Pharmacogenomic Modeling, S-1 Chemotherapy, Benefits Patients with Pancreatic Cancer

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(ChemotherapyAdvisor) – Patients with pancreatic cancer may benefit from pharmacogenomic (PGx) modeling that profiles response to chemotherapy, as well as from treatment with the agent S-1, two studies reported in advance of the 10th annual Gastrointestinal Cancers Symposium being held January 24-26 in San Francisco, CA.

PGx profiling “is a promising and exploratory tool for predicting treatment response in pancreatic cancer,” said Kenneth Yu, MD, assistant attending physician in the Gastrointestinal Oncology Service of Memorial Sloan-Kettering Cancer Center, New York, NY. “This research lays important groundwork for customizing treatments according to a patient's genetic composition.”

Preliminary results from an ongoing prospective study, with 50 of the planned 60 patients accrued, found isolation and gene expression profiling of tumor progenitor cells were reliably performed in patients with unresectable pancreatic adenocarcinoma, Dr. Yu said.

Patients had 10 mL of peripheral blood collected prior to receipt of chemotherapy and at disease progression. PGx models for 12 different drug combinations—including FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin), gemcitabine, and docetaxel—were created from GI50 data obtained from NCI-60 cells lines.

Patients who received treatment predicted by the model to be more effective did better, Dr. Yu said. Median time to progression was 7.3 months for those sensitive to chemotherapy (n=6); 5.3 months for those with intermediate sensitivity (n=6), and 3.7 months for those resistant (n=8) to chemotherapy (P=0.017).

“Changes in chemo-sensitivity patterns were evident at disease progression, reflecting treatment resistance,” Dr. Yu said. “Hedgehog pathway overexpression was associated with resistance to gemcitabine but with clinical response to 5-FU-based treatment. Pathway analysis revealed that ErbB3, ARE/Nrf2 and Insulin pathways distinguished patients with disease progression.” Among patients with stage IV cancers who experienced progression, major differences were seen in the E2F1 and NFκB pathways.

Using this strategy, “treatments can be modified at the earliest molecular sign of disease worsening,” Dr. Yu said, without the need for a biopsy.

Early results from a phase 3 trial conducted in Japan (JASPAC-01) showed patients with pancreatic cancer who received adjuvant chemotherapy with S-1 following resection had superior 2-year overall survival compared with gemcitabine (70% vs. 53%; HR, 0.56 [0.42-0.74]; P<0.0001 for non-inferiority and P<0.0001 for superiority [log-rank test]), reported Katsuhiko Uesaka, MD, PhD, medical deputy director at Shizuoka Cancer Center Hospital, Shizuoka, Japan.

S-1, an oral fluoropyrimidine, is not yet available in the United States; previous studies have shown that S-1 induces more adverse events, such as diarrhea, in Caucasian patients.

Dr. Yu reported no disclosures; his co-authors included employees and advisors to CellPath Therapeutics. Dr. Uesaka reported honoraria from Taiho Pharmaceutical and Lilly.

The 2013 Gastrointestinal Cancers Symposium is co-sponsored by the American Gastroenterological Association (AGA) Institute, the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO) and the Society of Surgical Oncology (SSO).

Abstracts:

Dr. Yu (Sangar is first author)

Dr. Uesaka

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