with TAC 8 compared with TAC 6 (hazard ratio [HR], 0.78; 95% CI, 0.62 to 0.97; P .026) and in early nonresponders treated with TAC NX compared with TAC 6 (HR, 0.59; 95% CI, 0.49 to 0.82; P .001). No significant difference in OS was observed in these two groups, though there was a trend toward improved OS in responders receiving TAC 8 compared with TAC 6 (HR, 0.76; 95% CI, 0.57 to 1.01; P .060). As the sample size was calculated to provide adequate power for the primary end point, the study is underpowered for the end points of DFS and OS. In addition, though the groups were reasonably balanced in terms of baseline characteristics, there were fewer patients with grade 3 tumors in the nonresponder group treated with TAC NX (25%) compared with TAC 6 (36%), and this difference was statistically significant. The unexpected finding, namely, that response-guided therapy influences disease-free survival only in hormone receptor– positive and not hormone receptor–negative breast cancer, rests on a secondary exploratory subgroup analysis and therefore needs to