Lung cancer is one of the most common cancers in the western world, and closely related to smoking. The majority of the patients can not be offered treatment with curative intent. Palliative chemotherapy has limited effect but a considerable level of toxicity. Predictive markers are therefore urgently needed. Single Nucleotide Polymorphisms (SNPs) are stable markers of potential clinical value and the study aimed at evaluating their use in lung cancer patients given standard chemotherapy. Genomic DNA was extracted from a pre-treatment blood sample drawn from patients with advanced Non-Small Celled Lung Cancer (NSCLC), referred to palliative chemotherapy (Carboplatin and Vinorelbine) at the Department of Oncology, Vejle Hospital, between 2007 and 2010. Eighty-seven patients were included in a test cohort, and 161 patients in an independent validation cohort. A panel of 107 SNPs in the EGF, VEGF and DNA-excision repair systems was investigated. The primary endpoint was response rates (RR). Secondary endpoints were progression free survival (PFS) and overall survival (OS). SNPs with significant association to outcome in the test cohort were further tested in the validation cohort. Haplotypes were estimated and analyzed when relevant. There were no significant associations between SNPs in the EGF system or the DNA-repair system and RR, PFS or OS. In contrast, the VEGF+405, VEGF-460 and VEGF-2579, heterozygous patients had a higher response rate and longer PFS than homozygous patients. Haplotype analysis of the VEGF+405 and VEGF-460 supported our findings. These results were, however, not confirmed in the validation cohort. Although significant results regarding VEGF related SNPs, in the primary analysis, no predictive value of a broad panel of SNPs in NSCLC was found in the validation cohort, underlining the importance of independent validation of biomarker analysis.
KeywordsNSCLCEGFVEGFDNA excision repairSNPs
S. S. Hecht, “Tobacco Smoke CarciNogens and Lung Cancer,” Journal of the National Cancer Institute, Vol. 91, No. 14, 1999, pp. 1194-1210.
P. Jacoulet, J. L. Breton, V. Westeel, M. Mercier, G. Garnier and A. Depierre, “Phase I Study of ViNorelbine and Car-boplatin in Advanced Non-small Cell Lung Cancer,” Lung Cancer, Vol. 12, No. 3, 1995, pp. 247-257.
C. Santomaggio, E. Tucci, M. Rinaldini, R. Algeri, R. Righi, F. Pepi, P. Ghezzi, A. Andrei and A. Bellezza, “Carboplatin and ViNorelbine in the Treatment of Advanced Non-small-cell Lung Cancer: a Multicenter Phase II Study,” American Journal of Clinical Oncology, Vol. 21, No. 1, 1998, pp. 67-71.
N. Helbekkmo, S. H. Sundstrom, U. Aasebo, P. F. Brunsvig, Plessen C. von, H. H. Hjelde, O. K. Garpestad, A. Bailey and R. M. Bremnes, “ViNorelbine/Car- boplatin vs Gemcit-abine/Carboplatin in Advanced NSCLC Shows Similar Effi-cacy, but Different Impact of Toxicity,” British Journal of Cancer, Vol. 97, No. 3, 2007, pp. 283-289.
Masters, G., “Carboplatin and ViNorelbine in Advanced Non-small Cell Lung Cancer: A Phase I/II Study,” Oncologist., Vol. 6 Suppl 1, 2001, pp. 12-15.
Harmon, D. L., Shields, D. C., Woodside, J. V., McMaster, D., Yarnell, J. W., Young, I. S., Peng, K., Shane, B., Evans, A. E., and Whitehead, A. S., “Methionine Synthase D919G Polymor-phism is a Significant but Modest Determinant of Circulating Homocysteine Concentrations,” Genetic Epidemiology., Vol. 17, No. 4, 1999, pp. 298-309.
D. S. Salomon, R. Brandt, F. Ciardiello and N. NormanNo, “Epidermal Growth Factor-related Peptides and Their Recep-tors in Human Malignancies,” Critical Reviews in Oncol-ogy/Hematology, Vol. 19, No. 3, 1995, pp. 183-232.
M. Nomura, H. Shigematsu, L. Li, M. Suzuki, T. Takahashi, P. Estess, M. Siegelman, Z. Feng, H. Kato, A. Marchetti, J. W. Shay, M. R. Spitz, I. I. Wistuba, J. D. Minna and A. F. Gazdar, “Polymorphisms, Mutations, and Amplification of the EGFR Gene in Non-small Cell Lung Cancers,” PLoS. Medicine, Vol. 4, No. 4, 2007, pp. e125.
K. L. Spindler, R. F. Andersen, L. H. Jensen, J. Ploen and A. Jakobsen, “EGF61A>G Polymorphism as Predictive Marker of Clinical Outcome to First-line Capecitabine and Oxaliplatine in Metastatic Colorectal Cancer,” Annual Oncology, 22-10-2009.
P. J. McHugh, V. J. Spanswick and J. A. Hartley, “Repair of DNA Interstrand Crosslinks: Molecular Mechanisms and Clinical Relevance,” Lancet Oncology, Vol. 2, No. 8, 2001, pp. 483-490.
P. Carmeliet and R. K. Jain, “Angiogenesis in Cancer and Other Diseases,” Nature, Vol. 407, No. 6801, 2000, pp. 249-257.
N. Ferrara, H. P. Gerber and J. LeCouter, “The Biology of VEGF and Its Receptors,” Nature Medicine, Vol. 9, No. 6, 2003, pp. 669-676.
J. Folkman, “What is the Evidence that Tumors are Angiogene-sis Dependent?” Journal of the National Cancer Institute, Vol. 82, No. 1, 1990, pp. 4-6.
M. I. Koukourakis, D. Papazoglou, A. GiatromaNolaki, G. Bougioukas, E. Maltezos and E. Sivridis, “VEGF Gene Se-quence Variation Defines VEGF Gene Expression Status and Angiogenic Activity in Non-small Cell Lung Cancer,” Lung Cancer, Vol. 46, No. 3, 2004, pp. 293-298.
C. J. Watson, N. J. Webb, M. J. Bottomley and P. E. Brenchley, “Identification of Polymorphisms within the Vascular Endothe-lial Growth Factor (VEGF) Gene: Correlation with Variation in VEGF Protein Production,” Cytokine, Vol. 12, No. 8, 2000, pp. 1232-1235.
Q. Jin, K. Hemminki, K. Enquist, P. Lenner, E. Grzybowska, R. Klaes, R. Henriksson, B. Chen, J. Pamula, W. Pekala, H. Zientek, J. Rogozinska-Szczepka, B. Utracka-Hutka, G. Hallmans and A. Forsti, “Vascular Endothelial Growth Factor Polymorphisms in Relation to Breast Cancer Development and ProgNosis,” Clinical Cancer Research, Vol. 11, No. 10, 2005, pp. 3647-3653.
C. C. Lin, H. C. Wu, F. J. Tsai, H. Y. Chen and W. C. Chen, “Vascular Endothelial Growth Factor Gene-460 C/T Polymor-phism is a Biomarker for Prostate Cancer,” Urology, Vol. 62, No. 2, 2003, pp. 374-377.
Y. S. Chae, J. G. Kim, S. K. Sohn, Y. Y. Cho, B. M. Ahn, J. H. Moon, S. W. Jeon, J. Y. Park, I. T. Lee, G. S. Choi and S. H. Jun, “Association of Vascular Endothelial Growth Factor Gene Polymorphisms with Susceptibility and Clinicopathologic Characteristics of Colorectal Cancer,” Journal of Korean Medical Science, Vol. 23, No. 3, 2008, pp. 421-427.
J. G. Kim, Y. S. Chae, S. K. Sohn, Y. Y. Cho, J. H. Moon, J. Y. Park, S. W. Jeon, I. T. Lee, G. S. Choi and S. H. Jun, “Vascular Endothelial Growth Factor Gene Polymorphisms Associated with ProgNosis for Patients with Colorectal Cancer,” Clinical Cancer Research, Vol. 14, No. 1, 2008, pp. 62-66.
I. H. Onen, E. Konac, M. Eroglu, C. Guneri, H. Biri and A. Ekmekci, “No Association Between Polymorphism in the Vas-cular Endothelial Growth Factor Gene at Position -460 and Sporadic Prostate Cancer in the Turkish Population,” Molecu-lar Biology Reports, Vol. 35, No. 1, 2008, pp. 17-22.
M. Yamamori, M. Taniguchi, S. Maeda, T. Nakamura, N. Okamura, A. Kuwahara, K. Iwaki, T. Tamura, N. Aoyama, S. Markova, M. Kasuga, K. Okumura and T. Sakaeda, “VEGF T-1498C Polymorphism, a Predictive Marker of Differentiation of Colorectal AdeNocarciNomas in Japanese,” International Journal of Medicial Science, Vol. 5, No. 2, 2008, pp. 80-86.
T. F. Hansen, K. L. Spindler, K. A. Lorentzen, D. A. Olsen, R. F. Andersen, J. Lindebjerg, I. Brandslund and A. Jakobsen, “The Importance of -460 C/T and +405 G/C Single Nucleotide Polymorphisms to the Function of Vascular Endothelial Growth Factor A in Colorectal Cancer,” Journal of Cancer Research and Clinical Oncology, Vol. 136, No. 5, 2010, pp. 751-758.
P. Therasse, S. G. Arbuck, E. A. Eisenhauer, J. Wanders, R. S. Kaplan, L. Rubinstein, J. Verweij, M. Van Glabbeke, A. T. van Oosterom, M. C. Christian and S. G. Gwyther, “New Guide-lines to Evaluate the Response to Treatment in Solid Tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada,” Journal of the National Cancer Institute, Vol. 92, No. 3, 2000, pp. 205-216.
M. Stephens, N. J. Smith and P. Donnelly, “A New Statistical Method for Haplotype Reconstruction from Population Data,” American Journal of Human Genetics, Vol. 68, No. 4, 2001, pp. 978-989.
H. Linardou, I. J. Dahabreh, D. Bafaloukos, P. Kosmidis and S. Murray, “Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC,” Nature Reviews Clinical Oncol-ogy, Vol. 6, No. 6, 2009, pp. 352-366.
J. W. Neal and L. V. Sequist, “First-line Use of EGFR Tyrosine Kinase Inhibitors in Patients with NSCLC Containing EGFR Mutations,” Clinical Advances in Hematology and Oncology, Vol. 8, No. 2, 2010, pp. 119-126.
H. G. Kang, J. E. Choi, W. K. Lee, S. Kam, S. I. Cha, C. H. Kim, T. H. Jung and J. Y. Park, “+61A>G Polymorphism in the EGF Gene Does Not Increase the Risk of Lung Cancer,” Res-pirology, Vol. 12, No. 6, 2007, pp. 902-905.
C. H. Bosken, Q. Wei, C. I. Amos and M. R. Spitz, “An Analy-sis of DNA Repair as a Determinant of Survival in Patients with Non-small-cell Lung Cancer,” Journal of the National Cancer Institute, Vol. 94, No. 14, 2002, pp. 1091-1099.
L. Cheng, M. R. Spitz, W. K. Hong, and Q. Wei, “Reduced Expression Levels of Nucleotide Excision Repair Genes in Lung Cancer: A Case-control Analysis,” CarciNogenesis, Vol. 21, No. 8, 2000, pp. 1527-1530.
K. H. Lee, H. S. Min, S. W. Han, D. Y. Oh, S. H. Lee, D. W,Kim, S. A. Im, D. H. Chung, Y. T. Kim, T. Y. Kim, D. S. Heo, Y. J. Bang, S. W. Sung and J. H. Kim, “ERCC1 Expres-sion by ImmuNohistochemistry and EGFR Mutations in Re-sected Non-small Cell Lung Cancer,” Lung Cancer, Vol. 60, No. 3, 2008, pp. 401-407.
D. Isla, C. Sarries, R. Rosell, G. Alonso, M. Domine, M. Taron, G. Lopez-Vivanco, C. Camps, M. Botia, L. Nunez, M. San-chez-Ronco, J. J. Sanchez, Lopez-Brea, M. I. Barneto, A. Paredes, B. Medina, A. Artal and P. Lianes, “Single Nucleotide Polymorphisms and Outcome in Docetaxel-Cisplatin-Treated Advanced Non-Small-Cell Lung Cancer,” Annual Oncology, Vol. 15, No. 8, 2004, pp. 1194-1203.
A. Kalikaki, M. Kanaki, H. Vassalou, J. Souglakos, A. Voutsina, V. Georgoulias and D. Mavroudis, “DNA Repair Gene Polymorphisms Predict Favorable Clinical Outcome in Advanced Non-small-cell Lung Cancer,” Clinical Lung Cancer, Vol. 10, No. 2, 2009, pp. 118-123.
C. Camps, C. Sarries, B. Roig, J. J. Sanchez, C. Queralt, E. Sancho, N. Martinez, M. Taron and R. Rosell, “Assessment of Nucleotide Excision Repair XPD Polymorphisms in the Pe-ripheral Blood of Gemcitabine/Cisplatin-treated Advanced Non-small-cell Lung Cancer Patients,” Clinical Lung Cancer, Vol. 4, No. 4, 2003, pp. 237-241.
The International HapMap Project, Nature, Vol. 426, No. 6968, 18-12-2003, pp. 789-796.
R. Zhai, G. Liu, W. Zhou, L. Su, R. S. Heist, T. J. Lynch, J. C. Wain, K. Asomaning, X. Lin and D. C. Christiani, “Vascular Endothelial Growth Factor GeNotypes, Haplotypes, Gender, and the Risk of Non-small Cell Lung Cancer,” Clinical Cancer Research, Vol. 14, No. 2, 2008, pp. 612-617.
R. S. Heist, R. Zhai, G. Liu, W. Zhou, X. Lin, L. Su, K., K. Asomaning, T. J. Lynch, J. C. Wain and D. C. Christiani, “VEGF Polymorphisms and Survival in Early-stage Non-small-cell Lung Cancer,” Journal of Clinical Oncology, Vol. 26, No. 6, 2008, pp. 856-862.
S. J. Lee, S. Y. Lee, H. S. Jeon, S. H. Park, J. S. Jang, G. Y. Lee, J. W. Son, C. H. Kim, W. K. Lee, S. Kam, R. W. Park, T. I. Park, Y. M. Kang, I. S. Kim, T. H. Jung and J. Y. Park, “Vas-cular Endothelial Growth Factor Gene Polymorphisms and Risk of Primary Lung Cancer,” Cancer Epidemiology, Biomarkers & Prevention, Vol. 14, No. 3, 2005, pp. 571-575.