Relapsed Classic E-Cadherin (CDH1)―Mutated Invasive Lobular Breast Cancer Shows a High Frequency of HER2 (ERBB2) Gene Mutations

• Published in: Clinical cancer research Vol. 19; no. 10; pp. 2668 - 2676
• Main Authors: ROSS, Jeffrey S, KAI WANG, YELENSKY, Roman, LIPSON, Doron, PALMER, Gary, MILLER, Vincent A, STEPHENS, Philip J, SHEEHAN, Christine E, BOGUNIEWICZ, Ann B, OTTO, Geoff, DOWNING, Sean R, SUN, James, JIE HE, CURRAN, John A, ALI, Siraj
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.2013
• Subjects: Adult; Aged; Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cadherins - genetics; Cadherins - metabolism; Carcinoma, Ductal, Breast - genetics; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Ductal, Breast - pathology; Carcinoma, Lobular - genetics; Carcinoma, Lobular - metabolism; Carcinoma, Lobular - pathology; Exons - genetics; Female; Gynecology. Andrology. Obstetrics; High-Throughput Nucleotide Sequencing; Histocytochemistry; Humans; Mammary gland diseases; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Mutation Rate; Neoplasm Metastasis; Neoplasm Recurrence, Local; Paraffin Embedding; Pharmacology. Drug treatments; Receptor, ErbB-2 - genetics; Receptor, ErbB-2 - metabolism; Tissue Fixation; Tumors; Relapse; Cell adhesion molecule; erbB2 Gene; Malignant tumor; Breast lobular carcinoma; Mammary gland diseases; Frequency; Genetics; Invasive cancer; Mutation; E Cadherin; Protooncogene; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-13-0295

We queried whether comprehensive genomic profiling using a next-generation sequencing-based assay could identify novel and unanticipated targets of therapy for patients with relapsed invasive lobular carcinoma (ILC). 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. 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 = 0.0006). 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.