Abstract
Previous studies have shown that pharmacogenomic modeling of circulating tumor and invasive cells (CTICs) can predict response of pancreatic ductal adenocarcinoma (PDAC) to combination chemotherapy, predominantly 5-fluorouracil-based. We hypothesized that a similar approach could be developed to predict treatment response to standard frontline gemcitabine with nab-paclitaxel (G/nab-P) chemotherapy. Gene expression profiles for responsiveness to G/nab-P were determined in cell lines and a test set of patient samples. A prospective clinical trial was conducted, enrolling 37 patients with advanced PDAC who received G/nab-P. Peripheral blood was collected prior to treatment, after two months of treatment, and at progression. The CTICs were isolated based on a phenotype of collagen invasion. The RNA was isolated, cDNA synthesized, and qPCR gene expression analyzed. Patients were most closely matched to one of three chemotherapy response templates. Circulating tumor and invasive cells’ SMAD4 expression was measured serially. The CTICs were reliably isolated and profiled from peripheral blood prior to and during chemotherapy treatment. Individual patients could be matched to distinct response templates predicting differential responses to G/nab-P treatment. Progression free survival was significantly correlated to response prediction and ΔSMAD4 was significantly associated with disease progression. These findings support phenotypic profiling and ΔSMAD4 of CTICs as promising clinical tools for choosing effective therapy in advanced PDAC, and for anticipating disease progression.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) currently represents the 3rd leading cause of cancer mortality in the U.S Of the five most lethal cancers, incidence and death rates are only increasing for pancreatic ductal adenocarcinoma (PDAC)
Analysis failure could be attributed to errors in qPCR, typically isolated to failure of a single gene to amplify, bad passive dye readings and exponential algorithm failures
A strong negative correlation was seen between profiles predicting sensitivity to gemcitabine with nab-paclitaxel (G/nab-P) and FOLFIRINOX
Summary
Pancreatic ductal adenocarcinoma (PDAC) currently represents the 3rd leading cause of cancer mortality in the U.S Of the five most lethal cancers, incidence and death rates are only increasing for PDAC. The emergence of active combination chemotherapy regimens during the past three years has led to incremental improvements in overall survival. Combination chemotherapy regimens, such as 5-fluorouracil (5-FU), leucovorin, irinotecan, Cancers 2018, 10, 467; doi:10.3390/cancers10120467 www.mdpi.com/journal/cancers. Tumor tissue-based biomarkers have been identified as predictive of drug effect. This strategy has been effective where the biomarker is linked to the mechanism of action of the agent, i.e., Her expression and trastuzumab or activating EGFR mutation and erlotinib. A recent example attempting to predict response to cytotoxic chemotherapy involved the human equilibrative nucleoside transporter-1 (hENT1), a transporter protein thought important for cellular uptake of gemcitabine
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