Department of Obstetrics and Gynaecology, University of Ottawa, Ottawa, Ontario.
Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Ontario.
Ann Oncol. 2016 Sep;27(9):1696-705. doi: 10.1093/annonc/mdw242. Epub 2016 Jun 20.
The incidence of vulvar squamous cell carcinoma (VSCC) has been on the rise since the 1990s. There has been no new treatment for advanced and recurrent disease in decades, with most women succumbing to the disease. Despite two distinct etiologies of VSCC, human papillomavirus (HPV)-associated and HPV-independent disease, there is no difference in therapeutic options.
A literature review was carried out by searching EMBASE and Medline databases between January 1990 and March 2016 by pairing the keywords of vulvar carcinoma, vulva cancer, vulvar and vulva with molecular markers involved in the cell cycle, apoptosis and angiogenesis. Molecular targets of prognostic significance were identified and targeted agents of therapeutic relevance to both HPV-independent and HPV-associated VSCC were then reviewed.
Recent advances in our understanding of the molecular biology of VSCC provide insight into the future management of VSCC with molecular targeted therapies. Aberrant cell cycle activity is common in both HPV-associated and HPV-independent VSCC and is characterized by overexpression of p53, Rb and cyclin D1, supporting targeting of these protein products and their downstream pathways. Extracellular regulators of cellular activity, such as EGFR, as well as inhibitors of angiogenesis are being clinically evaluated in VSCC. HPV-independent VSCC is characterized by actionable mutations, including PI3K, CDKN2A and PTEN. In HPV-associated disease, therapeutic vaccines targeting the E6 and E7 HPV oncogenes and immune-based therapies are under investigation.
There has been a paucity of clinical trials in recent years in this neglected women's cancer. Directed therapy against cell cycle regulatory molecules and extracellular proteins and the inhibition of angiogenesis are of broad therapeutic relevance in VSCC. Therapeutic strategies that target actionable mutations should be explored. In HPV-associated VSCC, novel treatments that exploit the virology of HPV and/or enhance the host immune response merit further study.
自 20 世纪 90 年代以来，外阴鳞状细胞癌（VSCC）的发病率一直在上升。几十年来，对于晚期和复发性疾病，除了大多数女性死于该疾病外，一直没有新的治疗方法。尽管 VSCC 有两种不同的病因，即人乳头瘤病毒（HPV）相关和 HPV 不相关疾病，但治疗选择没有区别。
通过在 EMBASE 和 Medline 数据库中搜索 1990 年 1 月至 2016 年 3 月之间的关键词，对有关细胞周期、细胞凋亡和血管生成中涉及的分子标记物的外阴癌、外阴癌、外阴和外阴的文献进行了综述。确定了具有预后意义的分子靶点，然后综述了与 HPV 不相关和 HPV 相关 VSCC 相关的治疗靶点的靶向药物。
近年来，我们对 VSCC 分子生物学的认识的进展，为利用分子靶向治疗来管理 VSCC 提供了新的思路。HPV 相关和 HPV 不相关 VSCC 中普遍存在异常的细胞周期活性，其特征是 p53、Rb 和细胞周期蛋白 D1 的过度表达，支持靶向这些蛋白产物及其下游途径。细胞外细胞活性调节剂，如 EGFR，以及血管生成抑制剂，正在 VSCC 中进行临床评估。HPV 不相关的 VSCC 的特征是存在可靶向的突变，包括 PI3K、CDKN2A 和 PTEN。在 HPV 相关疾病中，针对 E6 和 E7 HPV 癌基因的治疗性疫苗和免疫治疗正在进行研究。
近年来，在这种被忽视的女性癌症中，临床试验的数量很少。针对细胞周期调节分子和细胞外蛋白的定向治疗以及血管生成的抑制作用在 VSCC 中具有广泛的治疗意义。应探索针对可靶向突变的治疗策略。在 HPV 相关的 VSCC 中，利用 HPV 的病毒学和/或增强宿主免疫反应的新型治疗方法值得进一步研究。
