MMP9 but Not EGFR, MET, ERCC1, P16, and P-53 Is Associated with Response to Concomitant Radiotherapy, Cetuximab, and Weekly Cisplatin in Patients with Locally Advanced Head and Neck Cancer

George Fountzilas, Anna Kalogera-Fountzila, Sophia Lambaki, Ralph M Wirtz, Angelos Nikolaou, Georgia Karayannopoulou, Mattheos Bobos, Vassiliki Kotoula, Samuel Murray, Alexandros Lambropoulos, Gerasimos Aravantinos, Konstantinos Markou, Eleni Athanassiou, Despina Misailidou, Konstantine T Kalogeras, Demosthenis Skarlos, George Fountzilas, Anna Kalogera-Fountzila, Sophia Lambaki, Ralph M Wirtz, Angelos Nikolaou, Georgia Karayannopoulou, Mattheos Bobos, Vassiliki Kotoula, Samuel Murray, Alexandros Lambropoulos, Gerasimos Aravantinos, Konstantinos Markou, Eleni Athanassiou, Despina Misailidou, Konstantine T Kalogeras, Demosthenis Skarlos

Abstract

Concomitant administration of radiotherapy with cisplatin or radiotherapy with cetuximab appear to be the treatment of choice for patients with locally advanced head and neck cancer. In the present retrospective analysis, we investigated the predictive role of several biomarkers in an unselected cohort of patients treated with concomitant radiotherapy, weekly cisplatin, and cetuximab (CCRT). We identified 37 patients treated with this approach, of which 13 (35%) achieved a complete response and 10 (27%) achieved a partial response. Severe side effects were mainly leucopenia, dysphagia, rash, and anemia. Tumor EGFR, MET, ERCC1, and p-53 protein and/or gene expression were not associated with treatment response. In contrast, high MMP9 mRNA expression was found to be significantly associated with objective response. In conclusion, CCRT is feasible and active. MMP9 was the only biomarker tested that appears to be of predictive value in cetuximab treated patients. However, this is a hypothesis generating study and the results should not be viewed as definitive evidence until they are validated in a larger cohort.

Figures

Figure 1
Figure 1
Waterfall for the response of target lesions according to RECIST criteria (N = 24).
Figure 2
Figure 2
Immunohistochemistry performed on tissue microarrays. (a) EGFR protein expression in all tumor cells with focal intense complete membranous staining (+3); (b) EGFR negative case showing mild cytoplasmic focal staining; (c) ERCC1 protein strong nuclear positivity; (d) ERCC1 protein expression with equal intensity in neoplastic cells and stromal fibroblasts (regarded as negative staining); (e) MET strong cytoplasmic and membraneous protein expression; (f) Lack of MET protein expression in tumor cells; (g) p-53 strong nuclear protein expression; (h) p-53 expression in a small fraction of tumor cells (regarded as negative staining). Original magnification x20; insets (a), (c), and (g) x200; insets (b), (d), (e), and (h) x400.
Figure 3
Figure 3
Fluorescence in situ hybridization with gene and centromeric specific probes. (a) and (b) Neoplastic nuclei showing polysomy of chromosome 7 (CEP7, green signals) and EGFR high level gene gain (red signals, arrowheads); (c) Neoplastic nuclei showing trisomy or polysomy of the MET gene (red signals) and SE7 (green signals); (d) Representative area from a case without genetic alterations. The majority of the neoplastic nuclei have 2 copies of the MET gene and SE7; (e) High polysomy of the D7S486 locus (red signals); (f) Deletion of the D7S486 gene locus in tumor cells, as defined by the presence of a single gene locus probe signal (red signals) and two CEP7 signals (green signals), or by the simultaneous lack of both of the gene locus signals and the presence of CEP7 signals (hemizygous and homozygous deletion, resp.).

References

    1. Posner M. Evolving strategies for combined-modality therapy for locally advanced head and neck cancer. Oncologist. 2007;12(8):967–974.
    1. Pignon JP, Bourhis J, Domenge C, Designé L. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. The Lancet. 2000;355(9208):949–955.
    1. Forastiere AA, Goepfert H, Maor M, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. New England Journal of Medicine. 2003;349(22):2091–2098.
    1. Seiwert TY, Salama JK, Vokes EE. The concurrent chemoradiation paradigm—general principles. Nature Clinical Practice Oncology. 2007;4(2):86–100.
    1. Salama JK, Seiwert TY, Vokes EE. Chemoradiotherapy for locally advanced head and neck cancer. Journal of Clinical Oncology. 2007;25(26):4118–4126.
    1. Calais G, Alfonsi M, Bardet E, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. Journal of the National Cancer Institute. 1999;91(24):2081–2086.
    1. Fountzilas G, Tolis C, Kalogera-Fountzila A, et al. Paclitaxel, cisplatin, leucovorin, and continuous infusion fluorouracil followed by concomitant chemoradiotherapy for locally advanced squamous cell carcinoma of the head and neck: a Hellenic Cooperative Oncology Group phase II study. Medical Oncology. 2005;22(3):269–279.
    1. Schütze C, Dörfler A, Eicheler W, et al. Combination of EGFR/HER2 tyrosine kinase inhibition by BIBW 2992 and BIBW 2669 with irradiation in FaDu human squamous cell carcinoma. Strahlentherapie und Onkologie. 2007;183(5):256–264.
    1. Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Research. 2002;62(24):7350–7356.
    1. Maurizi M, Almadori G, Ferrandina G, et al. Prognostic significance of epidermal growth factor receptor in laryngeal squamous cell carcinoma. British Journal of Cancer. 1996;74(8):1253–1257.
    1. Almadori G, Cadoni G, Galli J, et al. Epidermal growth factor receptor expression in primary laryngeal cancer: an independent prognostic factor of neck node relapse. International Journal of Cancer. 1999;84(2):188–191.
    1. Akimoto T, Hunter N, Buchmiller L, Mason K, Ang KK, Milas L. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clinical Cancer Research. 1999;5(10):2884–2890.
    1. Milas L, Mason KA, Hunter N, Li C, Wallace S. Poly(L-glutamic acid)-paclitaxel conjugate is a potent enhancer of tumor radiocurability. International Journal of Radiation Oncology Biology Physics. 2003;55(3):707–712.
    1. Sancar A, Lindsey-Boltz LA, Unsal-Kaçmaz K, Linn S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual Review of Biochemistry. 2004;73:39–85.
    1. Chen DJ, Nirodi CS. The epidermal growth factor receptor: a role in repair of radiation-induced DNA damage. Clinical Cancer Research. 2007;13(22):6555–6560.
    1. Huang S-M, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Research. 1999;59(8):1935–1940.
    1. Huang S-M, Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics, and tumor angiogenesis. Clinical Cancer Research. 2000;6(6):2166–2174.
    1. Thariat J, Milas L, Ang KK. Integrating radiotherapy with epidermal growth factor receptor antagonists and other molecular therapeutics for the treatment of head and neck cancer. International Journal of Radiation Oncology Biology Physics. 2007;69(4):974–984.
    1. Nyati MK, Morgan MA, Feng FY, Lawrence TS. Integration of EGFR inhibitors with radiochemotherapy. Nature Reviews Cancer. 2006;6(11):876–885.
    1. Dietl B, Marienhagen J, Schaefer C, Pohl F, Kölbl O. Frequency and distribution pattern of distant metastases in patients with ENT tumors and their consequences for pretherapeutic staging. Strahlentherapie und Onkologie. 2007;183(3):138–143.
    1. Studer G, Luetolf UM, Glanzmann C. Locoregional failure analysis in head-and-neck cancer patients treated with IMRT. Strahlentherapie und Onkologie. 2007;183(8):417–423.
    1. Milas L, Mason K, Hunter N, et al. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clinical Cancer Research. 2000;6(2):701–708.
    1. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. New England Journal of Medicine. 2006;354(6):567–578.
    1. Mendelsohn J, Fan Z. Epidermal growth factor receptor family and chemosensitization. Journal of the National Cancer Institute. 1997;89(5):341–343.
    1. De Herdt M-J, Baatenburg de Jong RJ. HGF and c-MET as potential orchestrators of invasive growth in head and neck squamous cell carcinoma. Frontiers in Bioscience. 2008;13(7):2516–2526.
    1. Zamble DB, Mu D, Reardon JT, Sancar A, Lippard SJ. Repair of cisplatin-DNA adducts by the mammalian excision nuclease. Biochemistry. 1996;35(31):10004–10013.
    1. Olaussen KA, Dunant A, Fouret P, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. New England Journal of Medicine. 2006;355(10):983–991.
    1. Quintela-Fandino M, Hitt R, Medina PP, et al. DNA-repair gene polymorphisms predict favorable clinical outcome among patients with advanced squamous cell carcinoma of the head and neck treated with cisplatin-based induction chemotherapy. Journal of Clinical Oncology. 2006;24(26):4333–4339.
    1. Sengupta N, MacDonald TT. The role of matrix metalloproteinases in stromal/epithelial interactions in the gut. Physiology. 2007;22(6):401–409.
    1. Zhang S, Li L, Lin J-Y, Lin H. Imbalance between expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in invasiveness and metastasis of human gastric carcinoma. World Journal of Gastroenterology. 2003;9(5):899–904.
    1. Liu A, Garg P, Yang S, et al. Epidermal growth factor-like repeats of thrombospondins activate phospholipase Cγ and increase epithelial cell migration through indirect epidermal growth factor receptor activation. Journal of Biological Chemistry. 2009;284(10):6389–6402.
    1. Ahn G-O, Brown JM. Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell. 2008;13(3):193–205.
    1. Rubin Grandis J, Melhem MF, Gooding WE, et al. Levels of TGF-α and EGFR protein in head and neck squamous cell carcinoma and patient survival. Journal of the National Cancer Institute. 1998;90(11):824–832.
    1. Dabbs DJ, editor. Diagnostic Immunohistochemistry. 1st edition. Philadelphia, Pa, USA: Churchill Livingstone; 2002.
    1. Skacel M, Skilton B, Pettay JD, Tubbs RR. Tissue microarrays: a powerful tool for high-throughput analysis of clinical specimens: a review of the method with validation data. Applied Immunohistochemistry and Molecular Morphology. 2002;10(1):1–6.
    1. Hanawa M, Suzuki S, Dobashi Y, et al. EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus. International Journal of Cancer. 2006;118(5):1173–1180.
    1. Nakajima M, Sawada H, Yamada Y, et al. The prognostic significance of amplification and overexpression of c-met and c-erb B-2 in human gastric carcinomas. Cancer. 1999;85(9):1894–1902.
    1. Hafkamp HC, Manni JJ, Haesevoets A, et al. Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas. International Journal of Cancer. 2008;122(12):2656–2664.
    1. Resnick MB, Routhier J, Konkin T, Sabo E, Pricolo VE. Epidermal growth factor receptor, c-MET, β-Catenin, and p53 expression as prognostic indicators in stage II colon cancer: a tissue microarray study. Clinical Cancer Research. 2004;10(9):3069–3075.
    1. Gunduz M, Ouchida M, Fukushima K, et al. Allelic loss and reduced expression of the ING3, a candidate tumor suppressor gene at 7q31, in human head and neck cancers. Oncogene. 2002;21(28):4462–4470.
    1. Walch A, Bink K, Hutzler P, et al. Sequential multilocus fluorescence in situ hybridization can detect complex patterns of increased gene dosage at the single cell level in tissue sections. Laboratory Investigation. 2001;81(10):1457–1459.
    1. Chung CH, Ely K, McGavran L, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. Journal of Clinical Oncology. 2006;24(25):4170–4176.
    1. Cappuzzo F, Hirsch FR, Rossi E, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. Journal of the National Cancer Institute. 2005;97(9):643–655.
    1. Koutras AK, Kalogeras KT, Dimopoulos M-A, et al. Evaluation of the prognostic and predictive value of HER family mRNA expression in high-risk early breast cancer: a Hellenic Cooperative Oncology Group (HeCOG) study. British Journal of Cancer. 2008;99(11):1775–1785.
    1. Zhou W, Gurubhagavatula S, Liu G, et al. Excision repair cross-complementation group 1 polymorphism predicts overall survival in advanced non-small cell lung cancer patients treated with platinum-based chemotherapy. Clinical Cancer Research. 2004;10(15):4939–4943.
    1. Murray S, Timotheadou E, Linardou H, et al. Mutations of the epidermal growth factor receptor tyrosine kinase domain and associations with clinicopathological features in non-small cell lung cancer patients. Lung Cancer. 2006;52(2):225–233.
    1. Fountzilas G, Bobos M, Kalogera-Fountzila A, et al. Gemcitabine combined with gefitinib in patients with inoperable or metastatic pancreatic cancer: a phase II study of the Hellenic Cooperative Oncology Group with biomarker evaluation. Cancer Investigation. 2008;26(8):784–793.
    1. Ogura H, Watanabe S, Fukushima K, Masuda Y, Fujiwara T, Yabe Y. Presence of human papillomavirus type 18 DNA in a pharyngeal and a laryngeal carcinoma. Japanese Journal of Cancer Research. 1991;82(11):1184–1186.
    1. Kyzas PA, Evangelou E, Denaxa-Kyza D, Ioannidis JP. 18F-fluorodeoxyglucose positron emission tomography to evaluate cervical node metastases in patients with head and neck squamous cell carcinoma: a meta-analysis. Journal of the National Cancer Institute. 2008;100(10):712–720.
    1. Yao M, Graham MM, Smith RB, et al. Value of FDG PET in assessment of treatment response and surveillance in head-and-neck cancer patients after intensity modulated radiation treatment: a preliminary report. International Journal of Radiation Oncology Biology Physics. 2004;60(5):1410–1418.
    1. Corry J, Rischin D, Hicks RJ, Peters LJ. The role of PET-CT in the management of patients with advanced cancer of the head and neck. Current Oncology Reports. 2008;10(2):149–155.
    1. Pfister DG, Su YB, Kraus DH, et al. Concurrent cetuximab, cisplatin, and concomitant boost radiotherapy for locoregionally advanced, squamous cell head and neck cancer: a pilot phase II study of a new combined-modality paradigm. Journal of Clinical Oncology. 2006;24(7):1072–1078.
    1. Bentzen SM, Atasoy BM, Daley FM, et al. Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial. Journal of Clinical Oncology. 2005;23(24):5560–5567.
    1. Chua DT, Nicholls JM, Sham JS, Au GK. Prognostic value of epidermal growth factor receptor expression in patients with advanced stage nasopharyngeal carcinoma treated with induction chemotherapy and radiotherapy. International Journal of Radiation Oncology Biology Physics. 2004;59(1):11–20.
    1. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. Journal of Clinical Oncology. 2003;21(12):2237–2246.
    1. Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA. Phase III randomized trial of cisplatin plus placebo compared with cisplatin plus cetuximab in metastatic/recurrent head and neck cancer: an eastern cooperative oncology group study. Journal of Clinical Oncology. 2005;23(34):8646–8654.
    1. Cohen EE. Role of epidermal growth factor receptor pathway-targeted therapy in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. Journal of Clinical Oncology. 2006;24(17):2659–2665.
    1. Temam S, Kawaguchi H, El-Naggar AK, et al. Epidermal growth factor receptor copy number alterations correlate with poor clinical outcome in patients with head and neck squamous cancer. Journal of Clinical Oncology. 2007;25(16):2164–2170.
    1. Wirth LJ, Haddad RI, Lindeman NI, et al. Phase I study of gefitinib plus celecoxib in recurrent or metastatic squamous cell carcinoma of the head and neck. Journal of Clinical Oncology. 2005;23(28):6976–6981.
    1. Cohen EE, Lingen MW, Martin LE, et al. Response of some head and neck cancers to epidermal growth factor receptor tyrosine kinase inhibitors may be linked to mutation of ERBB2 rather than EGFR. Clinical Cancer Research. 2005;11(22):8105–8108.
    1. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. New England Journal of Medicine. 2004;350(21):2129–2139.
    1. Loeffler-Ragg J, Witsch-Baumgartner M, Tzankov A, et al. Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. European Journal of Cancer. 2006;42(1):109–111.
    1. Lee JW, Soung YH, Kim SY, et al. Somatic mutations of EGFR gene in squamous cell carcinoma of the head and neck. Clinical Cancer Research. 2005;11(8):2879–2882.
    1. Zucali PA, Ruiz MG, Giovannetti E, et al. Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors. Annals of Oncology. 2008;19(9):1605–1612.
    1. Cappuzzo F, Jänne PA, Skokan M, et al. MET increased gene copy number and primary resistance to gefitinib therapy in non-small-cell lung cancer patients. Annals of Oncology. 2009;20(2):298–304.
    1. Handra-Luca A, Hernandez J, Mountzios G, et al. Excision repair cross complementation group 1 immunohistochemical expression predicts objective response and cancer-specific survival in patients treated by cisplatin-based induction chemotherapy for locally advanced head and neck squamous cell carcinoma. Clinical Cancer Research. 2007;13(13):3855–3859.
    1. Fountzilas G, Bamias A, Kalogera-Fountzila A, et al. Induction chemotherapy with docetaxel and cisplatin followed by concomitant chemoradiotherapy in patients with inoperable non-nasopharyngeal carcinoma of the head and neck. Anticancer Research. 2009;29(2):529–538.
    1. Dünne AA, Mandic R, Falkenberg S, Dalchow CV, Sesterhenn AM, Werner JA. RT-PCR expression profiling of matrix metalloproteinases and their specific inhibitors in cell lines and fresh biopsies of squamous cell carcinomas of the head and neck. In Vivo. 2005;19(5):943–948.
    1. Bindhu OS, Ramadas K, Sebastian P, Pillai MR. High expression levels of nuclear factor kappa B and gelatinase in the tumorigenesis of oral squamous cell carcinoma. Head and Neck. 2006;28(10):916–925.
    1. Krivak TC, Darcy KM, Tian C, et al. Relationship between ERCC1 polymorphisms, disease progression, and survival in the gynecologic oncology group phase III trial of intraperitoneal versus intravenous cisplatin and paclitaxel for stage III epithelial ovarian cancer. Journal of Clinical Oncology. 2008;26(21):3598–3606.
    1. Beroukhim R, Lin M, Park Y, et al. Inferring loss-of-heterozygosity from unpaired tumors using high-density oligonucleotide SNP arrays. PLoS Computational Biology. 2006;2(5, article e41)
    1. Mort R, Mo L, McEwan C, Melton DW. Lack of involvement of nucleotide excision repair gene polymorphisms in colorectal cancer. British Journal of Cancer. 2003;89(2):333–337.
    1. Haddad RI, Shin DM. Recent advances in head and neck cancer. New England Journal of Medicine. 2008;359(11):1143–1154.
    1. Psyrri A, DiMaio D. Human papillomavirus in cervical and head-and-neck cancer. Nature Clinical Practice Oncology. 2008;5(1):24–31.
    1. Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus—associated oropharyngeal cancers with favorable prognosis. Journal of Clinical Oncology. 2006;24(5):736–747.
    1. Termine N, Panzarella V, Falaschini S, et al. HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988–2007) Annals of Oncology. 2008;19(10):1681–1690.
    1. Romanitan M, Näsman A, Ramqvist T, et al. Human papillomavirus frequency in oral and oropharyngeal cancer in Greece. Anticancer Research. 2008;28(4):2077–2080.
    1. Vlachtsis K, Nikolaou A, Markou K, Fountzilas G, Daniilidis I. Clinical and molecular prognostic factors in operable laryngeal cancer. European Archives of Otorhinolaryngol. 2005;262(11):890–898.
    1. Lindel K, Beer KT, Laissue J, Greiner RH, Aebersold DM. Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. Cancer. 2001;92(4):805–813.
    1. Hafkamp HC, Speel EJ, Haesevoets A, et al. A subset of head and neck squamous cell carcinomas exhibits integration of HPV 16/18 DNA and overexpression of p16INK4A and p53 in the absence of mutations in p53 exons 5–8. International Journal of Cancer. 2003;107(3):394–400.
    1. Begum S, Cao D, Gillison M, Zahurak M, Westra WH. Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clinical Cancer Research. 2005;11(16):5694–5699.
    1. Smeets SJ, Hesselink AT, Speel E-J, et al. A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. International Journal of Cancer. 2007;121(11):2465–2472.
    1. Bianchini D, Jayanth A, Yu JC, Cunningham D. Epidermal growth factor receptor inhibitor-related skin toxicity: mechanisms, treatment, and its potential role as a predictive marker. Clinical Colorectal Cancer. 2008;7(1):33–43.
    1. Baselga J, Trigo JM, Bourhis J, et al. Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. Journal of Clinical Oncology. 2005;23(24):5568–5577.
    1. Herbst RS, Arquette M, Shin DM, et al. Phase II multicenter study of the epidermal growth factor receptor antibody cetuximab and cisplatin for recurrent and refractory squamous cell carcinoma of the head and neck. Journal of Clinical Oncology. 2005;23(24):5578–5587.
    1. Bölke E, Gerber PA, Lammering G, et al. Development and management of severe cutaneous side effects in head-and-neck cancer patients during concurrent radiotherapy and cetuximab. Strahlentherapie und Onkologie. 2008;184(2):105–110.

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