Advances in Treatment of Refractory Advanced and Recurrent Cervical Adenocarcinoma: Molecular Heterogeneity and Differences from Squamous Cell Carcinoma

Treatment for locally advanced and recurrent cervical cancer has advanced substantially with immune checkpoint inhibitors, induction chemotherapy, bevacizumab, and antibody-drug conjugates. However, subgroup analyses of major phase III trials suggest that cervical adenocarcinoma (AC) may respond differently from squamous cell carcinoma (SCC). Therefore, novel treatment strategies based on the distinct biological characteristics of AC are needed. This review aimed to evaluate the efficacy of current treatments for AC by examining histology-specific subgroup analyses from major clinical trials and to identify potential therapeutic strategies for AC. We also reviewed ongoing AC-focused clinical trials of novel molecularly targeted agents and combination therapies for advanced or recurrent disease. A structured search of PubMed and ClinicalTrials.gov through 1 June 2026, identified studies of advanced or recurrent cervical adenocarcinoma. Randomized trials, prospective studies, and histology-specific subgroup analyses were included, while case reports, preclinical studies, and SCC-only studies were excluded. Survival and response outcomes were extracted, with histology-specific findings considered exploratory. AC exhibits distinct molecular and immunological features compared with SCC, including frequent alterations in ERBB2/3, KRAS, PIK3CA, PTEN, ARID1A, and STK11 and a relatively immune-cold tumor microenvironment. HPV-independent AC, particularly gastric-type adenocarcinoma, shows aggressive clinical behavior and resistance to conventional therapies. Although bevacizumab, immune checkpoint inhibitors, and tisotumab vedotin have improved outcomes in cervical cancer, evidence specific to AC remains limited because most pivotal trials predominantly enrolled SCC or reported combined AC/adenosquamous subgroups. Emerging strategies targeting HER2, CLDN18.2, TROP2, Nectin-4, FAK, PI3K/AKT/mTOR, and ROS1 may provide new therapeutic opportunities for AC. AC represents a biologically heterogeneous disease distinct from SCC, supporting treatment strategies based on histology and molecular characteristics. Future AC-specific clinical trials and molecular stratification according to HPV association, histological subtype, and actionable alterations are needed to establish biomarker-driven personalized therapy, particularly for treatment-resistant HPV-independent AC.