BRCA1 promoter methylation confers a more favorable prognosis to systemically untreated young triple-negative breast cancer patients than tumour BRCA1 mutation

Abstract

Background The prognoses of systemically treated, triple-negative breast cancer (TNBC) patients with a pathogenic tumor BRCA1 mutation (tBRCA1m) or BRCA1 promoter methylation (BRCA1 PM) have been widely studied. However, the prognosis for systemically untreated women remains unknown. This study investigates the prognosis of systemically untreated young N0 TNBC patients according to tumor BRCA1 status. Methods Dutch women aged < 40 years, diagnosed with TanyN0M0 TNBC between 1989 and 2000 were selected from the Netherlands Cancer Registry. In that era, N0 patients were considered low risk and not given (neo)adjuvant systemic therapy. We analyzed tBRCA1m and BRCA1 PM using DNA from formalin-fixed paraffin-embedded tumor tissues. We built Cox and competing risk regression models, for invasive disease-free survival (iDFS), and distant recurrence-free survival (DRFS) with secondary primary tumors (SPTs) as competing events. Both models were adjusted for tumor characteristics and locoregional treatment. Results For 373 patients, tBRCA1m and BRCA1 PM status were available. Of these, 28% had pathogenic tBRCA1m, 36% had BRCA1 PM and the rest were classified as BRCA1 dual-negative. Compared to patients with BRCA1 dual-negative tumors, patients with BRCA1 PM had a favorable iDFS (adjusted hazard ratio [aHR] = 0.66, 95% confidence interval [CI] = 0.45 – 0.98) but similar DRFS (subdistribution hazard ratio [sHR] = 0.86, 95% CI = 0.50 – 1.46), while patients with tBRCA1m had poorer iDFS (aHR = 1.86, 95% CI = 1.30 – 2.65) and also similar DRFS (sHR = 1.04, 95% CI = 0.61 – 1.76). Furthermore, patients with BRCA1 PM had lower risk for SPTs (sHR = 0.38, 95% CI = 0.17 – 0.83), while patients with tBRCA1m had higher risk (sHR = 3.12, 95% CI = 1.79 – 5.45). Conclusions Although tBRCA1m and BRCA1 PM both cause BRCA1 gene inactivation, the iDFS differed significantly between systemically untreated young TNBC patients with these tumor types. This can be mainly attributed to substantially different risk for SPTs. Interventions to prevent SPTs, such as contralateral prophylactic mastectomy or secondary chemoprevention, should be considered for young tBRCA1m TNBC patients.