ctDNA for Colorectal Cancer – Early and Metastatic Settings

In the inaugural event of the Global Cancer Movement, initiated by OncoDaily, Dr. Julien Taieb explores the transformative role of circulating tumor DNA (ctDNA) in revolutionizing colorectal cancer care. The virtual event, held from December 6-8, 2024, brought together global experts to discuss innovations reshaping cancer diagnostics and treatment strategies.

Julien Taieb introduces the session focused on circulating tumor DNA (ctDNA) and its applications in managing colorectal cancer, discussing its use in both early and late-stage disease settings. He explains that all cells shed DNA into the bloodstream, known as cell-free DNA, with tumor cells releasing DNA that contains specific molecular alterations such as point mutations, gene amplifications, rearrangements, and methylation patterns.

These molecular alterations can now be detected due to advances in molecular biology, even when present as a single abnormal tumor DNA strand among thousands of normal DNA strands.

Taieb highlights two main approaches to ctDNA testing: the tumor-informed approach, which requires profiling a patient’s tumor to identify specific mutations, and the tumor-agnostic approach, which tests for common mutations or methylation profiles without prior tumor profiling. While tumor-informed tests are costly and time-consuming but highly sensitive and specific, tumor-agnostic tests offer faster results and lower costs but may lack comparable sensitivity and specificity.

Taieb emphasizes that ctDNA testing holds potential across various stages of colorectal cancer management, from screening and diagnosis to monitoring treatment response, detecting minimal residual disease (MRD) post-surgery, identifying recurrence, and profiling tumors in metastatic settings. He presents findings that show ctDNA detection correlates with disease stage and tumor burden, noting that low-stage diseases or tumors in certain metastatic sites, like peritoneal disease or isolated lung nodules, shed less ctDNA.

Recent studies, including publications in the New England Journal of Medicine, suggest that ctDNA could eventually become a critical tool in screening programs, although this remains a future prospect. Taieb delves into the use of ctDNA in MRD detection, underscoring its prognostic value in determining which patients may benefit from adjuvant chemotherapy and which do not require treatment. Despite its high performance in predicting recurrence, ctDNA testing is not flawless, with some patients showing false-negative or false-positive results.

He reviews significant studies, including those from Australia and Japan, which validate ctDNA as a powerful prognostic tool in the adjuvant setting but notes limitations such as small sample sizes and variable recurrence rates. Taieb highlights recent findings that suggest combining ctDNA with other prognosticators, like clinical, pathological, transcriptomic, and immunoscore data, could enhance its predictive accuracy.

He discusses a study with a long follow-up of seven years, demonstrating ctDNA’s robust prognostic value while showing room for improvement through integration with other biomarkers. He also explores the concept of combining ctDNA with transcriptomic signatures to refine prognostication further, citing ongoing research that indicates such combinations can achieve better discrimination of outcomes in stage 2 and stage 3 colorectal cancer patients.

Taieb shifts to clinical trial applications, describing how ctDNA is being integrated into treatment decision-making frameworks. He outlines a pivotal randomized trial, the “DYNAMIC” study, which showed that ctDNA-guided adjuvant chemotherapy decisions could reduce overtreatment while maintaining comparable disease-free survival outcomes. However, he critically examines the trial results, raising concerns about the significant jump in recurrence-free survival rates for stage 2 patients and emphasizing the need for further exploration of adjuvant therapies, particularly for ctDNA-negative patients with high-risk features like T4 disease.

Taieb introduces ongoing French trials, such as PRODIGE 70 and PRODIGE 103, aimed at refining treatment strategies for ctDNA-positive and negative stage 2 and 3 patients, respectively. He concludes by noting the FDA’s recent approval of MRD clearance as a primary endpoint in multiple myeloma trials and predicts that this precedent could influence ctDNA’s role in colorectal cancer research, enabling faster evaluations of novel therapies for resistant patients.

In the metastatic disease setting, ctDNA offers significant utility in identifying actionable genomic alterations and establishing a molecular profile for patients. Current guidelines already recommend using ctDNA for tumor profiling, as it is non-invasive, fast, and reflects the real-time status of the tumor. It may also capture tumor molecular heterogeneity, a feature tissue biopsies can miss. However, limitations exist, such as clonal hematopoiesis and non-shedding sites, which may result in undetectable ctDNA in certain patients.

Various techniques have been developed for ctDNA profiling, all showing high performance in characterizing molecular aspects of colorectal cancer. Notably, a study presented by Kohei Shitara from Japan compared ctDNA with traditional tumor profiling in a metastatic colorectal cancer trial involving panitumumab and bevacizumab as first-line therapies. The results revealed discrepancies, with some patients being misclassified as RAS wild-type based on tumor profiling but showing RAS mutations in ctDNA.

This demonstrates ctDNA’s potential to refine patient selection for treatment, particularly in hyperselected populations lacking mutations that confer resistance to EGFR inhibitors. For both left- and right-sided tumors, panitumumab outperformed bevacizumab in hyperselected populations, emphasizing the relevance of ctDNA in optimizing therapeutic strategies.

Additionally, ctDNA serves as an essential tool when tissue biopsies are not feasible or when rapid results are needed to guide treatment decisions. However, its effectiveness depends on careful consideration of factors such as disease burden, metastatic sites, and the potential for false positives or negatives.

Another valuable application of ctDNA is its role as an early treatment surrogate marker for progression-free survival (PFS) and overall survival (OS). Several studies have shown that a rapid decrease in ctDNA levels within weeks of treatment initiation correlates with improved outcomes. For example, in trials, PFS ranged from as low as 1.9 months in patients without ctDNA reduction to as high as 18.8 months in those with significant decreases. This prognostic value holds across various therapies, including chemotherapy and immunotherapy.

In a forthcoming study examining immunotherapy in microsatellite instability-high (MSI-high) colorectal cancer, ctDNA dynamics discriminated outcomes even more effectively than in chemotherapy-treated patients, likely due to the distinct immune response associated with immunotherapy.

Monitoring clonal evolution through ctDNA is another innovative application. For instance, in a trial by Andrea Sartore Bianchi, ctDNA was used to identify patients with RAS, BRAF, and EGFR ectodomain wild-type tumors for EGFR rechallenge. These patients experienced better response rates, PFS, and OS compared to historical data, underscoring ctDNA’s utility in guiding rechallenge strategies.