Defining a globally accessible and pragmatic predictive signature (GAPPS) for locally advanced cervical cancer - Cervical cancer is a chronic condition for both cancer survivors who experience long–term toxicity from radiation therapy (RT) and those who experience relapse and require treatment for the remaining years of their lives. Standard treatment includes chemotherapy, external and internal RT. The Food and Drug Administration (FDA), recently approved use of the immune checkpoint inhibitor pembrolizumab for patients with International Federation of Gynecology and Obstetrics (FIGO) 2014 Stage III-IVA cervical cancer. There are currently no means to perform risk stratification to personalize this complex and often toxic treatment regimen. We propose that widely implementable response-based biomarkers (e.g., imaging techniques and blood biomarkers) hold great promise for risk stratifying cervical cancer patients in the immediate future. Almost all cervical cancers are associated with prior infection with human papillomavirus (HPV), and despite an uptick of worldwide vaccination rates for HPV, cervical cancer remains the fourth most common malignancy amongst women. Women in low-resource settings lack advanced imaging techniques, with access only to computed tomography (CT) imaging, and current efforts to develop predictive and prognostic biomarkers for cervical cancer involve state-of the- art next generation sequencing and other “omics” platforms that are not easily implementable in low-resource areas with the highest cervical cancer incidence. There are no well-established predictors of treatment response to inform RT dose decisions to balance the risks of toxicity to disease control. Thus, there is a need to develop evidence-based, globally applicable, early-treatment biomarkers so that treatment regimens and RT doses can be optimized. The proposed project hypothesizes that a globally accessible and pragmatic predictive signature (GAPPS) for risk stratification utilizing serially sampled circulating biomarkers along with imaging response and clinical FIGO stage will accurately predict recurrence after CRT and response to immune checkpoint blockade with the ultimate goal of ensuring that patients requiring intensified treatments receive them, while those effectively treated with standard RT are spared from unnecessary, chronic debilitating toxicity and cost. To test this hypothesis, Aim 1 will focus on identifying a GAPPS using pre-treatment and early response circulating blood-based and CT-based biomarkers. Next, in Aim 2, the utility of a GAPPS will be validated in prospectively predicting two-year OS in a multi-site cohort of patients treated with CRT including pembrolizumab when indicated and available. Successful completion of the project will have an immediate impact on women with cervical cancer in different resource settings. Risk stratification tailored to individual patients will render treatments more effective and affordable with compounding benefits
