Distribution of HER2 Low in Tumors of Patients With Hereditary Breast Cancer According to Germline Pathogenic or Likely Pathogenic Genetic Variants.

OBJECTIVE

To evaluate the presentation of the HER2 "Low" subtype in high-risk hereditary breast cancer according to the presence of germline variants detected through a multigene panel.

METHODS

This prospective cohort study, conducted between November 2021 and October 2022, included women attending the high-risk outpatient clinic at the University of Campinas (UNICAMP), who were diagnosed before age 45 or met NCCN (version 3.2021) criteria for germline genetic testing, or had at least 1 first-degree relative with breast, ovarian, and/or prostate cancer. Patients completed a questionnaire before undergoing genetic testing and received counseling based on their test results.

RESULTS

A total of 184 patients and 198 breasts were studied. Pathogenic or likely pathogenic variants (PV/LPV) were detected in 36% (67/184) of patients. In general analysis, using HER2 +3 as the reference, other HER2 expressions were associated with PV/LPV as follows: 0 (OR = 5.58; CI 2.29-13.58), +1 (OR = 5.76; CI 2.0-16.59), +2 (ISH-), (OR = 4.31; CI 1.11-16.59), +2 (ISH +) (OR = 4.77; CI 1.75-12.95). In the analysis of BRCA1 and BRCA2 genes only, the HER2 +2 (ISH-) subtype was not associated with PV/LPV; associations for other subtypes included 0 (OR = 6.61; CI 2.70-16.19), +1 (OR = 5.01; CI 1.68-14.94), +2 (ISH +) (OR = 3.63; CI 1.35-9.82). For non-BRCA genes, neither HER2 0 nor HER2 + (ISH-) was associated with PV/LPV; however, +1 (OR = 4.71; CI 1.25-17.67) and +2 (ISH +) (OR = 4.74; CI 1.32-17.01) showed associations.

CONCLUSION

Pathogenic or likely pathogenic variants in genes associated with hereditary breast cancer are associated with different HER2 expression patterns, including the HER2 Low group.