Project Summary: Circulating tumor DNA (ctDNA) is emerging as a biomarker in oncology with several transformative clinical applications. One application may be the ability to detect clinically undetectable minimal residual disease (MRD) following curative intent treatment. In Stage III colorectal cancer (CRC), the primary means of cure is surgical resection, but if any tumor cells remain post-surgery, this can lead to eventual recurrence. In Stage III CRC, adjuvant chemotherapy also reduces recurrence risk, but 30% of patients will still recur. ctDNA detection may predict which patients have the highest recurrence risk, but a key question is whether an effective method to detect MRD can also identify patients who may benefit from additional therapy and increase cure rates. In Aims 1 and 2 with a 500 patient, multi-institutional Stage III CRC trial, ACT3, funded by Stand Up 2 Cancer, we will test the ability of ctDNA to identify patients who would recur without additional therapy and evaluate if additional treatment allows for ctDNA “clearance.” ctDNA “clearance” will be used as a rapid read-out for adjuvant therapy efficacy and subsequently evaluate if “clearance” correlates with improved recurrence-free survival. With ACT3, we will also evaluate emerging technologies for MRD detection and identify the optimal timing for MRD detection. This could create a novel approach for adjuvant clinical trials, providing a opportunity to salvage more cures. A second potentially transformative, clinical application of ctDNA is real-time monitoring of response to systemic therapy. While radiographic imaging remains the gold standard for measuring treatment response and disease progression, the ability to detect early evidence of treatment response or failure—before it is evident by standard radiographic imaging—could allow clinicians to rapidly adapt therapies to optimize patient outcomes. A patient could be switched early on from an ineffective therapy to a potentially effective therapy to achieve more rapid benefit, while minimizing the toxicity from continuing an ineffective therapy. In Aim 3, we will test the hypothesis that serial ctDNA monitoring may provide a real-time, non-invasive means to track early therapeutic response for metastatic GI cancers in a 200-patient prospective study. We will compare ctDNA changes to changes in standard tumor markers and patient reported outcomes assessing the ability of each modality alone or in combination to predict radiographic response. In parallel, we will evaluate novel technologies of ctDNA for response prediction. The primary work will take place at Massachusetts General Hospital and expands upon my established relationships with my mentorship team consisting of internationally recognized experts in liquid biopsies and clinical trials (primary mentor: Ryan Corcoran, MD PhD and co mentors Luis M. Diaz, MD and David B Ryan, MD). A scientific advisory committee with complementary expertise will also provide guidan...