Neoadjuvant treatment: the MD Anderson experience

Adjuvant chemotherapy has traditionally been administered in the postoperative setting. However, numerous studies have evaluated its use preoperatively. The potential benefits of neoadjuvant chemotherapy (NACT) include downstaging the primary tumor to allow breast-conserving surgery and assessment of a tumor's in vivo sensitivity to individual chemotherapeutic regimens. Our group at the MD Anderson Cancer Center initiated clinical trials with neoadjuvant chemotherapy in 1974, and over the past three decades we have treated several thousand patients in prospective clinical trials. Initially, NACT was reserved for the treatment of patients with locally advanced and/or inflammatory breast cancers. These studies clearly demonstrated that most patients had a marked reduction in tumor volume with anthracycline–cyclophosphamide–fluorouracil based regimens. Inoperable tumors became operable for most patients, and later studies indicated that even large tumors became candidates for breast-conserving therapies. We described 20 years ago the prognostic value of pathological complete remission (pCR), and subsequent studies included pCR as a surrogate end-point for long-term efficacy. These findings were later confirmed by the largest study evaluating the impact of neoadjuvant chemotherapy, the NSABP B-18. In this study, 1523 women were randomized to receive four cycles of doxorubicin and cyclophosphamide either prior to or after surgical resection. Another large study of similar design was performed by the EORTC, with similar results. The timing of chemotherapy did not affect the disease-free or overall survival for the entire cohort, although more patients who received preoperative therapy were able to undergo breast conservation rather than mastectomy in comparison to those treated postoperatively. These studies confirmed the clear correlation of pathological complete response (pCR) in the breast (absence of invasive cancer cells) with survival. Using a single, anthracycline-containing chemotherapy regimen, a pCR rate of about 10–13% can be obtained. The definition of pCR used by our group includes the absence of lymph node involvement, in contrast to the definitions used by NSABP and other groups. The pCR rate has become one of the most important intermediate trial endpoints in assessing the efficacy of new adjuvant chemotherapy regimens. Published studies of anthracycline-based preoperative chemotherapy demonstrate pCR rates of up to 17%. Several recently reported studies including the sequential use of anthracycline-based regimens and taxanes have achieved significantly higher pathologic responses, ranging from 25% to 34%. Our studies focused on the sequential use of anthracyclines and taxanes, showing excellent tolerance and efficacy of this strategy. In addition, we demonstrated the therapeutic superiority of weekly paclitaxel in this setting. These findings were subsequently confirmed by much larger, randomized trials conducted by another cooperative group. We used the neoadjuvant strategy for the initial evaluation of trastuzumab in patients with primary breast cancer. That small randomized trial indicated an almost threefold increase in pCR with the addition of trastuzumab to chemotherapy. Currently, we conduct studies with gene profiling in the neoadjuvant setting to determine predictors of pCR, and therefore long-term prognosis, and to develop individualized medicine for patients with primary breast cancer. There are multiple remaining questions related to the use of this strategy, however. Some pertain to optimal local-regional therapies: when should axillary assessment be performed in relation to NACT, what should be the criteria for administration of postmastectomy radiation therapy following NACT, and how to optimally perform breast-conserving surgery following NACT. The role and relative timing of neoadjuvant hormone therapy (NAHT) is also under intensive evaluation at this time. This is solely relevant to the group of patients with hormone receptor-positive tumors, but has potential impact on the type and sequence of local, regional and systemic therapies.