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

Authors

Sheron Perera; Gun Ho Jang; Yifan Wang; Deirdre Kelly; Michael Allen; Amy Zhang; Robert E. Denroche; Anna Dodd; Stephanie Ramota; Shawn Hutchinson; Mustapha Tehfe; Ravi Ramjeesingh; James Biagi; Bernard Lam; Julie Wilson; Sandra E. Fischer; George Zogopoulo; Faiyaz Notta; Steven Gallinger; Robert C. Grant; Jennifer J. Knox; Grainne M. O’Kane

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 χ² 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 overall survival (OS) was 10.0 months in hENT1^high versus 7.9 months in hENT1^low (P = 0.02). In patients receiving mFFX, there was no difference in overall response rate (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 hENT1^high compared with hENT1^low tumors (43% vs. 21%, P = 0.038). Median OS in this GnP-treated cohort was 10.6 months in hENT1^high versus 6.7 months hENT1^low (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.