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INTRODUCTION: Cisplatin, nab-paclitaxel, capecitabine, and gemcitabine (PAXG) regimen activity was assessed in a single institution phase II trial (PACT-19) on pancreatic ductal adenocarcinoma (PDAC). The PACT-31 study explored the external validity of PACT-19 results. MATERIALS AND METHODS: Patients aged ≥18 and ≤75 years with KPS ≥70, and PDAC diagnosis receiving PAXG in the participating institutions were eligible and categorized as follows: A) PACT-19; B) PACT-31-HSR; C) PACT-31-non-HSR. With a sample of 175 patients, assuming a target 1-year overall survival of 60 % for metastatic and of 80 % for non-metastatic patients, the trial will be considered successful with the 1-year OS falling into the 95 % CI. RESULTS: Data from 68 PACT-19 and 168 PACT-31 patients were retrieved. After 124 events, 1yOS was 52.5 % (95 %CI: 44.6-60.4 %) for metastatic and 80.5 % (95 %CI: 71.9-89.1 %) for non-metastatic patients. Survival overlapped between PACT-19 and PACT-31-HSR (median 17.6 and 17.4 months, p = 0.21) and was significantly shorter in PACT-31-non-HSR (median 11.3 months; p = 0.03). Differences of dose-intensity, use of maintenance therapy, and treatment after progression between PACT-31-HSR and non-HSR were evidenced. DISCUSSION: PACT-19 results have external validity. The outcome difference between HSR and non-HSR centers endorses the need of creating a hub-and-spoke network aimed at sharing the expertise on rare-diseases.
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Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRASG12) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRASG12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRASG12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRASG12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRASG13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRASG12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRASG12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies.