1832P - Centralized screening for homologous recombination repair (HRR) genes in metastatic castration-resistant prostate cancer (mCRPC): A feasibility study from a multicenter Spanish cohort

Background

The presence of pathogenic variants (PV) in BRCA1-2 in mCRPC patients has been associated with improved response to PARP inhibitors (PARPi) and better survival outcomes. Thus, tumor testing for somatic alterations in HRR genes in mCRPC patients has been recently incorporated to the main clinical guidelines. However, its implementation in daily practice could represent a challenge due to lack of access to testing. Moreover, there is scarce data about PV prevalence and distribution in Spain. This study aims to characterize the feasibility of centralized genetic testing for HRR mutations in mCRPC samples and to describe the PV prevalence and distribution from a large multicenter Spanish cohort.

Methods

From January-22 to April-23, formalin-fixed paraffin-embedded (FFPE) samples from patients with mCRPC pre-treated with ≥1 novel hormonal agent and who were eligible for a successive line of treatment (ECOG 0-1 and hemoglobin >10 mg/dl) were collected. Samples older than 5 years were excluded in order to guarantee the quality of the genetic material. The molecular analysis and the interpretation of the results were centralized at Hospital Marqués de Valdecilla, where an HRR panel which included BRCA1, BRCA2, CHEK2, ATM, and CDK12 genes was used. Bioinformatics analysis was performed on DataGenomics platform.

Results

633 samples from 70 centers from 14 Spanish regions were analyzed. 49 (8%) samples were rejected, 67% due to poor DNA quality and 33% due to insufficient material. In total, 74 variants of uncertain significance and 111 PV were detected. The global prevalence of HRR PV was 19%. The PV detected in order of frequency were: BRCA2 (39%), ATM (28%), CDK12 (17%), BRCA1 (10%), and CHEK2 (6%).

Conclusions

Centralization of HRR genetic screening in reference centers is a feasible option to provide HRR mutation to practice physicians. Aspects such as FFPE conservation and processing are vital for the success of the technique and one of the points that could potentially be improved. A better understanding of the distribution of PV can help to detect those patients that could benefit from PARPi treatment, as well as guide the indication of family genetic studies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

AstraZeneca Spain.

Funding

AstraZeneca Spain.

Disclosure

M. Orellana, M. Lencina, C. Mordillo: Financial Interests, Institutional, Full or part-time Employment: AstraZeneca. All other authors have declared no conflicts of interest.