Gemcitabine Response Depends on Gene Expression in Patients With Pancreatic Cancer

Patients who express low levels of a critical gene involved in transporting gemcitabine into pancreatic tumor cells have virtually no overall survival (OS) advantage from treatment with the drug in the adjuvant setting, according to research presented at the ESMO 15th World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Christophe Louvet, MD, PhD, Hopital Saint Antoine, Paris, France, reviewed a series of studies in which patients with pancreatic cancer who received gemcitabine following surgical resection of the tumor had dramatically different outcomes based on whether they were high- or low- to moderate-expressers of the human equilibrative nucleoside transporter (hENT1) protein responsible for activating gemcitabine. In the French-Belgium experience, for example, (Marechal R et al. Gastroenterology, 2012 ;143(3) :664-74), a total of 434 evaluable patients were assigned to either adjuvant treatment following surgical resection of their tumor or no adjuvant treatment.

Those who were assigned to adjuvant treatment received either gemcitabine or a non-gemcitabine regimen consisting of radiotherapy alone or radiotherapy plus 5-fluorouracil (5-FU). At 60 months follow-up, OS in patients who had high levels of hENT1 expression and who had received gemcitabine had a 66% longer survival time versus those with low- to moderate-hENT1 expression (P<.001).

The same clinically meaningful difference in OS was also seen in moderate to high-expressers of deoxycytidine kinase (dCK) where high dCK expression was associated with a 43% longer survival time compared with low-dCK expressers. dCK is involved in the activation of gemcitabine once inside the tumor cell.

In contrast, no difference in OS was seen among the French-Belgium cohort who received non-gemcitabine adjuvant therapy regardless of their level of hENT1 or dCK expression. In the randomized ESPAC1/3 trial presented by Neoptolemos et al at ASCO this year, “investigators found exactly the same thing,” Louvet observed. Again stratified into high- versus low-hENT1 expressers, median survival was 26.2 months in high-hENT1 expressers following treatment with gemcitabine versus 17.1 months among those who expressed low levels of the same protein (P = .002).

Again in contrast, median OS between high hENT1 expressers at 25.6 months and low hENT1 expressers at 21.9 months was not statistically significant following adjuvant treatment with 5-FU (P = .0362). “Unfortunately, we still have problems diagnosing hENT1 and we cannot be sure which antibody test is best to test patients for hENT1 expression,” Louvet said.

However, looking at results from several different trials of pancreatic cancer patients—the RTOG in primary tumor patients and two meta-analyses—Louvet estimated that approximately two-thirds of patients with pancreatic cancer are low- to null-expressers of hENT1. Given this, “we can say that gemcitabine might be considered as placebo for two-thirds of pancreatic cancer patients in the adjuvant setting because gemcitabine is unable to enter the tumor cell,” Louvet said.

It also suggests that the majority of pancreatic cancer patients who receive any sort of couplet regimen containing gemcitabine following surgical resection are really only receiving single-agent therapy, he added.

In the future, Louvet argued that pancreatic cancer patients should be stratified into high- versus low- to moderate-hENT1 expressers; based on their levels of expression, gemcitabine would be a good choice for those with high levels of hENT1 expression whereas FOLFIRINOX would be a better choice for those with low to moderate levels of hENT1 expression.

“Adjuvant treatment with 6 months of gemcitabine remains the 2013 gold standard after pancreatic cancer resection,” Louvet concluded. “But in the very near future, treatment will be based on molecular approaches in order to customize treatment and improve overall outcomes of patients with pancreatic cancer.”

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