Pancreatic adenocarcinoma (PDAC) is a molecular 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.
CONKO-001, was a prospective randomized phase III study and investigated the role of adjuvant gemcitabine (Gem) as compared to observation (Obs). Formaline-fixed 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.
Patient’s characteristics were balanced between Gem (n = 49) and Obs (n = 48) group. KRAS, TP53, SMAD4 mutation was found in 73% (Gem/Obs n = 33/38), 59% (n = 28/29), 8% (n = 4/4) of patients. KRAS/SMAD4 mutation status was not associated with (treatment-related) survival. TP53 mutation was identified as a negative prognostic factor for untreated patients: hazard ratio (HR) for disease free-survival (DFS) TP53 mutant vs TP53 wildtype 2.90 (95% CI 1.55 -5.41). Furthermore, TP53 mutation was found to be a positive predictive factor for Gem: HR for DFS Gem vs Obs in TP53 wildtype patients was 0.87 (95% CI 0.46-1.66) in comparison to TP53 mutated patients with a HR of 0.22 (95% CI 0.12-0.39). Test of TP53-by-treatment-interaction was statistically significant; p = 0.002.
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.
Clinical trial identification
Legal entity responsible for the study
Charite Universitätsmedizin Berlin, CONKO-study group.
Charite Forschungsförderung, German Cancer Consortium (DKTK), Rahel-Hirsch grant.
M. Sinn: Honoraria, Advisory board: Baxalta. Research funding: Leo Pharma. Travel support: Amgen. All other authors have declared no conflicts of interest.