Next-Generation Sequencing Reveals Molecular Subtypes Beyond Those Defined by Hormone Receptor Expression

Based on the expression of hormone receptors, breast cancers can generally be classified into 4 major molecular subtypes: basal, luminal A, luminal B, and human epidermal growth factor receptor 2 overexpressed. Although this classification scheme allows clinicians to treat patients based on known characteristics of each subtype, heterogeneity among tumors within those subtypes can have substantial effects on patient prognosis. Next-generation genomic sequencing offers one option to understand this heterogeneity. “Comprehensive genomic profiling, or CGP, can reveal targetable genomic alterations and redefine breast cancer classification into therapeutically relevant subtypes,” said Dr Jeffrey Ross, of Foundation Medicine in Cambridge, MA, who was affiliated with a study to confirm the capabilities of CGP in identifying molecular subtypes in breast cancer.

In this study, CGP was performed on ≥50 ng of DNA extracted from formalin-fixed, paraffin-embedded samples from 8654 breast carcinomas. Using hybridization-captured, adaptor ligation-based libraries (mean coverage >500-fold), the researchers were able to evaluate up to 315 cancer-related genes. The total mutational burden (TMB) of these samples was determined on 1.2 Mbp of sequenced DNA. Clinically relevant genomic alterations were defined as those targeted by drugs on the market or under evaluation in clinical trials. Immunotherapy (IO) sensitivity was defined as having a TMB >20 mutations/Mbp, or mutation of specific DNA repair pathways. Finally, homologous recombination (HR) deficiency was defined as mutation of the BRCA genes, other genes of the FANC complex, or DNA repair genes that have been shown to confer sensitivity to PARP inhibitors.

Of the samples examined in this study, 6959 (80.4%) tumors harbored a genomic alteration in at least 1 targetable pathway, and 2697 (31.2%) harbored alterations in only a single targetable pathway. The most commonly mutated pathway was the PI3K/AKT/mTOR pathway (51%), followed by the FGFR (31%), CDK (31%), and ERBB (15%) pathways. Fifteen percent of tumors were found to be HR deficient, 9% were found to be hormone therapy resistant, 5% were found to be IO sensitive, and 5% were found to have mutations in other targetable kinases, including RET, ROS1, and RAF.

These data confirm that the several distinct pathways altered in breast cancer can be stratified by CGP for potential targeting by already approved therapies. Many of these genomic alterations would not be identified by immunohistochemistry or hotspot testing, but are only accessible through next-generation sequencing. “CGP is a powerful tool for guiding treatment across therapeutically distinct, but targetable, pathways,” said Dr Ross.

Ross J, et al. ESMO 2016. Abstract 229PD.