Abstract P2-03-05: 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 , Cutler RE , Lalani AS , Wildiers H 
Published: May 2019

Background

Metastatic breast cancer (MBC) is seen as incurable and advances in new therapies or targets are necessary. Targeted therapies against human epidermal growth factor receptor 2 (ERBB2) (also known as HER2) in tumors with ERBB2 overexpression due to gene amplification have improved patients outcomes. Besides ERBB2 amplification, this receptor can also be altered by somatic mutations (without ERRB2 amplification) that likely drive tumorigenesis. Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has recently been demonstrated to potently inhibit breast cancers that have amplification or activating mutations in ERBB2. This is the first study that thoroughly investigates the natural history of ERBB2 mutations in MBC patients. The primary study objectives are to 1) evaluate the frequency of ERBB2 mutations in a large MBC cohort, 2) understand standard clinical, pathological and patient characteristics associated with ERBB2 mutations, 3) identify other gene mutations/aberrations that may co-occur with ERRB2 mutations, 4) characterize treatment responses and outcomes to standard therapies in patients with ERBB2 mutant vs. wild-type tumors, and 5) determine if ERBB2 mutations can be detected from plasma ctDNA samples collected at baseline (not reported here).

Patients and Methods

This retrospective study included all MBC patients (primary metastatic or developed metastases during follow-up), independent of hormone receptor or HER2 amplification status, diagnosed between January 1st 2000 and July 31st 2015 at the Multidisciplinary Breast Center of University Hospitals Leuven, and for whom sufficient tumor material was available for DNA extraction. Extracted DNA from primary breast cancer tissues were subject to targeted NGS-based sequencing, to identify single nucleotide variants, insertion, deletion, and indels within exons 8, 17, 19, 20 and 21 of the ERBB2 gene.

Results

We established and validated a research use only next-generation sequencing assay across five exons of the ERBB2 gene. 1062 MBC patients were included and so far 177 patients were successfully screened for ERBB2 mutations resulting in an occurrence of n=10 (5.6%) in this population. The remaining patients are currently being screened for ERBB2 mutations and the overall results on all described endpoints will be available at the meeting.

Conclusion

ERBB2 mutations seem more frequent in MBC than previously thought based on the general early breast cancer population. In depth analysis of this large MBC cohort evaluating clinical characteristics and standard treatment outcomes of ERBB2 mutant MBC may provide further knowledge on this breast cancer subtype that may benefit from HER2-directed therapies which are currently under investigation in clinical trials.

Citation Format: Jongen L, Floris G, Lambrechts D, Laenen A, Neven P, 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 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-03-05.