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

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.

Implementation of multigene panel testing for breast and ovarian cancer in South Africa: A step towards excellence in oncology for the public sector

“…The expansion of routine genetic testing from conventional BRCA1/2 testing to multigene testing led to a relatively high diagnostic yield of 15%, with approximately one-third of positive cases (12/34, 35.3%) found to be known South African founder variants. Although no official cost-effectiveness analysis has been performed in South Africa, these results justify the incorporation of BRCA1/2 founder variant testing in the screening algorithm recommended by Mampunye et al (16). Since transcriptional gene profiling routinely used in the private sector to prevent chemotherapy overtreatment in patients with early-stage hormone receptor-positive breast cancer is not available in the state sector, we modified the screening algorithm by omitting the assessment of RNA extracted from formalin-fixed paraffin embedded tumor biopsies.…”

“…Since transcriptional gene profiling routinely used in the private sector to prevent chemotherapy overtreatment in patients with early-stage hormone receptor-positive breast cancer is not available in the state sector, we modified the screening algorithm by omitting the assessment of RNA extracted from formalin-fixed paraffin embedded tumor biopsies. This is shown in Figure 2, starting While electronic gatekeeping regarding requirements for genetic testing has been implemented by the Department of Health to ensure that referring clinicians adhere to the new national guidelines, use of the newly designed point-of-care (POC) assay (8,16) as a first-tier test for all breast and ovarian cancer patients has the potential to not only reduce cancer incidence but also improve survival by identifying high-risk variants in patients in need of risk-reducing treatments. The rapid POC assay is inexpensive (estimated purchase price ZAR 1 000) and can be used for all breast and ovarian cancer patients, irrespective of the Manchester score, ethnicity, tumour subtype or a history of cancer in other family members.…”

Feasibility of point of care testing for prevention and management of breast cancer therapy associated comorbidities in 6 African countries: short communication

“…These women were from colored population from Western Cape Province of South Africa. demographics data were published in the main studies [ 7 , 10 , 11 ]. The 6 African countries surveyed including DRC, Burundi, South Africa, Eswatini, Ghana and Mali.…”

“…The characteristics of South African breast cancer survivors may not be similar to those studies used in the current computations. Other studies should be conducted at large public health scales to consider a disruptive commissioning model that includes reimbursement and other incentives to affect the large-scale adoption of suitable multi-array POC devices, including specified CYP19A1 alleles with the potential to reduce cost and maximize patient benefits [8][9][10][11].…”

Genomics in Egypt: Current Status and Future Aspects

“…In a resource limited African setting such as Egypt, this could lead to loss-in-follow-up and thereby ineffective risk management. The South African experience from using rapid, cost-effective point of care (PoC) DNA assays to speed up the process of genetic testing and decrease cost demonstrated the feasibility of this approach in a pilot study ( Mampunye et al, 2021 ) POC BRCA1/2 testing combined with genetic counselling to inform patients about the limitations and benefits of mutation-specific PoC tests versus comprehensive sequencing methods will increase access to genomic medicine, given the clinical dilemma caused by a relatively high frequency of variants of uncertain clinical significance (VUS) uncovered by gene panel testing and whole exome/genome sequencing (WES/WGS). PSGT is used to identify the target group most likely to benefit from germline DNA testing and/or tumour gene profiling and facilitate clinical interpretation of genetic results to add value in combination and beyond pathology test results.…”