Circulating tumor DNA (ctDNA) as a marker of residual disease and recurrence in resected stage I-IV epithelial ovarian cancer (EOC).
Authors: Ananda Sumitra , Wang Yuxuan , Hong Wei , Richardson Gary Edward , Lombard Janine Margaret , Goss Geraldine , Mileshkin Linda R. , Steer Christopher B. , Lennon Anne Marie , McNally Orla , Douville Christopher B , Popoli Maria , Ptak Janine , Silliman Natalie , Dobbyn Lisa , Papadopoulos Nickolas , Kinzler Kenneth W. , Vogelstein Bert , Tie Jeanne , Gibbs Peter 
Published: June 2023

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Background: The management of EOC remains challenging, with a high risk of relapse despite surgery, chemotherapy and maintenance therapy. Detection of ctDNA after surgery and adjuvant chemotherapy (CT) may identify patients (pts) at highest risk of recurrence suitable for treatment escalation. Our primary aim was to investigate the use of ctDNA as a marker of residual disease following both surgery and adjuvant CT that might predict later recurrence. Methods: In this multi-centre observational study, we collected blood samples post-op and 6-8 weeks post-CT completion from pts with debulked stage I-IV EOC planned for adjuvant CT. Pre-cycle 1 CT and pre-op blood was also collected from some pts who received neoadjuvant CT. We used a tumor-informed approach for ctDNA analysis with whole exome sequencing of tumor tissue followed by detection of up to 50 variants in the plasma with the SaferSeqS assay. The primary outcome was recurrence-free survival (RFS), calculated using the Cox proportional-hazards model. Results: 81 pts who had post-op ctDNA results were included. 84% had high grade serous histology and 23% had BRCA mutations. Median number of tumor-informed variants analyzed in the plasma was 44 (range 3-60). Overall, post-operative ctDNA was detected in 63 of 81 (78%) of pts, 18 of 26 (69%) in Stage I-II and 45 of 55 (82%) in Stage III-IV. Pts who were ctDNA negative post-surgery had longer RFS versus who were ctDNA positive (HR 3.28, 95% CI 1.39 to 7.72, p = 0.007). Estimated RFS at 2 years was 78% among pts who were ctDNA negative post-surgery and 44% among the ctDNA positive group. Pts with BRCA mutations were less likely to have positive post op ctDNA (OR 0.12, 95% CI 0.036 to 0.39, p < 0.001). For post-CT ctDNA, estimated RFS at 2 years was 74% in the ctDNA negative pts versus 43% in the ctDNA positive group but this was not statistically significant (HR 1.64, 95% CI 0.84 to 3.18, p = 0.15). Pts with zero residual disease were more likely to be ctDNA negative post-surgery (OR 12.36, 95% CI 1.54 to 99.4, p = 0.018). Post-op ctDNA outperformed post-op CA-125 in predicting recurrence; pts with elevated CA-125 post-surgery had shorter RFS compared to those with normal CA-125 post-surgery (HR 1.99, 95% CI 1.15 to 3.42, p = 0.013). Of 18 pts who had neoadjuvant CT, pre-treatment ctDNA was detected in 17 (94%). Only two pts had clearance of ctDNA post neoadjuvant CT and both had zero residual disease at surgery. For the pts that maintained positive ctDNA results post-op, 7/15 (47%) pts had zero residual disease. Conclusions: ctDNA detection after ovarian cancer cytoreduction identifies pts at very high risk of recurrence. Pts with BRCA mutations were more likely to have negative ctDNA post-op. The role of ctDNA in guiding neoadjuvant and adjuvant therapy to improve outcomes, warrants further investigation. Clinical trial information: ACTRN12617001119381 .