Germline sequencing in men with metastatic castration-resistant prostate cancer from the BARCODE2 study reveals a wide range of pathogenic variants in DNA repair genes

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2024年2月15日

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Sarah Benafif,
Ann-Britt Jones,
Susan Merson,
Reshma Rageevakumar,
Eva McGrowder,
Matthew Tyler,
Fay Cafferty,
Matthew Hogben,
Nafisa Hussain,
Elizabeth Bancroft,
Alison Reid,
Sarah Wakerell,
Questa Karlsson,
Edward Saunders,
Ian Whitmore,
Karina Dalsgaard Sorensen,
Nening Dennis,
Evie Black,
Angela Wood,
Kate Richards,
Kathryn Lees,
Carla Perna,
Alison Falconer,
Jamie Mills,
Robert Hughes,
Shiyam Kumar,
Christos Mikropoulos,
Stephanie Burnett,
Gerhardt Attard,
Emma Hall,
Zsofia Kote-Jarai,
Ros Eeles

摘要

Background

The presence of germline mutations plays an increasingly important role in risk assessment and treatment of prostate cancer (PrCa). Screening for high-risk mutations in subsets of patients is becoming routine. We explore the prevalence of germline genetic mutations in men with metastatic castration-resistant prostate cancer (mCRPC) recruited to the BARCODE2 trial.

Methods

The BARCODE2 trial is a two-part study investigating the response to carboplatin chemotherapy in mCRPC patients carrying a germline variant in a DNA repair gene (DRG). We report interim data from Part 1, in which participants are recruited for germline genetic testing using a customised next-generation sequencing panel consisting of 115 genes.

Results

These interim results (N = 220) demonstrate a similar frequency of germline DRG variants in mCRPC patients compared with previously published data (15% detection rate). No significant clinical differences were identified between all carriers and non-carriers, though BRCA2/ATM carriers were found to have a shorter time to mCRPC diagnosis.

Conclusions

Germline pathogenic/likely pathogenic (P/LP) variants in BRCA2 and ATM genes are associated with a shorter time to progression and rarer P/LP variants in other DRG genes may play a role in mCRPC. This justifies the use of routine screening of men with advanced PrCa for germline variants and supports the need for an expanded panel test.