Mutational Spectrum And Tumor Response In Metastatic Breast Cancer

Background : While several comprehensive genomic sequencing tests are clinically available for breast cancer(BC), little is known about the spectrum of findings reported in the general population and clinical utility of findings for patients(pts). Here we report tumor sequencing from the METAMORPH study, a comprehensive genomic testing approach in pts with metastatic(met) BC. Methods : Pts with either known or suspected BC mets consented to and clinically underwent concurrent diagnostic and research tumor biopsies(bx). FFPE specimens were profiled via Illumina TruSeq Cancer Panel next generation sequencing platform covering 212 amplicons in 47 cancer genes. Pathology, treatment and outcome data were prospectively collected and tracked. Aside from Her2-directed treatment, therapy was not mutation (mut)-matched. Results : 64 pts enrolled between 11/2013 – 05/2015. Of these, 48 had bx successfully sequenced (75%). Of those without sequencing, 5 had negative/insufficient tissue, 2 had insufficient DNA, remainder no bx/pending. Median age of those sequenced was 56 (range 31-78); 81% Caucasian, 17% African American. 25% (12 pts) presented with de novo stage IV disease. Of those with recurrence (n=36), 83% had prior adjuvant chemotherapy; 81% hormone receptor positive(HR+) had prior endocrine therapy. Median # prior lines of therapy for met disease was 2 (IQR 0 – 8). Tumor characteristics, including mut analyses, are shown in Table 1. # muts did not differ significantly by subtype(p=0.22). Frequency of TP53 and PIK3CA hotspot muts was nearly identical to TCGA. Median # muts was 1 for pts with both de novo mets and recurrence(p=0.79). # of muts was not associated with time to recurrence(p=0.80). Excluding pts found to have TP53 mut only or ERBB2 alterations in known Her2+ disease, 42% of pts were identified as having at least one potentially actionable alteration ( PIK3CA mut, AKT1 mut or EGFR amplification). Median time to treatment failure(TTF) on subsequent therapy was 4.1 months for overall group, and 4.1, 6.2, and 1.6 months for HR+/Her2-, any Her2+ and TN, respectively, adjusted for line of therapy(p=0.03). After adjustment for # lines of prior met therapy, TTF was 4.7 vs. 4.1 months for pts with any mut vs. none(p=0.89); 5.7 vs 4.1 months for PIK3CA + vs. not (p=0.94); 3.3 vs. 6.5 months for TP53 + vs. not (p=0.03). Conclusion : Pts with met BC have frequent and potentially actionable muts.While overall # of muts did not affect response, tumors with TP53 muts had shorter response to subsequent therapy in this cohort. Additional data are needed to determine the clinical utility of mut testing in met BC, for both standard and mut-matched therapy. Citation Format: Soucier-Ernst D, Colameco C, Troxel AB, Clark C, Shih N, Maxwell KN, Morrissette J, Lieberman D, Feldman M, Goodman N, Bradbury A, Clark A, Domchek S, Fox K, Glick J, Matro J, Nathanson K, Chodosh L, DeMichele A. Mutational spectrum and tumor response in 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 P6-07-05.