TP53 mutation predicts sensitivity to adjuvant gemcitabine in pancreatic cancer: Results from the CONKO-001 study

Abstract

Background: Pancreatic adenocarcinoma (PDAC) is amolecular heterogeneous disease, but clinically relevant genetic biomarkers are still missing. There are no data from prospective studies after curatively intended surgery and adjuvant chemotherapy so far. Methods: CONKO-001, was a prospective randomized phase III study and investigated the role of adjuvant gemcitabine (Gem) as compared to observation (Obs). Formalinefixed paraffin-embedded tissue samples of 187 patients (pts) could be collected, of which 97 could be analysed after DNA-extraction by targeted next generation sequencing (NGS), using a predefined sequencing panel including mutation hotspot regions of 36 genes (ACTN4, ACVR1B, APC, ARID1A, ARID1B, ARID2, ATM, BRAF, CDK6, CDKN2A, CNDP2, CREBBP, CTNNB1, ERBB2, FGFR1, GATA6, KDM6A, KMT2C, KMT2D, KRAS, MAP2K4, MET, MYC. PBRM1, PIK3CA, PREX2, RNF43, RPA1, SF3B1, SMAD4, SMARCA2, SMARCA4, SOX9, STK11, TGFBR2, TP53). Mutational status was correlated with survival by fitting a cox proportional hazard model. Results: Patient's characteristicswere balanced between Gem (n=49) and Obs (n=48) group. KRAS, TP53, SMAD4mutationwas found in 73%(Gem/Obs n=33/38), 59% (n=28/29), 8%(n=4/4) of patients. KRAS/SMAD4mutation status was not associated with (treatment-related) survival. TP53mutation was identified as a negative prognostic factor for untreated patients: hazard ratio (HR) for disease free-survival (DFS) TP53mutant vs TP53 wildtype 2.90 (95%CI 1.55 -5.41). Furthermore, TP53mutation was found to be a positive predictive factor forGem:HR for DFS Gem vs Obs in TP53 wildtype patients was 0.87 (95% CI 0.46-1.66) in comparison to TP53 mutated patientswith aHRof 0.22 (95%CI 0.12-0.39). Test of TP53-by-treatment-interaction was statistically significant; p=0.002. Conclusions: To the best of our knowledge, we present the first NGS data from a prospective clinical study in PDAC. In contrast to previous data, we could not identify KRAS or SMAD4 mutation as clinically relevant factors in primarily resectable PDAC. In CONKO-001, TP53 mutated patients had an unfavorable prognosis when randomized to Obs and profited strongly from adjuvant Gem, while adjuvant treatment did not significantly prolong DFS in TP53 wildtype patients.