Comprehensive genomic profiling of 8,654 breast carcinoma reveals therapeutically targetable molecular subtypes beyond those defined by hormone-receptor expression

Background

Breast carcinomas (BC) are commonly classified into 4 subtypes based on hormone receptor expression: basal, luminal A, luminal B, and HER2 overexpressed. Comprehensive genomic profiling (CGP) can reveal targetable genomic alterations (GA) and redefine BC classification into therapeutically relevant subtypes.

Methods

DNA was extracted from 40 µm of FFPE sections for 8654 consecutive BCs. CGP was performed on hybridization-captured, adaptor ligation-based libraries (mean coverage >500X) for up to 315 cancer-related genes. Total mutational burden (TMB) was determined on 1.2 Mbp of sequenced DNA. Clinically relevant GA (CRGA) are GA linked to drugs on the market or under evaluation in clinical trials. Immunotherapy (IO) sensitivity is defined as TMB >20 mut/Mbp or mutation of specific DNA repair pathways. Homologous recombination (HR) deficiency is defined as mutation of the BRCA genes, other genes in the FANC complex, or DNA repair genes that have been shown to confer sensitivity to PARP inhibitors.

Results

Several distinct pathways are altered in BC, and these pathways are targetable with therapies that are FDA approved for oncology indications. Rare mutations can also be found in targetable kinases such as RET, ROS1, and RAF. 6959 (80.4%) tumors harbor a GA in at least one pathway, and 2697 (31.2%) BC harbor alterations in just one pathway (unique cases). Only 9.8% of BC would be HER2-positive by IHC. Table: 229PD

Conclusions

CGP can identify CRGA that can stratify tumors by predicted sensitivity to a variety of therapies, including HER2- or mTOR-targeted therapies, immunotherapies, and other kinase inhibitors. 80% of BC harbor targetable GA, and 30% of samples harbor mutations in only one pathway. Many GA would not be identified by IHC or hotspot testing, but can be detected by next-generation sequencing. CGP is a powerful tool for guiding treatment across therapeutically distinct, but targetable, pathways.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine, Inc.

Funding

Foundation Medicine, Inc.

Disclosure

J.S. Ross: Foundation Medicine, Inc. (compensated), Research Support: Foundation Medicine, Inc. (un-compensated), Stock Ownership: Foundation Medicine, Inc. (compensated). L.M. Gay, J.A. Elvin, J. Suh, J-A. Vergilio, S. Ramkissoon, S. Ali: Employee of and stockholder in Foundation Medicine, Inc. V.A. Miller, P.J. Stephens: Employee of, stockholder in, and holds a leadership position for Foundation Medicine, Inc.