Imaging Biomarkers and Liquid Biopsy to Predict Therapy Response in Cervical Cancer

Objectives: 1. Review current practice in radiological treatment monitoring of cervical cancer. 2. Understand challenges with accurately assessing response of cervical cancer treated with concurrent chemoradiotherapy. 3. Highlight several promising imaging biomarkers as well as circulating tumor DNA (ctDNA) from liquid biopsy to monitor cervical cancer response to therapy. Abstract Summary: Cervical cancer is one of the most common cancers in women worldwide and approximately 40% of patients present with locally advanced cervical cancer (LACC). Cisplatin-based chemoradiotherapy (CRT) is the standard of care for LACC, however, approximately one-third of patients experience recurrence after CRT. Currently, contrast enhanced computed tomography (CT) and magnetic resonance imaging (MRI) are most commonly used to assess therapy response in cervical cancer using Response Evaluation Criteria in Solid Tumors (RECIST 1.1) but it is often difficult to distinguish residual or recurrent disease from post-treatment changes, and disease within sub-centimeter lymph nodes may be missed. FDG-PET/CT is advantageous for assessment of sub-centimeter lymph nodes in high grade disease using PET Response Criteria in Solid Tumors (PERCIST) but is less sensitive for lower grade malignancy. Given these drawbacks, there is a need to incorporate additional imaging techniques and biomarkers into assessment of treatment response. In this work we review potential approaches on incorporating liquid biopsy with CT, PET and MR imaging biomarkers for assessment of therapy response and recurrence in cervical cancer. There are several such imaging biomarkers under investigation that show promise in this arena. FDG PET/CT and PET/MRI may be especially useful modalities for this purpose. Imaging biomarkers which can be obtained with FDG PET include the change in maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) before and after treatment. Furthermore, methods to determine boundaries for MTV and TLG may include fixed SUVmax threshold, relative percentage of SUVmax and an adaptive region-growing method. Recent studies measuring whole-body MTV and TLG demonstrated prognostic significance in several cancers and are being evaluated in cervical cancer. Diffusion-weighted imaging (DWI) is a promising MRI technique that provides unique information regarding tumor cellularity and integrity of the cell membrane. In particular, changes in the apparent diffusion coefficient (ADC) have been show to precede reductions of tumor size. However, no single imaging biomarker may be sufficient for the accurate assessment of treatment response of cervical cancer. Future work should be aimed at not only combining different imaging biomarkers, but also on incorporating molecular markers such as circulating tumor DNA (ctDNA). It has recently been shown that longitudinal monitoring of metastatic relapsed cervical cancer (MRCC) with ctDNA in liquid biopsy samples provides both predictive and prognostic information during treatment. A system that incorporates PET, CT, MRI and ctDNA levels may provide early and accurate prediction of LACC and MRCC response to CRT.