E. Forester1,2, A. Belsare1,3, D. W. Kim4, K. Whitaker5, E. Obeid6, L. J. Goldstein4, R. J. Bleicher1, M. B. Daly7, A. D. Williams1,7 1Fox Chase Cancer Center, Division Of Breast Surgical Oncology, Department Of Surgical Oncology, Philadelphia, PA, USA 2Rowan-Virtua School of Osteopathic Medicine, Stratford, NJ, USA 3Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA 4Fox Chase Cancer Center, Department Of Hematology/Oncology, Philadelphia, PA, USA 5MedStar Health Research Institute, Department Of Medical Oncology, Washington, DC, USA 6Hackensack Meridian Health Network, Edison, NJ, USA 7Fox Chase Cancer Center, Department Of Clinical Genetics, Philadelphia, PA, USA
Introduction:
DESTINY-B04 provided clinical meaning to a new classification of human epidermal growth factor 2 (HER2) expression in breast cancer (BC): HER2-low. HER2-low is defined as a score of 1+ on immunohistochemistry (IHC) or an IHC score of 2+ with negative results on in situ hybridization (ISH). The improved outcomes using trastuzumab-deruxtecan (T-DXd) in DESTINY-B04 introduced a targeted treatment option for metastatic HER2-low patients, many of whom previously had no targeted option due to their original classification as triple negative (TNBC). Patients with germline pathogenic variants (PVs) in BRCA1 often develop TNBC, and the proportion who could be classified as HER2-low, and qualify for the additional targeted therapy option, is unknown. This study aims to characterize the phenotype of BRCA-related BC using this new classification.
Methods:
We performed a retrospective chart review of patients with BRCA1/2 PVs or likely PVs treated at our institution for invasive BC from 2000-2021. Cancers diagnosed prior to 2000 were excluded since prior to this time HER2 status was infrequently used to categorize BC. Synchronous or metachronous contralateral BCs were recorded separately. HER2 status was determined by IHC and ISH according to standard guidelines, and we excluded patients without complete HER2 data.
Results:
Among the 95 BCs identified in our cohort of 84 BRCA1/2 patients, 41 (43%) were TNBC, 38 (40%) were HR+/HER2-, and 16 (17%) were HER2-positive based on standard conventions. We analyzed the 79 cancers that would be described as HER2-negative following standard conventions and found that 82% of the HR+/HER2- cancers and 66% of TNBCs would be reclassified as HER2-low. After stratifying by BRCA gene, we found that most patients with BRCA1 PVs had TNBC (66%), while patients with BRCA2 PVs had a greater proportion of HR+/HER2- (54%) and HER2+ (25%) BCs. After re-classification, 64% of cancers in patients with BRCA1 PVs and 58% of cancers in patients with BRCA2 PVs were HER2-low overall (Table). Of the cancers that were HER2-negative by standard convention, 70% and 78% were HER2-low, among BRCA1 and BRCA2 patients, respectively.
Conclusion:
After re-classification, a majority of the cancers diagnosed in patients with BRCA PVs are HER2-low. Many of these cancers would have previously been classified as TNBC, and PARP inhibitors would be the only targeted therapy option. The inclusion of T-DXd as an additional option for BRCA patients having metastatic BC may help to improve outcomes as transition to new treatment regimens is indicated when disease progression is detected. The application of T-DXd in the early breast cancer setting is under investigation, but likely holds similar promise.
