Abstract P2-02-12: Cell free DNA analysis identifies actionable ERBB2 amplifications in patients with HER2 negative breast cancer
Authors: Raymond VM , Diaz J , Banks KC , Ahn E , Brufsky A , Ellis M , Lippman M , Lee C , Pluard T , Schreeder M , Schwab R , Lanman RB 
Published: February 2018

Identification of ERBB2 (HER2) overexpression in metastatic breast cancer informs utilization of HER2 targeted therapy. The NCCN recommends HER2 expression re-evaluation at the first disease recurrence in patients with negative or equivocal tissue status given results discrepancies due to inadequate tissue biopsy, tumoral heterogeneity, biopsy technique or fixation as well as discordance in ERBB2 (HER2) expression between primary and metastatic lesions. We examined the incidence of ERBB2 (HER2) negative to positive “flips” (e.g. to ERBB2-amplified in plasma) in a cohort of patients who underwent a blood-based cell-free DNA (cfDNA) assay at a CLIA-certified/CAP-accredited/NYSDOH-approved molecular diagnostic laboratory.

Laboratory database was queried for samples from patients with a breast cancer diagnosis. The query was filtered to ensure patients with multiple cfDNA timepoints were counted only once. Patients without a pathology report submitted at any cfDNA collection timepoint or the pathology report did not include ERBB2 (HER2) status, results were inconclusive or quantity not sufficient were excluded. Between March 2014 and April 2017, 1,853 unique patients were identified with reported ERBB2 (HER2) status. For patients with more than one cfDNA timepoint collected (N=349; 18.8%), the earliest pathology report was referenced. 1,386 patient tumor samples were negative for HER2 overexpression (74.8%), 325 (17.5%) were positive, and 142 (7.7%) were equivocal. Twenty-nine of the 1,386 patients with reported tumor negative HER2 status had amplification on subsequent cfDNA analysis (2.1%).

All 29 patients were female. Most patients (N=21) had a single cfDNA timepoint collected. Median age at cfDNA blood draw was 58 years (range 28–68). Median length of time between reported tissue negative status and cfDNA blood draw was 405 days (range 21–4,060). Median plasma ERBB2 copy number was 2.44 (greater than 50th-centile per laboratory data) (range 2.15–16.5).

Clinical follow-up was obtained for 19 patients (65%). Nine patients were lost to follow-up or succumbed to disease prior to initiation of a new therapeutic regimen. One patient was known HER2 positive prior to receipt of the cfDNA results. In the remaining nine patients, six initiated targeted HER2 therapy following receipt of the cfDNA results, with five of six (83%) demonstrating a clinical response. In one patient with known ER/PR positive, HER2 negative disease, progressing through multiple lines of therapy, addition of trastuzumab and pertuzumab to her paclitaxel regimen following identification of the cfDNA ERBB2 amplification resulted in a significant reduction in CEA levels (238 to 37.9 ng/mL) by week five. In a second patient, following identification of the cfDNA ERBB2 amplification, she was treated with trastuzumab and pertuzumab along with docetaxel and had a dramatic response. She continues on trastuzumab and pertuzumab alone.

Although a modest sample size, this is the second cfDNA series demonstrating that ERBB2 (HER2) status may flip from negative to positive upon recurrence or metastasis, and that targeting plasma-detected ERBB2 amplification with anti-HER2 has clinical benefit. cfDNA is a viable alternative to tissue rebiopsy in this patient population.

Citation Format: Raymond VM, Diaz J, Banks KC, Ahn E, Brufsky A, Ellis M, Lippman M, Lee C, Pluard T, Schreeder M, Schwab R, Lanman RB. Cell free DNA analysis identifies actionable ERBB2 amplifications in patients with HER2 negative breast cancer [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 P2-02-12.