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

Germline pathogenic variants in BRCA2, BRCA1, PALB2, ATM and CHEK2, sought first in the tumour, with tumour analysis used to select patients referred for germline testing

Integrated tumour and germline testing is recommended for all patients with metastatic prostate cancer, yet real-world implementation varies widely, and the tumour-first workflow (TFW), which uses tumour analysis to select patients for germline testing, remained insufficiently characterised relative to family history-based referral. The authors analysed paired tumour and germline sequencing data from 452 patients in the prospective PROMPT study, with germline testing as the reference standard, for BRCA2, BRCA1, PALB2, ATM and CHEK2. Germline testing identified pathogenic variants in 36 of 452 patients (7.8%), with a technical sensitivity of 97%; under the predefined referral criteria, 22 of the 36 carriers (61%) were referred for germline testing, and all variants in high-risk genes (BRCA2, BRCA1, PALB2) were identified. Compared with a modelled family history-based referral, TFW identified significantly more carriers (22 versus 8; p < 0.001), with a higher positive predictive value (51% versus 13%) and a lower number needed to test (2.0 versus 7.9), at an estimated diagnostic cost per detected variant of €998 versus €12,246. The authors conclude that it is efficient and pragmatic and should be the preferred triage approach whenever integrated testing of all patients is not feasible.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The figure to remember is selectivity: the tumour-first strategy identifies all variants in high-risk genes (BRCA2, BRCA1, PALB2) with 2.0 patients to test per carrier detected, versus 7.9 for family history-based referral. Three reservations: the comparator is modelled rather than observed, the estimate rests on only 36 carriers, and the strategy refers only 61% of carriers, the rest escaping germline testing; the cost ratio (€998 versus €12,246) also depends on Dutch diagnostic tariffs. It is therefore a solid argument for organising triage when systematic germline testing is impossible, not for giving it up when it is feasible.

Analysis by Dr Thibaut Benquey