Impact of germline DNA repair gene variants on prognosis and treatment of men with advanced prostate cancer

Abstract

The clinical importance of germline variants in DNA repair genes (DRGs) is becoming increasingly recognized, but their impact on advanced prostate cancer prognosis remains unclear. A cohort of 221 newly diagnosed metastatic castration-resistant prostate cancer (mCRPC) patients were screened for pathogenic germline variants in 114 DRGs. The primary endpoint was progression-free survival (PFS) on first-line androgen signaling inhibitor (ARSI) treatment for mCRPC. Secondary endpoints were time to mCRPC progression on initial androgen deprivation therapy (ADT) and overall survival (OS). Twenty-seven patients (12.2%) carried a germline DRG variant. DRG carrier status was independently associated with shorter PFS on first-line ARSI [HR 1.72 (1.06-2.81), P = 0.029]. At initiation of ADT, DRG carrier status was independently associated with shorter progression time to mCRPC [HR 1.56, (1.02-2.39), P = 0.04] and shorter OS [HR 1.99, (1.12-3.52), P = 0.02]. Investigating the contributions of individual germline DRG variants on PFS and OS revealed CHEK2 variants to have little effect. Furthermore, prior taxane treatment was associated with worse PFS on first-line ARSI for DRG carriers excluding CHEK2 (P = 0.0001), but not for noncarriers. In conclusion, germline DRG carrier status holds independent prognostic value for predicting advanced prostate cancer patient outcomes and may potentially inform on optimal treatment sequencing already at the hormone-sensitive stage.

Figure 1

Patients and germline DNA repair gene variants. (a) Swimmer plot showing an overview of disease progression, ordered by DRG carrier status and time from initiation of ADT to mCRPC diagnosis. (b) Distribution of the pathogenic/likely pathogenic germline variants identified in the cohort. DRG DNA-repair genes, ADT Androgen deprivation therapy, ARSI androgen signaling inhibitor, PSA prostate-specific antigen, FS Frameshift.

Figure 2

Outcomes of DRG carriers. Kaplan–Meier curves (left panel) and forest plots of multivariate cox regression analysis (right panel) for: (a) PFS on first-line ARSI; (c, d) OS from time of mCRPC diagnosis; and (e) progression to mCRPC on ADT. (b) Waterfall plot of best confirmed PSA change (PSA nadir) during first-line ARSI treatment in each patient. DRG DNA-repair genes, ADT Androgen deprivation therapy, ALP alkaline phosphate, M1 metastases, mCRPC metastatic castration-resistant prostate cancer, ARSI androgen signaling inhibitor, PFS progression-free survival, OS overall survival, PSA prostate-specific antigen.

Figure 3

Impact of individual DNA repair genes on patient outcomes. Forest plots of univariate cox regression analysis for: (a) PFS on first-line ARSI; (b) OS from time of mCRPC diagnosis; (c) progression to mCRPC on ADT; and (d) OS from initiating ADT. DRG DNA-repair genes, ADT Androgen deprivation therapy, mCRPC metastatic castration-resistant prostate cancer, ARSI androgen signaling inhibitor, PFS progression-free survival, OS overall survival.

Figure 4

Outcomes of DRG carriers excluding CHEK2 variants. Kaplan–Meier curves (left panel) and forest plots of multivariate cox regression analysis (right panel) for: (a) PFS on first-line ARSI; (b) OS from mCRPC diagnosis; (c) progression to mCRPC on ADT; and (d) OS from initiating ADT. DRG  DNA-repair genes, ADT Androgen deprivation therapy, ALP alkaline phosphate, M1 metastases, mCRPC metastatic castration-resistant prostate cancer, ARSI androgen signaling inhibitor, PFS progression-free survival, OS overall survival.

Figure 5

Outcomes of DRG carriers and noncarriers based on prior taxane treatment. (a, b) Kaplan–Meier curves for PFS on first-line ARSI treatment. DRG DNA repair genes, PFS progression-free survival on first-line androgen signaling inhibitor treatment.