Breast Cancer With a HER2 FISH Group 2 Result: Should HER2 Tests be Repeated?

Breast cancer with fluorescence in situ hybridization (FISH) group 2 pattern (HER2 <4 and HER2/CEP17 ratio ≥2, a subset of monosomy CEP17) was historically considered HER2-positive, but mostly HER2-negative according to updated 2018 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines unless 3+ by immunohistochemistry (IHC). Therapeutic relevance of this group remained elusive, therefore we assessed if repeat IHC and FISH can assist final HER2 classification.We retrospectively reviewed HER2 FISH performed at our institution from 2014 to 2018 and identified 23 of 3554 (0.6%) breast cancer cases with at least one-time measurement of HER2 FISH categorized as group 2. Repeat HER2 tests were performed for cases with available alternative tumor samples and compared with initial testing following 2018 ASCO/CAP guidelines.Only 1 of 23 group 2 cases was HER2-positive, 0/18 in primary and 1/5 in metastatic/recurrent tumors. Of 13 primary tumors with repeat HER2 results; 10 (77%) remained HER2-negative; 3 (23%) changed from HER2-negative (group 2 and IHC 2+) to HER2-positive (group 1 and IHC 2+). Among 8 of these 13 patients receiving neoadjuvant systemic therapy containing anti-HER2 agent, 3 (38%) achieved pathologic complete response (pCR). Two of 3 pCR cases were HER2-positive converters on repeat testing. Three pCR cases were ER-negative or -low positive and Ki67 ≥40%, while 5 partial responders were ER-positive and Ki67 <40% (P < .05).Breast cancer with HER2 FISH group 2 result may represent heterogeneous populations of tumor cells being originated de novo or preferentially selected secondary to therapy. Repeat HER2 tests on alternative samples may be considered to guide anti-HER2 therapy.