Liquid Biopsy Has Mixed Performance for Predicting Colon Cancer Outcomes

Derick Alison
Derick Alison
9 Min Read

SAN FRANCISCO — In separate studies, liquid biopsy produced mixed results for guiding colon cancer treatment.

Adjuvant chemotherapy guided by postoperative circulating tumor (ct) DNA did not lead to higher rates of DNA clearance as compared with patients who did not get chemotherapy. However, ctDNA did show promise for identifying patients with molecular residual disease (MRD) that might benefit from chemotherapy. Additionally, patients who had sustained ctDNA clearance had superior disease-free survival (DFS) as compared with patients who had transient clearance, which was associated with better DFS as compared with no clearance.

In the first study, three of seven patients with detectable ctDNA subsequently had clearance during observation, as compared with one of 11 patients assigned to chemotherapy. The study ended for futility after an interim analysis.

“Using the selected ctDNA assay in this clinically low-risk population, we did not observe an improvement in ctDNA clearance with 6 months of adjuvant chemotherapy, relative to surveillance in this colon cancer population who had detectable ctDNA at baseline,” said Van K. Morris, MD, of MD Anderson Cancer Center in Houston, at the Gastrointestinal Cancers Symposium.

“We saw steady enrollment across the conduct of the study, and we believe that this precedent confirms that prospective randomized, controlled trials assessing circulating tumor DNA as an integral biomarker and as a surrogate for minimal residual disease are not only feasible but remain necessary for us to test and confirm clinically relevant hypotheses in oncology,” he added.

In future studies, investigators should bank extra blood samples to take into account the continuous evolution and improvements in ctDNA methodologies and assay performances, he added.

In the second study, patients who were ctDNA-positive (+) after surgery but had ctDNA clearance 6 months after adjuvant chemotherapy had a 24-month DFS of 90%. A patient’s ctDNA status outperformed clinicopathologic factors for predicting DFS, said Hiroki Yukami, MD, of Osaka Medical and Pharmaceutical University in Japan.

Despite the mixed results from the two studies, ctDNA remains the most powerful prognostic factor for recurrence in colorectal cancer, said invited discussant Aparna Parikh, MD, of Mass General Cancer Center in Boston.

“The tests may change, but the questions remain,” she said. “It’s critically important to adapt to improving technologies, but as we are demonstrating clinical utility at the same time, we can’t wait. There is tremendous opportunity for a better test. We need to start harmonizing the timing of testing. Clearance will be necessary but not sufficient, at least, not yet.”

Parikh agreed with Morris that storing samples will be needed in order to compare tests.

“As a community, we should absolutely encourage, and sort of demand, that this happens,” she said. “We need larger prospective cohorts with strategies to facilitate efficiency. There is still tremendous opportunity for following the biology of MRD and continuing onward.”

COBRA Study

Morris reported interim findings from the phase II/III COBRA study to evaluate ctDNA as a predictive marker for adjuvant chemotherapy in stage II colon cancer. The study included patients with stage IIA colon cancer for whom the treating physician decided adjuvant chemotherapy was not necessary.

Patients were randomized to active surveillance (standard of care) or to ctDNA assay-directed chemotherapy. Patients with detectable ctDNA received 6 months of adjuvant chemotherapy, and those who were ctDNA- entered active surveillance. Investigators chose the Guardant LUNAR tumor-agnostic assay that incorporates both mutation/genomic and methylation/epigenomic markers for ctDNA detection.

Data analysis included 635 patients, 16 of whom tested ctDNA+ — seven assigned to active surveillance and nine to adjuvant chemotherapy. Six months after baseline detection of ctDNA, 43% of those assigned to active surveillance had ctDNA clearance as compared with 11% of those randomized to chemotherapy. The p-value of 0.98 exceeded the prespecified significance level of 0.35, leading to early termination of the trial for futility.

GALAXY Trial: Key Findings

Yukami reported an updated analysis of the GALAXY trial, including 24-month DFS. The analysis included 2,998 patients with pathological stage I-IV colon cancer and postoperative ctDNA status available. Investigators chose the Natera Signatera assay for ctDNA detection. Assessment of ctDNA status occurred between 2 and 10 weeks after surgery (MRD window).

An analysis of all patients irrespective of disease stage showed a 24-month DFS of 85.9% for patients with ctDNA- status versus 28.9% for ctDNA+ patients (HR 10.53, 95% CI 8.74-12.69, P<0.0001). A separate analysis of patients with stage II/III disease yielded a 24-month PFS of 89.2% for the ctDNA- group and 33.5% for the ctDNA+ group (HR 12.95, 95% CI 9.46-15.34, P<0.0001).

“CT-DNA positivity in the MRD window is predictive of inferior DFS,” said Yukami.

Investigators stratified patients according to ctDNA clearance status: sustained, transient, and no clearance. Patients who had sustained clearance had yet to reach median DFS, as compared with a median of 9 months for patients with transient clearance and 3.5 months for no clearance. The 24-month DFS was 90.1% with sustained clearance, 2.3% with transient clearance, and 2.0% with persistently ctDNA+ status (P<0.0001).

Among patients with transient ctDNA clearance, 98% had reversion to ctDNA+ status within 18 months after surgery, said Yukami. Patients who had ctDNA clearance or a reduction in mean tumor molecules (MTM)/mL 6 months after adjuvant chemotherapy had superior DFS (HR 6.72, 95% CI 384-11.76, P<0.0001, HR 2.41, 95% CI 1.42-4.09, P=0.001).

Clearance of ctDNA at 6 months was associated with a 24-month DFS of 57.1% versus not-estimable for ctDNA+ patients. Patients with MTM/mL reductions of 50-100% at 6 months had a 24-month DFS of 51.1% versus 29.0% for reductions of 0-50%.

“CT-DNA status during surveillance is significantly associated with DFS,” said Yukami. “Reduction in ctDNA concentration [MTM/mL] at 6 months can also be used to predict clinical outcomes. CT-DNA guided adjuvant strategies will further be established by the ongoing randomized interventional VEGA and ALTAIR clinical trials.”

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Disclosures

The COBRA trial was supported by the NIH and Guardant Health.

Morris disclosed relationships with Incyte, Regeneron, Bicara Therapeutics, BioNTech, Bristol Myers Squibb, EMD Serono, Novartis, and Pfizer.

The GALAXY study was supported by the Japan Agency for Medical Research and Development, the National Research and Development Agency, the National Cancer Center, and Alpha-A.

Yukami disclosed having no relevant relationships with industry.

Parikh disclosed relationships with Pfizer, Seagen, AbbVie, Array Biopharma, Taiho Oncology, and Bayer HealthCare.

Primary Source

Gastrointestinal Cancers Symposium

Source Reference: Morris VK, et al “Phase II results of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA) phase II/III study” GiCS 2024; Abstract 5.

Secondary Source

Gastrointestinal Cancers Symposium

Source Reference: Yukami H, et al “Circulating tumor DNA (ctDNA) dynamics in colorectal cancer (CRC) patients with molecular residual disease: Updated analysis from GALAXY study in the CIRCULATE-JAPAN” GiCs 2024;Abstract 6.

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