Genomics of cervical, vulvar and vaginal cancers and the potential of precision medicine

Most cases of cervical cancer are still caused by persistent infection with high-risk human papillomavirus (HPV) variants, which also drives the development of ~30% of vulvar and ~76% of vaginal malignancies. Implementation of HPV vaccination has significantly decreased the incidence of high-grade pre-cancerous cervical, vulvar and vaginal lesions. However, cervical, vulvar and vaginal cancers can still develop (with or without HPV integration) and treatment options are limited compared to more common cancers. As with many other cancer types, molecular studies should identify targeted agents that could be added to treatment regimens to improve response rates and survival. Combination regimens involving chemoradiotherapy, anti-angiogenics and immune checkpoint inhibitors should be considered in the first instance. Then, depending on the molecular profile of a particular tumour, more targeted therapies should be considered. In particular, HER2-targeted therapies are likely to be a viable treatment option for many individuals, including those with cervical adenocarcinoma of gastric-type and vulvar Paget’s disease. In cervical cancer, TGFβ, PI3K, ATR and PARP inhibitors have shown some benefit and warrant further investigation. In vulvar cancer, combination therapies involving EGFR inhibitors require ongoing evaluation. In vaginal cancer, combination therapies targeting the PI3K and MAPK pathways should be investigated for squamous cell carcinoma and melanoma, respectively. Finally, with the rapid expansion of antibody-drug conjugates in recent years, this is an especially exciting area of investigation. For cervical, vulvar and vaginal cancers specifically, trastuzumab deruxtecan and tisotumab vedotin could be important therapeutic options in the right context. In this review, we describe the molecular features of different cervical, vulvar and vaginal cancer types, current genomically-matched therapies being investigated and discuss treatment strategies with future potential.