BMC Medicine (Jan 2024)

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

  • Yuwei Wang,
  • Gwen M. H. E. Dackus,
  • Efraim H. Rosenberg,
  • Sten Cornelissen,
  • Leonora W. de Boo,
  • Annegien Broeks,
  • Wim Brugman,
  • Terry W. S. Chan,
  • Paul J. van Diest,
  • Michael Hauptmann,
  • Natalie D. ter Hoeve,
  • Olga I. Isaeva,
  • Vincent M. T. de Jong,
  • Katarzyna Jóźwiak,
  • Roelof J. C. Kluin,
  • Marleen Kok,
  • Esther Koop,
  • Petra M. Nederlof,
  • Mark Opdam,
  • Philip C. Schouten,
  • Sabine Siesling,
  • Charlaine van Steenis,
  • Adri C. Voogd,
  • Willem Vreuls,
  • Roberto F. Salgado,
  • Sabine C. Linn,
  • Marjanka K. Schmidt

DOI
https://doi.org/10.1186/s12916-023-03233-7
Journal volume & issue
Vol. 22, no. 1
pp. 1 – 14

Abstract

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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.

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