Abstract 4509: Clinical genomic profiling of 1000 metastatic breast cancer patients: actionable targets, novel alterations, and clinical correlations
Authors: Razavi Pedram , Chang Matthew T. , Middha Sumit , Ross Dara S. , Zehir Ahmet , Proverbs-Singh Tracy A. , Kandoth Cyriac , Chandarlapaty Sarat , Dickler Maura N. , Reis-Filho Jorge S. , Patil Sujata , Seshan Venkatraman , Smyth Lillian , Iyengar Neil M. , Jhaveri Komal , Modi Shanu , Dang Chau T. , Robson Mark E. , Norton Larry , Hudis Clifford A. , Ladanyi Marc , Scaltriti Maurizio , Schultz Nikolaus , Hyman David , Berger Michael F. , Taylor Barry S. , Solit David B. , Baselga. José 
Published: July 2016

Most large genomic profiling efforts in breast cancer have focused on primary breast tumors. Profiling of metastatic breast cancer (MBC) could more accurately define actionable genomic alterations and reveal novel alterations that arise under the selective pressure and clonal evolution of prior therapy. Utilizing a 410-gene targeted capture-based sequencing platform (MSK-IMPACT), we analyzed 920 tumors (62% metastatic, 38% primary) from 874 MBC patients for somatic mutations, DNA copy number alterations, and structural rearrangements (planned final analysis 1000 patients). Detailed clinical data including treatment outcomes was collected for all patients. The cohort was representative of the well characterized clinical subtypes of breast cancer with 71% ER+ or PR+ and HER2-, 17% HER2+, and 12% triple negative breast cancer (TNBC).

Our analysis revealed recurrent alterations in multiple pathways including PI3K/AKT/mTOR (56%), cell cycle regulation (42%), RTK signaling (40%), epigenetic regulation (33%) and MAPK/ERK (19%) pathways. The most frequent actionable alterations include: PIK3CA mutation (36%), ERBB2 amplification (15%), FGFR1 amplification (12%), ESR1 mutation (11%), PTEN mutation/deletion (10%), AKT1 mutation (6%), and ERBB2 mutation (5%). The genomic landscape was significantly different across breast cancer subtypes. For example, the PI3K/AKT/mTOR pathway was altered in ER+ MBC mainly through activating PIK3CA mutations whereas PTEN deletion/mutations were most common in TNBC. We also identified significant differences in the genomic profiles of metastatic and primary tumor samples. Gene enrichment analyses revealed a subset of genes more frequently altered in metastatic tumors (STK11: 13 vs 2; ROS1: 14 vs 2; FGFR4: 15 vs 1) suggesting that mutations in these genes may play a role in breast tumor metastasis and/or therapy resistance. ESR1 mutations were predominantly present in metastatic tumors (88%) and were significantly associated with duration of prior hormonal therapy (P&lt;0.0001). ESR1 mutations were also associated with a poor response to the ER degrader fulvestrant (median PFS: 4.8 vs 13.7 months, mutated vs wild type; P = 0.01). Analysis for potentially novel hotspot mutations revealed recurrent RHOA G17 mutations in 6 MBC patients, nominating RHOA, a GTPase transducer of membrane receptors, as a candidate driver in a subset of breast cancers. While identified previously in other tumors, RHOA G17 has never been implicated in breast cancer.

In summary, our genomic analyses of this large cohort of MBC patients revealed actionable alterations in over 60% of the patients. 29% of patients with these alterations were enrolled in clinical trials of matched targeted therapies to date (PIK3CA 27%, AKT1 30%, ESR1 23%, ERBB2 39%) suggesting that prospective genomic characterization can accelerate enrollment of patients with MBC onto therapeutic clinical trials.

Citation Format: Pedram Razavi, Matthew T. Chang, Sumit Middha, Dara S. Ross, Ahmet Zehir, Tracy A. Proverbs-Singh, Cyriac Kandoth, Sarat Chandarlapaty, Maura N. Dickler, Jorge S. Reis-Filho, Sujata Patil, Venkatraman Seshan, Lillian Smyth, Neil M. Iyengar, Komal Jhaveri, Shanu Modi, Chau T. Dang, Mark E. Robson, Larry Norton, Clifford A. Hudis, Marc Ladanyi, Maurizio Scaltriti, Nikolaus Schultz, David Hyman, Michael F. Berger, Barry S. Taylor, David B. Solit, José Baselga. Clinical genomic profiling of 1000 metastatic breast cancer patients: actionable targets, novel alterations, and clinical correlations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4509.