Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status
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Published:2024-01-09
Issue:1
Volume:22
Page:
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ISSN:1741-7015
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Container-title:BMC Medicine
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language:en
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Short-container-title:BMC Med
Author:
Wang Yuwei, Dackus Gwen M. H. E., Rosenberg Efraim H., Cornelissen Sten, de Boo Leonora W., Broeks Annegien, Brugman Wim, Chan Terry W. S., van Diest Paul J., Hauptmann Michael, ter Hoeve Natalie D., Isaeva Olga I., de Jong Vincent M. T., Jóźwiak Katarzyna, Kluin Roelof J. C., Kok Marleen, Koop Esther, Nederlof Petra M., Opdam Mark, Schouten Philip C., Siesling Sabine, van Steenis Charlaine, Voogd Adri C., Vreuls Willem, Salgado Roberto F., Linn Sabine C., Schmidt Marjanka K.ORCID
Abstract
Abstract
Background
Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account.
Methods
We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients’ outcomes were compared using Cox regression and competing risk models.
Results
Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18–3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78–0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9–100%). Conversely, among the 61 patients with gBRCA1m and < 50% sTILs, we observed poor 15-year OS (50.8%; 95% CI, 39.7–65.0%). Furthermore, gBRCA1m was associated with higher (adjusted subdistribution HR, 4.04; 95% CI, 2.29–7.13) and tumor BRCA1-PM with lower (adjusted subdistribution HR, 0.42; 95% CI, 0.19–0.95) incidence of second primary tumors, compared to BRCA1-non-alteration.
Conclusions
Although both gBRCA1m and tumor BRCA1-PM alter BRCA1 gene transcription, they are associated with different outcomes in young, node-negative, chemotherapy-naïve TNBC patients. By combining sTILs and BRCA1 status for risk classification, we were able to identify potential subgroups in this population to intensify and optimize adjuvant treatment.
Funder
KWF Kankerbestrijding ZonMw Stichting A Sister's Hope Breast Cancer Research Foundation Ministerie van Volksgezondheid, Welzijn en Sport
Publisher
Springer Science and Business Media LLC
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