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Oncogenic Drivers Associated with Late Recurrence in Postmenopausal Women with ER-positive/HER2-negative Early Breast Cancer

Results from the BIG 1-98 study
10 Jul 2020
Translational Research
Breast Cancer

Prof. Sherene Loi of the Peter MacCallum Cancer Centre, University of Melbourne in Melbourne, Victoria, Australia and the BIG 1-98 study investigators reported on 8 July 2020 in the Annals of Oncology that in women with oestrogen receptor (ER)-positive/HER2-negative postmenopausal early breast cancer, PIK3CA mutations are associated with reduced risk of late distant recurrence, whereas amplifications on 8p11 and BRCA2 mutations are associated with increased risk of late distant recurrence. The characterisation of oncogenic driver alterations may aid in refining treatment choices for late disease recurrence in that setting and help in identifying potential drug targets for testing in future clinical trials.

The BIG 1-98 team wrote in the study background that in patients with postmenopausal, ER-positive/HER2-negative early breast cancer, the risk for distant recurrence extends beyond 5 years of adjuvant hormonal treatment.

In their study, the investigators aimed to identify genomic driver alterations associated with late distant recurrence. They used next generation sequencing to characterise driver alterations in primary tumours from a subset of 764 postmenopausal patients with ER-positive/HER2-negative breast cancer included in the BIG 1-98 randomised trial.

Late distant recurrence events were defined as at least 5 years from time of randomisation. 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 performed to adjust for clinicopathological factors. Weighted analysis methods were used in order to correct for over-sampling of distant recurrences.

In total, 538 of 764 samples (70%) were successfully sequenced including 88 early (63%) and 52 late (37%) 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.

The authors concluded that oncogenic driver characterisation may aid in refining prognostic estimates for late disease recurrence in women with ER-positive/HER2-negative postmenopausal early breast cancer.


Luen SJ, Asher R, Lee CK, et al. Identifying oncogenic drivers associated with increased risk of late distant recurrence in post-menopausal, estrogen receptor-positive, HER2-negative early breast cancer: results from the BIG 1-98 study. Annals of Oncology; Published 8 July 2020. DOI: https://doi.org/10.1016/j.annonc.2020.06.024

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