Researchers report that they may have found a way to identify patients with pancreatic cancer who are likely to respond to treatment with the gruelling chemotherapy combination FOLFIRINOX (5- fluorouracil, leucovorin, irinotecan, and oxaliplatin), which has been shown to improve survival but has substantial side effects.
The key may lie with the enzyme carboxylesterase 2 (CES2), according to a study published in the August 8 issue of the Journal of the National Cancer Institute.
"Response to irinotecan [Camptosar, Pfizer Inc] may well depend on whether the tumor expresses the enzyme [CES2] that metabolizes the drug. If this is validated in a prospective trial, testing for this protein would be predictive of response," commented lead author Samir Hanash, MD, PhD, director of the Red and Charline McCombs Institute for the Early Detection and Treatment of Cancer, at the University of Texas MD Anderson Cancer Center, Houston.
CES2 belongs to one of the largest classes of enzymes in humans, known as the serine hydrolases. These enzymes factor significantly in the development, growth, and spread of cancer and may also be important for drug metabolism. Although not completely understood, one of the main functions of CES2 seems to be to protect cells against toxins. In humans, CES2 converts the prodrug irinotecan to its active form SN38, a topoisomerase inhibitor that induces cell death in pancreatic ductal adenocarcinoma (PDAC).
For their study, Dr Hanash and colleagues used immunohistochemistry to evaluate CES2 expression in tumor and nontumor tissue from 118 patients with PDAC. Next, they analyzed CES2 activity by looking at the hydrolysis of the nonspecific esterase substrate para-nitrophenyl acetate (p-NPA) and correlating it with the half-maximal inhibitory concentration (IC50) of irinotecan.
Finally, they looked at overall survival and CES2 expression in 22 patients with high-risk profiles or borderline operable PDAC who received FOLFIRINOX before surgery. Patients received either an individualized protocol based on their clinical status or the following protocol: FOLFIRINOX (oxaliplatin 75 mg/m2 d1 + irinotecan 150 mg/ m2 d1 + 5-FU 2000 mg/m2 46h CI for 6 cycles) before radiotherapy (50.4 Gy with weekly gemcitabine (Gemzar, Eli Lilly and Company) 350 mg/m2) and surgery.
The results showed significant overexpression of CES2 mRNA and protein in PDAC tissue when compared with nontumor pancreatic tissue (P < .001).
Of 188 PDAC samples, 63.6% (75/118) showed CES2 expression, compared with 7.2% (7/97) of nontumor pancreatic tissue samples, with 48/118 (40.7%) tumors showing high CES2 expression.
In 11 PDAC cell lines, as CES2 activity increased, IC50 values decreased, showing that less irinotecan was needed for response (R = -0.68; P = .02).
Patients who received FOLFIRINOX before surgery and had resectable or borderline resectable tumors with high CES2 expression had longer overall survival compared with those with low and intermediate CES2 expression (hazard ratio [HR]; 0.11; 95% confidence interval [CI], 0.02 - 0.75; P =.01; and HR, 0.14; 95% CI, 0.04 - 0.51; P = .02, respectively).
Mutlivariable analyses suggested that CES2 expression and tumor size represented the only independent predictors of overall survival (log-rank P = .02; HR = 0.03; 95% CI = 0.002 - 0.58).
Patients with high CES2 expression also had significantly improved progression-free survival compared with those with low and intermediate CES2 expression (HR = 0.09; 95% CI = 0.01 - 0.36; P = .005; and HR = 0.22, 95% CI = 0.04 - 0.97; log-rank P = .05, respectively).
"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," Dr Hanash emphasized. "The bottom line is that genomic profiling alone may not be sufficient as a source of markers predictive of response to therapy."
"The findings [of this study] highlight the importance of understanding the pharmacology of chemotherapeutic drugs and how pharmacodynamic effects are influenced by both the normal and tumoral expressions of metabolizing and activating enzymes," commented Ryan Nipp, MD, of the Massachusetts General Hospital Cancer Center, Dana-Farber Cancer Institute, and Harvard Medical School, in Boston. Dr Nipp coauthored a linked editorial, along with David Ryan, MD, also of Massachusetts General Hospital.
Although the study provides "valuable information" that "should motivate additional study," Dr Nipp cautioned that definitive conclusions cannot yet be drawn from it.
More work is needed, he added, on the role of CES2 expression in FOLFIRONOX treatment outcomes in PDAC and other cancers. Aspects that call for investigation include whether treatment affects CES2 expression, whether CES2 expression fluctuates within an individual's tumor, and whether CES2 expression differs between the primary site and metastases.
"The results of this study were a welcome reminder that, after nearly 15 years of use in the clinic, we still have much to learn about irinotecan," Dr Nipp emphasized. "[T]his underscores the importance of understanding the pharmacology of the chemotherapies we frequently prescribe. We look forward to the research and investigations inspired by the findings of this work."
The authors, Dr Nipp, and Dr Ryan report no relevant financial relationships.
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