Abstract PD8-01: CDH1 mutated classic and pleomorphic invasive lobular breast carcinomas differ in genomic signatures and opportunities for targeted and immunotherapies
Authors: Ross JS , Chung J , Elvin JE , Vergilio J-A , Ramkissoon S , Suh J , Severson E , Daniel S , Frampton GM , Fabrizio D , Hartmaier RJ , Albacker LA , Ali SM , Schrock AB , Miller VA , Stephens PJ , Gay LM 
Published: February 2018

Abstract
Background: Typically defined by negative IHC staining for E-cadherin, classic (CILC) and pleomorphic (PILC) are often combined as a single breast cancer subtype. We queried whether patients with relapsed metastatic disease, mCILC and mPILC, would harbor contrasting genomic alterations (GA)and that molecular information could further differentiate the 2 tumor types and thereby influence therapy selection.
Methods: DNA was extracted from 40 µm of FFPE sections of 10,784 invasive breast carcinomas. 454 (4%) CDH1 mutated mILC were selected including 428 classic mCILC (94%) and 26 mPLIC (6%) subtypes. Comprehensive genomic profiling (CGP) was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth &gt;600X for up to 315 cancer-related genes. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA.
Results: mCILC and mPILC patients featured a median age of 63 years (Table). Slide based ER+ status and HER2+ status was significantly different in both groups (P&lt;0.0001). The frequency of base substitutions in ESR1 was significantly higher in mCILC, and this difference was also significantly higher in mCILC metastasis biopsies exposed to hormonal therapy than in pre-treatment primary tumors (P&lt;0.0001). ERBB2 (HER2) GA (amp + non-amp) detected by CGP were higher in mPILC than mCILC in both pre-and post-treatment samples (P&lt;0.0001 for both). The ERBB2 GA frequency was nearly twice as high after hormonal therapy in both mCILC and mPILC. ESR1 and ERBB2 GA were mutually exclusive overall and especially in the mCILC group. PIK3CA GA were the most frequent GA in both mCILC and mPILC. TP53 GA were significantly more frequent in mPILC than mCILC. At 19%, the frequency of TMB &gt; 15 mutations/MB in mPILC was more than twice as frequent than in mCILC (P=0.046). All (100%) of both the CILC and PILC groups were negative for mis-match repair deficiency or MSI high status. mCILC and mPILC patients with post primary therapy associated ESR1 and ERBB2 GA responding to targeted and immunotherapies will be presented.
Contrasting Clinical and Genomic Features of CILC and PILC Classic CILC (428 cases)Pleomorphic PILC (26 cases)Median Age6363*ER+98%74%*HER2 IHC/FISH+12 (3%)6 (22%)ESR1 GA Primary Pre-Rx6%0%ESR1 GA Metastatic Post-Rx17%0%ERBB2 GA Primary Pre-Rx7%18%ERBB2 GA Metastatic Post-Rx12%34%Other Significant GAPIK3CA (55%), CCND1 (21%), TP53 (17%), ARID1A, AKT3, MDM4, PTEN (all 11%)PIK3CA (58%), TP53 (30%), AKT1 22%), FGFR4, CCND1, PTEN (all 17%)TMB median (mut/Mb)2.73.6TMB &gt; 15%8%19%*when clinical status available
Conclusions: CGP of mCILC and mPILC reveals significant differences in the panorama of GA both in pre-treatment primary and metastatic disease lesions especially in therapy-impacting GA in ESR1 and ERBB2. mCILC is more often driven by ESR1 GA and mPILC by ERBB2 GA. Although both mCILC and mPILC feature subsets of tumors with high TMB, this is more frequent for mPILC likely indicating different potentials for immunotherapies to benefit these patients.
Citation Format: Ross JS, Chung J, Elvin JE, Vergilio J-A, Ramkissoon S, Suh J, Severson E, Daniel S, Frampton GM, Fabrizio D, Hartmaier RJ, Albacker LA, Ali SM, Schrock AB, Miller VA, Stephens PJ, Gay LM. CDH1 mutated classic and pleomorphic invasive lobular breast carcinomas differ in genomic signatures and opportunities for targeted and immunotherapies [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD8-01.