Tumour-first DNA testing as a gateway to germline screening in patients with metastatic prostate cancer.

INTRODUCTION: Integrated tumour and germline testing is recommended for all patients with metastatic prostate cancer (mPCa), yet real-world implementation varies widely. Use of tumour analysis to stratify patients for germline testing (tumour-first workflow (TFW)) has emerged as an efficient triage strategy, but its performance relative to family history (FH)-based referral remains insufficiently characterised. METHODS: We analysed paired tumour and germline sequencing data from 452 patients enrolled in the prospective PROMPT study. TFW performance for detecting germline pathogenic variants (gPVs) in BRCA2, BRCA1, PALB2, ATM and CHEK2 was assessed using germline testing as the reference standard. Diagnostic performance was compared with a modelled FH-based referral strategy. Diagnostic cost analysis was evaluated using standard Dutch diagnostic tariffs. RESULTS: Germline testing identified gPVs in 36/452 (7.8%) patients. Technical sensitivity was 97%. Under the predefined TWF referral criteria, 22/36 carriers (61%) were referred for germline testing. All high-risk gene variants (BRCA2, BRCA1, PALB2) were identified. Compared with modelled FH-based referral, TFW identified significantly more carriers (22 vs 8; p < 0.001), with markedly higher PPV (51% vs 13%) and lower number needed to test (2.0 vs 7.9). The estimated diagnostic cost per detected gPV was €998 vs €12,246. DISCUSSION AND CONCLUSION: TFW is an efficient and clinically pragmatic strategy for gPVs detection in mPCa, with complete identification of high-risk carriers actionable for treatment and cascade testing. TFW substantially outperforms FH-based referral and should be considered the preferred triage approach in routine precision oncology practice whenever integrated tumour and germline testing of all patients with mPCa is not feasible.