Title

eP077 - Germline pathogenic variants in Pakistani patients evaluated at a hereditary breast cancer clinic

Document Type

Conference Paper

Department

Paediatrics and Child Health; Haematology/Oncology; Breast Surgery

Abstract

Background: Breast cancer is the most common malignancy, impacting over 1.5 million women (25% of all women with cancer) every year, accounting for the highest number of cancer-related deaths in women globally. (Sun et al., 2017) (WHO, 2021).
Hereditary breast cancer (HBC), an important subset of breast cancer, accounts for 5–10% of total cases. (Sun et al., 2017) These cases are attributed to pathogenic (P) and likely pathogenic (LP) germline variants in genes that have a predisposition for breast cancer. However, in Low Middle-Income Countries (LMICs), the population-specific risk of hereditary breast cancer in different ethnicities and the correlation with clinical characteristics remains unexplored.
Objective:
• To see the spectrum of variants beyond BRCA1/2 in Pakistani breast cancer patients.
• To compare the clinical characteristics of patients who test positive, with patients who have variants of uncertain significance (VUS) and negative results.
• To show preliminary population specific data that can guide tailored genetic testing criteria in a resource-limited country.
Methods: A retrospective chart review of 284 patients who visited the hereditary breast cancer (HBC) clinic and proceeded with multi-gene panel testing (Invitae Genetics, USA) from May 2017 to April 2020. Descriptive and inferential statistics are used to analyze clinical characteristics of patients with positive results, comparing with patients with VUS and negative test results. Fisher’s exact, Pearson’s chi-squared tests and Logistic regression analysis were used for categorical variables and Wilcoxon rank-sum test for quantitative variables were used. For comparation between two independent groups, Mann-Whitney test was performed. Results were considered significant at a p value of <0.05.
Results and Discussion: Positive results included results for patients with pathogenic and likely pathogenic variants. Out of 284 patients, 22% (63/284) tested positive, 37% (104/284) had a VUS and 41% (117/ 284) had a negative result. Fifty-five percent of the positive patients were in either BRCA1 or BRCA2, while the other 45% of the positive results were attributed to other genes. The spectrum of the identified variants is summarized in Table 1. Patients with positive results had a younger age at diagnosis compared with those who had a VUS or a negative result; mean age (in years) = 38, IQR (32–48) vs 45, (37–51) vs 44 (38–50), (p value = 0.002). 73% of the positive results were found in patients under the age of 44. Having a positive result showed a positive association with triple negative breast cancer (TNBC) as well as higher disease grade (p = 0.024), using multi-variate analysis. Patients with TNBC were almost 3 times more likely to harbor a P or LP variant (OR = 2.8, CI = 1.42–5.48 p = 0.003). Of the patients who tested positive for BRCA1 or BRCA2, 67% had a diagnosis of TNBC. Of all patients with positive results, 25% of patients had a negative family history of breast and/or related cancers. The likelihood of the genetic test being positive was two times higher if there was a family history of cancer, as compared to no family history of cancer (OR = 2.13, Cl = 1.12–4.08, p = 0.021).
Conclusion: In our HBC clinic, we observed that our rate of positive results was twice of what is reported in populations of Caucasian descent. This could either be due to referral bias, or a true higher rate of hereditary breast cancer in our population. The importance of expanded, multi-gene panel testing is highlighted by the fact that almost half of the patients had P or LP variants in genes other than BRCA1/2, and that our test positivity rate would have only been 10% if only BRCA1/2 testing was done. Consistent with data from other countries, we also found that in our population, having TNBC or a young age at diagnosis increased the likelihood of a positive result. Up to a quarter of patients with positive result had a negative family history. As the database expands and protocol-driven referrals are made across the country, our insight about the genetic architecture of hereditary breast cancer in our population will continue to increase.

Publication

Molecular Genetics and Metabolism

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