Integrative liquid biopsy approaches to capture minimal residual disease and inform therapeutic decisions for patients with resectable cancers

CERSI Collaborators: Valsamo Anagnostou, M.D., PhD; Vincent Lam, M.D., Robert Scharpf PhD, Noushin Niknafs PhD, Qiong Meng, PhD

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

Project Start Date: September 22, 2024

Regulatory Science Challenge

Liquid biopsies are tests to measure cell-free DNA that is shed in the bloodstream by dying cells. In the setting of cancer, a small fraction of this fragmented cell-free DNA is tumor derived, known as circulating tumor DNA or ctDNA. Analyses of ctDNA have shown promise for tracking minimal residual disease (MRD) after surgery for patients with early stage (i.e., non-metastatic) cancers. However, several challenges have hindered the widespread adoption of ctDNA MRD assays in early-stage cancer clinical decision-making, including their modest clinical sensitivity and the labor-intensive, costly nature of personalized ctDNA assays.

This project will evaluate ctDNA MRD for predicting long-term clinical outcomes in clinical trials of early-stage cancers as well as understanding the analytical performance of ctDNA MRD assays.

Project Description and Goals:

The goal of this project is to evaluate the performance of a tumor-informed whole genome sequencing (WGS) MRD liquid biopsy approach for patients undergoing neoadjuvant immunotherapy followed by surgery for early-stage solid tumors and compare this approach to commonly used tumor-naive approaches. Tumor-informed liquid biopsies are blood-based tests that sequence a patient's tumor sample to identify specific mutations present in the tumor. Then, circulating cell-free tumor DNA from the patient's blood is analyzed to detect these known mutations. Such methods are highly sensitive and beneficial for MRD detection for patients with early stage cancers. In contrast, tumor-naive liquid biopsies utilize fixed gene panels to detect tumor mutations without prior knowledge of the specific genetic makeup of the patient’s tumor. The use of matched white blood cell DNA sequencing helps to distinguish between tumor-derived mutations and those arising from normal (non-tumor) sources such as hematopoietic cells. Tumor-naive liquid biopsies are typically less sensitive as they are not designed specifically for known mutations in the patient’s tumor.

Investigators will leverage longitudinal plasma and tumor biospecimens collected under clinical trials of neo-adjuvantly treated cancers. The analytical sensitivities and specificities across treatment timepoints will be compared to the performance of the tumor-informed cfDNA WGS and non-tumor informed hybrid capture gene panel NGS assays. Performance metrics such as limit of detection and concordance rates will also be assessed.

Anticipated Outcomes/Impact:

This research aims to provide valuable insights into the analytical performance of ctDNA MRD liquid biopsies and support the clinical value of ctDNA MRD in predicting long-term clinical outcomes for patients, the latter representing critical steps for the development of ctDNA MRD as a biomarker and enrichment tool for the selection of patients in clinical trials.

Upon successful completion of the proposed work, investigators plan to immediately expand their efforts for clinical validation of ctDNA MRD in the context of a clinical trial in a separate study.Dr. Valsamo Anagnostou (JHU CERSI) is currently developing a prospective neoadjuvant immunotherapy biobanking clinical protocol within the Eastern Cooperative Oncology Group, powered to definitively determine the clinical utility of ctDNA MRD for predicting disease recurrence. The results from the study will be published upon completion.