Abstract A30: RATHER: High-resolution molecular profiling of invasive lobular breast cancers

Abstract

Abstract Introduction: RATHER (Rational Therapy for Breast Cancer) is an international multi-site collaborative effort that aims to use high resolution molecular profiling techniques to identify novel kinase targets for two subtypes of breast cancer, invasive lobular cancers (ILC) and triple negatives (TN) where no targeted therapies are available at present. Experiments: DNA, RNA and protein were extracted from 137 ILC and 155 TN samples with an average of 5 years clinical follow-up. A variety of high resolution molecular profiling methods were used such as copy number analysis (Affymetrix SNP6), gene expression profiling (Agilent 4x44K gene arrays), targeted sequencing (Agilent customized kinome panel & Illumina Nextera Custom Enrichment), whole transcriptomic sequencing and reverse phase protein lysate array (RPPA) analysis. Results: Combining copy number and gene expression data, we have classified the ILC tumors into the intergrative Cluster (IntClust) subgroups that we have previously identified from our large-scale breast cancer study, METABRIC (Molecular Taxonomy of Breast Cancer International Consortium). The ILC tumors were predominantly in IntClust3 (37.2%) and IntClust8 (21.2%). Only two genes were found to be frequently mutated (>10%) ie. CDH1 (40.8%) and PIK3CA (35%ILC). The PI3K pathway has been found to be frequently altered in ILCs by either mutations (PIK3CA and AKT1) or copy number alterations (PTEN). Integrating with transcriptomic and proteomic data, two main subtypes of ILCs were identified: (i) an immune responsive subtype with mRNA up-regulation of PDL1, PD1 and CTLA4 and greater sensitivity to DNA-damaging agents in representative cell line models; (ii) a hormone receptor signalling subtype, associated with Epithelial to Mesenchymal Transition (EMT), and gain of chromosomes 1q and 8q and loss of chromosome 11q. Using somatic mutation rate and eIF4B protein level, we identified three groups with different clinical outcomes, including a group with extremely good prognosis. Conclusion: We provide a comprehensive overview of the molecular alterations driving ILC and have explored links with therapy response. This molecular characterization will help to tailor treatment of ILC through the application of specific targeted, chemo- and/or immune-therapies. Citation Format: Suet-Feung Chin, Magali Michault, Ian Majewski, Tesa M. Severson, Tycho Bismeijer, Leanne De Korning, Justine Peeters, Phillip Schouten, Oscar M. Rueda, Astrid Bosma, Finbarr Tarrant, Yue Fan, BeiLei He, Bernard Pereira, Helen A. Bardwell, Elena Provenzano, Darran P. O'Connor, Sabine Linn, Thierry Dubois, Iris Simon, William Gallagher, Lodewyk Wessels, Rene Bernards, Carlos Caldas. RATHER: High-resolution molecular profiling of invasive lobular breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr A30.