Differential expression of circulating biomarkers of tumor phenotype and outcomes in previously treated non-small cell lung cancer patients receiving erlotinib vs. cytotoxic chemotherapy
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Mary Jo Fidler1, Casey Frankenberger2, Richard Seto1, Gabriela C. Lobato3, Cristina L. Fhied2, Selina Sayidine2, Sanjib Basu4, Mark Pool2, Reem Karmali5,6, Marta Batus1, Wen-Rong Lie7, David Hayes7, Jehangir Mistry7, Philip Bonomi1 and Jeffrey A. Borgia2,3
1Section of Medical Oncology, Rush University Medical Center, Chicago, IL 60612, USA
2Pathology, Rush University Medical Center, Chicago, IL 60612, USA
3Biochemistry, Rush University Medical Center, Chicago, IL 60612, USA
4Preventative Medicine, Rush University Medical Center, Chicago, IL 60612, USA
5Hematology, Oncology and Cell Therapy at Rush University Medical Center, Chicago, IL 60612, USA
6Present address: Division of Hematology and Oncology, Northwestern University, Chicago, IL 60612, USA
7EMD Millipore Corporation, St. Charles, MO 63304, USA
Jeffrey A. Borgia, email: Jeffrey_Borgia@Rush.edu
Keywords: biomarker, non-small cell lung cancer (NSCLC), Luminex, erlotinib, epithelial-to-mesenchymal transition (EMT)
Received: October 11, 2016 Accepted: February 06, 2017 Published: April 28, 2017
Background: The objective of this study was to identify serum biomarkers capable of predicting clinical outcomes in previously-treated NSCLC patients with wild-type for EGFR activating mutations or insufficient tissue for mutation status determination.
Methods: Sixty-six Luminex immunoassays representative of biological themes that emerged from a re-analysis of transcriptome data from the Cancer Genome Atlas (TCGA) were evaluate against pretreatment serum specimens from previously-treated advanced NSCLC patients received either cytotoxic chemotherapy (n=32) or erlotinib (n=79). Known EGFR mutation positive cases were excluded from analysis. Associations of biomarkers with outcome parameters and their differential interaction with treatment for survival outcomes were assessed using multivariate Cox PH analyses.
Results: Our EMT-based transcriptomic analysis revealed a range of biological processes associated with angiogenesis, apoptosis, cachexia, inflammation, and metabolism emerging as those most highly associated with patient outcome. These processes were evaluated via surrogate serum biomarkers. A treatment-biomarker interaction analysis revealed that higher pretreatment levels of c-Met signaling biomarkers (i.e. HGF levels), pro-inflammatory/ pro-cachexia (e.g. IL-8, sIL-2Rα, FGF-2) processes and a pro-angiogenic (e.g. TGF-α, IL-8, VEGF) milieu were associated with inferior survival (HR=0.35, 0.29, 0.58, 0.50, 0.61, 0.45, respectively; all p<0.05) for patients receiving chemotherapy, relative to erlotinib. In contrast, high levels of decoy receptor for IL-1, sIL-1RII, and a high tissue vimentin/E-cadherin ratio were associated with a poor OS (HR=3.78; p=0.00055) in the erlotinib cohort.
Conclusions: Contemporary precision medicine initiatives that pair patient tumor characteristics with the optimal therapy type may maximize the use of agents targeting EGFR in the treatment of NSCLC.
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