Pioneering BRCA1/2 Point-Of-Care Testing for Integration of Germline and Tumor Genetics in Breast Cancer Risk Management: A Vision for the Future of Translational Pharmacogenomics.

Lwando Mampunye,Nerina C Van Der Merwe,Armand V Peeters,Martin Kidd,Maritha J Kotze,Petrus C Van Eeden,Kathleen A Grant,Fredrieka M Pienaar,David J French,Rispah Torrorey-Sawe,Kelebogile E Moremi

doi:10.3389/fonc.2021.619817

Abstract

Research performed in South African (SA) breast, ovarian and prostate cancer patients resulted in the development of a rapid BRCA point-of-care (POC) assay designed as a time- and cost-effective alternative to laboratory-based technologies currently used for first-tier germline DNA testing. In this study the performance of the new assay was evaluated for use on a portable screening device (ParaDNA), with the long-term goal to enable rollout at POC as an inventive step to meet the World Health Organization’s sustainable development goals for Africa. DNA samples for germline testing were obtained retrospectively from 50 patients with early-stage hormone receptor-positive breast cancer referred for genomic tumor profiling (MammaPrint). Currently, SA patients with the luminal-type breast cancer are not routinely selected for BRCA1/2 testing as is the case for triple-negative disease. An initial evaluation involved the use of multiple control samples representing each of the pathogenic founder/recurrent variants included in the BRCA 1.0 POC Research Assay. Comparison with a validated laboratory-based first-tier real-time polymerase chain reaction (PCR) assay demonstrated 100% concordance. Clinical utility was evident in five patients with the founder BRCA2 c.7934delG variant, identified at the 10% (5/50) threshold considered cost-effective for BRCA1/2 testing. BRCA2 c.7934delG carrier status was associated with a significantly younger age (p=0.03) at diagnosis of breast cancer compared to non-carriers. In three of the BRCA2 c.7934delG carriers a high-risk MammaPrint 70-gene profile was noted, indicating a significantly increased risk for both secondary cancers and breast cancer recurrence. Initiating germline DNA testing at the POC for clinical interpretation early in the treatment planning process, will increase access to the most common pathogenic BRCA1/2 variants identified in SA and reduce loss to follow-up for timely gene-targeted risk reduction intervention. The ease of using cheek swabs/saliva in future for result generation within approximately one hour assay time, coupled with low cost and a high BRCA1/2 founder variant detection rate, will improve access to genomic medicine in Africa. Application of translational pharmacogenomics across ethnic groups, irrespective of age, family history, tumor subtype or recurrence risk profile, is imperative to sustainably implement preventative healthcare and improve clinical outcome in resource-constrained clinical settings.

Highlights

Breast cancer (BC) is a leading cause of cancer among women globally, with poor survival and higher mortality rates reported in Africa
Uptake of laboratory-based BRCA1/2 testing in affected families was relatively low, despite the knowledge that gene-targeted therapy and surgical intervention could be life-saving. These findings provided a strong incentive for development of a novel point-of-care (POC) test kit including eight of the pathogenic founder/recurrent variants previously identified in South Africa (SA) [17]: BRCA1 c.68_69delAG, c.1374delC, c.2641G>T, c.5266dupC] and BRCA2 c.5771_5774delTTCA, c.5946delT, c.6447_6448dupTA, c.7934delG
As a targeted genetic testing approach proved valuable as a first-tier test in the age of low-cost next-generation sequencing (NGS) [18], this study aimed to evaluate the BRCA 1.0 POC Research Assay as a robust, costeffective alternative to currently-used laboratory-based testing protocols in BC patients unselected by family history

Summary

Introduction

Breast cancer (BC) is a leading cause of cancer among women globally, with poor survival and higher mortality rates reported in Africa These are generally ascribed to late-stage presentation and a delay in diagnosis, partly due to sub-optimal healthcare systems [1,2,3]. From studies conducted in Sub-Saharan Africa, more advanced breast disease is seen in patients living in rural areas than those in urban centers [2, 4] This is the case for South Africa (SA), where the stage of cancer and age at diagnosis differs according to geographic location as well as psychosocial and personal financial status [5, 6]. Lack of community awareness relating to genetic testing and the benefits of presymptomatic diagnosis of BC contribute to the increased mortality [3]

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