Pharmacogenomic modeling of circulating tumor and invasive cells for prediction of chemotherapy response and resistance in pancreatic cancer Journal Article
| Authors: | Yu, K. H.; Ricigliano, M.; Hidalgo, M.; Abou-Alfa, G. K.; Lowery, M. A.; Saltz, L. B.; Crotty, J. F.; Gary, K.; Cooper, B.; Lapidus, R.; Sadowska, M.; O'Reilly, E. M. |
| Article Title: | Pharmacogenomic modeling of circulating tumor and invasive cells for prediction of chemotherapy response and resistance in pancreatic cancer |
| Abstract: | Purpose: Despite a challenging prognosis, modern cytotoxic therapy can induce tumor responses and extend life in pancreatic adenocarcinoma (PDAC). Pharmacogenomic (PGx) modeling of tumor tissue can predict the efficacy of chemotherapeutic agents in preclinical cancer models. We hypothesized that PGx profiling of circulating tumor and invasive cells (CTIC) isolated from peripheral blood could predict tumor response, progression, and resistance. Experimental Design: A PGx model was created and validated in preclinical models. A prospective clinical trial was conducted. Fifty patients with advanced PDAC were enrolled. Before treatment, 10 mL of peripherally drawn blood was collected. CTICs isolated from this blood sample were expression profiled and the PGx model was used to predict effective and ineffective chemotherapeutic agents. The treating physicians were blinded to PGx prediction. Results: We found that CTICs could be reliably isolated, total RNA extracted and profiled from 10 mL of peripheral blood from patients with unresectable PDAC before chemotherapy treatment and at disease progression. Using previously created PGx models to predict chemotherapy sensitivity, we found that clinical benefit was seen for study participants treated with chemotherapy regimens predicted to be effective versus chemotherapy regimens predicted to be ineffective with regard to progression-free (10.4 mo vs. 3.6 mo; P < 0.0001; HR, 0.14) and overall survival (17.2 mo vs. 8.3 mo; P < 0.0249; HR, 0.29). Conclusions: These findings suggest that PGx profiling of CTICs can predict treatment response. |
| Keywords: | controlled study; human tissue; treatment response; aged; human cell; major clinical study; overall survival; erlotinib; fluorouracil; advanced cancer; drug efficacy; monotherapy; treatment duration; capecitabine; gemcitabine; paclitaxel; cancer radiotherapy; antineoplastic agent; prospective study; gene; progression free survival; controlled clinical trial; gene expression profiling; combination chemotherapy; prediction; cancer resistance; docetaxel; irinotecan; cancer inhibition; drug distribution; cell isolation; pancreas adenocarcinoma; reliability; drug metabolism; inoperable cancer; epithelial cell adhesion molecule; cytokeratin; oxaliplatin; drug sensitivity; drug transport; cd45 antigen; rna extraction; circulating tumor cell; tumor invasion; pharmacogenomics; abcc3 gene; human; male; female; article; circulating tumor and invasive cell; cyp2s1 gene; cyp3a5 gene; cyp51a1 gene; slc16a3 gene; slc17a5 gene; slc1a1 gene; slc20a1 gene; slc25a13 gene; slc25a3 gene; slc25a39 gene; slc25a5 gene; slc25a6 gene; slc2a10 gene; slc35b1 gene; slc39a14 gene; slc40a1 gene; slc44a1 gene; slc45a3 gene; slc6a8 gene; slc7a1 gene; slc9a3r1 gene |
| Journal Title: | Clinical Cancer Research |
| Volume: | 20 |
| Issue: | 20 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2014-10-15 |
| Start Page: | 5281 |
| End Page: | 5289 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-14-0531 |
| PROVIDER: | scopus |
| PUBMED: | 25107917 |
| PMCID: | PMC4346320 |
| DOI/URL: | |
| Notes: | Export Date: 1 December 2014 -- Source: Scopus |
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