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

Abstract

Background Due to inherent disease heterogeneity, targeted therapies have eluded TNBC, and biomarkers predictive of treatment response have not yet been identified. This study was designed to determine if the mTOR inhibitor everolimus with cisplatin and paclitaxel would provide synergistic anti-tumor effects in TNBC. Methods Stage II/III patients with 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 pathological complete response (pCR); secondary endpoints included clinical responses, breast conservation rate, safety, and discovery of molecular features associated with outcome. Results Between 2009 and 2013, 145 patients were accrued; 36% patients in the everolimus arm and 49% 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. Conclusion 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.

Neoadjuvant Chemotherapy in Triple Negative Breast Cancer: Correlation between Androgen Receptor Expression and Pathological Response

“…Furthermore, we reported that the rate of pCR to NAC was 24.1% for TNBC AR+ group compared with 60% of QNBC group. These findings matched with voluminous previous reports (Hilborn et al, 2016;Gerratana et al, 2018;Masuda et al, 2013;Asano et al, 2016;Asano et al, 2017, andovanović et al, 2017).…”

“…In a recent randomized phase II trial to evaluate the NAC (cisplatin, paclitaxel ± everolimus) in 145 patients with TNBC showed that low expression level of AR was linked to higher pCR than higher AR levels. Moreover, the investigators demonstrated a lack of significant changes in AR levels (before, during or after NAC), suggesting that the chemotherapy did not affect AR expression (Ovanović et al, 2017).…”

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

“…Responses were limited to patients with NGS aberrations in PIK3CA, AKT, or PTEN. In the neoadjuvant setting, the addition of everolimus to cisplatin and paclitaxel did not increase pCR in molecularly unselected TNBC, and exploratory analyses showed that those who achieved pCR were not enriched for mutations in the PI3K/ AKT/mTOR pathway (47).…”

A Population of Heterogeneous Breast Cancer Patient-Derived Xenografts Demonstrate Broad Activity of PARP Inhibitor in BRCA1/2 Wild-Type Tumors

“…Lehmann et al identified six distinct TNBC subtypes, each displaying a unique biology, with recent studies merging these into four transcriptionally defined subtypes (8,9). These subtypes, have been found to be associated with response to chemotherapy (2,8,10). Balko et al have further evaluated the molecular profiles of residual disease in patients with TNBC who received NeoCT and reported a variety of genomic alterations (mutations and copy number changes) including alterations in cell cycle, phosphoinositide 3-kinase (PI3K)/mTOR alterations, growth factor receptor amplifications, Ras/mitogen-activated protein kinase (MAPK) alterations, DNA repair alterations (11).…”