Abstract 972: Non-invasive detection of homologous recombination deficiency in metastatic prostate cancer patients

Abstract

Abstract Background: The recent endorsement of poly ADP ribose polymerase inhibitors (PARPi) has been a breakthrough in managing prostate cancer (PCa) with homologous recombination deficiency (HRD). However, due to its propensity to metastasize to the bone, HRD assessment in tissue biopsy poses a challenge in advanced PCa. Circulating tumor DNA (ctDNA) as a tumor surrogate may be a promising substitute for pinpointing patients who may benefit from PARPi treatment. Methods: To test whether causes and consequences of HRD can be detected non-invasively in plasma, we pre-selected 139 plasma samples from PCa patients based on aneuploidy screening (mFAST-SeqS). We then applied targeted sequencing using a QIAseq panel including homologous recombination repair (HRR)-related genes as well as genes involved in cell cycle regulation (TP53, RB1, PTEN). Putative, pathogenic germline variants were sequencing in constitutional DNA using Sanger sequencing. Moreover, we performed low pass whole genome sequencing to determine the levels of genomic instability using the shallow HRD (sHRD) algorithm. Results: In our cohort, at least one pathogenic mutation was detected in 68/139 (48.9%) of the patients, of which the majority consisted of alterations in PTEN, TP53 or RB1 (44/139, 31.7%). Pathogenic BRCA1/2 mutations were detected in 13/139 patients (9.4%), the majority of which originated from the germline. In 8/139 patients (5.6%) a pathogenic variant in other HRR genes could be observed and in 3/139 patients (2.2%) CKD12 mutations were detected. As expected, samples with pathogenic HRR mutations and elevated tumor fraction, presented high sHRD scores (<20) in plasma DNA. In contrast, the majority of high ctDNA samples with mutations in PTEN, TP53 or RB1 had sHRD score below the cut-off of 20. However, the detection of genomic instability was clearly depending on tumor fractions. Conclusion: Our study indicates that a non-invasive assessment of root causes and subsequent effects of the HRD phenotype in prostate cancer is feasible, and that mutations in HRR correlate with a high genomic instability. However, to detect and quantify genomic instability in plasma, elevated ctDNA levels are required. Based on in-house data from mFAST-SeqS aneuploidy screening of over 900 plasma samples from advanced prostate cancer, approximately 30% of cfDNA samples would have sufficiently high ctDNA fractions for a combined assessment of causes and consequences of HRD, which might be most informative to direct PARPi treatment in PCa. Citation Format: Georgios Vlachos, Tina Moser, Anna Eberhard, Lisa Glaswitch, Jasmin Blatterer, Emil Bauernhofer, Nina Monsberger, Karl Kashofer, Jochen Geigl, Thomas Bauernhofer, Ellen Heitzer. Non-invasive detection of homologous recombination deficiency in metastatic prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 972.