title: Pharmacogenomic modeling of circulating tumor and invasive cells for prediction of chemotherapy response and resistance in pancreatic cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Memorial Sloan Kettering, Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York. yuk1@mskcc.org.
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Yu
authors.affiliation: CellPath Therapeutics, Baltimore, Maryland.
authors.forename: Mark
authors.initials: M
authors.lastname: Ricigliano
authors.affiliation: Clinical Research Programme, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.affiliation: Memorial Sloan Kettering, Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Ghassan K
authors.initials: GK
authors.lastname: Abou-Alfa
authors.affiliation: Memorial Sloan Kettering, Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Maeve A
authors.initials: MA
authors.lastname: Lowery
authors.affiliation: Memorial Sloan Kettering, Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
authors.affiliation: Memorial Sloan Kettering, Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Crotty
authors.affiliation: Memorial Sloan Kettering, Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Kristen
authors.initials: K
authors.lastname: Gary
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore, Maryland.
authors.forename: Brandon
authors.initials: B
authors.lastname: Cooper
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore, Maryland.
authors.forename: Rena
authors.initials: R
authors.lastname: Lapidus
authors.affiliation: University of Maryland Greenebaum Cancer Center, Baltimore, Maryland.
authors.forename: Mariola
authors.initials: M
authors.lastname: Sadowska
authors.affiliation: Memorial Sloan Kettering, Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: O'Reilly
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008954:Models, Biological; D009360:Neoplastic Cells, Circulating / Q000187:drug effects / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D010597:Pharmacogenetics; D015203:Reproducibility of Results; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents
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