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Using ctDNA to Measure Molecular Residual Disease in Patients With Colorectal Cancer


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A team of investigators in Japan used a personalized assay for circulating tumor DNA (ctDNA) levels in plasma to monitor molecular residual disease following surgery in patients with resectable colorectal cancer. Their subgroup analysis found statistically significant associations between ctDNA levels and the pathologic disease stage. No association with RAS, BRAF V600E, and microsatellite instability (MSI) was found. These findings from the prospective observational study GALAXY, part of the CIRCULATE-Japan trial, were presented by Shirasu et al at the ESMO World Congress on Gastrointestinal Cancer 2021 (Abstract O-11).

While explaining the rationale leading to this investigation, lead author Hiromichi Shirasu, MD, of the Division of Gastrointestinal Oncology at Shizuoka Cancer Centre in Sunto-Gun, Japan, noted that identifying molecular residual disease after curative surgery by analysis of ctDNA could facilitate the personalization of adjuvant therapies and early intervention in patients with colorectal cancer.

Multiple Studies Investigating ctDNA

Dr. Shirasu and colleagues conducted the CIRCULATE-Japan adaptive platform trial, which comprised a large-scale patient-screening registry, GALAXY, to monitor molecular residual disease status. GALAXY was followed by two ctDNA-guided phase III trials, VEGA and ALTAIR, which aimed to refine adjuvant therapy using ctDNA analysis of molecular residual disease in patients with resectable colorectal cancer.

These studies evaluated the plasma ctDNA status prior to and after surgery periodically for up to 2 years. The investigators used Signatera, a personalized, tumor-informed ctDNA assay that was designed to track 16 patient-specific somatic variants based on whole-exome sequencing of the tumor tissue and matched normal blood. Median ctDNA levels were measured and expressed as mean tumor molecules per milliliter of plasma. RAS and BRAF V600E mutations, as well as the mismatch repair status in tumor tissue, were assessed using polymerase chain reaction–based methods. The investigators also evaluated the association of ctDNA status with tumor biomarkers.

Preoperative ctDNA Levels and Pathologic Disease Stage

As of February 2021, the GALAXY study had enrolled 1,236 patients, with 808 patients being included in the analysis presented at the ESMO World Congress on Gastrointestinal Cancer 2021. Preoperative baseline ctDNA was detected in 799 patients. ctDNA was available in 797 patients 4 weeks postsurgery, in 531 patients 12 weeks postsurgery, and in 263 patients 24 weeks postsurgery. Six hundred and fifty-four patients had stage I to III colorectal cancer, and 154 patients had stage IV disease.

In this cohort, 347 (43%) patients had RAS mutations and 55 (7%) had BRAF V600E mutations. In addition, 71 (9%) patients had MSI-high status.

Among 65, 280, and 301 patients with pathologic stages I, II, and III disease, preoperative ctDNA was detected in 50 (77%), 267 (95%), and 288 (96%), respectively.

The investigators found that pT was significant for preoperative ctDNA positivity, while pN was significant for postoperative positivity at 4 weeks after surgery.

No association with RAS, BRAF V600E, or MSI was found.

Longitudinal ctDNA positivity at weeks 4, 12 and 24 postsurgery was significantly associated with inferior disease-free survival, with a hazard ratio of 46.8. Sensitivity of relapse detection was 93.1%.

Positivity at postoperative week 4 was significantly associated with inferior disease-free survival, with a hazard ratio of 19.5 overall and a hazard ratio of 24.4 in patients with pathologic stage I to III disease, indicating it may be a suitable timepoint for ctDNA-based adjuvant study.

Multivariate analysis showed that ctDNA was the only significant factor beyond known prognostic factors.

Dr. Shirasu concluded that further investigation into whether ctDNA status could become a new surrogate endpoint beyond disease-free survival is warranted.

Disclosure: This study received funding from the Japan Agency for Medical Research and Development. For full disclosures of the study authors, visit annalsofoncology.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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