Homologous recombination repair (HRR) genes and overall survival prognosis within the STRATOS-P classification in metastatic hormone-sensitive prostate cancer (mHSPC).

Abstract

5108 Background: DNA repair genomic alterations are associated with worse overall survival (OS) in patients with metastatic hormone sensitive prostate cancer (mHSPC). It is less clear whether other genomic alterations may affect prognosis of actionable homologous recombination repair (HRR) and mismatch repair (MMR) genes in mHSPC. Methods: Retrospective cross-sectional study of veterans diagnosed with mHSPC (n=4401). Tumors with no alterations in HRR/MMR genes (DDRneg) were classified by the Somatic Tumor Risk Assessment for Overall Survival-Prostate (STRATOS-P) genomic system which stratifies patients into favorable, intermediate and unfavorable survival groups based on oncogenic alterations: Favorable, SPOP or no alterations; Intermediate, alterations in AR, BRCA2, CCND1, CDK12, FGF19, FGF3, FGF4, LYN, MYC, PTEN, RAD21, or TP53 ; Unfavorable, alterations in FGFR1, PRCK1, RB1 ,or both TP53 and PTEN . OS from metastatic diagnosis was determined using a multivariate Cox model controlling for age, Charleston comorbidity index (CCI) and PSA at diagnosis. Results: Among 4401 mHSPC patients, 1027 (23%) patient tumors had at least one oncogenic alteration in an HRR or MMR gene. Of 3374 DDR-Neg tumors, 1593 were classified as STRATOS-P-Favorable, 1357 as STRATOS-P-Intermediate, and 424 as STRATOS-P-Unfavorable. Comparing patients with tumors with oncogenic alterations in an HRR or MMR gene to patients with DDR-neg tumors showed that prognosis was worse in patients with tumor alterations in ATM, BRCA2, CHEK2, CDK12, ATR, PALB2, NBN and MMR genes compared to patients with STRATOS-P-Favorable tumors (Table). Prognosis was better in patients with tumor alterations in ATM, BRCA2, CHEK2, CDK12, BRCA1, FANCA and Lynch genes compared to STRATOS-P-Unfavorable tumors (Table). Conclusions: In patients with mHSPC, patients with HRR and MMR altered tumors have a worse prognosis compared to patients with STRATOS-P favorable tumors and better prognosis compared to patients with STRATOS-P unfavorable tumors. Overall, HRR and MRR gene alterations impact prognosis of mHSPC patients within the STRATOS-P classification and should be classified as intermediate risk. STRATOS-P-Favorable, DDRneg, n=1593 STRATOS-P-Unfavorable, DDRneg,n=424 Gene 1 n HR (95% CI) HR (95% CI) BRCA2 243 2.00 (1.62, 2.47) 0.69 (0.55, 0.87) CDK12 116 2.07 (1.66, 2.57) 0.74 (0.58, 0.94) ATM 259 1.55 (1.24, 1.96) 0.51 (0.39, 0.66) CHEK2 212 1.75 (1.21, 2.52) 0.50 (0.33, 0.76) ATR 38 2.05 (1.27, 3.31) 0.71 (0.43, 1.17) BRCA1 37 1.41 (0.81, 2.46) 0.48 (0.27, 0.84) FANCA 32 1.53 (0.82, 2.87) 0.51 (0.27, 0.97) NBN 23 2.59 (1.43, 4.68) 0.93 (0.51, 1.69) PALB2 21 2.31 (1.23, 4.37) 0.79 (0.40, 1.56) Lynch 128 1.72 (1.28, 2.33) 0.64 (0.47, 0.88) 1 All tumors with alterations in indicated gene regardless of STRATOS-P subgroup were compared to the indicated DDRneg STRATOS-P subgroup.