Abstract P5-20-02: HER2 mutations detected by ctDNA in ER+/HER2- metastatic breast cancer patients: Incidence and impact on clinical outcomes
Authors: Medford A , Juric D , Niemierko A , Malvarosa G , Park H , Shellock M , Spring L , Moy B , Isakoff S , Ellisen L , Bardia A 
Published: February 2018

Background: While the human epidermal growth factor receptor 2 (HER2) gene has long been linked with the pathogenesis and prognosis of breast cancer, its significance has been recognized only when the receptor has been amplified. However, rare, but actionable, somatic mutations in HER2, without HER2 gene amplification, have been described in breast cancer based on molecular analysis of metastatic specimens (frequency ˜ 1%). Little is known about the incidence based on blood-based genotyping assays, as well as impact of HER2 mutations on clinical outcomes in patients with ER+/HER2- metastatic breast cancer (MBC).

Methods: We evaluated the presence of HER2 mutations based on routine tissue and blood-based genotyping assays, ordered by treating oncologists at our institution, for patients with estrogen receptor positive (ER+)/HER2 negative MBC. The tissue analysis was based on SNAPSHOT-NGS, an anchored multiplex polymerase chain reaction assay that detects single nucleotide variants (SNV) and insertions/deletions (indel), and the blood-based genotyping analysis was based on circulating tumor DNA (ctDNA) detection using the Guardant 360 panel, a next-generation sequencing (NGS) assay capable of detecting mutations with comparable sensitivity to SNAPSHOT. Patients with acquired HER2 mutations were identified, and multivariate analysis was performed to evaluate the hazard ratio (HR) for the association between HER2 mutations and progression free survival (PFS), adjusting for age and number of prior therapies.

Results: Among the ER+/HER2- MBC patients (N=118), 11% (N= 13) were found to have acquired HER2 mutation by ctDNA analysis, but no HER2 mutations were identified in any of patients based on tissue-based molecular analysis of archival specimens. Among patients with HER2 mutant, ER+/HER2- MBC, the median age at metastatic diagnosis was 57.34 (range 51.5-67.1) years, 7.7% had de-novo metastatic disease, and 30.8% had prior CDK 4/6 inhibitor therapy. In terms of outcomes, in the multivariate model, patients with HER2 mutant breast cancer had similar PFS when treated with endocrine and targeted therapy combination (HR = 0.24; p = 0.21), and trended towards worse PFS with chemotherapy (HR = 2.69; p = 0.06), as compared to non-HER2 mutant group, albeit duration of follow up was limited (median duration = 6.7 months). Of note, most of the detected HER2 mutations were activating or deleterious, but not all were clonal. Updated outcome data, including overall survival, will be presented at the meeting.

Conclusions: A much larger subset of patients with ER+/HER2- MBC have HER2 mutations detectable by ctDNA, but not by tissue, which highlights the need for blood-based biomarker monitoring for identification of actionable mutations, as well as the potential clinical utility in development of genotype driven trials for patients with HER2 mutant, ER+/HER2- MBC.

Citation Format: Medford A, Juric D, Niemierko A, Malvarosa G, Park H, Shellock M, Spring L, Moy B, Isakoff S, Ellisen L, Bardia A. HER2 mutations detected by ctDNA in ER+/HER2- metastatic breast cancer patients: Incidence and impact on clinical outcomes [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 P5-20-02.