Influence of Variant of Uncertain Significance (VUS) Genetic Testing Results on Mastectomy Choice in Lumpectomy-Eligible Patients

PURPOSE: Our objective was to evaluate whether having a germline variant of uncertain significance (VUS) influenced the decision to undergo bilateral mastectomy (BLMast) among lumpectomy-eligible patients with unilateral breast cancer. METHODS: This retrospective cohort study included 326 lumpectomy-eligible patients with non-metastatic breast cancer who underwent genetic testing at a single academic center between April 2020 and November 2021. Patients with pathogenic/likely pathogenic variants or contraindications to breast-conserving therapy based on treating surgeon documentation were excluded. The primary outcome was BLMast. Multivariate logistic regression was used to assess the association between VUS results and surgical choice, while adjusting for age, stage, body mass index, family history, and other clinical factors. RESULTS: Among the 326 patients who underwent genetic testing and did not carry a pathogenic/likely pathogenic variant, 235 (72.1%) had negative results and 91 (27.9%) had a VUS. A higher proportion of patients with a VUS underwent BLMast than those with negative results (39.7% vs. 24.8%, p = 0.026). On multivariate analysis, patients with VUS were more than twice as likely to undergo BLMast (odds ratio [OR] 2.213; 95% confidence interval [CI] 1.113-4.400; p = 0.023). Other independent predictors included age < 50 years (OR 3.203; 95% CI 1.615-6.354; p < 0.001) and American Joint Committee on Cancer stage III disease (OR 7.065; 95% CI 1.067-46.788; p = 0.043). CONCLUSIONS: Among lumpectomy-eligible patients with unilateral breast cancer, a VUS result on germline genetic testing was independently associated with an increased likelihood of BLMast. These findings should be viewed as hypothesis-generating and underscore the need for improved education and standardized counseling surrounding VUS results to support informed surgical decision-making.