Abstract P3-07-41: Genomic alterations indicative of a luminal A subtype associate with clinical benefit to buparlisib and letrozole in endocrine-resistant ER+/HER2– metastatic breast cancer
Authors: Balko JM , Hicks M , Berger MF , Solit DB , Bouvier N , Sanders ME , Estrada MV , Won H , Cantley LC , Mayer IA , Arteaga CL 
Published: May 2016

Background: Activation of the phosphoinositide-3-kinase (PI3K) pathway has been associated with resistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer. Recently, we reported a Stand Up 2 Cancer (SU2C) Phase Ib trial of buparlisib, an oral, reversible, pan-PI3K inhibitor in combination with the aromatase inhibitor letrozole in patients with metastatic ER+/HER2– breast cancer (n=51) who had previously progressed on endocrine therapy. In this study, 31% of patients demonstrated clinical benefit (CR, PR and SD ≥6 months; Mayer et al. JCO 2014). Clinical activity was observed in patients with PIK3CA-wild type (PIK3CA-WT) and PIK3CA-mutant (PIK3CA-MUT) tumors. We performed targeted next-generation sequencing (tNGS) to identify somatic alterations associated with clinical benefit to the combination therapy.

Methods: tNGS was performed using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) in DNA extracted from tumors of 33 study patients (22 samples from archived primary/untreated and 11 from metastatic biopsies). Detected alterations were tested for association with clinical benefit (Fisher's exact test) and progression-free survival (PFS; log-rank test). For PFS analysis, patients were censored if they discontinued buparlisib for toxicity.

Results: The most commonly detected alterations occurred in PIK3CA (36%), TP53 (30%), MAP3K1 (27%), GATA3 (24%), CCND1 (24%), CDH1 (21%) and PTEN (21%). Additional alterations of note included FGFR1 amplification (15%), MYC amplification (12%), ESR1 mutations (6%) and ERBB2 mutations (6%). Probable inactivating mutations occurring in MAP3K1 (MAP3K1-MUT) were significantly associated with improved clinical benefit, regardless of other mutations (6/9 patients, 67%, P=0.044). PIK3CA-MUT tumors trended toward greater clinical benefit (7/12, 58%, P=0.067). Patients with coexisting PIK3CA-MUT and MAP3K1-MUT tumors derived the largest clinical benefit (5/7, 70% P=0.07) compared to patients with only PIK3CA-MUT (2/5; 40%, P=1.0) or only MAP3K1-MUT tumors (1/2; 50%, P=1.0). Only 2/19 (11%) patients with PIK3CA-WT/MAP3K1-WT cancers benefitted from treatment. Both MAP3K1 and PIK3CA alterations were each also associated with increased PFS (p=0.03 and p=0.009, respectively). Three of 5 (60%) patients with tumors with FGFR1 amplification achieved clinical benefit (including a MAP3K1-MUT tumor and a PIK3CA-MUT/MAP3K1-MUT tumor), suggesting that FGFR1 may preferentially signal via PI3K and/or FGFR1 amplifications are not associated with resistance to the combination of aromatase inhibitors and PI3K inhibitors.

Conclusions: Both MAP3K1 and PIK3CA are mutated at higher frequencies in luminal A breast cancer, suggesting that this alteration pattern (MAP3K1-MUT + PIK3CA-MUT) is a surrogate for low grade ER+ breast cancers with PI3K dependence. It is also possible that MAP3K1 mutations may predispose tumor cells to sensitivity to PI3K inhibition, but this speculation requires further investigation. Finally, patients with ER+/FGFR1-amplified cancers appeared to derive clinical benefit from combined therapy with letrozole and buparlisib.

Citation Format: Balko JM, Hicks M, Berger MF, Solit DB, Bouvier N, Sanders ME, Estrada MV, Won H, Cantley LC, Mayer IA, Arteaga CL. Genomic alterations indicative of a luminal A subtype associate with clinical benefit to buparlisib and letrozole in endocrine-resistant ER+/HER2– metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-41.