The frequency of HER2-low breast cancer among BRCA1, BRCA2, and PALB2 mutation carriers.

person Lindsay Goldblatt Hospital of University of Pennsylvania, Philadelphia, PA info_outline Lindsay Goldblatt, Paulina Coutifaris, Payal Deepak Shah

Authors person Lindsay Goldblatt Hospital of University of Pennsylvania, Philadelphia, PA info_outline Lindsay Goldblatt, Paulina Coutifaris, Payal Deepak Shah Organizations Hospital of University of Pennsylvania, Philadelphia, PA, Penn Medicine Abramson Cancer Center, Philadelphia, PA Abstract Disclosures Research Funding No funding sources reported Background: Human epidermal growth factor 2 (HER2) expression in breast cancer (BC) has historically been characterized as negative (0 or 1+ by immunohistochemistry (IHC); 2+ by IHC and not amplified by in-situ hybridization, ISH) or positive (2+ by IHC and amplified by ISH or 3+ by IHC). Recently developed therapies highlight the importance of identifying tumors that are HER2-low (IHC 1+, or 2+ with negative ISH). A minority of BC associated with germline BRCA1, BRCA2 ( BRCA1/2 ) or PALB2 pathogenic variants (PV) are HER2-positive, but the proportion of BRCA1/2 - and PALB2 -associated HER2-negative BC that are HER2-low and may benefit from novel HER2-low therapies is unknown.This study aims to retrospectively identify the frequency of HER2-low BC in BRCA1/2 and PALB2 mutation carriers whose cancers were identified as HER2-negative. Methods: We conducted a retrospective chart review of 170 patients diagnosed with HER2-negative BC in the context of a BRCA1/2 or PALB2 PV at the University of Pennsylvania from 2003 to 2023. Genomic and cancer-specific characteristics including variant classification and receptor status were collected and are descriptively reported. Results: 170 individuals with BRCA1/2 or PALB2 PV developed 190 HER2-negative BC. Forty-seven percent of primary tumors that had been identified as HER2-negative were HER2-low (39% of BRCA1- , 56% of BRCA2-, 60% of PALB2- associated BC; see Table). 17 individuals had 17 metastatic site biopsy reports available for review. Of these, 10 (59%) were HER2-low (1 BRCA1- , 8 BRCA2- , and 1 PALB2- associated). 6 of 17 (35%) individuals had discordant HER2 status in primary and metastatic samples; in all cases, the primary tumor was HER2 IHC 0 and the metastatic site was HER2-low. Conclusions: Despite the lower frequency of conventionally HER2-positive BC among individuals with BRCA1 / 2 and PALB2 PVs, the proportion of these BC that have low HER2 expression is substantial and similar to that of sporadic breast cancer. Discordance in HER2 status between primary and metastatic samples is observed. Individuals with BRCA1/2 and PALB2 HER2-negative BC may benefit from therapies for HER2-low BC; reevaluation of HER2 status on metastatic samples may identify additional candidates for such therapies. HER2 Status of Primary Tumor BRCA1 (n = 100) BRCA2 (n = 80) PALB2 (n = 10) Total (n = 190) HER2 IHC 0 61 (61%) 35 (44%) 4 (40%) 100 (53%) HER2-low 39 (39%) 45 (56%) 6 (60%) 90 (47%) HER2 1+ 27 (27%) 15 (19%) 4 (40%) 46 (24%) HER2 2+/ISH non amplified 12 (12%) 30 (37%) 2 (20%) 44 (23%)