Authors
E. Van Nieuwenhuysen, R. Grisham, I.L. Ray-Coquard, C. Anderson, A.R. Clamp, C. Lee, M.J. Rubio Pérez, A.M. Priebe, N. Colombo, L. Knowles, E. Kalbacher, D.S. Miller, T. Van Gorp, E.P. Hamilton, A. Santillan-Gomez, A. Thummala, C. Tweed, S. Coma, S. Hidy, S. Banerjee
Background – Low-grade serous ovarian cancer (LGSOC) is a rare and distinct cancer broadly driven by alterations in the MAPK pathway, including KRAS mutations in approximately 30% of patients. Although tumor tissue-based biopsy procedures are the standard practice for determining KRAS status in patients with LGSOC, blood-based liquid biopsies could offer less invasive testing if circulating tumor DNA (ctDNA) can reliably detect KRAS mutations in these patients.
Methods – Samples from a phase II study (ENGOT-OV60/GOG-3052; RAMP-201; NCT04625270) evaluating the combination of avutometinib (RAF/MEK clamp) + defactinib (FAK inhibitor) versus avutometinib monotherapy in patients with LGSOC were assessed. Blood samples from 65 patients were analysed to determine ctDNA fraction and presence of mutations in 105 cancer-related genes including KRAS using the Tempus xF panel. These 65 patients were selected based on their KRAS status in tumor tissue and included 50 patients with a KRAS mutation and 15 KRAS wild-type patients.
Results – Among 65 patients with LGSOC, 32% (21/65) showed ctDNA tumor fraction above the limit of detection of 0.25% (range 0.4% to 19%). Among the 50 patients for whom KRAS mutations were detectable in tumor tissue, 44% (22/50) showed KRAS mutation by blood-based ctDNA testing, whereas more than half of patients (56%; 28/50) showed a false negative result by blood-based KRAS testing. No correlation between high KRAS VAF in tumor tissue samples and detection rate of KRAS mutation in blood samples was observed. Among the 22 patients with a KRAS mutation detected using both blood and tumor tissue samples, the same KRAS mutation variants were detected in blood and tumor. In patients for whom KRAS mutations were not detectable in tumor tissue, none tested positive for a KRAS mutation in ctDNA.
Conclusions – Only 32% of patients exhibited a ctDNA tumor fraction above the limit of detection, suggesting that LGSOC is a low shedding tumor. In patients for whom KRAS mutations were detectable in tumor tissue, only 44% showed KRAS mutation by blood-based testing. These findings suggest that blood-based KRAS ctDNA testing is not a sufficiently robust method for detecting KRAS mutations in patients with LGSOC.
Clinical trial identification – NCT04625270.
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