HER2 testing in metastatic breast cancer - Is reflex ISH testing necessary on HER2 IHC-equivocal (2+) cases?

Current guidelines recommend HER2 testing on all primary invasive breast cancers and re-biopsy at disease relapse. The discordance rate between HER2-negative primaries and HER2 IHC2+ metastases that are ISH-amplified is unknown. We hypothesize that the majority of such cases are non-amplified. ISH testing is time-consuming and resource-intensive, and there may be situations where it is unnecessary. A retrospective review of IHC2+ metastatic lesions assessed with ISH at our center from 2013 to 2021 was undertaken. 105 cases were identified after exclusion of cases missing HER2 results, with primaries of unconfirmed origin, and cases of synchronous primary and metastatic disease. IHC and ISH results were recorded with detailed slide review of discordant cases. 91/105 metastases had HER2-negative primaries (87%). A metastasis was significantly more likely to be HER2-negative when the primary was HER2-negative (93%) versus positive (43%) (p < 0.0001). 54/91 primaries were IHC2+/ISH-non-amplified, and 50/54 (93%) corresponding metastases had identical results. Of the 37 HER2-negative primaries that were IHC0/1+, 35 (95%) corresponding metastases were ISH-non-amplified. Six metastases in cases with HER2-negative primaries were discordant. Characteristics of metastases suggesting ISH testing was warranted to assess for discordance included IHC heterogeneity, morphological discordance, increased staining of moderate intensity, and ER/PR discordance. One or more of these factors were present in all discordant metastases. Our results suggest selective ISH testing on HER2 IHC2+ breast cancer metastases in the context of HER2-negative primary disease may be appropriate when there is careful review of the IHC. Validation of our findings awaits further studies with larger sample sizes.

Donor-Specific Human Leukocyte Antigen Antibody Formation After Distal Tibia Allograft and Subsequent Graft Resorption.

The association between donor-specific human leukocyte antigen (HLA) antibody formation and small bone allograft resorption has not been studied. We present the case of a patient treated for glenoid bone loss using a distal tibial allograft with Bankart repair who formed donor-specific HLA antibodies against the allograft and had subsequent graft resorption. X-ray and computed tomography (CT) scans were performed before and after surgery at standard checkpoints. Patient blood and serum samples were collected before and after surgery for HLA typing and HLA antibody testing. Human leukocyte antigen antibodies against the donor-specific HLA-A2 antigens were identified 6 weeks after surgery and were still detected at 5 months after surgery. At 6 months after surgery, a CT arthrogram revealed significant graft resorption. This case shows a temporal correlation between HLA antibody formation and clinical findings, potentially suggesting an association between HLA antibody formation and graft resorption. Further study is required to confirm this.