In a prospective cross-sectional study reported in JCO Global Oncology, Sudeep Gupta, MBBS, MD, DM, of Tata Memorial Centre, and colleagues found that Indian women with ovarian cancer not selected for study based on clinical factors had a high prevalence of germline pathogenic or likely pathogenic BRCA variants.1
As stated by the investigators: “There are deficient data on prevalence of germline mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/BRCA2) in Indian patients with ovarian cancer who are not selected by clinical features.”
Sudeep Gupta, MBBS, MD, DM
The study enrolled 239 women with newly diagnosed or relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer at nine centers across India between March 2018 and December 2018. Patients were enrolled irrespective of family history of breast or ovarian cancer or histology. Testing for germline BRCA1/BRCA2 mutations was performed using a standard next-generation sequencing assay.
Prevalence of BRCA Variants
Among the 239 women, median age was 53.0 years (range = 23.0–86.0 years), 203 (84.9%) had newly diagnosed disease, 36 (15.1%) had a family history of ovarian or breast cancer, and 159 (66.5%) had the serous subtype of epithelial ovarian cancer. Overall, 230 patients (96.2%) had ovarian cancer, 8 (3.3%) had primary peritoneal cancer, and 1 (0.4%) had fallopian tube cancer.
Germline pathogenic or likely pathogenic BRCA1 or BRCA2 variants were detected in 51 women (21.3%; 95% confidence interval [CI] = 16.3%–27.1%), including BRCA1 variants in 37 (15.5%, 95% CI = 11.1%–20.7%) and BRCA2 variants in 14 (5.9%, 95% CI = 3.2%–9.6%); no women carried both variants. Variants of uncertain significance were detected in BRCA1 in four women (1.7%, 95% CI = 0.5%–4.2%) and in BRCA2 in six women (2.5%, 95% CI = 0.9%–5.4%). Overall, pathogenic or likely pathogenic variants of uncertain significance mutations were found in 61 women (25.5%).
Among the 61 women with BRCA1/2 pathogenic or likely pathogenic variants of uncertain significance mutations, 31 (50.8%) had frameshift mutations (51.2% of BRCA1 and 45.0% of BRCA1 variants), 13 (21.3%) had missense mutations (14.6% and 35.0%), 8 (13.1%) had nonsense mutations (12.2% and 15.0%), 4 (6.6%) had splice site mutations (9.8% and 0%), and 5 (8.2%) had other mutations (12.2% and 5.0%).
The most common single pathogenic mutation in the cohort was the 187delAG in BRCA1 (c.68_69delAG), identified in four patients. As noted by the investigators, this variant is a frameshift, loss of function, and founder mutation in the Ashkenazi Jewish population that has been reported in prior Indian studies with variable frequency; the patients in the current study were not of Ashkenazi Jewish descent and were from different geographic regions in India. Among patients with BRCA2 mutations, the most common was c.5851_5854del, identified in two unrelated patients; the investigators noted that to their knowledge, this variant had not been reported in prior Indian studies.
Association With Clinicopathologic Characteristics
A higher prevalence of pathogenic or likely pathogenic variants was associated with a family history of breast or ovarian cancer, with such variants observed in 20 of 36 patients with (55.6%, 95% CI = 38.1%–72.1%) vs 41 of 203 patients without (20.2%, 95% CI = 14.9%–26.4%) a family history (P < .0001).
A trend toward a higher prevalence of pathogenic or likely pathogenic mutations was observed among women with the serous subtype of disease, with such variants found in 40 of 159 of these women (25.2%, 95% CI = 18.6%–32.6%) compared with 11 of 80 women (13.8%, 95% CI = 7.1%–23.3%) with nonserous subtypes (P = .064). Among 34 women with known endometrioid, clear cell, or mucinous histology, 2 of 34 (5.9%, 95% CI = 0.7%–19.7%) had germline BRCA1/2 mutations, including 0 of 15 with clear cell or mucinous histology.
No significant association of pathogenic or likely pathogenic BRCA1/2 mutations with age was observed, with such variants found in 20 of 90 women aged ≤ 50 years (22.2%, 95% CI = 14.1%–32.2%) and in 31 of 149 aged > 50 years (20.8%, 95% CI = 14.6%–28.2%; P = .796). No significant association of pathogenic or likely pathogenic variants with the number of prior lines of treatment was observed, with such variants found in 36 of 182 (76.2% of the total population; 19.8%, 95% CI = 14.3%–26.3%) who had received no more than one line of treatment vs 15 of 57 (26.3%, 95% CI = 15.5%–39.7%) who had received at least two lines of treatment (P = .293).
The investigators noted that the numerically greater prevalence of pathogenic or likely pathogenic variants among patients who had received at least two vs no more than one prior line of treatment was of interest. They observed that, although the finding needs additional evaluation, it is possible that patients who survive long enough to receive multiple lines of treatment are enriched for BRCA mutations, since such mutations are known to be associated with sensitivity to repeated courses of chemotherapy.
The investigators stated: “[O]ur analysis suggests that, although the prevalence of BRCA1/2 mutations was higher in patients with [a] family history of breast and/or ovarian cancer, a considerable minority of patients without such [a] history (20.2%) also harbored the mutations. This suggests that the absence of [a] family history is not adequate as a screening strategy for germline testing. The prevalence of these mutations was higher in patients with serous histology, and no patient with known clear cell or mucinous tumors had a pathogenic mutation, suggesting that histologic subtype may be used to triage patients for testing. Age was not associated with the prevalence of these mutations and should not be incorporated in clinical decision making to test for germline predisposition.”
They concluded: “There is a high prevalence of pathogenic or likely pathogenic germline BRCA mutations in Indian patients with ovarian cancer.”
DISCLOSURE: The study was supported by AstraZeneca Pharma India Ltd. Dr. Gupta has received institutional research funding from Amgen, AstraZeneca, Celltrion, Intas, Johnson & Johnson, Novartis, Oncostem Diagnostics, Roche, and Sanofi.
1. Gupta S, Rajappa S, Advani S, et al: Prevalence of BRCA1 and BRCA2 mutations among patients with ovarian, primary peritoneal, and fallopian tube cancer in India: A multicenter cross-sectional study. JCO Global Oncol 7:849-861, 2021.
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