Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection

Abstract

Purpose: Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.

Experimental design: We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: BRCA1, BRCA2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1 HRm status was grouped as: (i) germline versus somatic; (ii) core (BRCAs and PALB2) versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden.

Results: Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median [95% confidence interval (CI)] follow-up was 21.9 (1.4-57.0) months. Median OS and PFS were 15.5 (14.6-19) and 7 (6.1-8.1) months, respectively. Patients with HRD had improved PFS compared with no HRD when treated with first-line (1L) platinum [HR, 0.44 (95% CI: 0.29-0.67); P < 0.01], but not with 1L-non-platinum. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum.

Conclusions: Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD.

Figure 1.

Oncoprint: pathogenic alterations of homologous recombination-genes and recurrent gene alterations from 50 patients with HRD are depicted (One patient had both germline and somatic BRCA variants). For each sample, mutation profile is shown in a column including 8 recurrently mutated genes (upper panel), 9 candidate HR-genes (lower panel). Pathogenic alterations included frameshift, truncating, splice site, or known pathogenic missense mutations, annotated by OncoKB. The labeling priority was in the order of hotspot alteration, pathogenic alteration, and missense variants of unknown significance (VUS). Core HRm (BRCA1, BRCA2, and PALB2) is shown as a track with green and yellow color bar. The level of genomic instability of each sample is depicted by LST score and TMB (mutation/MB) in the bars below. Biallelic HRm is annotated with a diagonal line whereas germline mutations are annotated with circles inside the square. Abbreviations: HRD, homologous recombination defect; LST, large-scale state transition; TMB, tumor mutation burden. HRm, HR mutation(s)

Figure 2.

Outcome of pancreatic cancer patients with homologous recombination deficiency depending on 1L-platinum or 1L-non-platinum. Abbreviations: HDR, homologous recombination defect; HRm, homologous recombination-gene mutation(s); 1L-Platinum, first-line platinum; 1L-Non-platinum, first-line non-platinum

Figure 2.

Outcome of pancreatic cancer patients with homologous recombination deficiency depending on 1L-platinum or 1L-non-platinum. Abbreviations: HDR, homologous recombination defect; HRm, homologous recombination-gene mutation(s); 1L-Platinum, first-line platinum; 1L-Non-platinum, first-line non-platinum

Figure 3.

Correlation of homologous recombination-gene mutational status with large-scale state transition. (A) LST and zygosity: biallelic HRm (n=29) had higher LST than monoallelic HRm (n=21) and wild type (n=212), (B) LST with core HRm: cHRm (n=31) and biallelic cHRm (n=22) had higher LST than WT (n=212), (C) LST with germline and somatic HRm: sHRm, biallelic gHRm, and biallelic sHRm all had higher LST than WT (n=212), however, no statistical difference was seen among gHRm, sHRm, biallelic gHRm, and sHRm. P-values are annotated with star symbols *, with one star indicating p<0.05, two stars indicating p<0.005, and three stars indicating p<0.0005. Abbreviation: LST, large-scale state transition; WT, wild type; HRm, homologous recombination gene mutation(s); cHRm, core HRm; ncHRm, non-core HRm; gHRm, germline HRm; sHRm, somatic HRm