MS4-1: The Neoadjuvant Setting, HER2−Driven and Triple Negative Breast Cancer.
Authors: LA Carey
Journal: Cancer Research (2011)

Abstract The benefits of neoadjuvant therapy include: tumor cytoreduction, minimizing surgical resection volume, conversion to breast conservation, and the opportunity to test new drugs and regimens because response in the breast is a surrogate for long-term survival. Off-trial, neoadjuvant regimens should mimic adjuvant regimens in drug, dose, and schedule; “tailored” approaches or treatment to best response have not been adequately studied. In HER2+ and triple negative (ER−, PR-, and HER2−negative, TNBC) BrCa, the backbone of neoadjuvant treatment is chemotherapy, with HER2−targeting added to the former. In hormone receptor-positive, HER2−negative BrCa, randomized clinical trials suggest similar efficacy of endocrine therapy and chemotherapy in response, however pathologic complete response (pCR) is rare. HER2−targeting with the anti-HER2 antibody trastuzumab (H) added to chemotherapy for HER2+ BrCa augments pCR, with 1 year of H completed adjuvantly. Off-trial options include AC-docetaxel (D) + H, AC-paclitaxel (T) + H, and D + carboplatin + H (DCH). It is likely that small, node-negative HER2+ BrCa are overtreated by these regimens; a challenge is to develop less chemotherapy-intensive regimens for the lower-risk setting. Several studies have examined other HER2−targeted drugs. In NeoALTTO, HER2+ patients received either TH, T + HER1/HER2 inhibitor lapatinib (TL), or the combination THL. pCR was lower (and toxicity higher) in TL; THL had the highest pCR rate (47%). GeparQuinto compared EC-DH to EC-DL and also found lower pCR rate and higher toxicity in the L-containing arm. NeoSPHERE examined the anti-HER2 heterodimerization domain antibody pertuzumab (P), pCR rates were higher with combination DHP (46%) vs. DH (29%) and DP (24%). The all-biologic HP arm had a 17% pCR rate. In TBCRC006, HL alone resulted in a 28% pCR rate. These studies support combination HER2−targeting-based regimens in adjuvant trials. TNBC lacks the known targetable molecules, ER, PR, or HER2, leaving chemotherapy the mainstay of treatment. Early TNBC is sensitive to conventional agents, and possesses one of the highest pCR rates to neoadjuvant anthracycline/taxane-based chemotherapy. The use of DNA-damaging drugs in TNBC is based on the association of Basal-like BrCa with BRCA1 germline mutations. Neoadjuvant studies are small and heterogeneous but supportive of a high pCR rate (&amp;gt;70%) to platinums in known carriers, however studies of sporadic TNBC are less clear. CALGB 40603, an ongoing randomized phase II study of taxane with or without carboplatin and with and without the antiVEGF antibody bevacizumab (B), will provide direct evidence. Although lacking known targeted therapy, subset analysis of the HER2−negative component of GeparQuinto suggested that TNBC had higher pCR rates with EC-D + B (45%) compared with chemotherapy alone (36%). The biology and identification of novel targets in TNBC as well as optimization of the chemotherapy remain subjects of intense study. Neoadjuvant therapy is an excellent approach for patients with clinical stage II-III in whom the nature of systemic therapy is clear. It also provides a rich laboratory for drugs, regimens, and the identification of predictive markers and subtype biology in a timely and efficient manner. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr MS4-1.