Neoadjuvant versus adjuvant systemic therapy for operable breast cancer: equivalent outcomes?

T he central goals of breast cancer treatment are maximizing survival, reducing risk of recurrence, and preserving the normal appearance of the breast. Achieving these goals requires use of local therapies including surgery and radiation in combination with systemic chemotherapy and endocrine therapy. Discussion continues as to the optimum extent of each treatment and sequence of each modality relative to the others.1 Increasingly, treatments and treatment sequences are individualized on the basis of the features of the individual patient and her tumor. For most breast cancer patients, the first intervention is surgery, followed by “adjuvant” systemic therapy. Use of systemic therapy before surgery was initially reserved for patients with inoperable and locally advanced tumors. This preoperative or “neoadjuvant” approach can reduce the size of tumor deposits at primary and nodal sites and can convert inoperable tumors into an operable state. Systemic therapy has also been explored as the first treatment modality in patients with operable breast cancers. In theory, delivery of systemic therapy first might improve overall survival by eliminating occult metastatic tumor deposits earlier in the course of treatment. It was also hoped that administering chemotherapy first would allow adjustment of systemic therapy regimens based on the primary tumor response, making it possible to discontinue ineffective drugs and try alternative agents until an effective regimen was found. Unfortunately, neither of these hopes has yet been realized. Survival was no better (but no worse) with preoperative versus postoperative chemotherapy in any of the prospective randomized trials.2–4 Thus, although systemic therapy is clearly beneficial for overall and disease-free survival in breast cancer patients, the timing of systemic therapy relative to surgery is not important. It has also not been possible to tailor treatment regimens to primary tumor response, largely due to the lack of reliable early markers of tumor response. Despite these negative results, use of preoperative chemotherapy in operable breast cancers has provided several useful therapeutic insights. Perhaps most important is the observation that approximately 80% of primary breast tumors shrink with a course of neoadjuvant chemotherapy. Neoadjuvant therapy can reduce the size of large operable breast cancers, permitting breast conservation in some patients who would have required mastectomy on the basis of their initial tumor size.3–5 This neoadjuvant approach has now been extended to patients already eligible for breast conservation to reduce the primary tumor size, allowing for a smaller lumpectomy and a better cosmetic result. The degree of primary tumor response to neoadjuvant therapy also provides prognostic information. Long-term survival is consistently higher in the 10% to 25% of patients with a pathological complete response to preoperative therapy. As a result, the rate of pathological complete response has become a useful early readout for assessing the efficacy of new systemic therapy agents in clinical trials. In summary, in its present form, neoadjuvant therapy can reduce the extent of surgery required for operable breast cancers, with no decrease in overall survival. Neoadjuvant therapy may also be used to test new treatment regimens and may provide favorable prognostic information for patients who have a pathological complete response. However, there has been concern that these benefits of neoadjuvant therapy may come at the cost of higher rates of in-breast local recurrence after a lumpectomy. In the NSABP B-18 trial, there was a trend toward higher local recurrence rates after neoadjuvant therapy4; in-breast tumor, recurrence was seen in 10.7% of patients who underwent a lumpectomy after neoadjuvant chemotherapy compared with 7.6% of patients who had a lumpectomy followed by chemotherapy (P = 0.12). Although this difference was not statistically significant, concerns about local recurrence risk have persisted.