131O - A composite biomarker for evaluation of homologous recombination repair deficiency in a pan-cancer cohort

Background

Assessing the functional state of homologous recombination repair (HRR) is crucial to predict an effective response to PARP inhibitor (PARPi) treatment or platinum-based chemotherapy in cancer patients. Drug approvals are currently mostly based on mutations in BRCA1 and BRCA2 or genomic scarring alone. Composite biomarkers may extend the discriminative power and make targeted treatment approaches available to a wider range of patients and entities.

Methods

Whole-genome or -exome sequencing (WGS or WES) data from 739 patients including various rare cancers were evaluated for germline and somatic alterations in one of 183 genes related to HRR as well as for genomic patterns of HRR deficiency (HRD), i.e. exposure to single-base substitution signature 3, quantification of HRD-derived loss of heterozygosity (LOH-HRD), and the number of large-scale state transitions (LST). The individual markers were integrated into a composite biomarker, the TOP-ART score, with a scoring system (0-7) and compared to the other published HRR biomarkers. Currently, this biomarker is used to determine eligibility for the TOP-ART trial (ClinicalTrials.gov identifier: NCT03127215, olaparib/trabectedin vs. physician's choice, estimated study completion: December 2023).

Results

The occurrence and severity of HRD predicted by the TOP-ART score varies between entities. Strong associations were found between genomic patterns of HRD and mutations affecting several genes, including but not limited to BRCA1 and BRCA2. The phenotypic susceptibility to BRCA1 and BRCA2 impairment varies between entities and depends on zygosity. TOP-ART score positivity (score ≥3; 312 cases) overlaps with but is more inclusive than HRDetect (55 cases) and CHORD (26 cases). In particular, we identify patients who were biomarker-negative for HRDetect and CHORD, but positive in the TOP-ART score, and achieved long-lasting disease control upon treatment with olaparib/trabectedin.

Conclusions

The TOP-ART score is a novel composite HRR biomarker developed and validated in an observational precision oncology cohort. It has the potential to broaden access to targeted treatments and is prospectively used to determine eligibility for the TOP-ART trial.

Clinical trial identification

NCT03127215 Study of Olaparib/Trabectedin vs. Doctor's Choice in Solid Tumors (NCT-PMO-1603) Estimated Primary Completion Date: December 2023 Estimated Study Completion Date: December 2023.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

German Cancer Consortium (DKTK).

Disclosure

C.E. Heilig: Financial Interests, Institutional, Research Funding: AstraZeneca, Pfizer, Roche, PharmaMar. M. Hlevnjak: Financial Interests, Personal, Stocks/Shares: Illumina, GSK, PharmaMar. S. Fröhling: Financial Interests, Personal, Advisory Board: Bayer, Illumina, Roche; Financial Interests, Personal, Invited Speaker: Amgen, Eli Lilly, Illuminna, PharmaMar, Roche. R.F. Schlenk: Financial Interests, Institutional, Research Funding: AstraZeneca, Boehringer Ingelheim, Pfizer, PharmaMar, Roche, Daiichi Sankyo; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo, Pfizer; Financial Interests, Personal, Advisory Board: AbbVie, Daiichi Sankyo, Jazz, Pfizer. All other authors have declared no conflicts of interest.