Developing circulating tumor DNA as a biomarker in a surgery-sparing approach for patients with mismatch repair deficient colorectal cancer

CERSI Collaborators: Yuxuan Wang, MD, PhD; Eric Christenson, MD; Nickolas Papadoulos, PhD; Bert Vogelstein, MD; Dung Le, MD; Hao Wang, PhD

FDA Collaborators: Reena Philip, PhD; Paz Vellanki, M.D, PhD; Rama Kamesh Bikkavilli, PhD; Joshua Donaldson. MD, PhD

Project Start Date: September 21, 2024

Regulatory Science Challenge: 

Patients with resectable colorectal cancer (i.e., cancer that has not spread to other parts of the body) often undergo unnecessary surgery after neoadjuvant immunotherapy; however, there is no reliable biomarker to identify who needs surgery. Circulating tumor DNA (ctDNA) refers to small pieces of DNA released from cancer cells into the bloodstream. This study will evaluate using ctDNA as a biomarker of residual cancer, referred to as minimal residual disease, after immunotherapy for colorectal cancer to identify the patients who should proceed to surgery. We will apply a highly sensitive, quantitative ctDNA assay to samples acquired from a clinical trial at our institution to help develop ctDNA as a biomarker to guide treatment decisions in clinical practice and for use in future clinical trials. 

Project Description and Aims/Goals: 

The goal of the project is to test how ctDNA performs as a biomarker of tumor burden during and after neoadjuvant immunotherapy for patients with resectable colorectal cancers. We will design personalized mutation panels based on tumor tissue from each patient. Blood samples before, during, and after neoadjuvant immunotherapy will be analyzed using these personalized mutation panels to detect ctDNA as evidence of residual disease. In addition, the change in the level of ctDNA in serial blood samples throughout treatment can provide an early readout of treatment response. 

Anticipated Outcomes/Impact:

We expect ctDNA to be a more sensitive and specific biomarker that can predict early treatment response and minimal residual disease during and after treatment compared to conventional diagnostics, such as imaging and endoscopies. As a noninvasive biomarker that may provide an early readout of treatment response, ctDNA may help identify patients who are not responding to their current treatment. As a biomarker of minimal residual disease, ctDNA may help identify the patients who should receive additional treatment, such as surgery, after initial treatment with immunotherapy. The results from the study will be published upon completion.