Dale Oliver T, Aleksic Tamara, Shah Ketan A, Han Cheng, Mehanna Hisham, Rapozo Davy C M, Sheard Jon D H, Goodyear Paul, Upile Navdeep S, Robinson Max, Jones Terence M, Winter Stuart, Macaulay Valentine M
Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7LJ, UK, The Blenheim Head and Neck Unit, Churchill Hospital, Oxford OX3 7LE, UK, Present address: ENT Department, University Hospital Bristol, Bristol BS2 8EG, UK
Department of Oncology, University of Oxford, Old Road Campus Research Building, Oxford OX3 7LJ, UK.
Carcinogenesis. 2015 Jun;36(6):648-55. doi: 10.1093/carcin/bgv053. Epub 2015 Apr 20.
Head and neck squamous cell carcinomas (HNSCC) are treated with surgery, radiotherapy and cisplatin-based chemotherapy, but survival from locally-advanced disease remains poor, particularly in patients whose tumors are negative for Human papillomavirus (HPV). Type 1 IGF receptor (IGF-1R) is known to promote tumorigenesis and resistance to cancer therapeutics. Here, we assessed IGF-1R immunohistochemistry on tissue microarrays containing 852 cores from 346 HNSCC patients with primary tumors in the oropharynx (n = 231), larynx (85), hypopharynx (28), oral cavity (2). Of these, 236 (68%) were HPV-negative, 110 (32%) positive. IGF-1R was detected in the cell membrane of 36% and cytoplasm of 92% of HNSCCs; in 64 cases with matched normal tonsillar epithelium, IGF-1R was overexpressed in the HNSCCs (P < 0.001). Overall survival (OS) and disease-specific survival (DSS) were reduced in patients whose tumors contained high membrane IGF-1R [OS: hazard ratio (HR) = 1.63, P = 0.006; DSS: HR = 1.63, P = 0.016], cytoplasmic IGF-1R (OS: HR = 1.58, P = 0.009; DSS: HR = 1.58, P = 0.024) and total IGF-1R (OS: HR = 2.02, P < 0.001; DSS: HR = 2.2, P < 0.001). High tumor IGF-1R showed significant association with high-tumor T-stage (P < 0.001) and HPV-negativity (P < 0.001), and was associated with shorter OS when considering patients with HPV-positive (P = 0.01) and negative (P = 0.006) tumors separately. IGF-1R was independently associated with survival in multivariate analysis including HPV, but not when lymphovascular invasion, perineural spread and T-stage were included. Of these factors, only IGF-1R can be manipulated; the association of IGF-1R with aggressive disease supports experimental incorporation of anti-IGF-1R agents into multimodality treatment programs for HPV-negative and high IGF-1R HPV-positive HNSCC.
头颈部鳞状细胞癌（HNSCC）的治疗方法包括手术、放疗和基于顺铂的化疗，但局部晚期疾病患者的生存率仍然很低，尤其是肿瘤中人乳头瘤病毒（HPV）检测呈阴性的患者。已知1型胰岛素样生长因子受体（IGF-1R）可促进肿瘤发生并导致癌症治疗耐药。在此，我们对组织芯片进行了IGF-1R免疫组化分析，该组织芯片包含来自346例HNSCC患者的852个组织芯，这些患者的原发肿瘤位于口咽（n = 231）、喉（85）、下咽（28）、口腔（2）。其中，236例（68%）为HPV阴性，110例（32%）为阳性。在HNSCC中，36%的肿瘤细胞膜和92%的肿瘤细胞质中检测到IGF-1R；在64例匹配的正常扁桃体上皮组织中，HNSCC中IGF-1R表达上调（P < 0.001）。肿瘤细胞膜IGF-1R水平高的患者总生存期（OS）和疾病特异性生存期（DSS）缩短[OS：风险比（HR）= 1.63，P = 0.006；DSS：HR = 1.63，P = 0.016]，肿瘤细胞质IGF-1R水平高的患者也是如此（OS：HR = 1.58，P = 0.009；DSS：HR = 1.58，P = 0.024），肿瘤总IGF-1R水平高的患者同样如此（OS：HR = 2.02，P < 0.001；DSS：HR = 2.2，P < 0.001）。肿瘤IGF-1R水平高与肿瘤高T分期（P < 0.001）和HPV阴性（P < 0.001）显著相关，在分别考虑HPV阳性（P = 0.01）和阴性（P = 0.006）肿瘤患者时，也与较短的OS相关。在多因素分析中，包括HPV因素时，IGF-1R与生存率独立相关，但当纳入淋巴管浸润、神经周围扩散和T分期时则不然。在这些因素中，只有IGF-1R可以被调控；IGF-1R与侵袭性疾病的关联支持将抗IGF-1R药物实验性地纳入HPV阴性和IGF-1R水平高的HPV阳性HNSCC的多模式治疗方案中。
