Early Assessment of Response Using ctDNA as a Non-Invasive Biomarker in Patients with Gynecologic Malignancies Undergoing Radiotherapy

Purpose/Objective(s)

Radiotherapy (RT) causes toxicity and outcomes of treatment may not be known for months post-therapy. Early identification of response with a ctDNA blood draw may provide a non-invasive way to predict response to treatment. In this study, we used ctDNA to assess response to RT in patients with GYN cancers as early as mid-way during treatment.

Materials/Methods

After IRB approval, patients with vulvar, cervical, and recurrent endometrial cancer were treated with RT at our institution between 2022 and 2024. The ctDNA was obtained using personalized molecular residual disease assay pre-RT, mid-way through RT, pre-boost with brachytherapy or SBRT, at the end and in follow-up at 1, 3, 6, and every 6 months -post RT, respectively. A detectable value of ctDNA was defined as any level above 0.00 mean tumor molecules (MTM)/mL, whereas 0.00MTM/mL was undetectable. During and after RT, ctDNA of 0.00MTM/mL was defined as complete metabolic response (cMR) but a reduction without achieving the value 0.00MTM/mL in ctDNA was deemed partial metabolic response (pMR). Correlation between ctDNA levels and imaging (PET-CT, MRI, and CT) was also assessed. Statistical analyses used were descriptive statistics, t-test, Chi-square test and a spearman-rank correlation coefficient (ρ).

Results

A total of 105 serial ctDNA blood draws were obtained from 21 patients with 8 (38%) vulvar, 7 (33%) cervical, 2 (10%) neuroendocrine, and 3 (19%) recurrent endometrial cancers (reEMCa). Median age was 59 years (range = 35-90 years). Median number of ctDNA draws per patient was 6 (range = 1-9). Median radiation dose was 5900 cGy (range = 4500-7000 cGy), brachy boost of 28 Gy/4 fx T&O and SBRT 30 Gy/5 fx for 7 cervix cases, and SBRT boost 2750 cGy/5 fx for reEMCa. There was 100% reduction in ctDNA values (metabolic response) from pre-to post-RT (mean = 2.04 vs. 0, P = 0.03): 75% cMR and 25% pMR. In patients who sustained response to RT, mid- and end-RT ctDNA draw exhibited 0.00MT/ml (undetectable), which continued in follow-up. A strong correlation was observed between elevated ctDNA and SUV/measurable disease on imaging pre-treatment (ρ = 0.64, P = 0.01), as well as undetectable ctDNA and decline of SUV/complete resolution of SUV at 3-6 months following RT (P = 0.045).

Conclusion

The ctDNA in patients with gynecological malignancies drawn at pre-, mid- and post-RT sustained metabolic response and correlated with response to treatment by imaging and clinical examinations. Our early findings suggest that a mid-treatment ctDNA test identified responders to RT and thus may serve as an early predictive biomarker of response. A larger prospective evaluation is warranted.