The tandem duplicator phenotype may be a novel targetable subgroup in pancreatic cancer

Abstract

Tandem duplicator phenotype (TDP) consists of distinct genomic rearrangements where tandem duplications are randomly distributed. In this study, we characterized the prevalence and outcomes of TDP in a large series of prospectively sequenced tumors from patients with pancreatic ductal adenocarcinomas (PDAC). Whole-genome sequencing (WGS) was performed in 530 PDAC cases from the PanCuRx Initiative, COMPASS and PanGen/POG trials in Canada. Of 530 cases, 52 were identified as TDP (9.8%; 13 resected, 39 advanced). Etiological subgroups of TDP included BRCA1 (n = 9), CCNE1 (n = 4), and unknown (n = 39). Presence of TDP was not prognostic in resected specimens (p = 0.77) compared with non-HRD and non-TDP cases, described as typicals. In advanced cases, when stratified for only classical subtype cases, platinum therapy was correlated with longer response in non-BRCA1 TDP vs. typicals (p = 0.0036). There was no difference in overall survival between TDP and typicals (p = 0.5).TDP represents a potential novel targetable subgroup for chemotherapy selection in PDAC.

Fig. 1. Venn Diagram showing the breakdown of TDP samples compared to HRD.

a *Of these 10 samples, 9 have confirmed BRCA1 complete loss. The remaining sample shares features with our BRCA1 TDPs (positive Menghi score and duplication ratio > 0.205) and was identified as HRD, but we were unable to identify the BRCA1 hit. We identified this sample as HRD and treated it as such throughout the analysis. b Oncoprint depicting HRD, TDP and typical cohorts Genomic profile of a subset of samples from our cohort. This subset includes all HRD, TPD, and a random sample of 30 typical cases. Each column represents individual samples separated by their etiology. Tumor mutational burden (TMB) is colored based on the amount of burden. The Moffit classification is depicted if available. The first and second genomic alternations found in key driver genes are displayed. c Subclasses of TDP samples The density of the tandem duplication size distribution is separated by etiology. The difference is statistically significant (Kruskal-Wallis test p = 1.9e-196).

Fig. 2. Genomic differences across etiologies in resected and advanced cohorts.

a HRDetect scores between HRD, nonBRCA1-TDP, and typical samples. Wilcox test was performed to compare the groups. b Ploidy differences for resected (Stage I-II) and advanced stage (Stage III-IV) samples across subtypes etiologies. Wilcoxon mean rank-sum tests were run in pairwise fashion on the top panels. The Kruskal-Wallis test was performed on the bottom 2 panels. Box plots indicate median (central line), 25–75% IQR (bounds of box), and whiskers extend from box bounds to the largest value no further than 1.5 times the IQR c Proportion of all samples with mutant and wildtype counts in key driver genes (KRAS, TP53, CDKN2A and SMAD4) across subtypes. Fisher’s exact test was run on all comparisons with p-values depicted in the figure. d Moffitt classification of resected (Stage I-II) and advanced stage (Stage III-IV) samples across subtypes. Fisher’s exact test was run on all comparisons with p-values depicted on the figure. e (i) Best tumor response to treatment (by RECIST 1.1) across SVs that have been split equally into low and high tumors. Wilcox test was performed between the 2 groups. (ii) Duplication load with a decrease or increase in tumor size. Wilcox test run between the 2 groups. (iii) SV load in response to treatment as per RECIST. Wilcox test run between the 2 groups. iv) Scatterplot of tumor response with increasing duplication load. Pearson correlation was run on the data.

Fig. 3. Survival analysis in resected cases comparing nonBRCA1-TDP with typicals.

Kaplan-Meier curves showing the overall and disease free survival for early stage (Stage I and II) patients. The right panel shows Moffitt classical samples only. Log-rank p values are shown.

Fig. 4. Response to chemotherapy in advanced cases.

a Waterfall plot comparing response to platinum for advanced (stage III and IV) patients in the COMPASS/PanCuRx cohort on the left and for response to platinum for moffitt classic patients in the COMPASS/PanCuRx cohort on the right. b Kaplan-Meier curves for all advanced (Stage III/IV) patients, those receiving platinum based chemotherapy and Moffit classical cases that received platinum based therapy. c Kaplan-Meier curves of advanced patients receiving platinum based chemotherapies. (ii) Boxplot of chemotherapy duration across the etiologies. d Kaplan-Meier curves of advanced patients (Stage III/IV) receiving platinum-based chemotherapy by group 1 vs. group 2 TDP. BRCA1 samples are included in the HRD group while CCNE1 samples are in group 2.