O-11 Monitoring molecular residual disease by circulating tumor DNA in resectable colorectal cancer: Molecular subgroup analyses of a prospective observational study GALAXY in CIRCULATE-Japan

3608 Background: Circulating tumor DNA (ctDNA) analysis can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). We are conducting a prospective observational study to monitor MRD status in patients with clinical stage II–IV or relapsed CRC amenable to radical surgical resection (GALAXY study), as part of the CIRCULATE-Japan, a nationwide ctDNA-guided precision adjuvant therapy project. Methods: Analysis of ctDNA is being performed at pre- and post-surgery timepoints and will continue periodically for up to 2 years using Signatera, a personalized, tumor-informed ctDNA assay that is designed to track 16 patient-specific somatic variants based on whole-exome sequencing of tumor tissue. The association of peri-operative ctDNA status with clinicopathological characteristics was investigated. Results: As of January 13, 2021, 941 patients have been enrolled in the GALAXY study, of which 400 patients had their pre-operative ctDNA status evaluated. Of the 400 patients, baseline ctDNA was detected in 92% (367/400) of the patients: consisting of 35 patients with pathological stage (pStage) I, 135 with pStage II, 152 with pStage III, and 78 with pStage IV or relapsed disease (pStage IV/R). Patient-specific Signatera assays targeting 16 variants were designed for 100% of the patients. Out of the 6400 designed variants 99.3% passed quality control in the plasma analysis and produced the final results. Among 4425 genes selected for 400 patients, 3330 genes were selected for only one patient, while TP53 was the most commonly selected in 113 patients (28%). Median ctDNA levels, measured in mean tumor molecules per mL of plasma and ctDNA detection rate, stratified by stage are presented in table. Positive ctDNA status post-surgery was significantly associated with advanced pStage, pT and pN, and lymphovascular invasion. Of the 13 patients with recurrence, 10 were detected with a positive ctDNA at 4-weeks post-surgery, before confirmation of recurrence by the radiological imaging. Conclusions: Preoperative ctDNA detection rates were observed to be in >90% in patients with pStage II–III by personalized ctDNA assay based on unique somatic variants, specific to each patient. ctDNA- based MRD detected post-surgery (4W) was significantly associated with certain known clinicopathological factors for recurrence with ctDNA positivity associated with a very short-term of recurrence. Clinical trial information: 000039205. [Table: see text]

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SO-34 Clinical experience of a personalized and tumor-informed circulating tumor DNA assay for minimal residual disease detection in oligometastatic colorectal cancer patients

Annals of Oncology ◽

10.1016/j.annonc.2020.04.049 ◽

2020 ◽

Vol 31 ◽

pp. S229

Author(s):

S. Cohen ◽

N. Hook ◽

S. Krinshpun ◽

L. Westbrook ◽

K. Loranger ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Patients ◽

Minimal Residual Disease ◽

Clinical Experience ◽

Residual Disease ◽

Circulating Tumor Dna ◽

Dna Assay ◽

Colorectal Cancer Patients ◽

Tumor Dna ◽

Minimal Residual

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Circulating tumor DNA in stage III colorectal cancer, beyond minimal residual disease detection, towards assessment of adjuvant therapy efficacy and clinical behavior of recurrences

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-21-2404 ◽

2021 ◽

pp. clincanres.2404.2021

Author(s):

Tenna Vesterman Henriksen ◽

Noelia Tarazona ◽

Amanda Frydendahl ◽

Thomas Reinert ◽

Francisco Gimeno-Valiente ◽

...

Keyword(s):

Colorectal Cancer ◽

Adjuvant Therapy ◽

Minimal Residual Disease ◽

Residual Disease ◽

Circulating Tumor Dna ◽

Stage Iii ◽

Clinical Behavior ◽

Therapy Efficacy ◽

Tumor Dna ◽

Minimal Residual

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Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases

JCO Precision Oncology ◽

10.1200/po.21.00101 ◽

2021 ◽

pp. 1166-1177

Author(s):

Fotios Loupakis ◽

Shruti Sharma ◽

Madiha Derouazi ◽

Sabina Murgioni ◽

Paola Biason ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Trial ◽

Overall Survival ◽

Systemic Therapy ◽

Residual Disease ◽

Prognostic Biomarker ◽

Circulating Tumor Dna ◽

Significant Prognostic Factor ◽

Resection Of Metastases ◽

Tumor Dna

PURPOSE More than 50% of patients with stage IV colorectal cancer (metastatic colorectal cancer [mCRC]) relapse postresection. The efficacy of postoperative systemic treatment is limited in this setting. Thus, these patients would greatly benefit from the use of a reliable prognostic biomarker, such as circulating tumor DNA (ctDNA) to identify minimal or molecular residual disease (MRD). PATIENTS AND METHODS We analyzed a cohort of 112 patients with mCRC who had undergone metastatic resection with curative intent as part of the PREDATOR clinical trial. The study evaluated the prognostic value of ctDNA, correlating MRD status postsurgery with clinical outcomes by using a personalized and tumor-informed ctDNA assay (bespoke multiple PCR, next-generation sequencing assay). Postresection, systemic therapy was given to 39.2% of the patients at the discretion of the treating physician. RESULTS Postsurgical, MRD positivity was observed in 54.4% (61 of 112) of patients, of which 96.7% (59 of 61) progressed at the time of data cutoff (hazard ratio [HR]: 5.8; 95% CI, 3.5 to 9.7; P < .001). MRD-positive status was also associated with an inferior overall survival: HR: 16.0; 95% CI, 3.9 to 68.0; P < .001. At the time of analyses, 96% (49 of 51) of patients were alive in the MRD-negative arm compared with 52.4% (32 of 61) in the MRD-positive arm. Patients who did not receive systemic therapy and were MRD-negative in the combined ctDNA analysis at two time points had an overall survival of 100%. In the multivariate analysis, ctDNA-based MRD status was the most significant prognostic factor associated with disease-free survival (HR: 5.78; 95% CI, 3.34 to 10.0; P < .001). CONCLUSION This study confirms that in mCRC undergoing resection of metastases, postoperative MRD analysis is a strong prognostic biomarker. It holds promises for being implemented in clinical decision making, informing clinical trial design, and further translational research.

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Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

Cancers ◽

10.3390/cancers13184547 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4547

Author(s):

Jun Gong ◽

Andrew Hendifar ◽

Alexandra Gangi ◽

Karen Zaghiyan ◽

Katelyn Atkins ◽

...

Keyword(s):

Colorectal Cancer ◽

Neoadjuvant Therapy ◽

Minimal Residual Disease ◽

Residual Disease ◽

Circulating Tumor Dna ◽

Stage I ◽

Phase Iii ◽

Resected Stage ◽

Tumor Dna ◽

Minimal Residual

Emerging data suggest that circulating tumor DNA (ctDNA) can detect colorectal cancer (CRC)-specific signals across both non-metastatic and metastatic settings. With the development of multiple platforms, including tumor-informed and tumor-agnostic ctDNA assays and demonstration of their provocative analytic performance to detect minimal residual disease, there are now ongoing, phase III randomized clinical trials to evaluate their role in the management paradigm of CRC. In this review, we highlight landmark studies that have formed the basis for ongoing studies on the clinically applicability of plasma ctDNA assays in resected, stage I–III CRC and metastatic CRC. We discuss clinical settings by which ctDNA may have the most immediate impact in routine clinical practice. These include the potential for ctDNA to (1) guide surveillance and intensification or de-intensification strategies of adjuvant therapy in resected, stage I–III CRC, (2) predict treatment response to neoadjuvant therapy in locally advanced rectal cancer inclusive of total neoadjuvant therapy (TNT), and (3) predict response to systemic and surgical therapies in metastatic disease. We end by considering clinical variables that can influence our ability to reliably interpret ctDNA dynamics in the clinic.

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