In a study reported in the Journal of Clinical Oncology, Ang et al developed a model for predicting carrier status of pathogenic variants in BRCA1 or BRCA2 among Asian women with breast cancer.
As stated by the investigators: “With the development of poly (ADP-ribose) polymerase [PARP] inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer subtype distributions are different from [those] in Asian women.”
Study Details
The cross-sectional population-based study involved data on Chinese, Indian, and Malay women recruited in the Malaysian Breast Cancer Genetic study (two centers in Malaysia) and the Singapore Breast Cancer Cohort study (six centers in Singapore). Prediction models were developed using 5,714 breast cancer cases (228 BRCA carriers) and validated using 2,448 cases (95 BRCA carriers).
Key Findings
The final predictive model, termed the Asian Risk Calculator (ARiCa), for predicting overall likelihood of BRCA pathogenic variant carrier status included younger age at diagnosis, Indian ethnicity, bilateral breast cancer, estrogen receptor negativity, HER2 negativity, higher tumor grade, and presence of first-degree family history of breast or ovarian cancer. The model had a receiver operating characteristic area under the curve (AUC) of 0.80 (95% confidence interval [CI] = 0.75–0.84) for discriminating BRCA and non-BRCA carriers.
The same variables, excluding grade, were associated with BRCA1 pathogenic variant carrier status. The AUC for discriminating BRCA1 from non-BRCA1 carriers was 0.85 (95% CI = 0.78–0.92).
BRCA2 carrier status was associated with younger age at diagnosis, HER2 negativity, higher grade, and first-degree family history of breast cancer. The AUC for discriminating BRCA2 from non-BRCA2 carriers was 0.75 (95% CI = 0.70–0.81).
Analysis in the validation set showed that at a BRCA mutation prevalence of 4%, 31% (95% CI = 29%–33%) of patients with breast cancer would require germline BRCA genetic testing and 71% (95% CI = 61%–80%) of BRCA pathogenic variant carriers would be identified.
The addition of grade to existing clinical genetic testing criteria targeting patients younger than 45 years would reduce the proportion of patients referred for genetic counseling and testing from 37% to 33% (P = .003).
The investigators concluded: “Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients.”
Soo Hwang Teo, PhD, of Cancer Research Malaysia, is the corresponding author of the Journal of Clinical Oncology article.
Disclosure: The study was supported by Wellcome Trust and others. For full disclosures of the study authors, visit ascopubs.org.
