Featured Article Matrix Metalloproteinase 3 Polymorphism: A Predictive Factor of Response to Neoadjuvant Chemotherapy in Head and Neck Squamous Cell Carcinoma He ´le `ne Blons, 1 Sophie Gad, 1 Franck Zinzindohoue ´, 1,4 Isabelle Manie `re, 1 Janie Beauregard, 1 David Tregouet, 2 Daniel Brasnu, 3,4 Philippe Beaune, 1 Ollivier Laccourreye, 3,4 and Pierre Laurent-Puig 1,4 1 Inserm 490 Laboratoire de Toxicologie Mole ´culaire, Universite ´ Rene ´ Descartes ParisV, Paris; 2 Inserm U525 Faculte ´ de Me ´decine Ho ˆpital Pitie ´-Salpe ´trie `re, Paris; 3 Service d’Oto-Rhino-Laryngologie et de Chirurgie Cervico-Faciale, Paris; and 4 Po ˆle d’oncologie et de spe ´cialite ´ Ho ˆpital Europe ´en Georges Pompidou Assistance Publique– Ho ˆpitaux de Paris, Paris, France ABSTRACT Purpose: Treatment of head and neck cancer often associates different therapeutic modalities, including sur- gery, radiotherapy, and chemotherapy. In an attempt to optimize therapeutics, the identification of molecular mark- ers linked to response to chemotherapy remains important. Recently, the involvement of metalloproteinases in resist- ance to chemotherapy was suggested through their inter- action with the Fas/Fas ligand pathway. Indeed metallo- proteinases enhance Fas ligand shedding modulating chemotherapy efficiency. On the basis of these findings, we tested the existence of a correlation between response to chemotherapy and four metalloproteinase polymorphisms in a prospective series of 148 head and neck cancer patients. Experimental Design: Patients were genotyped using automated fragment analysis and 5-nuclease allelic discrim- ination assay. Response to chemotherapy was clinically as- sessed without knowledge of the genotype status. Results: A significant relation between the metallopro- teinase type 3 (MMP3) 1612insA polymorphism and re- sponse to chemotherapy was identified. Indeed, patients with the 6A/6A genotype responded more frequently (86%) to treatment as compared with patients with the 5A/6A (65%) or 5A/5A (55%) genotypes (P  0.04). A multivariate analysis, including tumor stage, gender, TP53 mutations, and MMP3 polymorphism, showed that the 6A/6A genotype was an independent factor of response to 5-fluorouracil- cisplatin chemotherapy in head and neck cancer patients with an odds ratio of 6.7 as compared with the 5A/5A genotype. Conclusions: This work showed that genotyping the MMP3 gene enhancer polymorphism 1612insA could help predict chemosensitivity in head and neck cancer patients. INTRODUCTION Head and neck squamous cell carcinoma (HNSCC) is a disease associated with major morbidity and mortality and has a worldwide incidence of 500,000 cases/year (1). Despite the frequent success of surgical and chemotherapeutic measures in controlling tumor growth, some primary tumors and most met- astatic diseases are seldom curable and display resistance to chemotherapy. A different mechanism can lead to resistance to chemotherapy, including modification of drugs, pharmacoki- netic properties, or expression of the multidrug resistance gene, ABCB1 (MDR1), but there is also evidence that the ability of cancer cells to evade apoptosis plays a major role in tumor survival (2). Cisplatin and 5-fluorouracil (5FU) combination therapy showed objective response rates of 70% with complete responses ranging from 14 to 31% in different randomized trials (3). This regimen considered as the standard in HNSCC treat- ment is of interest in terms of organ preservation strategies in responder patients (4). Understanding the mechanisms linked to resistance to chemotherapy in HNSCC patients could help select patients that would benefit from neoadjuvant chemotherapy and organ preservation. The anticancer action of drugs such as cisplatin and 5FU is largely attributed to their ability to induce programmed cell death (5). The integrity of signaling pathways that drive cell death is crucial for cells to commit apoptosis. Head and neck cancer cells demonstrate alterations in apoptosis pathways that allow them to override control cell death. For example, muta- tions in the TP53 gene, which has a pivotal role in apoptosis, have been reported to correlate with resistance to treatment in HNSCC (6, 7). More recently, the involvement of the TNFRSF6/TNFSF6 [Fas/Fas ligand (FasL)] pathway in geno- toxic agent-induced apoptosis has been reported previously (8). Indeed, FasL is up-regulated in cells treated with geno- toxic agents, including cisplatin and 5FU, and could act as an autocrine/paracrine mediator of apoptosis. FasL is normally expressed in T lymphocytes, macrophages, and splenocytes but also in tumor cells, including HNSCC, in which its role in cytotoxic agent-induced cell death can therefore be hy- pothesized (9). In terms of resistance to treatment, it would be expected that the down-regulation of FasL, at the surface of HNSCC tumor cells, decreases the activity of anticancer drugs. Matrix metalloproteinases (MMPs) are a family of proteins with many biological functions, including extracel- Received 7/30/03; revised 12/15/03; accepted 1/21/04. Grant footnote: La re ´gion Ile de France, La ligue Nationale de Lutte Contre le Cancer, and La Fondation de France. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Pierre Laurent-Puig, Inserm 490 Laboratoire de Toxicologie Mole ´culaire, Universite ´ Rene ´ Descartes Paris V, 45 rue des Saints-Pe `res, 75006 Paris, France. Phone: 33142862081; Fax: 33142862072; E-mail: pierre.laurent-puig@biomedicale.univ-paris5.fr. 2594 Vol. 10, 2594 –2599, April 15, 2004 Clinical Cancer Research Research. on April 13, 2017. © 2004 American Association for Cancer clincancerres.aacrjournals.org Downloaded from