Zupancic Mark, Kostopoulou Ourania N, Marklund Linda, Dalianis Tina
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Medical Unit Head, Neck, Lung, and Skin Cancer, Theme Cancer, Karolinska University Hospital, Stockholm, Sweden.
J Intern Med. 2025 Jun;297(6):608-629. doi: 10.1111/joim.20088. Epub 2025 Apr 17.
The incidences of human papillomavirus-positive (HPV) tonsillar and base tongue squamous cell carcinomas (TSCC and BOTSCC) have increased in recent decades. Notably, HPV TSCC and BOTSCC have a significantly better prognosis than their HPV-negative counterparts when treated with current surgical options, radiotherapy, or intensified chemoradiotherapy. However, a cure is not achieved in 20% of patients with HPV TSCC/BOTSCC. Meanwhile, cured patients often present with severe chronic side effects. This necessitates novel tailored alternatives, such as targeted therapy, immune checkpoint inhibitors (ICIs), and treatment de-escalation, together with better follow-up. Current precision medicine therefore focuses on detecting predictive and driver cancer genes to better stratify patient treatment, provide those with poor prognostic markers targeted therapy, and select those with favorable markers for de-escalated therapy. Moreover, detecting cell-free HPV DNA (cfHPV DNA) in plasma before and after treatment has been attempted to improve follow-up. In this context, this perspective discusses the significance of optimally defining HPV status, which requires HPV DNA and p16 overexpression, using prognostic markers, such as high CD8 T-cell counts and HPV E2 mRNA expression, tumor size, and following cfHPV DNA for patient selection for specific therapies. Clinical trials with ICI with/without chemotherapy, targeted therapy with specific inhibitors-such as phosphoinositide 3-kinase and fibroblast growth factor receptor inhibitors-or immune therapy with various HPV-based vaccines for treating recurrences have yielded promising results.
近几十年来，人乳头瘤病毒阳性（HPV）扁桃体和舌根鳞状细胞癌（TSCC和BOTSCC）的发病率有所上升。值得注意的是，与HPV阴性的患者相比，HPV阳性的TSCC和BOTSCC患者在接受当前的手术治疗、放射治疗或强化放化疗时，预后明显更好。然而，20%的HPV阳性TSCC/BOTSCC患者无法治愈。同时，治愈的患者往往伴有严重的慢性副作用。这就需要有新的针对性替代方案，如靶向治疗、免疫检查点抑制剂（ICI）和治疗降级，同时要有更好的随访。因此，当前的精准医学专注于检测预测性和驱动性癌症基因，以便更好地对患者治疗进行分层，为那些具有不良预后标志物的患者提供靶向治疗，并为那些具有良好标志物的患者选择降级治疗。此外，人们还尝试通过检测治疗前后血浆中的游离HPV DNA（cfHPV DNA）来改善随访。在此背景下，本观点讨论了最佳定义HPV状态的意义，这需要同时检测HPV DNA和p16过表达，并使用高CD8 T细胞计数和HPV E2 mRNA表达、肿瘤大小等预后标志物，以及跟踪cfHPV DNA来选择特定治疗的患者。使用ICI联合/不联合化疗、使用特定抑制剂（如磷酸肌醇3激酶和成纤维细胞生长因子受体抑制剂）进行靶向治疗或使用各种基于HPV的疫苗进行免疫治疗以治疗复发的临床试验已取得了有前景的结果。
