Precision medicine for KRAS wild-type pancreatic adenocarcinomas

Background: KRAS mutation is the most common molecular alteration in pancreatic adenocarcinoma (PDAC), and around 10% of patients harbor KRAS wild-type tumors (KRAS_WT). Methods: A retrospective chart review of clinical/molecular data was performed including all PDAC patients with a determined KRAS status (tumor molecular profiling on tissue or liquid biopsy). Results: 342 patients were included with 54 KRAS_WT PDAC (16%) compared to 288 patients with KRAS_m PDAC. Median age was 61 years [IQR:54.0;67.0] and 164 pts (48%) were female. At diagnosis, KRAS_WT patients (63%) were more frequently diagnosed at a non-metastatic stage compared to KRAS_m patients (41%) (p = 0.003). Regarding metastatic sites, liver was less frequent in KRAS_WT (39%, p < 0.0001). Median overall survival (mOS) from initial diagnosis was significantly higher in the KRAS_WT group compared to KRAS_m (50.8 months, CI95% [32.0-NR] vs 21.1 months, CI95% [18.9–23.4] (p < 0.004 after adjustment on age, ECOG and stage at diagnosis). In first-line systemic treatment, (mostly FOLFIRINOX) progression-free survival (PFS) was also higher in KRAS_WT. Based on ESCAT classification, a putative actionable alteration (ESCAT I-III) was identified in 19 (36%) KRAS_WT pts and 46 (16%) KRAS_m patients (p < 0.0001) with more alterations in FGFR2, BRAF(V600E), NRTK and more MSI tumors. KRAS_WT harbored also fewer alterations in TP53, CDKN2A, and SMAD4. 12 KRAS_WT patients received a molecularly-matched treatment with clinical benefit and improved outcomes compared to KRAS_m patients. Conclusions: KRAS_WT patients display distinct disease characteristics and outcomes with prolonged overall survival. KRAS_WT patients also harbor more actionable molecular alterations, leading to higher survival rates after receiving molecularly matched treatments.