The study published in JNCI has identified CES2 expression as a predictor of response to FOLFIRINOX.
Proteomic analysis to assess differential expression and localization of a specific class of enzymes called serine hydrolases—known to regulate several pathophysiological process in cancer—has identified carboxylesterase 2 (CES2) as a predictor of response to FOLFIRINOX sensitivity in pancreatic cancer.
A disease with the most dismal prognosis, pancreatic cancer has the highest mortality rate of all major cancers: 94% of patients die within 5 years of diagnosis and nearly 75% die within the first year after being diagnosed. Treatment options are restrictive, with surgery possible in less than 20% of patients and chemotherapy with or without radiation is then administered.
For a long period, gemcitabine was the standard of care for metastatic pancreatic cancer; however FOLFIRINOX or gemcitabine with nab-paclitaxel have presented promising results as first-line treatment for the disease. The FOLFIRINOX regimen, a combination of 4 drugs (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) is however, quite harsh on patients.
In their study published in the Journal of the National Cancer Institute, the authors compared the expression of CES2 in 118 pancreatic ductal adenocarcinoma (PDAC) samples with the adjacent normal tissue. CES2 has been known to activate irinotecan, which is a prodrug, into SN-38 in PDAC. They also analyzed enzyme activity in these samples and then collected overall survival data in 22 patients. The analysis found statistically significant overexpression of CES2 (RNA and protein) in PDAC compared with the paired normal tissue, with 40.7% of tumors exhibiting high CES2 expression. High expression of CES2 in the 22 patients who had high-risk profiles of borderline operable PDAC and who had received FOLFIRINOX prior to their surgery survived longer than patients with low and intermediate expression of CES2. High expression of CES2 was also significantly associated with improved progression-free survival compared with low and intermediate expression of the protein.
CES2 expression and activity, by mediating the intratumoral activation of irinotecan, is a contributor to FOLFIRINOX sensitivity in pancreatic cancer and CES2 assessment may define a subset of patients likely to respond to irinotecan based therapy, the authors write.
Samir Hanash, MD, PhD, senior author on the study, said in an interview with Medscape, “This study clearly points out that predicting response to drug may depend on molecular features of the tumor that may not be predictable from a tumor's mutational or genomic profile. The bottom line is that genomic profiling alone may not be sufficient as a source of markers predictive of response to therapy.”