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

BACKGROUND: 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. PATIENT AND METHODS: 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. RESULTS: 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). CONCLUSION: 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.

Newly designed breakapart FISH probe helps to identify cases with true MECOM rearrangement in myeloid malignancies.

A home-brew, tri-color MECOM breakapart FISH probe with a full MECOM coverage labeled with a separate dye is compared in parallel with a 2-color commercial MECOM breakapart probe in 17 cases of hematologic malignancies. Cases with a typical positive signal pattern (or "balanced" signal pattern) (n = 2) and a negative result (n = 3) using the commercial probe achieved the same results using the new probe (100% concordance), whereas 9 of 12 (75%) remaining cases with an atypical signal pattern (or "unbalanced" signal pattern) using the commercial probe showed a "balanced" signal pattern using the new probe. Three cases with undetermined MECOM rearrangement status by the commercial probe were further clarified with no MECOM rearrangement in 2 cases and presence of a subclone with simultaneous gain and rearrangement of MECOM in 1 case. More importantly, the new probe is capable of determining the presence, location and integrity of MECOM after rearrangement. In conclusion, atypical signal patterns obtained using a commercial FISH probe for MECOM can be solved through re-design and optimization of a new BAP probe, especially in those cases with a true MECOM rearrangement. The potential of the new probe for use in the clinical laboratory will be further investigated. (Word count: 196).