Defining the benefits of neoadjuvant chemotherapy for breast cancer.

Preoperative or neoadjuvant chemotherapy is an option in patients with early-stage breast cancer. Neoadjuvant treatment has been compared with standard, postoperative adjuvant chemotherapy with the dual goals of improving survival and facilitating local therapies. Unfortunately, neoadjuvant chemotherapy does not seem to improve overall survival, as demonstrated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B18 trial, among others. Neoadjuvant chemotherapy may convert a previously unresectable, locally advanced breast cancer to an operable tumor, and in primarily operable tumors, downstaging results in a small increase (7% to 12%) in breast conservation rates. However, many patients experience insufficient response or are not candidates for breast preservation, irrespective of response, because of either skin or chest wall involvement or multicentric or multifocal disease. Furthermore, an estimated 10% of American women choose mastectomy as a personal preference despite their surgeons’ recommendation of breast-conserving therapy. Aside from the potential clinical benefits that are achieved by downstaging, neoadjuvant therapy allows direct and early observation of the response to treatment, which in theory could lead to modifications of the treatment plan in the event of poor response. However, clinical and radiographic monitoring during neoadjuvant chemotherapy to predict pathologic complete response (pCR) is notoriously inaccurate. Furthermore, although it is clear that those patients with a poor initial response have a worse prognosis, modification of chemotherapy after observed poor response has not resulted in clinically meaningful improvements in outcome. On the basis of the limited clinical advantages of neoadjuvant chemotherapy, postoperative adjuvant systemic therapy is considered the standard of care. The preoperative setting could provide an opportunity to study the impact of systemic therapies on breast cancer biology. As a research tool, neoadjuvant chemotherapy is useful because of the availability of tumor response as an end point and the availability of tissue for biopsy and biomarker development. To facilitate neoadjuvant trials, empirical definitions of pCR have been developed with the goal of using pCR as a surrogate for long-term outcomes. Numerous studies have demonstrated that the burden of pathologically detected residual disease after neoadjuvant chemotherapy is associated with long-term prognosis. However, there has been little if any agreement regarding the precise definition of pCR. In the article that accompanies this editorial, von Minckwitz et al address this controversy in a review of their experience with more than 6,000 patients treated in a series of seven prospectively conducted clinical trials of neoadjuvant anthracycline and taxane–based chemotherapy (some including trastuzumab). They compared multiple existing definitions of pCR to determine how robustly each definition serves as a surrogate for patient survival outcomes. Not surprisingly, they found that the pCR definition that allowed the least residual cancer in the breast and nodes was most highly correlated with the best survival. Although some authors have reported that small amounts of residual invasive or in situ cancer do not seem to be prognostic, the data from this highly powered, pooled analysis of prospectively performed neoadjuvant trials suggest otherwise: any finding of residual cancer—in situ, invasive, or in axillary lymph nodes—was associated with a worse prognosis compared with absolutely no evidence of residual disease. This result, by itself, would probably not have warranted publication in such a high-impact journal as Journal of Clinical Oncology. However, the authors have provided clarity with respect to the results of neoadjuvant chemotherapy by further evaluating the prognostic implications of pCR, using their best definition, within the separate intrinsic breast cancer biologic subtypes. In their large data set, von Minckwitz et al clearly demonstrate that pCR to anthracycline and taxane–based chemotherapy (or lack thereof) had no substantial prognostic value in patients with luminal A (estrogen receptor [ER] positive and/or progesterone receptor [PgR] positive, human epidermal growth factor receptor 2 [HER2] negative, grade 1 or 2) tumors. In fact, the pCR rate is so low in this group (6.7%) that residual disease after treatment with cytotoxic chemotherapy should be expected. Perhaps more surprisingly, pCR in luminal B/HER2-positive tumors (ER positive and/or PgR positive, HER2 positive, all grades) was relatively uncommon (11% to 22%), even with the use of trastuzumab, and achievement of pCR in this subgroup was also not prognostic for survival. In contrast, patients whose subtype is typically associated with a worse prognosis (triple negative, or ER negative and HER2 positive) were much more likely to have pCR (28% to 32%), and those who achieved pCR had a much better outcome. Although the reasons for these findings are not entirely clear from these data, a possible explanation is that lack of pCR to chemotherapy in less proliferative JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 15 MAY 2