Abstract P3-04-03: Identification, clinical characteristics and treatment outcomes of somatic human epidermal growth factor receptor 2 (ERBB2) mutations in metastatic breast cancer patients
Authors: Jongen L , Floris G , Lambrechts D , Laenen A , Neven P , Mann G , Cutler RE , Lalani AS , Wildiers H 
Published: February 2018

Abstract
Background The human epidermal growth factor receptor 2 (ERBB2) can be altered by somatic mutations (with/without ERRB2 amplification) that likely drive tumorigenesis. Here, we present the first study that thoroughly investigates the behavior of patients with ERBB2 mutated tumors in a large unselected cohort of metastatic breast cancer (MBC) patients.
Patients and Methods We included retrospectively all MBC patients with sufficient tumor material available, independent of hormone receptor or ERBB2 amplification status, diagnosed between 2000 and 2015 at the Multidisciplinary Breast Center of University Hospitals Leuven. Genomic DNA extracted from primary breast tumors was subjected to deep targeted re-sequencing using an assay covering 5 exons (exons 8, 17, 19, 20 and 21) known to accumulate ERBB2 hotspot mutations. Clinical characteristics, treatment response and outcomes (excluding bilateral BC) were compared between patients with and without ERBB2 mutations.
Results We established and validated a research use only next-generation sequencing assay across five exons of ERBB2. Somatic ERBB2 mutations with an allelic frequency of ≥5% in at least one independent analysis, were observed in 1.8% (13/721) of MBC patients. MBC patients with ERBB2 mutant primary tumors appear to have similar patient and tumor characteristics (TNM stage, grade, and receptor and HER2 status) compared to non-mutant patients and ERBB2 mutations occur in all molecular subtypes (7 ER+/HER2-, 4 HER2+, 2 triple negative). However, we see a small trend towards enrichment in the invasive lobular carcinomas (ILC) in the ERBB2 mutant patients vs. the non-mutant patients (4/13 (31%) vs. 97/695 (14%), p=0.086). ER+ patients with an ERBB2 mutant tumor who received first line aromatase inhibitor (AI) (n=3) had a worse median time to progression (TTP) compared to non-mutant patients (n=156) (TTP 103 vs. 311 days, p=0.04), AI use in any line had also a worse TTP (n=8 vs. 376; TTP 74 vs. 213 days, p=0.006). TTP was not significantly different for other standard therapies, but numbers were small. Median distant disease free survival (DDFS) defined as time from primary diagnosis to first metastasis, was slightly shorter for ERBB2 mutant tumors (n=9 vs 514; DDFS 1.4 vs. 2.9 years, p=0.066). However, in ER+/HER2- ERBB2 mutant tumors, median DDFS was significantly shorter in non-mutant patients (n=5 vs. 328; DDFS 0.8 vs. 4.0 years, p=0.02). Median overall survival (OS) after diagnosis of MBC was numerically lower for mutant patients in all subtypes vs. non-mutant patients (n=11 vs. 669; OS 1.1 vs. 2.3 years, p=0.457), and in ER+/HER2- disease (n=6 vs. 431; OS 1.0 vs. 2.9 years, p=0.07).
Conclusion In our large MBC cohort, patients with ERBB2 mutant tumors appear to have similar tumor and patient characteristics as ERBB2 non-mutant tumors. ERBB2 mutations do not seem to occur more or less often in specific breast cancer subtypes except for a slight increase for ILC. In ER+/HER2- MBC, patients with ERBB2 mutant tumors appear to be adversely prognostic; having a shorter DDFS after early breast cancer treatment, and in metastatic disease, they respond worse on AI and have a trend for worse OS compared to non-mutant cases.
Citation Format: Jongen L, Floris G, Lambrechts D, Laenen A, Neven P, Mann G, Cutler Jr. RE, Lalani AS, Wildiers H. Identification, clinical characteristics and treatment outcomes of somatic human epidermal growth factor receptor 2 (ERBB2) mutations in metastatic breast cancer patients [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 P3-04-03.