Long-term outcomes of young, node-negative, chemotherapy-naïve, triple-negative breast cancer patients according to BRCA1 status

Wang, Y.W.; Dackus, G.M.H.E.; Rosenberg, E.H.; Cornelissen, S.; Boo, L.W. de; Broeks, A.; ... ; Schmidt, M.K. (2024)

Article / Letter to editor

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-na & iuml;ve 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-na & iuml;ve 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.

• BRCA1 status
• Tumor-infiltrating lymphocytes
• Triple-negative breast cancer
• Chemotherapy-naive
• Long-term outcomes
• Risk classification

• All authors: Wang, Y.W.; Dackus, G.M.H.E.; Rosenberg, E.H.; Cornelissen, S.; Boo, L.W. de; Broeks, A.; Brugman, W.; Chan, T.W.S.; Diest, P.J. van; Hauptmann, M.; Hoeve, N.D. ter; Isaeva, O.I.; Jong, V.M.T. de; Jozwiak, K.; Kluin, R.J.C.; Kok, M.; Koop, E.; Nederlof, P.M.; Opdam, M.; Schouten, P.C.; Siesling, S.; Steenis, C. van; Voogd, A.C.; Vreuls, W.; Salgado, R.F.; Linn, S.C.; Schmidt, M.K.
• Date: 2024-01-09
• Journal: BMC Medicine
• Volume: 22
• Issue: 1
• DOI: doi:10.1186/s12916-023-03233-7