GATA6 expression with CA19-9 levels as biomarkers in resectable pancreatic adenocarcinoma treated with neoadjuvant modified FOLFIRINOX in the NeoPancONE trial.

Abstract

772 Background: The increasing use of neoadjuvant systemic therapy for resectable pancreatic adenocarcinoma (rPDAC) highlights the need for biomarkers for patient selection in this setting. High GATA6 expression has been shown to be useful in identifying the classical subtype, compared to the GATA6 low basal-like subtype associated with chemoresistance. GATA6 expression and CA19-9 levels have been evaluated independently as potential biomarkers, with their respective limitations. We therefore sought to assess whether the use of both, in tandem, may enhance their prognostic utility in the phase 2 NeoPancONE trial where CA19-9 levels were not part of exclusion. Methods: Patients with rPDAC were analyzed within four subgroups based on GATA6 ISH (high vs low) and baseline CA19-9 level (≥200 vs <200 U/mL), following the cut-off used in the PRODIGE48 study. CA19-9 non-secretors (≤2 U/mL) were excluded. Overall survival (OS) and event-free survival (EFS) were assessed using the Kaplan-Meier method and log-rank test. The prognostic effect of GATA6 expression and CA19-9 levels were assessed by uni- and multivariate analyses. Results: Out of 84 patients enrolled between 09/2020 to 09/2023, 74 (88%) had GATA6 ISH baseline testing and 78 (93%) had CA19-9 secreting disease, while 68 (81%) had both and were included in this analysis. Median OS was significantly longer in subgroup A compared to subgroups C and D, but not B (p<0.001, p<0.001, p=0.149). Median EFS was shorter in subgroup D compared to the other subgroups but not significant with B (p<0.001, p=0.014, p=0.104). The remaining pairwise comparisons did not reach statistical significance, however the subgroups were small. In univariate analysis, GATA6 high was associated with improved OS (HR 0.47; 95% CI: 0.22-0.98; p=0.043), while CA19-9 ≥200 U/mL was associated with worse OS (HR 3.52; 95% CI: 1.74-7.12; p<0.001). Both remained significant in multivariate analysis (p=0.044, p<0.001), and no significant interaction was observed. The findings on univariate analysis for EFS were not significant for GATA6. Conclusions: This study explores potential biomarkers at baseline in rPDAC treated with neoadjuvant FOLFIRINOX. GATA6 and CA19-9 are independent prognostic markers and so their prognostic utility is improved when used in tandem. High GATA6 expression with low CA19-9 was associated with best OS, while low GATA6 expression with high CA19-9 was associated with worse EFS, suggesting a strong rationale for stratification at baseline. Further studies are warranted to establish biomarkers in rPDAC to guide patient selection for neoadjuvant therapy. Clinical trial information: NCT04472910 . Survival outcomes by subgroup. Subgroup Median OS (months) Median EFS (months) A: CA19-9 <200 U/mL, GATA6 high (n=31) 40.9 27.1 B: CA19-9 <200 U/mL, GATA6 low (n=7) 36.9 21.8 C: CA19-9 ≥200 U/mL, GATA6 high (n=24) 26.9 15.8 D: CA19-9 ≥200 U/mL, GATA6 low (n=6) 15.0 6.4