Population risk stratification in the early detection and personalized treatment for breast cancer

With the aim of improving the morbidity and mortality rates of breast cancer in different populations, several studies have been conducted to investigate the etiology and pathogenesis of aggressive molecular subtypes, particularly among young women of African ancestry.1 Dr. Olufunmilayo I Olopade, MD, FACP, Walter L. Palmer Distinguished Service Professor of Center for Clinical Cancer Genetics and Global Health, the University of Chicago in the United States, delivered a lecture in the European Society for Medical Oncology (ESMO) Congress 2021, highlighting the importance of comprehensive risk assessment and stratification for the early detection and treatment decisions of breast cancer among African diaspora.1 

The genetic landscape of African ancestry is perceived to be “the root” of outrageously high breast cancer death rate among African women.1 Basal-like or triple-negative (ER negative/PR negative/HER2 negative) breast cancer, is reportedly more prevalent in African Americans than in the white populations, but this remains understudied.1  

In order to show the importance of integrating genetic predisposition into the early treatment decision, in 2018, Dr. Olopade and her team applied BROCA gene testing in 1,136 Nigerian women to identify the loss-of-function mutations in unknown and breast cancer candidate genes, and explore the close relationship between inherited mutations and significantly high-risk breast cancer.1 Approximately 12%-13% of Nigerian women with breast cancer were associated with critical mutations in breast cancer 1 (BRCA1), breast cancer 2 (BRCA2) or partner and localizer of BRCA2 (PALB2) genes.1 Of note, Dr. Olopade emphasized the appearance of mutation carriers for BRCA1 and BRCA2 at every age group showing that age alone could not manifest the actual risk of developing aggressive breast cancer.1 

And recently, the Breast Cancer Association Consortium (BCAC) released a report to demonstrate a clear association between the risk of breast cancer and protein-truncating variants in 8 genes, including the high-risk genes BRCA1, BRCA2 and PALB2, which reflected an underestimation of breast cancer susceptibility in diverse populations.1 In order to prevent similar cases of “missing heritability”, detailed investigation in all relevant variations and the application of wide range of gene testing models are recommended.1 

A further study conducted by Dr. Olopade and her team, in collaboration with Dr. Michaela Gack, PhD, Scientific Director and Chair of Cleveland Florida Research and Innovation Center, also revealed the immunogenic role of BRCA1 Pseudogene (BRCA1P1) in regulating the antiviral and antitumor defense mechanisms against breast cancer cells, which thus may become the direction of immunotherapy for breast cancer moving on.1

“The ethnic-specific risk stratification is important because we cannot do one-size-fits-all approach. The paper we published was looking at the genome-type-specific breast cancer screening for its early detection,” said Dr. Olopade. She mentioned that the Cross-ancestry Genome-wide Association Study (GWAS) meta-analysis released recently uncovered the genetic variants shared across ancestry.1 An unpublished study also focused on the population risk stratification with genome-wide approach, with about 5% of African women found to have over 90% of risk of breast cancer before the age of 40.1 Dr. Olopade elaborated that the time interval of practicing genotype specific screening, including mammogram and magnetic resonance imaging (MRI), should be shortened to half a year for BRCA1 mutation carriers in order to detect the early onset of aggressive breast cancer and minimize harms from treatment.1 

To sum up, Dr. Olopade asserted that precision oncological care will be the future development of breast cancer treatment, which comprises of comprehensive risk assessment, genomic testing and specific biomarker-driven clinical trials in all populations.1 It is anticipated that the disparities in breast cancer outcomes across different populations could be alleviated with global concerted efforts.

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