Detection of tumor epidermal growth factor receptor pathway dependence by serum mass spectrometry in cancer patients.
BACKGROUND
We hypothesized that a serum proteomic profile predictive of survival benefit in non-small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) reflects tumor EGFR dependency regardless of site of origin or class of therapeutic agent.


METHODS
Pretreatment serum or plasma from 230 patients treated with cetuximab, EGFR-TKIs, or chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC) were analyzed by mass spectrometry. Each sample was classified into "good" or "poor" groups using VeriStrat, and survival analyses of each cohort were done based on this classification. For the CRC cohort, this classification was correlated with the tumor EGFR ligand levels and KRAS mutation status.


RESULTS
In the EGFR inhibitor-treated cohorts, the classification predicted survival (HNSCC: gefitinib, P = 0.007 and erlotinib/bevacizumab, P = 0.02; CRC: cetuximab, P = 0.0065) whereas the chemotherapy cohort showed no survival difference. For CRC patients, tumor EGFR ligand RNA levels were significantly associated with the proteomic classification, and combined KRAS and proteomic classification provided improved survival classification.


CONCLUSIONS
Serum proteomic profiling can detect clinically significant tumor dependence on the EGFR pathway in non-small cell lung cancer, HNSCC, and CRC patients treated with either EGFR-TKIs or cetuximab. This classification is correlated with tumor EGFR ligand levels and provides a clinically practical way to identify patients with diverse cancer types most likely to benefit from EGFR inhibitors. Prospective studies are necessary to confirm these findings.
Chung
Christine H
CH
Division of Hematology/Oncology, Department of Medicine, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232-6307, USA. Christine.Chung@Vanderbilt.edu
Seeley
Erin H
EH
Roder
Heinrich
H
Grigorieva
Julia
J
Tsypin
Maxim
M
Roder
Joanna
J
Burtness
Barbara A
BA
Argiris
Athanassios
A
Forastiere
Arlene A
AA
Gilbert
Jill
J
Murphy
Barbara
B
Caprioli
Richard M
RM
Carbone
David P
DP
Cohen
Ezra E W
EE
D000230:Adenocarcinoma / Q000145:classification / Q000188:drug therapy / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000032:analysis*; D002289:Carcinoma, Non-Small-Cell Lung / Q000145:classification* / Q000188:drug therapy / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000145:classification / Q000188:drug therapy / Q000378:metabolism; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000145:classification / Q000188:drug therapy / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000145:classification / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000145:classification* / Q000188:drug therapy / Q000378:metabolism; D013058:Mass Spectrometry; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D040901:Proteomics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D018631:ras Proteins / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab; D000077156:Gefitinib