Abstract P5-21-20: Integrating comprehensive genomic profiling with treatment decisions – Experience gained while treating 139 advanced breast carcinomas
Authors: Mahtani R , Gay LM , Chung J , Hartmaier R , Sokol E , Elvin JA , Daniel S , Ramkissoon S , Severson E , Suh J , Vergilio J-A , Stephens PJ , Ross JS 
Published: February 2018

Background: Comprehensive Genomic Profiling (CGP) using next-generation sequencing (NGS) technology can provide insight into potentially clinically relevant genomic alterations (CRGA) within a patient's breast cancer. For example, HER2 amplification status and targetable short variants (SV), acquired ESR1 or BRCA1/2 resistance mutations, and the presence of targetable alterations in the PI3K kinase. We retrospectively reviewed CGP results and subsequent outcomes at one cancer center to illustrate the experience of using molecular subtyping to inform treatment decisions.

Methods: DNA extracted from FFPE tumor tissue or blood samples obtained during routine clinical care for patients (n=139) with predominantly relapsed, refractory or metastatic breast cancer was analyzed by hybrid-capture, NGS for all classes of GA: 1. base substitutions, 2. insertion and deletions, 3. rearrangements, and 4. copy number changes. Treatment decisions based on comprehensive genomic profiles were captured retrospectively. Tumor mutational burden (TMB), scored as mutations (mut)/Mb, was calculated on 0.8-1.2 Mb of sequenced DNA. Alterations affecting the ERBB family included amplification of or oncogenic mutations in ERBB2 (HER2), ERBB3, and EGFR.

Results: From Jan 2013 to May 2017, FFPE tissue samples for 136 patients with advanced breast cancer were analyzed by CGP and 3 additional patients had circulating tumor DNA analyzed for alterations; 11 patients received profiling on multiple biopsies. Tumors analyzed were carcinomas (Ca) NOS (n=84), invasive ductal Ca (n=46), invasive lobular Ca (n=7), a neuroendocrine Ca, and a phyllodes tumor. In total, 118/139 (84.9%) samples harbored CRGA in a targetable pathway: PI3K/MTOR (n=67; 48.2%), CDK cell-cycle (n=40; 28.8%), ERBB family (n=24; 17.3%), FGFR (n=24; 17.3%), ESR1 (n=16; 11.5%), homologous repair (HRD)( n=14; 10.1%), and RAS/RAF/MEK (n=11; 7.9%). Targetable alterations in other cancer-related kinases were found in 10 (7.2%) samples and 10 (7.2%) samples were TMB high (≥20 mut/Mb) or had CD274 (PD-L1) amplification. There were 3 patients (2.1%) with HER2 short variants detected in the absence of ERBB2 amplification; these patients may respond to HER2-targeted therapies but would be HER2-negative by IHC. Many samples had alterations in ≥1 pathway, and overlap is particularly high for the CDK and FGFR pathways (12 samples). Alterations in pathways targeted by MTOR inhibitors, HER2-targeted therapies, or the CDK inhibitors were found in 93/136 (66.9%) tumors. Evaluation of outcomes for these 139 patients is ongoing and will be presented.

Conclusions: Genomic profiling of breast carcinomas, using either tissue or liquid biopsies, provides potentially actionable information to guide treatment decisions. Overall, 84.9% of patient samples harbored oncogenic alterations in a targetable pathway, with two-thirds of tumors having alterations in pathways targeted by therapies with FDA approval for breast cancer and 7.2% of patients having high levels of TMB or amplification of PD-L1, suggesting that checkpoint inhibitors may be relevant options.

Citation Format: Mahtani R, Gay LM, Chung J, Hartmaier R, Sokol E, Elvin JA, Daniel S, Ramkissoon S, Severson E, Suh J, Vergilio J-A, Stephens PJ, Ross JS. Integrating comprehensive genomic profiling with treatment decisions – Experience gained while treating 139 advanced breast carcinomas [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-20.