Abstract P1-05-08: Comprehensive genomic profiling of 8,654 breast carcinoma reveals therapeutically targetable molecular subtypes beyond those defined by hormone-receptor expression
Authors: Ross JS , Gay LM , Elvin JA , Suh J , Vergilio J-A , Ramkissoon S , Schrock A , Ali S , Miller VA , Stephens PJ 
Published: March 2017

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) reveals targetable genomic alterations (GA) across all four mutation classes, as well measuring tumor mutational burden (TMB), and can redefine BC classification into therapeutically relevant subtypes. Testing with immunohistochemistry or hotspot testing can miss a substantial number of targetable alterations and cannot measure TMB.

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 &gt;500X) for up to 315 cancer-related genes and select introns from up to 28 genes frequently rearranged in cancer. Sequences were analyzed for substitutions, small insertions/deletions, copy number changes, and rearrangements. TMB was determined by counting non-driver, non-germline alterations across 1.1 Mbp of sequenced DNA. Clinically relevant GA (CRGA) are GA linked to therapies on the market or under evaluation in clinical trials. Immunotherapy (IO) sensitivity is defined as TMB &gt;20 mut/Mbp or mutation of specific DNA repair pathways.

Results: The table below outlines 7 distinct functional or signal transduction pathways commonly altered in BC. Several are targetable with therapies that are FDA approved for an oncology indication. Mutations can also be found in other 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. Almost 4% (352/8654) of cases harbor rearrangements or gene fusions that may not be detectable with other assays. Mutations in ESR1 characterize an eighth category of tumors with acquired resistance to endocrine therapy; 796/8654 (9%) samples harbor ESR1 alterations.

Conclusions: CGP can identify CRGA and TMB 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. CGP can provide crucial information for identifying which of several treatment modalities is most appropriate for these 30% of patients. High levels of TMB and most 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.

 PI3K/AKT/mTOR pathwayFGFR pathwayCDK pathwayERBB pathwayHR deficientIO sensitiveOther kinasesTotal Cases43752650268512941266419424% Total Cases51%31%31%15%15%5%5%Unique Cases14422262312743094858% Unique Cases17%3%3%3%4%1%1%TherapiesEverolimus, TemsirolimusPazopanib, PonatinbPalbociclibTrastuzumab, Pertuzumab, Afatinib, Lapatinib, NeratinibOlaparibPembrolizumab, Nivolumab, Atezolizumab, IpilumumabSorafenib, Regorafenib, Dabrafenib, Vemurafenib, Crizotinib, Cabozantinib, Sunitinib

Citation Format: Ross JS, Gay LM, Elvin JA, Suh J, Vergilio J-A, Ramkissoon S, Schrock A, Ali S, Miller VA, Stephens PJ. Comprehensive genomic profiling of 8,654 breast carcinoma reveals therapeutically targetable molecular subtypes beyond those defined by hormone-receptor expression [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-05-08.