hENT1 Expression Predicts Response to Gemcitabine and Nab-Paclitaxel in Advanced Pancreatic Ductal Adenocarcinoma

Abstract

Purpose:Modified FOLFIRINOX (mFFX) and gemcitabine nab-paclitaxel (GnP) remain standard first line options for patients with advanced pancreatic ductal adenocarcinoma (PDAC). Human equilibrative nucleoside transporter 1 (hENT1) was hypothesized to be a biomarker of gemcitabine in the adjuvant setting, with conflicting results. In this study, we explore hENT1 mRNA expression as a predictive biomarker in advanced PDAC. Experimental Design: COMPASS was a prospective observational trial of patients with advanced PDAC. A biopsy was required prior to initiating chemotherapy, as determined by treating physician. Biopsies underwent laser capture microdissection prior to whole genome and RNA sequencing. The cut-off thresholds for hENT1 expression were determined using the maximal chi-squared statistic. Results: 253 patients were included in the analyses with a median follow-up of 32 months, with 138 patients receiving mFFX and 92 receiving GnP. In the intention to treat population, median OS was 10.0 months in hENT1 high vs. 7.9 months in hENT1low (p = 0.02). In patients receiving mFFX, there was no difference in ORR (35% vs. 28%, p = 0.56) or median OS (10.6 vs. 10.5 months, p = 0.45). However, in patients treated with GnP, the ORR was significantly higher in hENT1high compared to hENT1low tumors (43% vs. 21%, p = 0.038). Median OS in this GnP treated cohort was 10.6 months in hENT1high vs. 6.7 months hENT1low(p<0.001). In an interaction analysis, hENT1 was predictive of treatment response to GnP (interaction p = 0.002). Conclusions: In advanced PDAC, hENT1 mRNA expression predicts ORR and OS in patients receiving GnP.

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

“…A recent study demonstrated that hENT1 , a gemcitabine-specific gene, was predictive of response to gemcitabine-nab-paclitaxel in the COMPASS trial, suggesting that GemPred will most likely also predict the response to the dual regimen. 31 …”

“…Frequency of Maximal Toxicity Events recent study demonstrated that hENT1, a gemcitabinespecific gene, was predictive of response to gemcitabinenab-paclitaxel in the COMPASS trial, suggesting that GemPred will most likely also predict the response to the dual regimen. 31 We also tested the prognostic value of the GemPred1 status in patients treated who had postoperative adjuvant mFOL-FIRINOX and who received a gemcitabine-based chemotherapy after relapse. In this comparison, the GemPred1 status obtained on a chemotherapy-naive sample was not predictive of postrelapse CSS for patients retreated using gemcitabine-based therapy after mFOLFIRINOX failure.…”

hENT1’s role in adjuvant intra-arterial gemcitabine-based chemotherapy for resectable pancreatic cancer patients

“…Most clinical studies including systematic reviews and meta-analyses reached the conclusion that high hENT1 expression is predictive of gemcitabine sensitivity in the systematic chemotherapy of PDACpatients [ 30 – 34 ]. Especially in adjuvant chemotherapy, a number of studies already reported the hENT1 is a strong independent prognostic factor in PDAC patients who receive gemcitabine-based chemotherapy after surgery.…”

Serum Amyloid a Predicts Prognosis and Chemotherapy Efficacy in Patients with Advanced Pancreatic Cancer

“…This suggests that patients with APC with a low SAA may be preferentially treated with mFOLFIRINOX. Previous studies have found that the high expression of human Equilibrative Nucleoside Transporter 1 (hENT1) is related to longer OS in patients with APC received AG, 33 while Hepatocyte Nuclear Factor-1A (HNF1A) positive patients might benefit from FOLFIRINOX. 34 In contrast to these studies, SAA can be obtained from serum as a routine clinical biochemical test, which is more convenient, safer and economical.…”