Prediction of Adjuvant Gemcitabine Sensitivity in Resectable Pancreatic Adenocarcinoma Using the GemPred RNA Signature: An Ancillary Study of the PRODIGE-24/CCTG PA6 Clinical Trial

Abstract

Purpose: GemPred, a transcriptomic signature predictive of the efficacy of adjuvant gemcitabine (GEM), was developed from cell lines and organoids and validated retrospectively. The phase III PRODIGE-24/CCTG PA6 trial has demonstrated the superiority of modified folinic acid, fluorouracil, irinotecan, and oxaliplatin (mFOLFIRINOX) over GEM as adjuvant therapy in patients with resected pancreatic ductal adenocarcinoma at the expense of higher toxicity. We evaluated the potential predictive value of GemPred in this population.

Patients and methods: Routine formalin-fixed paraffin-embedded surgical specimens of 350 patients were retrieved for RNA sequencing and GemPred prediction (167 in the GEM arm and 183 in the mFOLFIRINOX [mFFX] arm). Survival analyses were stratified by resection margins, lymph node status, and cancer antigen 19-9 level.

Results: Eighty-nine patients' tumors (25.5%) were GemPred+ and were thus predicted to be gemcitabine-sensitive. In the GEM arm, GemPred+ patients (n = 50, 30%) had a significantly longer disease-free survival (DFS) than GemPred- patients (n = 117, 70%; median 27.3 v 10.2 months, hazard ratio [HR], 0.43 [95% CI, 0.29 to 0.65]; P < .001) and cancer-specific survival (CSS; median 68.4 v 28.6 months, HR, 0.42 [95% CI, 0.27 to 0.66]; P < .001). GemPred had no prognostic value in the mFFX arm. DFS and CSS were similar in GemPred+ patients who received adjuvant GEM and mFFX (median 27.3 v 24.0 months, and 68.4 v 51.4 months, respectively). The statistical interaction between GEM and GemPred+ status was significant for DFS (P = .008) and CSS (P = .004). GemPred+ patients had significantly more adverse events of grade ≥3 in the mFFX arm (76%) compared with those in the GEM arm (40%; P = .001).

Conclusion: This ancillary study of a phase III randomized trial demonstrates that among the quarter of patients with a GemPred-positive transcriptomic signature, survival was comparable with that of mFOLFIRINOX, whereas those receiving adjuvant gemcitabine had fewer adverse events.

FIG 1.

Kaplan-Meier estimates of (A) DFS and (B) CSS in each treatment group and according to GemPred status with respective median; (C) 3-year and 5-year survival and comparison of GemPred+ versus GemPred– in each treatment group for (C, left) DFS and (C, right) CSS. Crosses indicate censored data. Values in tables are shown with 95% CIs. CSS, cancer-specific survival; DFS, disease-free survival; sHR, stratified hazard ratio.

FIG 2.

Forest plot of GemPred subgroup analysis for comparison between mFFX versus GEM in terms of (A) DFS and (B) cancer-specific survival. P value int., P value of interaction; sHR, stratified hazard ratio.

FIG 3.

Distribution of highest-grade adverse events. The number of patients with each reported highest-grade adverse event in each group and corresponding percentage (excluding patients with unreported toxicity) are shown. Statistical comparison between groups is shown, as well as comparison of grade 3, 4, and 5 events versus grade 0, 1, and 2 events. Adverse events were not reported for eight patients, six in the mFFX group (one GemPred+, five GemPred–) and two in the Gemcitabine group (both GemPred–). Results of Fisher's exact test are shown.

FIG 4.

Postrelapse treatment and survival according to GemPred status. (A) Distribution of the number of patients receiving different chemotherapeutic regimens after relapsing in their initial randomized treatment. (B) Postrelapse cancer-specific survival among patients initially randomly assigned in the mFFX group and receiving a gemcitabine-based regimen after relapse. (C) Cancer-specific survival among GemPred+ patients with reported postrelapse chemotherapy. sHR, stratified hazard ratio. Cape, capecitabine; FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOX, fluorouracil, leucovorin, and oxaliplatin; NabP, nab-paclitaxel.

FIG A1.

Kaplan-Meier estimates of (A) DFS and (B) OS stratified by the inclusion of patients in the molecular profiling ancillary study. Crosses indicate censored data. DFS, disease-free survival; OS, overall survival.