Molecular alterations in metastatic breast cancer and efficacy of PI3K/AKT/mTOR inhibitors in early phase clinical trials

Abstract

Background: PI3K/AKT/mTOR (PAM) pathway alterations are frequent in metastatic breast cancer (MBC). Several PAM inhibitors are currently in clinical development. There is incomplete knowledge regarding biomarkers of response (and resistance) to these agents, as well as the clinical contexts in which they are most useful in. Primary objectives: (1) Characterize the prevalence of molecular alterations in a cohort of MBC patients, with a special focus on PAM pathway alterations. (2) Assess predictive factors of efficacy of PAM inhibitors in this population. Secondary objectives: (1) Characterize the prevalence of actionable alterations according to breast cancer subtype; (2) Assess the clonality of PIK3CA and AKT1 mutations; (3) Assess the rate of enrollment in clinical trials; (4) Explore predictive factors of efficacy to PI3Kα-specific inhibitors. Methods: Retrospective cohort study using prospectively acquired data from several research projects and clinical trials. Consecutive MBC patients screened for gene mutation by Sequenom (somatic mutation profiling of hotspot mutations in 24 oncogenes) or AmpliconSeq (>800 primer pairs targeting mutations in 61 oncogenes and tumor suppressors) were identified. Archival material (primary tumor or metastatic biopsy) was used for sequencing. Mutant Allele Fraction (MAF) was corrected for tumor purity (adjusted MAF) and categorized as clonal (>0.3) or subclonal (≤0.3). Efficacy of PAM inhibitors measured as Clinical Benefit Rate (CBR; proportion of patients with complete response, partial response or stable disease at 16 weeks by RECIST v.1.1) and Time to Treatment Failure (TTF; time from treatment start until discontinuation for any reason). Statistical analysis performed with R software (v 3.2). Nonparametric tests for comparisons of discrete counts (Fisher’s exact test) were performed. Cox Proportional Hazards modeling (univariable and multivariable) was performed using R package survival, with P values derived from Log-Rank test. Results: 327 MBC patients screened from January 2010 to December 2015. TP53 mutation was the most frequent alteration (34.2%), followed by PIK3CA mutation (24%), FGFR1 amplification (15.8%), and PTEN dysregulation (null expression 10.6%, mutation 5.7%). In HR+/HER2- tumors (61.5%), the most frequent actionable alterations were PIK3CA mutation (27.9%), FGFR1 amplification (15%), PTEN null (9.3%), ESR1 mutation (8.2%), and AKT1 mutation (5.5%). In HER2+ tumors (11%), PIK3CA mutation (27.8%), FGFR1 amplification (6%), and PTEN null (3.6%). In triple negative tumors (18%), PTEN dysregulation (null 20.5%, mutation 16%), FGFR1 amplification (10%), and PIK3CA mutation (8.5%). Both PIK3CA and AKT1 mutations were clonal (median adjusted MAF of 0.49 and 0.83, respectively). The rate of enrollment in genotype-matched clinical trials was 22.6%. PIK3CA mutation associated with better CBR (OR 2.95, P=0.008) and TTF (HR 0.66, 95%CI 0.45-0.96, P=0.031) to PAM inhibitors. Multivariate analysis showed that patients with PIK3CA mutation, treated early in their course of metastatic disease in trials testing combinations with endocrine or chemotherapy had better outcomes than the rest (P<0.05 for all comparisons). Clonality of PIK3CA mutation was not predictive of benefit to treatment with PAM inhibitors (HR 1.09, 95%CI 0.48-2.52; P=0.828) or to PI3Kα-specific inhibitors (HR 0.57, 95%CI 0.16-2.01; P=0.380), although patients with clonal PIK3CA treated with PI3Kα-specific inhibitors had numerically higher median TTF than those with subclonal events (11.4 months vs. 5.5 months). Conclusions: Molecular alterations were frequent events in this cohort. PIK3CA mutation (a clonal event) was the most common alteration. Patients with actionable alterations were enrolled in clinical trials with matched agents more frequently than in other datasets. Patients with PIK3CA mutation, treated early during their metastatic disease in trials testing combinations with endocrine or chemotherapy, benefit most from PAM inhibitors. Clonality of PIK3CA mutation does not correlate with efficacy of PAM inhibitors or PI3Kα-specific inhibitors.

Date of Award	10 Jul 2017
Original language	English
Awarding Institution	Vall d'Hebron University Hospital (HUVH)
Supervisor	Jorge Luis Giralt (Director) & Jorge Luis Giralt (Tutor)