COMPASS Trial Points To Biomarker Aiding Advanced Pancreatic Cancer Treatment Choice

COMPASS Trial Points To Biomarker Aiding Advanced Pancreatic Cancer Treatment Choice 

hENT1 mRNA expression may act as a biomarker for first-line chemotherapy choice in advanced pancreatic cancer 

By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Measuring messenger (m)RNA expression of human equilibrative nucleoside transporter 1 (hENT1) in pancreatic ductal adenocarcinoma may help physicians choose between first-line FOLFIRINOX and gemcitabine plus nab-paclitaxel for patients with advanced disease, suggests research reported at the 2021 ASCO Annual Meeting. 

hENT1 is a transmembrane glycoprotein that has a “critical role in the cellular uptake of gemcitabine” and there is conflicting evidence on the role of hENT1 protein and mRNA expression as possible biomarkers for pancreatic cancer prognosis, explained presenting author Sheron Perera, from the Princess Margaret Cancer Centre in Toronto, Ontario, Canada. 

The COMPASS trial included patients with advanced pancreatic cancer who were enrolled between 2016 and 2020 and had biopsy samples adequate for whole-genome and RNA sequencing using laser capture micro-dissection for tumour epithelium enrichment. 

In all, 106 patients received an investigator’s choice of first-line gemcitabine plus nab-paclitaxel and 146 were instead given FOLFIRINOX. 

Patients in the two chemotherapy arms were comparable in terms of sex, performance status and receipt of prior surgery, and around 85% of both groups had metastatic disease. But individuals given gemcitabine plus nab-paclitaxel were significantly older than their FOLFIRINOX-treated counterparts (median 67 vs 62 years), which the presenter described as “in keeping with current clinical practice where patients who are younger and fitter are often prescribed FOLFIRINOX preferentially.” 

The study defined mRNA hENT1 expression as high or low using the maximal chi-squared value and the median expression level – and the former was chosen for analysis as it best reflected percentage change in tumour size with hENT1 expression. 

Using the maximal chi-squared statistic, 52% of patients were classified as having high hENT1 mRNA expression and 48% as having low expression. 

The 132 hENT1-high patients showed a trend towards a better objective response rate (ORR) than the 121 hENT1-low participants (37 vs 26%) and significantly better median overall survival (OS, 9.81 vs 8.28 months), although the presenter commented that there was “little difference between these groups”. 

Among patients given gemcitabine plus nab-paclitaxel, individuals with high hENT1 expression had a significantly better ORR than those with low expression (43 vs 21%), whereas there was no significant difference among FOLFIRINOX-treated patients with high and low expression (32 vs 30%). 

And there was also a significant difference in median OS with high versus low expression among patients given gemcitabine plus nab-paclitaxel (9.67 vs 6.74 months, hazard ratio [HR]=1.98) that was not found for the FOLFIRINOX-treated patients (10.62 vs 10.55 months). 

Multivariable analysis indicated that OS was significantly worse in patients with metastatic versus locally advanced disease (HR=1.74) and those given gemcitabine plus nab-paclitaxel versus FOLFIRINOX (HR=2.10), but was significantly better in patients with homologous recombination deficient tumours (HR=0.42), and those with classical versus basal-like Moffitt type tumours (HR=0.57). 

However, further analysis revealed that the 50 hENT1-high patients given gemcitabine plus nab-paclitaxel had significantly better OS than all other patients in the COMPASS study grouped together, with a HR for death of 0.47. 

Sheron Perera concluded that this is the largest study to assess hENT1 mRNA expression in advanced pancreatic ductal adenocarcinoma and hENT1 expression is the first biomarker to significantly predict response to gemcitabine plus nab-paclitaxel chemotherapy in this patient population. 

She added that the findings are now being validated in the PASS-01 study, a randomised phase II trial comparing the two chemotherapy regimens. 

Session discussant Neeha Zaidi, from the Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, USA, said that the data for hENT1 expression are “very promising” for a tumour type with few biomarkers, but “not quite ready for prime time.” 

She welcomed the randomised trial validation and emphasized the need for standardisation of methodology for hENT1 assessment, such as the use of laser capture micro-dissection for tumour sampling, identification of an antibody that can allow immunohistochemistry detection of functional hENT1, and the assessment of heterogeneous expression of hENT1 in cancer cells.
 

Reference  

Perera S, Jang GH, Zhang A, et al. hENT1 gene expression as a predictor of response to gemcitabine and nab-paclitaxel in advanced pancreatic cancer. J Clin Oncol 2021;39(suppl 15; abstr 4011): DOI: 10.1200/JCO.2021.39.15_suppl.4011