Relapsed Classic E-Cadherin (CDH1)–Mutated Invasive Lobular Breast Cancer Shows a High Frequency ofHER2(ERBB2) Gene Mutations

Abstract

Purpose: We queried whether comprehensive genomic profiling using a next-generation sequencingbased assay could identify novel and unanticipated targets of therapy for patients with relapsed invasive lobular carcinoma (ILC).Experimental Design: DNA sequencing (Illumina HiSeq 2000) was conducted for 3,320 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer on indexed, adaptor-ligated, hybridization-captured libraries using DNA isolated from formalin-fixed paraffin-embedded sections from 22 histologically verified ILC.Results: A total of 75 genomic alterations were identified with an average of 3.4 alterations per tumor (range, 1-6), of which 35 were actionable for an average of 1.59 actionable alterations per patient (range, 0-3). Nineteen of 22 (86%) of the ILC samples harbored at least one actionable alteration. Six (27%) cases featured alterations in ERRB2 including 4 (18%) with ERBB2 mutation, 1 (5%) with an ERBB2 gene fusion, and 1 (5%) with an ERBB2 copy number gain (amplification). The enrichment of ERBB2 mutations/fusion in CDH1-mutated ILC (5 of 22, 23%) compared with the 5 ERBB2 mutations in a series of 286 non-CDH1-mutated breast cancers from which the ILC cases were obtained (5 of 286, 2%) was significant (P ¼ 0.0006).Conclusions: Comprehensive genomic profiling of relapsed CDH1-mutated ILC revealed actionable genomic alterations in 86% of cases, featured a high incidence of ERBB2 alterations, and can reveal actionable alterations that can inform treatment decisions for patients with ILC.

A High Frequency of Activating Extracellular Domain ERBB2 (HER2) Mutation in Micropapillary Urothelial Carcinoma

“…In the Bladder Urothelial Carcinoma TCGA dataset, although point mutations in ERBB2 are not described, amplification of ERBB2 was listed in 6% (9/150) of cases (The cBio Cancer Genomics Portal, April 2013). An enrichment of ERBB2 mutation within a common cancer subtype has also been recently described in a series of CDH1-mutated invasive lobular carcinomas of the breast with a frequency of 23% compared with a frequency of 2% in all breast cancers (19). Separate studies have reported ERBB2 amplification predominantly based on FISH analysis in 8% to 9% of primary urothelial carcinomas, and at a higher frequency in lymph node metastases (20).…”

Mutations in the Kinase Domain of the HER2/ERBB2 Gene Identified in a Wide Variety of Human Cancers

“…In contrast to the low rate of HER2 mutations (2%) observed in invasive ductal carcinomas, ILCs have a relatively high rate of HER2 mutations (23%) among those patients with relapsed disease, validated as ILC with identification of a CDH1 mutation. 17 Although this HER2 mutation rate in relapsed ILC is high, 17 HER2 mutations in primary invasive lobular carcinomas, although significant, are lower (approximately 9%). 14 Our study is consistent with these latter observations, finding that five (three classic and two pleomorphic lobular carcinomas, approximately 26% of the HER2 mutations) harbored kinase domain mutations.…”

Yield and Clinical Utility of Next-Generation Sequencing in Selected Patients With Lung Adenocarcinoma

“…The test has been validated to detect base substitutions at ≥10% mutant allele frequency with ≥99% sensitivity and indels at ≥20% mutant allele frequency with ≥95% sensitivity, with a false discovery rate of <1%. 16,17 CRGAs were defined broadly as those with a targeted FDA-approved anticancer drug available or those with a targeted drug in registered phase 2 or phase 3 clinical trials. The success of CGP was categorized as either yielding a full, unqualified report (full analysis); a qualified report with guideline driven performance caveats (qualified report); the inability to sequence the tumor secondary to insufficient DNA (tissue insufficient for analysis); or the inability to sequence the tumor secondary to test failure (testing failure).…”

“…At least 50 ng of DNA per specimen was isolated and sequenced to high, uniform coverage (mean 734X) on the Illumina HiSeq2500 instrument, as previously described 16,17. Genomic alterations (base substitutions, short insertions and deletions, focal gene amplifications, homozygous deletions…”