Background: In postmenopausal, estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer, the risk for distant recurrence can extend beyond 5 years of adjuvant endocrine therapy. This study aims to identify genomic driver alterations associated with late distant recurrence. Patients and methods: Next generation sequencing was used to characterize driver alterations in primary tumors from a subset of 764 postmenopausal estrogen receptor-positive/HER2-negative patients from the BIG 1-98 randomized trial. Late distant recurrence events were defined as ≥5 years from time of randomization). The association of driver alterations with distant recurrence-free interval in early and late time periods was assessed using Cox regression models. Multivariable analyses were carried out to adjust for clinicopathological factors. Weighted analysis methods were used in order to correct for over-sampling of distant recurrences. Results: A total of 538 of 764 (70%) samples were successfully sequenced including 88 (63%) early and 52 (37%) late distant recurrence events after a median follow up of 8.1 years. In univariable analysis for late distant recurrence, PIK3CA mutations (58.8%) were significantly associated with reduced risk [hazard ratio (HR) 0.40, 95% confidence interval (CI) 0.20–0.82, P = 0.012], whereas amplifications on chromosome 8p11 (10.9%) (HR 4.79, 95% CI 2.30–9.97, P < 0.001) and BRCA2 mutations (2.3%) (HR 5.39, 95% CI 1.51–19.29, P = 0.010) were significantly associated with an increased risk. In multivariable analysis, only amplifications on 8p11 (P = 0.002) and BRCA2 mutations (P = 0.013) remained significant predictors. Conclusions: In estrogen receptor-positive/HER2-negative postmenopausal early breast cancer, PIK3CA mutations were associated with reduced risk of late distant recurrence, whereas amplifications on 8p11 and BRCA2 mutations were associated with increased risk of late distant recurrence. The characterization of oncogenic driver alterations may aid in refining treatment choices in the late disease setting, and help identify potential drug targets for testing in future trials.
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