Challenges of implementing plasma cfDNA HPV testing in resource limited settings for locally advanced cervical cancer

This study evaluated the feasibility and implementation challenges of cell-free DNA testing for high-risk HPV (cfDNA-HPV) in patients with locally advanced cervical cancer treated in a resource-limited setting. The analysis was conducted within the AddChemo-CC trial, with the objective of exploring the potential use of cfDNA-HPV as a biomarker to guide adjuvant treatment strategies, while also examining epidemiological and health system factors that may influence its applicability in real-world clinical practice. The AddChemo-CC study was designed as a prospective, multicenter study enrolling women aged 18–70 years with FIGO 2018 stages IB3–IVA cervical cancer. Participants underwent cfDNA-HPV testing either before or after standard chemoradiation. According to the study design, patients with detectable cfDNA-HPV after treatment were planned to be randomized to receive adjuvant chemotherapy (cisplatin and gemcitabine) or observation. In Brazil, immunotherapy is not currently available within the Public Healthcare System for the treatment of locally advanced cervical cancer, making alternative strategies such as chemotherapy-based adjuvant approaches potentially feasible within existing treatment frameworks. The primary endpoint of the study was progression-free survival, with secondary endpoints including overall survival, treatment safety, and feasibility of biomarker implementation. Among the 153 patients tested before treatment, 30.0% (95% CI 23.3–38.8%) were cfDNA-HPV positive. However, among the 38 patients tested after treatment, none showed detectable cfDNA-HPV (0.0% 95% CI 0.0–9.2%). The study population predominantly comprised non-white women (53.8%) and individuals from low-income households (68% reporting monthly income ≤ 2 minimum wages), with 61% diagnosed at advanced stages. Delays in treatment initiation were frequent, with a median interval of 87 days from diagnosis to treatment start, and 61.3% of patients exceeded the recommended duration for completion of chemoradiation. Due to the extremely low rate of post-treatment cfDNA-HPV positivity, randomization was not performed and the study was discontinued before completion. Because no patients had detectable post-treatment cfDNA-HPV, no participants underwent randomization, precluding conclusions regarding the clinical utility of cfDNA-HPV-guided adjuvant treatment strategies. Nevertheless, these findings highlight significant challenges in implementing this biomarker in resource-limited settings. The absence of detectable post-treatment cfDNA-HPV may reflect a combination of biological, methodological, and population-specific factors, including laboratory methodology, tumor burden, prolonged treatment timelines, or population-specific characteristics; however, because these variables were not directly evaluated, their contribution remains speculative and should be interpreted as hypothesis-generating. These findings underscore the need for further research focused on addressing systemic barriers to optimize cervical cancer management in low-resource environments.