MRD Continues to Reliably Predict Disease Progression in CRC

Among 79 patients with UICC stage II/III colorectal cancer (CRC) who participated in the Molecular Signatures in Colorectal Cancer study, testing for minimal residual disease (MRD) in 8 revealed positive results for circulating tumor DNA (ctDNA) following R0 resection for nonmetastasized solid tumors. Four of these patients also were shown to have disease progression within 2 years.

These and additional study findings were presented recently at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium by investigators who compared outcomes of utilizing MRD status vs ultra-deep sequencing of cell-free DNA (cfDNA) for potential of disease progression.

“Detection of primary tumor mutations in cfDNA of postsurgery plasma of patients with R0-resected not-metastasized solid tumors is a strong indicator of recurrence of disease,” they explained. “We explored whether ultra-deep sequencing of cfDNA could improve sensitivity and specificity with regard to time-to-progression.”

Eight-four patients were recruited for the study, but samples for only 79 patients passed all quality controls and could be included in the final analysis of matched tumor tissue samples, plasma depleted blood cells, and cfDNA drawn a median 7 days post surgery. The investigators employed the Roche AVENIO Tumor Tissue and ctDNA Surveillance Kits for next-generation sequencing, and they used AVENIO Oncology Analysis software 2.0 to identify somatic variants.

Following the ultra-deep sequencing of the cfDNA to a median 180 Mio reads per sample, the 8 patients identified as ctDNA positive (ctDNA+) were shown to have 28 variants and an allele frequency (AF) of 0.15%. Results also identified a sensitivity of 44% (95% CI, 0.137-0.788), specificity of 94% (95% CI, 0.86-0.984), positive predictive value of 50% (95% CI, 0.157-0.843), and negative predictive value of 93% (95% CI, 0.843-0.977).

When outcomes were compared between ctDNA+ and ctDNA-negative (ctDNA­–) patients, P values of .0058 and .0333 were seen for comparison of time to disease progression and of survival times, respectively. Multivariate analysis of time to progression determined ctDNA status (HR, 7.098; P = .0022) and neoadjuvant therapy (HR, 6.618; P = .0010) to be significant parameters. In addition, “multivariate analyses of survival times resulted in ctDNA status (HR, 4.082; P = .0508) as the only borderline significant parameter of 9 tested parameters,” the authors wrote.

Nonsignificant parameters were gender, rectum tumor, right colon tumor, lymph node metastasis, lymphatic invasion, venous invasion or perineural invasion positive, Eastern Cooperative Oncology Group status of 0, neoadjuvant therapy, and adjuvant therapy.

For this study, patients were considered positive or negative for MRD (MRD+ and MRD­–, respectively) if there was or was not disease progression in the 2 years after surgery. Patients were followed for more than 2 years. For ctDNA+ status, a variant had to have an AF of at least 5% in tissue or at least 0.5% in postsurgery plasma and a patient had to have at least 1 ctDNA+ variant.

“Even in this small cohort of CRC UICC stage II/III patients, MRD detection in postsurgery plasma is the strongest predictor of shorter time to progression,” the authors concluded. “Ultra-deep sequencing of cfDNA samples did not influence MRD detection on a patient level.”

Reference

McNamara S, Patel RD, Adams HP, et al. Detection of minimal residual disease (MRD) in colorectal cancer (CRC) patients UICC stage II/III by ultra-deep sequencing of cfDNA from post-surgery plasma. Presented at: American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 20-22, 2022; San Francisco, CA, and virtual; poster 26. Accessed January 24, 2022. https://meetinglibrary.asco.org/record/204647/poster