Lung cancer is the leading cause of cancer-related death in the United States. Here, we evaluated the potential clinical utility of soluble human epidermal growth factor receptor 2 (sHER2) for the risk assessment, screening, and diagnosis of non-small cell lung cancer (NSCLC) using an unmatched case-control study design. Serum sHER2 concentrations were measured by immunoassay in 244 primary NSCLC cases and 218 healthy controls. Wilcoxon rank-sum tests, logistic regression models, and receiver operating characteristic plots were used to assess whether sHER2 is associated with lung cancer. Median serum sHER2 concentrations are higher in patients with adenocarcinoma than squamous cell carcinoma regardless of gender, and sHER2 is a weak, independent biomarker of adenocarcinoma, but not of squamous cell carcinoma, adjusted for age and gender. The age-adjusted relative risk (odds) of adenocarcinoma is 3.95 (95% CI: 1.22, 12.81) and 7.93 (95% CI: 2.26, 27.82) greater for women and men with high sHER2 concentrations (≥6.60 ng/mL) vs. low sHER2 concentrations (≤1.85 ng/mL), respectively. When adjusted for each other, sHER2, age, and gender discern healthy controls from patients with primary adenocarcinomas of the lung with 85.9% accuracy. We conclude that even though serum sHER2 is not a strong, stand-alone discriminatory biomarker of adenocarcinoma, sHER2 may be a useful, independent covariate in multivariate risk assessment, screening, and diagnostic models of lung cancer.
References
[1]
Altekruse, S.F.; Kosary, C.L.; Krapcho, M.; Neyman, N.; Aminou, R.; Waldron, W.; Ruhl, J.; Howlader, N.; Tatalovich, Z.; Cho, H.; et al. SEER Cancer Statistics Review, 1975–2007. Available online: http://seer.cancer.gov/csr/1975_2007 (accessed on 17 November 2012).
[2]
Siegel, R.; Naishadham, D.; Jemal, A. Cancer statistics, 2012. CA Cancer J. Clin. 2012, 62, 10–29, doi:10.3322/caac.20138.
[3]
Jemal, A.; Siegel, R.; Xu, J.; Ward, E. Cancer statistics, 2010. CA Cancer J. Clin. 2010, 60, 277–300, doi:10.3322/caac.20073.
[4]
Bach, P.B.; Kelley, M.J.; Tate, R.C.; McCrory, D.C. Screening for lung cancer: A review of the current literature. Chest 2003, 123, 72–82, doi:10.1378/chest.123.1_suppl.72S.
[5]
Bach, P.B.; Niewoehner, D.E.; Black, W.C. Screening for lung cancer: The guidelines. Chest 2003, 123, 83–88, doi:10.1378/chest.123.1_suppl.83S.
[6]
Gohagan, J.K.; Prorok, P.C.; Hayes, R.B.; Kramer, B.S. The prostate, lung, colorectal and ovarian (PLCO) cancer screening trial of the national cancer institute: History, organization, and status. Control. Clin. Trials 2000, 21, 251–272, doi:10.1016/S0197-2456(00)00097-0.
[7]
Prorok, P.C.; Andriole, G.L.; Bresalier, R.S.; Buys, S.S.; Chia, D.; Crawford, E.D.; Fogel, R.; Gelmann, E.P.; Gilbert, F.; Hasson, M.A.; et al. Design of the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Control. Clin. Trials 2000, 21, 273–309, doi:10.1016/S0197-2456(00)00098-2.
[8]
Oken, M.M.; Marcus, P.M.; Hu, P.; Beck, T.M.; Hocking, W.; Kvale, P.A.; Cordes, J.; Riley, T.L.; Winslow, S.D.; Peace, S.; et al. Baseline chest radiograph for lung cancer detection in the randomized prostate, lung, colorectal and ovarian cancer screening trial. J. Natl. Cancer Inst. 2005, 97, 1832–1839, doi:10.1093/jnci/dji430.
[9]
Pinsky, P.F.; Miller, A.; Kramer, B.S.; Church, T.; Reding, D.; Prorok, P.; Gelmann, E.; Schoen, R.E.; Buys, S.; Hayes, R.B.; Berg, C.D. Evidence of a healthy volunteer effect in the prostate, lung, colorectal, and ovarian cancer screening trial. Am. J. Epidemiol. 2007, 165, 874–881, doi:10.1093/aje/kwk075.
[10]
Marcus, P.M. Lung cancer screening: An update. J. Clin. Oncol. 2001, 19, 83–86.
[11]
Nawa, T.; Nakagawa, T.; Kusano, S.; Kawasaki, Y.; Sugawara, Y.; Nakata, H. Lung cancer screening using low-dose spiral CT*: Results of baseline and 1-year follow-up studies. Chest 2002, 122, 15–20, doi:10.1378/chest.122.1.15.
[12]
Ma, P.C.; Blaszkowsky, L.; Bharti, A.; Ladanyi, A.; Kraeft, S.K.; Bruno, A.; Skarin, A.T.; Chen, L.B.; Salgia, R. Circulating tumor cells and serum tumor biomarkers in small cell lung cancer. Anticancer Res. 2003, 23, 49–62.
[13]
Brambilla, C.; Fievet, F.; Jeanmart, M.; de Fraipont, F.; Lantuejoul, S.; Frappat, V.; Ferretti, G.; Brichon, P.Y.; Moro-Sibilot, D. Early detection of lung cancer: Role of biomarkers. Eur. Respir. J. Suppl. 2003, 39, 36–44.
[14]
Chanin, T.D.; Merrick, D.T.; Franklin, W.A.; Hirsch, F.R. Recent developments in biomarkers for the early detection of lung cancer: perspectives based on publications 2003 to present. Curr. Opin. Pulm. Med. 2004, 10, 242–247, doi:10.1097/01.mcp.0000130321.11513.13.
[15]
Hilbe, W.; Dirnhofer, S.; Greil, R.; Woll, E. Biomarkers in non-small cell lung cancer prevention. Eur. J. Cancer Prev. 2004, 13, 425–436, doi:10.1097/00008469-200410000-00011.
[16]
Yang, S.Y.; Xiao, X.Y.; Zhang, W.G.; Zhang, L.J.; Zhang, W.; Zhou, B.; Chen, G.; He, D.C. Application of serum SELDI proteomic patterns in diagnosis of lung cancer. BMC Cancer 2005, 5, doi:10.1186/1471-2407-5-83.
[17]
Hirsch, F.R.; Varella-Garcia, M.; Cappuzzo, F. Predictive value of EGFR and HER2 overexpression in advanced non-small-cell lung cancer. Oncogene 2009, 28 Suppl 1, S32–S37.
[18]
Hynes, N.E.; Stern, D.F. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim Biophys Acta 2009, 1198, 165–184.
[19]
Shi, D.; He, G.; Cao, S.; Pan, W.; Zhang, H.Z.; Yu, D.; Hung, M.C. Overexpression of the c-erbB-2/neu-encoded p185 protein in primary lung cancer. Mol. Carcinog. 1992, 5, 213–218, doi:10.1002/mc.2940050308.
[20]
Harpole, D.H., Jr.; Marks, J.R.; Richards, W.G.; Herndon, J.E., II; Sugarbaker, D.J. Localized adenocarcinoma of the lung: Oncogene expression of erbB-2 and p53 in 150 patients. Clin. Cancer Res. 1995, 1, 659–664.
[21]
Scheurle, D.; Jahanzeb, M.; Aronsohn, R.S.; Watzek, L.; Narayanan, R. HER-2/neu expression in archival non-small cell lung carcinomas using FDA-approved Hercep test. Anticancer Res. 2000, 20, 2091–2096.
[22]
Pellegrini, C.; Falleni, M.; Marchetti, A.; Cassani, B.; Miozzo, M.; Buttitta, F.; Roncalli, M.; Coggi, G.; Bosari, S. HER-2/Neu alterations in non-small cell lung cancer: A comprehensive evaluation by real time reverse transcription-PCR, fluorescence in situ hybridization, and immunohistochemistry. Clin. Cancer Res. 2003, 9, 3645–3652.
[23]
Heinmoller, P.; Gross, C.; Beyser, K.; Schmidtgen, C.; Maass, G.; Pedrocchi, M.; Ruschoff, J. HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin. Clin. Cancer Res. 2003, 9, 5238–5243.
[24]
Tateishi, M.; Ishida, T.; Mitsudomi, T.; Kaneko, S.; Sugimachi, K. Prognostic value of c-erbB-2 protein expression in human lung adenocarcinoma and squamous cell carcinoma. Eur. J. Cancer 1991, 27, 1372–1375.
[25]
Kern, J.A.; Slebos, R.J.; Top, B.; Rodenhuis, S.; Lager, D.; Robinson, R.A.; Weiner, D.; Schwartz, D.A. C-erbB-2 expression and codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas. J. Clin. Invest. 1994, 93, 516–520.
[26]
Zabrecky, J.R.; Lam, T.; McKenzie, S.J.; Carney, W. The extracellular domain of p185/neu is released from the surface of human breast carcinoma cells, SK-BR-3. J. Biol. Chem. 1991, 266, 1716–1720.
[27]
Pupa, S.M.; Menard, S.; Morelli, D.; Pozzi, B.; De Palo, G.; Colnaghi, M.I. The extracellular domain of the c-erbB-2 oncoprotein is released from tumor cells by proteolytic cleavage. Oncogene 1993, 8, 2917–2923.
[28]
Scott, G.K.; Robles, R.; Park, J.W.; Montgomery, P.A.; Daniel, J.; Holmes, W.E.; Lee, J.; Keller, G.A.; Li, W.L.; Fendly, B.M. A truncated intracellular HER2/neu receptor produced by alternative RNA processing affects growth of human carcinoma cells. Mol. Cell. Biol. 1993, 13, 2247–2257.
[29]
Codony-Servat, J.; Albanell, J.; Lopez-Talavera, J.C.; Arribas, J.; Baselga, J. Cleavage of the HER2 ectodomain is a pervanadate-activable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells. Cancer Res. 1999, 59, 1196–1201.
[30]
Doherty, J.K.; Bond, C.; Jardim, A.; Adelman, J.P.; Clinton, G.M. The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proc. Natl. Acad. Sci. USA 1999, 96, 10869–10874.
[31]
Brandt-Rauf, P.W. The c-erbB transmembrane growth factor receptors as serum biomarkers in human cancer studies. Mutat. Res. 1995, 333, 203–208.
[32]
Molina, R.; Jo, J.; Filella, X.; Bruix, J.; Castells, A.; Hague, M.; Ballesta, A.M. Serum levels of C-erbB-2 (HER-2/neu) in patients with malignant and non-malignant diseases. Tumour Biol. 1997, 18, 188–196, doi:10.1159/000218029.
[33]
Brandt-Rauf, P.W.; Luo, J.C.; Carney, W.P.; Smith, S.; De Vivo, I.; Milling, C.; Hemminki, K.; Koskinen, H.; Vainio, H.; Neugut, A.I. Detection of increased amounts of the extracellular domain of the c-erbB-2 oncoprotein in serum during pulmonary carcinogenesis in humans. Int. J. Cancer 1994, 56, 383–386, doi:10.1002/ijc.2910560316.
[34]
Osaki, T.; Mitsudomi, T.; Oyama, T.; Nakanishi, R.; Yasumoto, K. Serum level and tissue expression of c-erbB-2 protein in lung adenocarcinoma. Chest 1995, 108, 157–162, doi:10.1378/chest.108.1.157.
[35]
Yoshimura, C.; Nomura, S.; Yamaoka, M.; Ohtani, T.; Matsuzakiz, T.; Yamaguchi, K.; Fukuharal, S. Analysis of serum ErbB-2 protein and HLA-DRB1 in Japanese patients with lung cancer. Cancer Lett. 2000, 152, 87–95, doi:10.1016/S0304-3835(99)00437-1.
[36]
Filiberti, R.; Marroni, P.; Paganuzzi, M.; Izzo, V.; Padovani, P.; Cafferata, M.; Ardizzoni, A.; Neri, M.; Raimondi, L.; Puntoni, R. c-erbB-2 protein in serum of primary lung cancer patients. Cancer Detect. Prev. 2002, 26, 64–68, doi:10.1016/S0361-090X(02)00014-4.
[37]
Baron, A.T.; Lafky, J.M.; Connolly, D.C.; Peoples, J.; O'Kane, D.J.; Suman, V.J.; Boardman, C.H.; Podratz, K.C.; Maihle, N.J. A sandwich type acridinium-linked immunosorbent assay (ALISA) detects soluble ErbB1 (sErbB1) in normal human sera. J. Immunol. Method. 1998, 219, 23–43.
[38]
Yang, P.; Allen, M.S.; Aubry, M.C.; Wampfler, J.A.; Marks, R.S.; Edell, E.S.; Thibodeau, S.; Adjei, A.A.; Jett, J.; Deschamps, C. Clinical features of 5,628 primary lung cancer patients: experience at Mayo Clinic from 1997 to 2003. Chest 2005, 128, 452–462, doi:10.1378/chest.128.1.452.
[39]
Benjamini, Y.; Hochberg, Y. Controlling the false discovery rate: A practical and powerful approach to multiple testing. J. Roy. Stat. Soc. B 1995, 57, 289–300.
[40]
Storey, J.D.; Tibshirani, R. Statistical methods for identifying differentially expressed genes in DNA microarrays. Meth. Mol. Biol. 2003, 224, 149–157.
[41]
Dati, C.; Antoniotti, S.; Taverna, D.; Perroteau, I.; De Bortoli, M. Inhibition of c-erbB-2 oncogene expression by estrogens in human breast cancer cells. Oncogene 1990, 5, 1001–1006.
[42]
Read, L.D.; Keith, D., Jr.; Slamon, D.J.; Katzenellenbogen, B.S. Hormonal modulation of HER-2/neu protooncogene messenger ribonucleic acid and p185 protein expression in human breast cancer cell lines. Cancer Res. 1990, 50, 3947–3951.
[43]
Warri, A.M.; Laine, A.M.; Majasuo, K.E.; Alitalo, K.K.; Harkonen, P.L. Estrogen suppression of erbB2 expression is associated with increased growth rate of ZR-75-1 human breast cancer cells in vitro and in nude mice. Int. J. Cancer 1991, 49, 616–623.
[44]
Warri, A.M.; Isola, J.J.; Harkonen, P.L. Anti-oestrogen stimulation of ERBB2 ectodomain shedding from BT-474 human breast cancer cells with ERBB2 gene amplification. Eur. J. Cancer 1996, 32A, 134–140.
[45]
Taverna, D.; Antoniotti, S.; Maggiora, P.; Dati, C.; De Bortoli, M.; Hynes, N.E. erbB-2 expression in estrogen-receptor-positive breast-tumor cells is regulated by growth-modulatory reagents. Int. J. Cancer. 1994, 56, 522–528.
[46]
Jones, J.; Lagasse, L.D.; Karlan, B.Y. Steroid hormonal independence of HER-2/neu mRNA expression in four human ovarian carcinoma cell lines. Gynecol. Oncol. 1994, 55, 421–426, doi:10.1006/gyno.1994.1316.
[47]
Shi, Y.; Brands, F.H.; Chatterjee, S.; Feng, A.C.; Groshen, S.; Schewe, J.; Lieskovsky, G.; Cote, R.J. Her-2/neu expression in prostate cancer: High level of expression associated with exposure to hormone therapy and androgen independent disease. J. Urol. 2001, 166, 1514–1519.
[48]
Meden, H.; Mielke, S.; Marx, D.; Wuttke, W.; Kuhn, W. Hormonal treatment with sex steroids in women is associated with lower p105 serum concentrations. Anticancer Res. 1997, 17, 3075–3077.
[49]
Meden, H.; Mielke, S.; Schauer, A.; Kuhn, W. Serum levels of the c-erbB-2 (HER2/neu) encoded oncoprotein fragment p105 in normal pregnancies. In Vivo 1997, 11, 51–54.
[50]
Meden, H.; Mielke, S.; Wuttke, W.; Kuhn, W. Elevated serum levels of the c-erbB-2 encoded oncoprotein fragment in cases of pure preeclampsia and HELLP syndrome. J. Obstet Gynaecol. Res. 1997, 23, 213–217.
[51]
Mielke, S.; Meden, H.; Kuhn, W. Expression of the c-erbB-2-encoded oncoprotein p185 (HER-2/neu) in pregnancy as a model for oncogene-induced carcinogenesis. Med. Hypotheses 1998, 50, 359–362, doi:10.1016/S0306-9877(98)90205-5.
[52]
Meden, H.; Mielke, S.; Wuttke, W.; Kuhn, W. Increased serum level of c-erbB-2-coded protein p105 in patients with pre-eclampsia. Gynakologisch-geburtshilfliche Rundschau 1995, 35 Suppl 1, 157–160.
[53]
Windham, G.C.; Mitchell, P.; Anderson, M.; Lasley, B.L. Cigarette smoking and effects on hormone function in premenopausal women. Environ. Health Perspect. 2005, 113, 1285–1290.
[54]
Shiels, M.S.; Rohrmann, S.; Menke, A.; Selvin, E.; Crespo, C.J.; Rifai, N.; Dobs, A.; Feinleib, M.; Guallar, E.; Platz, E.A. Association of cigarette smoking, alcohol consumption, and physical activity with sex steroid hormone levels in US men. Cancer Cause. Control 2009, 20, 877–886, doi:10.1007/s10552-009-9318-y.
Field, J.K. Lung cancer risk models come of age. Cancer Prev. Res. 2008, 1, 226–228, doi:10.1158/1940-6207.CAPR-08-0144.
[57]
Freedman, A.N.; Seminara, D.; Gail, M.H.; Hartge, P.; Colditz, G.A.; Ballard-Barbash, R.; Pfeiffer, R.M. Cancer risk prediction models: A workshop on development, evaluation, and application. J. Nat. Cancer Inst. 2005, 97, 715–723.
[58]
Bach, P.B.; Kattan, M.W.; Thornquist, M.D.; Kris, M.G.; Tate, R.C.; Barnett, M.J.; Hsieh, L.J.; Begg, C.B. Variations in lung cancer risk among smokers. J. Nat. Cancer Inst. 2003, 95, 470–478, doi:10.1093/jnci/95.6.470.
[59]
Cassidy, A.; Duffy, S.W.; Myles, J.P.; Liloglou, T.; Field, J.K. Lung cancer risk prediction: A tool for early detection. Int. J. Cancer 2007, 120, 1–6.
[60]
Cassidy, A.; Myles, J.P.; van Tongeren, M.; Page, R.D.; Liloglou, T.; Duffy, S.W.; Field, J.K. The LLP risk model: An individual risk prediction model for lung cancer. Brit. J. Cancer 2008, 98, 270–276, doi:10.1038/sj.bjc.6604158.
[61]
Cronin, K.A.; Gail, M.H.; Zhaohui, Z.; Bach, P.B.; Virtamo, J.; Albanes, D. Validation of a model of lung cancer risk prediction among smokers. J. Nat. Cancer Inst. 2006, 98, 637–640, doi:10.1093/jnci/djj163.
[62]
Etzel, C.J.; Kachroo, S.; Liu, M.; D’Amelio, A.; Dong, Q.; Cote, M.L.; Wenzlaff, A.S.; Hong, W.K.; Greisinger, A.J.; Schwartz, A.G.; Spitz, M.R. Development and validation of a lung cancer risk prediction model for African-Americans. Cancer Prev. Res. 2008, 1, 255–265, doi:10.1158/1940-6207.CAPR-08-0082.
[63]
Peto, R.; Darby, S.; Doll, R.; Deo, H.; Silcocks, P.; Whitley, E. Smoking, smoking cessation, and lung cancer in the UK since 1950: Combination of national statistics with two case-control studies. Brit. Med. J. 2000, 321, 323–329.
[64]
Spitz, M.A.; Waun Ki, H.; Amos, C.I.; Xifeng, W.; Schabath, M.B.; Qiong, D.; Sanjay, S.; Etzel, C.J. A risk model for prediction of lung cancer. J. Nat. Cancer Inst. 2007, 99, 715–726, doi:10.1093/jnci/djk153.
[65]
Spitz, M.R.; Etzel, C.J.; Dong, Q.; Amos, C.I.; Wei, Q.; Wu, X.; Hong, W.K. An expanded risk prediction model for lung cancer. Cancer Prev. Res. 2008, 1, 250–254, doi:10.1158/1940-6207.CAPR-08-0060.
[66]
Prindiville, S.A.; Byers, T.; Hirsch, F.R.; Franklin, W.A.; Miller, Y.E.; Vu, K.O.; Wolf, H.J.; Barón, A.E.; Shroyer, K.R.; Zeng, C.; et al. Sputum cytological atypia as a predictor of incident lung cancer in a cohort of heavy smokers with airflow obstruction. Canc. Epidemiol. Biomarkers Prev. 2003, 12, 987–993.
[67]
Blay, J.-Y.; Le Cesne, A.; Alberti, L.; Ray-Coquart, I. Targeted cancer therapies. Bull. Cancer 2005, 92, E13–E18, doi:10.1038/sj.bjc.6602296.
[68]
Bacus, S.; Spector, N.L.; Yarden, Y. The era of ErbB-receptor-targeted therapies: Advances toward personalized medicine. Personalized Med. 2005, 2, 301–315, doi:10.2217/17410541.2.4.301.
[69]
Baselga, J.; Albanell, J. Epithelial growth factor receptor interacting agents. Hematol. Oncol. Clin. N. Amer. 2002, 16, 1041–1063, doi:10.1016/S0889-8588(02)00055-2.
Friedrich, M.J. Using EGFR status to personalize treatment: Lung cancer researchers reach a milestone. J. Nat. Cancer Inst. 2009, 101, 1039–1041, doi:10.1093/jnci/djp243.
[72]
Perez-Soler, R. Individualized therapy in non-small-cell lung cancer: Future versus current clinical practice. Oncogene 2009, 28 Suppl 1, S38–S45, doi:10.1038/onc.2009.200.
[73]
Johnson, B.E.; J？nne, P.A. Rationale for a phase II trial of pertuzumab, a HER-2 dimerization inhibitor, in patients with non-small cell lung cancer. Clin. Cancer Res. 2006, 12, 4436–4440, doi:10.1158/1078-0432.CCR-06-0629.
[74]
Yamamoto, N.; Nambu, Y.; Fujimoto, T.; Koshiji, M. A landmark point analysis with cytotoxic agents for advanced NSCLC. J. Thoracic Oncol. 2009, 4, 697–701, doi:10.1097/JTO.0b013e31819e7888.
[75]
Zinner, R.G.; Glisson, B.S.; Fossella, F.V.; Pisters, K.M.; Kies, M.S.; Lee, P.M.; Massarelli, E.; Sabloff, B.; Fritsche, H.A., Jr.; Ro, J.Y.; et al. Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease. Lung Cancer 2004, 44, 99–110, doi:10.1016/j.lungcan.2003.09.026.
[76]
Swanton, C.; Futreal, A.; Eisen, T. Her2-targeted therapies in non-small cell lung cancer. Clin. Cancer Res. 2006, 12, 4377–4383, doi:10.1158/1078-0432.CCR-06-0115.
[77]
Yatabe, Y. Molecular diagnosis of solid tumors. Nippon Rinsho. Jpn. J. Clin. Med. 2005, 63, 434–440.
[78]
Allison, M. The HER2 testing conundrum. Nat. Biotechnol. 2010, 28, 117–119.
