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Pietenpol Lab

A Randomized Phase II Neoadjuvant Study of Cisplatin, Paclitaxel With or Without Everolimus in Patients with Stage II/III Triple-Negative Breast Cancer (TNBC): Responses and Long-term Outcome Correlated with Increased Frequency of DNA Damage Response Gene Mutations, TNBC Subtype, AR Status, and Ki67

AUTHORS

Jovanović BBojana , Mayer IAIngrid A , Mayer ELErica L , Abramson VGVandana G , Bardia AAditya , Sanders MEMelinda E , Kuba MGM Gabriela , Estrada MVMonica V , Beeler JSJ Scott , Shaver TMTimothy M , Johnson KCKimberly C , Sanchez VVioleta , Rosenbluth JMJennifer M , Dillon PMPatrick M , Forero-Torres AAndres , Chang JCJenny C , Meszoely IMIngrid M , Grau AMAna M , Lehmann BDBrian D , Shyr YYu , Sheng QQuanhu , Chen SCSheau-Chiann , Arteaga CLCarlos L , Pietenpol JAJennifer A . Clinical cancer research : an official journal of the American Association for Cancer Research. 2017 03 07; 23(15). 4035-4045

ABSTRACT

Because of inherent disease heterogeneity, targeted therapies have eluded triple-negative breast cancer (TNBC), and biomarkers predictive of treatment response have not yet been identified. This study was designed to determine whether the mTOR inhibitor everolimus with cisplatin and paclitaxel would provide synergistic antitumor effects in TNBC. Patients with stage II/III TNBC were enrolled in a randomized phase II trial of preoperative weekly cisplatin, paclitaxel and daily everolimus or placebo for 12 weeks, until definitive surgery. Tumor specimens were obtained at baseline, cycle 1, and surgery. Primary endpoint was pathologic complete response (pCR); secondary endpoints included clinical responses, breast conservation rate, safety, and discovery of molecular features associated with outcome. Between 2009 and 2013, 145 patients were accrued; 36% of patients in the everolimus arm and 49% of patients in the placebo arm achieved pCR; in each arm, 50% of patients achieved complete responses by imaging. Higher rates of neutropenia, mucositis, and transaminase elevation were seen with everolimus. Clinical response to therapy and long-term outcome correlated with increased frequency of DNA damage response (DDR) gene mutations, Basal-like1 and Mesenchymal TNBC-subtypes, AR-negative status, and high Ki67, but not with tumor-infiltrating lymphocytes. The paclitaxel/cisplatin combination was well tolerated and active, but addition of everolimus was associated with more adverse events without improvement in pCR or clinical response. However, discoveries made from correlative studies could lead to predictive TNBC biomarkers that may impact clinical decision-making and provide new avenues for mechanistic exploration that could lead to clinical utility. .