Blood-Based KRAS Testing Fails in Ovarian Cancer

Medscape

5 hours ago

Blood-based circulating tumor DNA (ctDNA) testing has proven to be insufficient for detecting KRAS mutations in patients with low-grade serous ovarian cancer (LGSOC), according to a study.
The findings of the new research suggest that treatment decisions should continue to rely on traditional tumor tissue analysis rather than liquid biopsies for this rare cancer subtype, said study author Els Van Nieuwenhuysen, MD, at the European Society for Medical Oncology Gynecological Cancers Congress 2025.
Van Nieuwenhuysen, University Hospitals Leuven, Belgium, presented her analysis of samples from 65 patients enrolled in the RAMP-201 trial at the meeting. She found that blood-based testing missed KRAS mutations in 56% of patients who had detectable mutations in their tumor tissue.
The Potential of Liquid Biopsies
LGSOC represents less than 10% of all epithelial ovarian cancers but poses unique treatment challenges, Van Nieuwenhuysen said.
'Unlike its high-grade counterpart, LGSOC is driven by alterations in the RAS/MAPK pathway, with KRAS mutations present in approximately 30% of patients,' she said. These tumors show remarkable resistance to conventional chemotherapy, with response rates ranging between 0% and 13%, she added.
Based on the RAMP-201 results, the FDA granted accelerated approval in May 2024 for the combination of avutometinib (a RAF/MEK inhibitor) and defactinib (a FAK inhibitor) for patients with KRAS -mutated recurrent LGSOC who failed prior systemic therapy. The combination showed response rates of 44% in patients with KRAS mutations , compared with 17% in those with wild-type KRAS .
Van Nieuwenhuysen explained that the indication for patients with KRAS -mutated tumors makes accurate KRAS mutation detection crucial for selecting the most effective treatment.
'We can detect ctDNA because tumor cells can release or shed DNA into the bloodstream by either apoptosis or necrosis,' said Van Nieuwenhuysen during her presentation. However, she noted that ctDNA is only present in small amounts, ranging from approximately 0.1% to 10% of the total circulating DNA.
The potential for blood-based testing has generated significant interest as molecular profiling has become a standard practice for ovarian cancer patients. A previous small series of 13 KRAS -mutated patients had detected mutations in blood samples from six patients, which — according to Van Nieuwenhuysen — suggests promise for this less invasive approach.
Liquid Biopsy Falls Short in Detecting KRAS mutations
The RAMP-201 analysis examined blood samples from 65 patients with confirmed LGSOC; 50 patients had KRAS mutations detected in tumor tissue, and 15 had KRAS wild-type tumors. Using the Tempus xF panel, which tests 105 cancer-related genes, including KRAS , researchers found that only 32% of patients had detectable ctDNA levels above the 0.25% limit of detection.
Van Nieuwenhuysen emphasized that the most concerning was the high false-negative rate. Among the 50 patients with tumor tissue-confirmed KRAS mutations, blood-based testing detected mutations in only 22 patients (44%), while 28 patients (56%) showed false-negative results. Patients with wild-type KRAS in tumor samples also tested negative in the blood, indicating no false-positive results.
'These findings suggest that ctDNA screening is not a sufficiently robust method for detecting KRAS mutations in patients with LGSOC,' Van Nieuwenhuysen said, emphasizing that 'treatment decisions should not be made based on the lack of KRAS mutation detection in the blood.'
Technical Considerations
Kristina Lindemann, MD, of Oslo University Hospital, Norway, who served as discussant during the session, said that technical factors, including the choice of testing panel and timing of sample collection, might have influenced the study's findings.
Lindemann noted that the panel used, Tempus, includes 105 genes, explaining that 'the broader the panel, the less sensitivity you get in terms of the limit of detection.' She suggested that a more targeted approach focusing specifically on KRAS mutations
'would potentially have brought down the level limit of detection.'
Lindemann also raised questions about sample timing, noting the 'median of 2 years between tissue accessibility and entering the trial.' She emphasized that KRAS mutations typically arise very early in the development of cancer, and they 'may even be lost during the disease trajectory due to treatment pressure.'
Tumor Biology May Explain Poor Detection
According to Van Nieuwenhuysen, the amount of ctDNA in the blood varies by cancer type, and the low rate of detection of KRAS mutations in ctDNA may reflect the unique biology of LGSOC, suggesting that LGSOC may be a 'low-shedding tumor' compared with other ovarian cancer subtypes.
Lindemann provided additional perspective on tumor heterogeneity, citing data from lung cancer showing high discordance rates (primary tumor vs metastasis) in KRAS mutations in lymph node and lung metastases. She added that the location of metastasis might influence ctDNA shedding, as 'metastases with high accessibility of blood cells or sites potentially would be more likely to shed ctDNA.'
Looking Ahead
Lindemann noted that, despite the limited ability of liquid biopsy to detect KRAS mutations in LGSOC, the study confirms that when KRAS mutations are detected in blood, they correlate with tumor tissue findings. This conclusion was based on no false positives having been observed, she said.
However, she emphasized that the high false-negative rate means that negative blood tests cannot rule out the presence of actionable mutations.
For now, clinicians treating patients with LGSOC should continue to rely on tumor tissue-based molecular profiling to guide treatment decisions, she concluded.
The ongoing RAMP-301 phase 3 confirmatory trial will provide additional data on the clinical utility of KRAS mutation testing in LGSOC.
Van Nieuwenhuysen reports financial relationships with AstraZeneca, GSK, MSD, Oncoinvent, Regeneron, Bioncotech Therapeutics, Merck, Novartis, Roche, Seagen, and Verastem Oncology.
Lindemann reports financial relationships with GSK, MSD, AstraZeneca, Karyopharm, Eisai, and Genmab.