A transcriptomic signature can identify gemcitabine-sensitive patients with pancreatic cancer


Disease-free and overall survival in the PRODIGE-24/CCTG PA6 study were significantly higher in GemPred-positive versus GemPred-negative patients who received adjuvant gemcitabine

Data from the phase III PRODIGE-24/CCTG PA6 trial of gemcitabine (n=167) versus modified FOLFIRINOX (mFOLFIRINOX; n=183) in patients with resected pancreatic adenocarcinoma (PDAC) demonstrated the ability of the GemPred transcriptomic signature to predict gemcitabine sensitivity (Abstract 1297P).

The RNA-based GemPred signature was validated as a way to better stratify patients with PDAC and potentially reduce their exposure to higher-toxicity treatment like mFOLFIRINOX (Ann Oncol. 2021;32:250–260). In the gemcitabine arm of the analysis presented, GemPred+ patients (n=50, 30%) versus GemPred- patients (n=117, 70%) had significantly longer disease-free survival (DFS; median 27 months versus 10 months [hazard ratio (HR) 0.43 (95% confidence interval [CI] 0.29–0.65); p<0.001], and overall survival (OS; median 68 months versus 29 months [HR 0.42 (95% CI 0.27–0.66); p<0.001]). GemPred had no predictive value in the mFOLFIRINOX arm. DFS and OS were similar in GemPred+ patients who received gemcitabine and mFOLFIRINOX (median 27 months versus 24 months for DFS and 68 months versus 51 months for OS).

Dr Grainne O’Kane, from the Trinity St. James’s Cancer Institute, Dublin, Republic of Ireland, and Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, found these data to be very exciting as, “Around half of patients with PDAC are not fit enough to receive adjuvant chemotherapy, so a neoadjuvant strategy is increasingly being incorporated, with clinical trials ongoing.” She adds that, “PRODIGE-24 included a very fit population of patients who were able to receive mFOLFIRINOX post-surgery, yet only 66% completed mFOLFIRINOX treatment. The ability to enrich and predict for patients who could benefit from a gemcitabine-based approach rather than be exposed to the toxicities of mFOLFIRINOX is extremely powerful.”

According to O’Kane, there is now a need to build on these results in a prospective study in either the adjuvant or neoadjuvant setting and in the metastatic setting, and to look further at subgroup analyses. She advises that, “I strongly believe that all PDAC trials should include more biomarkers – this is how we can improve survival for patients.”

Patient stratification for chemotherapy in PDAC is still very limited, especially in the metastatic setting. “The only real enrichment stratification we have today is homologous recombination repair deficiency, and BRCA1/2 or PALB2 to help us determine a platinum-based strategy first, possibly followed by a PARP inhibitor maintenance strategy,” says O’Kane. “Some of our own work and that of others has focused on chemotherapy responsiveness; for example, as part of the COMPASS trial we used whole-genome and RNA sequencing to explore subtypes and RNA expression profiles. We identified a basal-like subtype with a particularly poor outcome when treated with mFOLFIRINOX, but not gemcitabine/nab-paclitaxel (Cancer Res. 2018;24:1344–1354). This is now being followed up in the phase II PASS-01 trial.”

O’Kane is convinced that assessing RNA-based signatures is the way forward in PDAC. “An important point in this study is that normal standard of care (formalin-fixed, paraffin-embedded) samples were used in resected PDAC. We now need to explore whether GenPred is feasible to stratify patients in clinical practice, including in the neoadjuvant and metastatic setting, with acceptable turn-around times,” she concludes.

Abstract presented:

Nicolle R, et al. Adjuvant gemcitabine is as efficient as MFOLFIRINOX in patients with GemPred+ tumor signature and resected pancreatic adenocarcinoma (PDAC): an ancillary study of the PRODIGE-24 clinical trial. ESMO Congress 2022, Abstract 1297P

Poster display, Hall 4. An e-Poster is also available on the Congress virtual platform

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