Background: Surgery is the only potentially curative option for PC. However, only a minority of patients (pts) undergo resection with current perioperative (periop)-chemotherapy (CT). In the absence of phase III trials, selection between mFOLFIRINOX and gemcitabine/nab-paclitaxel (gem-nab) is based on limited evidence. We assessed whether NGS–based tumor profiling can guide tailoring of CT.

Methods: pts with resected PC (resectable, borderline resectable, and downstaged locally advanced) that underwent Tempus xT, xF (DNA), and/or xR (RNA) testing were selected (89% tissue, 11% blood). Most samples (73%) were collected post-CT. Samples were stratified by KRAS status into KRAS-mutated (KRASmut) and KRAS wild-type (KRASwt). PD-L1 IHC was reported as tumor proportion score (TPS). Primary endpoint was median overall survival (mOS) defined from CT initiation to death with censoring of pts alive at the last follow-up or at a study cutoff of 5 years. Secondary endpoint was molecular profiling by KRAS status. Pearson chi-square and Wilcoxon rank-sum tests were used for descriptive comparisons; univariate Cox regression and log-rank tests (p < 0.05) for survival.

Results: We included 1,325 pts (median age 66 years [IQR 59–72]) with resected PC [stage II (15%), stage III (12%) and stage I (10%), unknown (62%)]. 95% had adenocarcinoma. Pts received neoadjuvant (50%), neoadjuvant plus adjuvant (26%), neoadjuvant with indeterminate adjuvant allocation (13%) or adjuvant CT (11%). First-line periop-CT was mFOLFIRINOX in 73% and gem-nab in 27% (median duration 4.3 months (mo) [range, 2.6–6.7]). KRAS mutations were present in 75% (G12X 91%: G12D 44%, G12V 34%, G12R 21%, G12C < 1%). mOS was 26.7 mo (95%CI, 22.4-35.7) in the total cohort; KRASmut pts showed a clinically meaningful worse mOS compared to KRASwt [24.1 vs 35.7 mo; HR 1.61 (95%CI, 0.98 – 2.63); p = 0.06]. In the KRAS G12D pts, mFOLFIRINOX showed a trend towards longer mOS compared to gem-nab [17.79 vs 14.53 mo; HR 0.75, (95% CI, 0.56 – 1); p = 0.050]; no significant differences were observed in other KRAS subgroups. Compared to KRASwt, KRASmut pts were enriched for TP53 (76% vs 22%; p < 0.001), SMAD4 (28% vs 5.8%; p < 0.001), CDKN2A (33% vs 8.5%; p < 0.001), MTAP deletions (7.7% vs 1.2%; p < 0.001), and chromatin-regulator alterations (ARID1A 7.8% vs 1.2%; p < 0.001; KMT2C 2.5% vs 0.6%; p = 0.034). KRASwt pts were enriched for BRAF V600E (1.5% vs 0%; p < 0.001). PD-L1 TPS ≥1% was more frequent in KRASmut compared to KRASwt (11.0% vs 8.1%; p = 0.033).

Conclusions: KRAS status does not predict benefit from mFOLFIRINOX vs gem-nab in resected PC. Interestingly, resected PC showed a higher prevalence of KRASwt compared to the metastatic setting. KRAS status is associated with distinct profiles of potentially targetable co-alterations. These findings may suggest the integration of genomic profiling in clinical trials to develop biomarker-driven tailored strategies in the early stage.

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