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. 2018 Nov 24;10(12):467.
doi: 10.3390/cancers10120467.

Circulating Tumor and Invasive Cell Gene Expression Profile Predicts Treatment Response and Survival in Pancreatic Adenocarcinoma

Kenneth H Yu  1   2 , Mark Ricigliano  3 , Brian McCarthy  4 , Joanne F Chou  5   6 , Marinela Capanu  7   8 , Brandon Cooper  9 , Andrew Bartlett  10 , Christina Covington  11 , Maeve A Lowery  12 , Eileen M O'Reilly  13   14
Affiliations

Circulating Tumor and Invasive Cell Gene Expression Profile Predicts Treatment Response and Survival in Pancreatic Adenocarcinoma

Kenneth H Yu et al. Cancers (Basel). .

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.

Keywords: 5-fluorouracil; FOLFIRINOX; SMAD4; circulating tumor and invasive cells; gemcitabine; nab-paclitaxel; pancreatic cancer.

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Conflict of interest statement

The following authors report no conflicts of interest: Joanne F. Chou, Marinela Capanu, Christina Covington, Maeve A. Lowery and Eileen M. O’Reilly. Kenneth H. Yu serves as an advisor to Adera Biolabs. Yu has no financial interest in and has not received compensation from Adera Biolabs. Brandon Cooper, Andrew Bartlett, Mark Ricigliano, and Brian McCarthy are employees of Adera Biolabs.

Figures

Figure 1
Figure 1
Kaplan–Meier analysis of progression-free survival (PFS) of patients treated with G/nab-P based on classification into one of three PGx profiles (A), and based on predicted G/nab-P sensitivity (B).
Figure 2
Figure 2
Performance of PGx profiling (A), G/nab-P sensitivity (B), ΔSMAD4 (C), and a combined analysis (D) to predict treatment response. Six-month PFS was used as a cut-off for predicting sensitivity and response (>6 months) or resistance and lack of response (<6 months).
Figure 3
Figure 3
Kaplan–Meier analysis of PFS based on ΔSMAD4 (A), ΔSMAD4 (S4), and G/nab-P sensitivity (GN+) or resistance (GN-); (B) decrease in carbohydrate antigen (CA) 19-9 by 50% (C) or 90% (D) after 2 months of treatment with G/nab-P.
Figure 4
Figure 4
Consort diagram.
See this image and copyright information in PMC

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