KRAS WT pancreatic adenocarcinomas: Another disease?

Abstract

750 Background: KRAS mutation is the most common molecular alteration (MA) in pancreatic adenocarcinoma (PDAC), and only 8-10% of patients (pts) harbor KRAS wild-type tumors (WT). This study describes clinical and molecular features of KRAS WT PDAC and compares it to mutant KRAS (m KRAS) PDAC. Methods: A retrospective chart review of clinical/molecular data was performed on all pts with PDAC who had contributive molecular profile at Gustave Roussy. KRAS status was determined on tumor molecular profiling as part of routine care using an in-house panel or Foundation Medicine NGS either on tissue (63%) or liquid biopsy (37%). Results: Overall, 41 pts with KRAS WT PDAC were compared to 197 pts with mKRAS PDAC. Median OS (mOS) from initial diagnosis was significantly higher in the KRAS WT group compared to mKRAS group (32.8 months (mts), CI95% [25.9-NR] vs 21.5 mts, CI95% [18.8-24.9] respectively), as mOS from metastatic diagnosis, 26 mts, CI95% [15.7-NR] for KRAS WT pts vs 17.7 mts CI95% [15.5-19.3] for mKRAS (all p<0.05)). After adjustment on gender, age, metastasis status at diagnosis, hazard ratio (HR) of OS from metastatic stage diagnosis associated with KRAS status was 1.9 [1.1;3.4], p=0.02 (similar for 1st line PFS and OS from initial diagnosis). MA were found in 31 KRAS WT pts (76%). KRAS WT and m KRAS pts harbored different molecular profiles with less alterations of TP53, SMAD4 and CDKN2A/B (p<0.05) in KRAS WT tumors, but more of BRAF (p<0.05), PALB2, RET and BRIP1 (p=NS) alterations. Interestingly, 3 MSI tumors were found in the KRAS WT group (one received immunotherapy), vs none in m KRAS group). Tumor mutational burden was similar (2.00 Mut/Mb in KRAS WT pts vs 2.7 Mut/Mb in m KRAS pts). Based on ESCAT classification, a putative therapeutic target (ESCAT I-IV, other than KRAS) was identified in 15 (36%) KRAS WT pts and 65 (33%) m KRAS pts, thus enriching the therapeutic panel for these patients. Indeed, for example 9 (22%) KRAS WT pts received an oriented therapy after palliative treatments (such as anti-RET or anti-PARPs) and showed higher survival rates compared to KRAS WT pts who did not (mOS from diagnosis in months NR (14.2; NR) and 28.3 (26; NR) respectively). Conclusions: In our cohort of 238 PDAC, we confirm that KRAS is a prognostic factor of OS. KRAS WT PDAC have a significantly longer OS compared to m KRAS. Moreover, 36% of KRAS WT PDAC pts had a potentially actionable MA, and 9 pts displayed higher survival rates after receiving oriented therapies. This study suggests that KRAS WT PDAC should be eligible for a large molecular screening.[Table: see text]