Circulating tumor DNA (ctDNA) as a marker of residual disease and recurrence in resected stage I-IV epithelial ovarian cancer (EOC).

person Sumitra Ananda Peter MacCallum Cancer Centre, Epworth Healthcare, Western Health, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, Australia info_outline Sumitra Ananda, Yuxuan Wang, Wei Hong, Gary Edward Richardson, Janine Margaret Lombard, Geraldine Goss, Linda R. Mileshkin, Christopher B. Steer, Anne Marie Lennon, Orla McNally, Christopher B Douville, Maria Popoli, Janine Ptak, Natalie Silliman, Lisa Dobbyn, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Jeanne Tie, Peter Gibbs

Authors person Sumitra Ananda Peter MacCallum Cancer Centre, Epworth Healthcare, Western Health, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, Australia info_outline Sumitra Ananda, Yuxuan Wang, Wei Hong, Gary Edward Richardson, Janine Margaret Lombard, Geraldine Goss, Linda R. Mileshkin, Christopher B. Steer, Anne Marie Lennon, Orla McNally, Christopher B Douville, Maria Popoli, Janine Ptak, Natalie Silliman, Lisa Dobbyn, Nickolas Papadopoulos, Kenneth W. Kinzler, Bert Vogelstein, Jeanne Tie, Peter Gibbs Organizations Peter MacCallum Cancer Centre, Epworth Healthcare, Western Health, Walter and Eliza Hall Institute, University of Melbourne, Melbourne, VIC, Australia, Johns Hopkins University, Baltimore, MD, Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia, Cabrini Research, Malvern, Australia, Calvary Mater Newcastle, Waratah, NSW, Australia, Boxhill Hospital and Monash Medical Centre, Melbourne, Australia, Peter MacCallum Cancer Centre, Mercy Hospital for Women, Melbourne, Australia, Border Medical Oncology Research Unit, East Albury, NSW, Australia, Johns Hopkins University School of Medicine, Baltimore, MD, The Royal Women's Hospital, Melbourne, Australia, John Hopkins University, Baltimore, MD, Department of Medical Oncology, Peter MacCallum Cancer Centre and Personalised Oncology Division, Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, Walter and Eliza Hall Institute of Medical Research & University of Melbourne, Melbourne, Australia Abstract Disclosures Research Funding Other Foundation Marcus Foundation, Epworth Medical Foundation Grant 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.

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