Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants

Abstract

Young breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR−]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I–III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60–0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94–2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients’ counseling on treatment, prevention, and surveillance strategies.

Cancer-Specific Survival Outcome in Early-Stage Young Breast Cancer: Evidence From the SEER Database Analysis

“…Over the past years, with an increasing prevalence of breast cancer worldwide ( 1 – 4 , 6 ), the comprehensive and individualized management for patients with this particular disease has gradually attracted much attention, especially in terms of young breast cancer ( 7 , 9 , 10 , 14 , 15 ). It was believed that age was an independent prognostic indicator among female breast cancer and younger age, especially under the age of 40 years, frequently presented a higher risk of locoregional metastasis, recurrence, and ultimately worse OS outcomes ( 7 , 10 , 12 ).…”

“…First, although the sample size of this study was considerable, the character of the retrospective design was inevitably flawed with bias. Second, some clinical risk factors like Ki-67 index ( 36 , 37 ) and BRCA1- and BRCA2- related mutation ( 15 , 38 ) as well as high 21-Gene Recurrence Score (21-GRS) ( 39 ) which have been proved to be related to worse OS in patients with breast cancer were unavailable in the SEER database. Third, the detailed information of hormone receptors (estrogen receptor and progesterone receptor) and Her-2 status were unavailable in the SEER database.…”

Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair–Related Genes

“…The apparent negative impact in breast cancer of g BRCA1 or g BRCA2 pathogenic variant carriers could not be demonstrated, even in young women. In this context, no statistically significant differences in OS were observed between BRCA -positive and BRCA -negative patients in the multicenter prospective POSH study, which genotyped 2,733 young women (< 40 years) with invasive breast cancer and included a total of 338 (12%) patients with g BRCA m. 37 In addition, analyzing a retrospective cohort of 1,236 patients with stage I-III invasive early breast cancer at age ≤ 40 years, Lambertini et al 16 importantly showed that irrespective of hormone receptor status, the type of BRCA gene did not have a prognostic impact on OS between patients harboring BRCA1 - and BRCA2 -mutated tumors.…”

“…9,10 Although the predictive value of germline BRCA pathogenic variants (g BRCA m) in breast cancer has been demonstrated for PARP inhibitor agents, the prognostic value of these mutations in the HR+ subgroup remains controversial. 11-16 In addition, estrogen receptor (ER)–positive breast cancers are more common in CHEK2 and ATM pathogenic variant carriers and the prognostic value of these alterations is being elucidated. 17-20…”

“…9,10 Although the predictive value of germline BRCA pathogenic variants (gBRCAm) in breast cancer has been demonstrated for PARP inhibitor agents, the prognostic value of these mutations in the HR+ subgroup remains controversial. [11][12][13][14][15][16] In addition, estrogen receptor (ER)-positive breast cancers are more common in CHEK2 and ATM pathogenic variant carriers and the prognostic value of these alterations is being elucidated. [17][18][19][20] To date, no prospective evidence supports particular recommendations regarding the use of CDK4/6 inhibitors in gBRCAm HR+ advanced breast cancer (aBC) patients since pivotal trials of CDK 4/6 inhibitors have not incorporated a prespecified subgroup analysis in BRCA1/2 pathogenic variant carriers.…”