A novel BRCA1 and BRCA2 mutation prediction model for South East Asian patients with breast cancer

Breast cancer is the most common form of cancer among women worldwide, with 2.3 million new cases and 685,000 deaths in 2020 globally.1 Currently, most of the mutation prediction models identifying BRCA pathogenic variants (PVs) are developed in Western countries.2 These models are based on clinical genetic data obtained from women of European or North American descent which are different from the Asian population, displaying different cancer-subtype distributions and younger age of diagnosis.2 In a recent study published in the Journal of Clinical Oncology, a logistic regression prediction model for Southeast Asian breast cancer patients to estimate the likelihood of carrying PVs in the BRCA1 or BRCA2 gene has been developed and validated.2 Named “Asian Risk Calculator (ARiCa)”, the prediction model was created based on the necessity of having an Asian population-specific prediction tool available to income-challenged Asian countries where the provision of genetic services can be difficult with a lack of supply.1,2

In this cross-sectional population-based study, 8,162 breast cancer patients were recruited from 2 hospitals in Malaysia (the Malaysian Breast Cancer Genetic study) and 6 hospitals in Singapore (the Singapore Breast Cancer Cohort study).2 The ethnicities of the patients pooled were Chinese, Indian and Malay, with a mean age of diagnosis of 52.3 years.2 The study sample was randomly divided into training (70%) and validation (30%) sets.2 Predictors of BRCA PV were the age of diagnosis, ethnic origin, bilateral breast cancer, pathologic characteristics, and familial history of ovarian or breast cancers.2

Some 5,714 breast cancer cases (228 BRCA carriers) were used to develop prediction models and validated using 2,448 cases (95 BRCA carriers).2 Six combinations of tumor biomarkers and predictors were used in the evaluation: 1) Triple-negative breast cancer (TNBC); 2) Estrogen receptor (ER); 3) ER and human epidermal growth factor receptor 2 (HER2); 4) Hormone receptor (HR) and HER2; and 5) Immune-histochemical subtypes.2

The model with the highest receiver operating curve (AUC) and the lowest non-significant Hosmer-Lemeshow (HL) test score was considered the best performance model for predicting the overall BRCA PV carrier status and named the ARiCa.2 The AUC for differentiating between BRCA vs. non-BRCA carriers was 0.80 (95% CI:0.75-0.84).2,3 The model was calibrated with an HL p=0.614.2 The evaluation of ARiCa by ethnicity possessed strong discriminatory power and was calibrated well among the ethnic groups.2 Variables associated with ARiCa’s overall BRCA PV carrier status were younger age of diagnosis, ER-negativity, HER2-negativity, higher tumor grade, Indian ethnicity, and the existence of first-degree family history with breast or ovarian cancer.2

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