GATA6amplification is associated with improved survival ofTP53-mutated pancreatic cancer

AbstractBackgroundMolecular profiling of pancreatic adenocarcinoma (PDAC) demonstrates that genomic and transcriptomic features are associated with prognosis and chemosensitivity. We evaluated treatment outcomes by genetic alterations inTP53andGATA6to determine the prognostic and predictive impact of co-mutations, among patients with pancreatic cancer in New York’s largest healthcare system.MethodsRetrospective analysis was performed of patients at Northwell Health diagnosed with PDAC between 2014 to 2022. Surgical status was used to segregate patients into two groups: resected and unresected.TP53genotype andGATA6amplification status were compared for overall survival (OS) as measured from time of diagnosis. Additionally, patient survival by chemotherapy regimen administered was evaluated. The Kaplan–Meier method was used to determine overall survival (OS) and the Wilcoxon test was used to compare survival curves. Previously established and published patient-derived organoids [1] were used to investigateGATA6expression, genetic status, and chemotherapy drug sensitivity.ResultsTumor mutation status was available for 128 patients.TP53mutations were found in 104 patients (81.3%),GATA6amplifications were found in 18 patients (14.0%), and 16 (12.5%) patients had mutations in both genes. Patients withTP53mutations had worse OS compared to the wild-typeTP53population (n = 22) (median OS 22.4 months, 95% CI 12.5 to 41.1, vs. 44.3 months, 95% CI 24.0 to 82.0, HR 2.03, p = 0.038). Among patients with aTP53mutation, a survival advantage was observed in those who had aGATA6amplification (n=16) compared to those who did not (n=86) (median OS 25.5 months vs. 19.4 months, HR 1.82, p = 0.027). Among patients with unresected PDAC who wereTP53-mutant, the presence ofGATA6amplification (n=11) was associated with a substantial survival advantage compared toGATA6wildtype (n=52) (median OS 25.5 months, vs. 10.1 months, HR 0.35, p = 0.004). In theTP53mutation group, among 33 patients who received gemcitabine and nab-paclitaxel as the first-line palliative chemotherapy, patients withGATA6amplification (n = 8) had significantly improved survival compared to those withoutGATA6amplification (n = 25) (mean OS 23.1 months vs 9.4 months, HR 0.52, p = 0.017). However, pancreatic cancer organoids withTP53mutation (n=34) did not exhibit increased drug sensitivity to GnP withGATA6amplification.ConclusionsGenetic mutations inTP53were associated with shorter OS than wild-typeTP53. We found thatGATA6amplification appeared to attenuate poor prognosis observed inTP53-mutant patients regardless of type of standard chemotherapy received.