LBA64 - Outcomes of BRCA and in-house homologous recombination deficiency (HRD) testing in women with ovarian and breast cancer: A multicentre registry study

Background

There is a lack of studies investigating the burden of BRCA1/2 in Northern African countries using NGS-based testing, as well as a lack of HRD testing due to costly centralized services.

Methods

We established a multicentre registry and conducted in-house genetic testing of unselected patients (pts) referred from 5 centres in Egypt from 2019 to 2022. Eligible pts should have histologically confirmed epithelial ovarian cancer (EOC) or triple-negative breast cancer (TNBC). Germline or somatic BRCA1/2 NGS testing was performed by target enrichment and sequencing was done using the Illumina NextSeq500. HRD testing included genomic scar score (GSS) categorized at ≥50 and tumor mutation BRCA1/2 status. A custom hybridization capture panel (AmoyDx® HRD Focus) that targets 24000 SNPs distributed across the genome was used to infer the GSS. Two Western cohorts, MSKCC (n= 1610) and UK Diagnostic Labs (n= 80722), were used for comparison.

Results

Our in-house genetic testing approach was feasible with a median turnaround time of 14 days (range 10-53 days). Genetic testing was successfully performed for 1349 of 1420 (95%) of pts tested (EOC=1031, TNBC=318). The median age was 55 (range 20-86 years). We identified 258 BRCA1/2 pathogenic variants (PVs) affecting 254 (18.8%) pts and 85 variants of uncertain significance (VUS) affecting 73 pts (5.3%). The majority of recurrent BRCA2 PVs but not BRCA1 were breast or ovarian lineage-unique (p=0.002). We developed a limited-resource conscious framework that provided a re-classification of 60% of identified VUS. Although the rate of PVs in our cohort was similar to the Western cancer population, there were significant differences in the enrichment at the variant level. A subgroup (n=589) of the EOC cohort underwent HRD testing with 240 (40.8%) HRD-positive, including 128 pts (21.7%) having a positive GSS alone without BRCA1/2 PVs. The top recurrent PV, BRCA1 V409*, was associated with the highest median GSS (97).

Conclusions

This is the largest experience from limited resource settings showing that locally performed BRCA and HRD testing was feasible and mitigated the high cost and lengthy turnaround time associated with central testing.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Cairo University; Ain Shams University; Cancer Research UK.

Disclosure

K.S. Shohdy: Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Institutional, Research Grant: AstraZeneca, Novartis; Financial Interests, Other, Educational Grant: Adaptimmune. All other authors have declared no conflicts of interest.