BRCA mutations and survival in breast cancer: an updated systematic review and meta-analysis

Abstract

BRCA mutations occur frequently in breast cancer (BC), but their prognostic impact on outcomes of BC has not been determined. We conducted an updated meta-analysis on the association between BRCA mutations and survival in patients with BC. Electronic databases were searched. The primary outcome measure was overall survival (OS), and the secondary outcome measures included breast cancer-specific survival (BCSS) and event-free survival (EFS). Hazard ratios (HR) and 95% confidence interval (CI) were abstracted and pooled with random-effect modeling. Data from 297, 402 patients with BC were pooled from 34 studies. The median prevalence rates of BRCA1 and BRCA2 mutations were 14.5% and 8.3%, respectively. BRCA mutations were associated with worse OS (BRCA1: HR = 1.69, 95% CI, 1.35 to 2.12, p < 0.001; BRCA2: HR = 1.50, 95% CI 1.03 to 2.19, p = 0.034). However, this did not translate into poor BCSS (BRCA1: HR = 1.14, 95% CI, 0.81 to 1.16, p = 0.448; BRCA2: HR = 1.16; 95% CI 0.82 to 1.66, p = 0.401) or EFS (BRCA1: HR = 1.10, 95% CI, 0.86 to 1.41, p = 0.438; BRCA2: HR= 1.09; 95% CI 0.81 to 1.47, p = 0.558). Several studies analyzed BRCA1 and BRCA2 mutations together and found no impact on OS (HR = 1.21; 95% CI, 0.73 to 2.00, p = 0.454) or EFS (HR = 0.94; 95% CI, 0.60 to 1.48, p = 0.787). BRCA1 and BRCA2 mutations were associated with poor OS in patients with BC, but had no significant impact on BCSS or EFS. An improved survival was observed in BC patients who had BRCA1 mutation and treated with endocrinotherapy. The results may have therapeutic and prognostic implications important for BRCA mutation carriers with BC.

BRCA1/BRCA2 Germline Mutation Carriers and Sporadic Pancreatic Ductal Adenocarcinoma

“…Mutations in BRCA are more commonly studied in the setting of breast or ovarian cancer. 22,23 Although the association between BRCA mutations and PDAC in both the familial and seemingly sporadic case is known, the rarity of the diagnosis compounded by the infrequent nature of genetic testing has led to few studies of BRCA mutation and its impact on patient survival. 24–28 In theory, BRCA mutations in PDAC may fall within the unstable genotype, representing a more mutagenic and aggressive tumor biology and subsequent worse survival.…”

High EMSY expression defines a BRCA‐like subgroup of high‐grade serous ovarian carcinoma with prolonged survival and hypersensitivity to platinum

“…Approximately one‐half of HGSOCs are described as having identifiable defects in the HR pathway, with the archetypal defects being germline or somatic BRCA inactivation . Surprisingly, the EMSY gene, the product of which has been shown to bind and inactivate BRCA2, has received relatively little attention in HGSOC, despite being associated with a poor prognosis in individuals with breast cancer …”

“…Similar to BRCA mutation, EMSY amplification has been associated with poor prognosis in patients with breast cancer and is most common in the HGS histological subtype of OC. 14,15,[18][19][20][21][22] However, to our knowledge, no association between EMSY expression and clinical outcome in patients with HGSOC has been made to date. In the current study, we sought to perform in silico analysis of available transcriptomic data to investigate whether patients with HGSOCs demonstrating high expression of EMSY experience differential clinical outcome or sensitivity to platinum-based chemotherapy.…”

“…Thus, tumors with EMSY amplification may mimic those demonstrating mutational inactivation of BRCA2 . Similar to BRCA mutation, EMSY amplification has been associated with poor prognosis in patients with breast cancer and is most common in the HGS histological subtype of OC …”

Clarifying the role of EMSY in DNA repair in ovarian cancer

“…Similar to BRCA1/2 mutations, EMSY amplification has been associated with poor survival in patients with breast cancer . However, this may only be the case when EMSY is coamplified with CCND1 , at least for patients with estrogen receptor–positive breast cancer .…”