Background: Next generation sequencing (NGS) has revealed significant heterogeneity among patients’ tumors. Molecular aberrations may be both prognostic and predictive.
Methods: We retrospectively analyzed 57 patients with advanced or metastatic breast cancer, with NGS profiling of their tumors, treated on Phase I trials at MD Anderson Cancer Center and UCSD-Moores Cancer Center. The objectives of this study were to: 1) characterize molecular aberrations and, 2) correlate molecular aberrations with response to targeted therapies.
Results: Fifty-seven patients with advanced or metastatic breast cancer with NGS profiling of their tumors were included. Fifty-six of 57 patients (98%) with NGS analysis of their tumors demonstrated at least one molecular aberration. A total of 216 somatic aberrations in 71 different genes were identified including variants in the same gene. There were 99 mutations, 97 amplifications, 11 deletions, 5 splices, 2 truncations, 1 fusion and 1 rearrangement. The most commonly mutated genes were: TP53 (26 patients, 46%); PIK3CA (18 patients, 32%); PIK3R1, GATA3 (5 patients, 9% each); BRCA2, CDH1, and NF1 (3 patients, 5% each). The most common amplifications occurred at: CCND1, MYC (12 patients, 21% each); HER2 (official gene name ERBB2), MCL1 (7 patients, 12% each); and FGFR1 (6 patients, 11%). In addition, PTEN deletion and CDKN2 deletion were found in 6 (11%) and 3 (5%) patients, respectively. Among those genes with the highest number of gene variants included: TP53 (26 variants); PIK3CA (7 variants); GATA (5 variants); PIK3R1 (4 variants); and BRCA 2 (4 variants). No two patients demonstrated the same spectrum of molecular aberrations. Forty-four of 57 patients were evaluable for response on targeted therapies excluding single-agent hormone therapy (13 patients did not receive targeted therapy). Thirty-seven patients received therapies that were either directly or indirectly matched to NGS aberrations resulting in 2 patients with complete responses (CR), 5 with partial response (PR), 10 with stable disease ≥ 6 months (SD) and, 20 with progressive disease (PD). Seven patients who did receive matched therapy demonstrated SD (3 patients) and PD (4 patients) 3 SD (Fisher's exact test, p=0.88).
Conclusion: Unique profiles of genomic aberrations in patients with breast cancer were demonstrated. Further evaluation NGS in larger patient cohorts is warranted including studies that prospectively match aberrations to targeted therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A212.
Citation Format: Jennifer J. Wheler, Barbara A. Parker, Jack Lee, Roman Yelensky, Stacy Moulder, Apostolia M. Tsimberidou, Filip Janku, Johnique T. Atkins, Ralph Zinner, Richard Q. Schwab, Maria Schwaederle, Vivek Subbiah, Siqing Fu, Philip J. Stephens, Razelle Kurzrock. Next generation sequencing (NGS) in 57 patients with advanced or metastatic breast cancer: Identification of unique genomic profiles and correlation with response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A212.