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

Abstract

Translation of genomic knowledge into public health benefits requires the implementation of evidence-based recommendations in clinical practice. In this study, we moved beyond BRCA1/2 susceptibility testing in breast and ovarian cancer patients to explore the application of pharmacogenetics across multiple genes participating in homologous recombination DNA damage repair. This involved the utilisation of next-generation sequencing (NGS) at the intersection of research and service delivery for development of a comprehensive genetic testing platform in South Africa. Lack of international consensus regarding risk categorization of established cancer susceptibility genes and the level of evidence required for prediction of drug response supported the development of a central database to facilitate clinical interpretation. Here we demonstrate the value of this approach using NGS to 1) determine the variant spectrum applicable to targeted therapy and implementation of prevention strategies using the 15-gene Oncomine™ BRCA Expanded Panel, and 2) searched for novel and known pathogenic variants in uninformative cases using whole exome sequencing (WES). Targeted NGS performed as a routine clinical service in 414 South African breast and/or ovarian cancer patients resulted in the detection of 48 actionable variants among 319 (15%) cases. BRCA1/2-associated cancers were identified in 70.8% of patients (34/48, including two double-heterozygotes), with the majority (35.3%, 12/34) representing known South African founder variants. Detection of actionable variants in established non-BRCA1/2 risk genes contributed 29% to the total percentage (14/48), distributed amongst ATM, CHEK2, BARD1, BRIP1, PALB2 and TP53. Experimental WES using a virtually constructed multi-cancer NGS panel in 16 genetically unresolved cases (and four controls) revealed novel protein truncating variants in the basal cell carcinoma gene PTCH1 (c.4187delG) and the signal transmission and transduction gene KIT (c.930delA) involved in crucial cellular processes. Based on these findings, the most cost-effective approach would be to perform BRCA1/2 founder variant testing at referral, followed by targeted multigene panel testing if clinically indicated and addition of WES in unresolved cases. This inventive step provides a constant flow of new knowledge into the diagnostic platform via a uniquely South African pathology-supported genetic approach implemented for the first time in this context to integrate research with service delivery.

Navigating the genetic landscape of breast cancer in South Africa amidst a developing healthcare system

“…A poll completed during a workshop hosted as part of the local biennial Southern African Society for Human Genetics (SASHG) conference revealed that 94% of the members attending approved the use of POCT as a cost-effective first-tier test if accompanied by genetic counseling ( Mampunye et al, 2021 ; Oosthuizen et al, 2021 ). As less than 10% of South Africa’s need for clinical genetic services is currently being met, the demand for skilled professionals who can provide and interpret clinically actionable genetic information will likely be met in two ways, namely, by upskilling primary care health professionals including general practitioners and nurses, and upscaling current training of GCs and medical geneticists ( van der Merwe et al, 2022b ).…”

“…With higher throughput and increased cost effectiveness, the patient selection criteria was broadened. Screening is now also performed for individuals without a family history but diagnosed at an early age (irrespective of tumor characteristics) or diagnosed at a late stage with aggressive disease (SADoH, 2019;van der Merwe et al, 2022a). In contrast, developed countries with fewer financial constraints use extended testing protocols ranging from somatic tumor testing to identify treatment targets, to multi-cancer gene panels or genome sequencing (WGS) that include newly identified, low-penetrance genes for individuals that do not meet the selection criteria.…”

“…The South African study further explored the additional clinical value of exome sequencing at the intersection of diagnostic service delivery and research. Limiting variant interpretation to an 84-gene hereditary cancer virtual panel reduced the time spent on variant interpretation involving a high rate of VUSes, and minimized the risk of incidental findings (van der Merwe et al, 2022a).…”

Navigating ethical challenges of integrating genomic medicine into clinical practice: Maximising beneficence in precision oncology

“…[14,23] While it was challenging to balance benefits to patients with conflicts of interest arising during the first health technology assessment (HTA) performed in 2009 by a SA medical insurer, the PM-ISR model developed because of this process opened new avenues for research focused on minimisation of healthcare costs. [24,25] Ethical analysis of PSGT by institutional review boards furthermore set new standards to protect patients and benefit the public, as evidenced by a transition from population risk stratification to personal utility in translational research projects. [15,26] This relates to the readiness checklist compiled by Jongeneel et al [12] for the implementation of genomic medicine in Africa.…”

Mitochondrial Deoxyribonucleic Acid (mtDNA), Maternal Inheritance, and Their Role in the Development of Cancers: A Scoping Review

“…Current evidence suggests that there is an increasing frequency of hereditary breast and ovarian cancers [ 39 ]. Additionally, there is an increased awareness of gene mutations that could predispose to the familial transfer of cancers [ 40 ]. However, there is a scarcity of such information regarding the role of mtDNA and its influence on the development of cancers.…”