The Next Wave of Cancer Care: ctDNA’s Emerging Role

Tumor microenvironment concept with cancer cells, T-cells, nanoparticles, cancer associated fibroblast layer of tumor microenvironment normal cells, molecules, and blood vessels: © HN Works - stock.adobe.com

With research constantly advancing, the role of circulating tumor DNA (ctDNA) in the diagnosis, treatment, and management of cancer is too.This technology has and continues to demonstrate its impact on oncology through enabling early detection, recognizing minimal residual disease (MRD), monitoring treatment response, and identifying genetic mutations for personalized therapies.

“It is a blood-based test, so it is noninvasive. It is very easy and tolerable for our patients to go through this and also gives us a lot of information on how the tumor is behaving,” explained Aakash Desai, MD, MPH, thoracic and phase 1 medical oncologist and assistant professor at the O’Neal Cancer Center at the University of Alabama, Birmingham, in an interview with Targeted Oncology^TM.

While the clinical utility of ctDNA continues to be evaluated, it is emerging as a useful tool across various cancer types, including gastrointestinal (GI) cancers, blood cancers, and other solid tumors.

Aakash Desai, MD, MPH

Early Detection and Monitoring

ctDNA is fragmented DNA that is shed by tumor cells into a patient's bloodstream, which can happen through apoptosis, necrosis, or active release by the tumor cells themselves.¹ Unlike traditional biopsies which can be invasive, ctDNA offers a noninvasive option for patients.

The promise of ctDNA has been shown when compared with traditional methods. Specifically, it plays a role in detecting cancer at earlier stages, when treatment is most effective, and identifying MRD that exists following treatment.

According to Pashtoon Kasi, MD, MS, ctDNA analysis is especially recommended to guide treatment selection in patients who do not have tissue-based next-generation sequencing (NGS) as an option due to comorbidities, poor performance status, tissue biopsy not feasible or noninformative, etc.²

"Liquid biopsy or circulating tumor DNA started with advanced next-generation sequencing-based platforms but has now moved into detecting minimal residual disease. This allows us to spare patients the toxicity of unnecessary treatments and focus on those who need it," explained Kasi, medical oncologist at Weill Cornell Medicine and NewYork-Presbyterian Hospital, highlighting the impact of ctDNA on patient care.

In clinical trials, some of the most common ctDNA applications include tumor molecular profiling at baseline, treatment response assessment, treatment stratification, early interception of molecular relapse, identification of molecular mechanisms responsible for acquired resistance to specific anticancer treatment, assessment of MRD after curative intent treatment, and more.²

Pashtoon Kasi, MD, MS

Additionally, ctDNA has a short half-life, which makes it a potentially useful option for early cancer detection. The same goes for real-time monitoring of tumor development, therapeutic response, and tumor outcomes.³

“One of the very interesting presentations was on the role of ctDNA in terms of the adjuvant space for EGFR,” noted Desai, highlighting the updates from the 2024 American Society of Clinical Oncology Annual Meeting. “There was a sort of subset analysis from the ADAURA trial [NCT02511106], which is a trial where osimertinib [Tagrisso] was given for 3 years after surgery, and based on that, the osimertinib approval came through from the FDA [for the adjuvant treatment of patients with EGFR mutation–positive non–small cell lung cancer (NSCLC)].”

From this trial, experts looked at patients whose ctDNA was measured and showed that for those who had positive ctDNA vs negative, the outcomes were different. In fact, ctDNA was able to detect progression much earlier than radiographic progression.

“I think this was something that does show the impact that ctDNA can have and the impact it can have in clinical decision making. I think some of those prospective studies need to be done. But I think from this retrospective analysis that is coming through, it shows that ctDNA could be an important tool for us in our toolbox,” added Desai.

In colorectal cancer, ctDNA can identify patients who may benefit from postsurgery chemotherapy or clinical trials of new therapies. It helps distinguish patients who have likely been cured by surgery alone from those who may be in need of additional treatment, thereby improving patient outcomes and quality of life.

According to Kasi, there is great importance in integrating ctDNA into clinical practice, as he noted it to be a strong prognostic tool for colorectal cancer.

“From the results of the trials, there is no doubt that ctDNA, in terms of colorectal cancer, is the strongest prognostic tool that we have. This has been compared across multiple platforms, across multiple studies, as the independent predictor of outcomes,” Kasi said.

Research in Solid Tumors

Mark Lewis, MD

In patients with advanced solid tumors, ctDNA has become an integral part of clinical practice. Research continues to explore the use of ctDNA in colorectal, breast, lung, pancreatic, bladder, and prostate cancers, as well as in melanoma.

The goal across the tumor types is similar to that in colorectal cancer: to guide treatment decisions and monitor response. According to Mark Lewis, MD, the potential of ctDNA is in nonoperative management and watchful waiting, specifically in colorectal cancer.

"Patients with a positive ctDNA signal after definitive treatment almost certainly fare worse. This tool could refine our understanding of who benefits from specific treatments and who is at risk," explained Lewis, director of gastrointestinal oncology at Intermountain Healthcare.

The FDA has already approved multiple ctDNA-based companion diagnostic assays, the first of which was approved by the FDA in 2020. Guardant360 CDx, a liquid biopsy NGS companion diagnostic test, was approved to help identify specific EGFR gene mutations in patients with metastatic NSCLC eligible for osimertinib.⁴

Shortly after, the FDA granted approval to FoundationOne Liquid CDx, a companion diagnostic for multiple targeted therapies across various solid tumors that can help aid in identifying BRCA1, BRCA2, and ATM mutations. The companion diagnostic also can guide treatment decisions for patients with metastatic castration-resistant prostate cancer being treated with agents like olaparib (Lynparza)⁵ and can detect mutations in additional genes that are relevant to targeted therapies for different solid tumors.

ctDNA-based assays are also being developed for use with immuno-oncology (IO)-based therapies.⁶ Previously, patient selection for IO therapy has relied on factors like tumor type and PD-L1 expression. Now, ctDNA analysis can reveal tumor mutational burden (TMB). The technology has shown that patients with high TMB may potentially respond better to IO therapy due to increased immune recognition.

Further, ctDNA can be used to dynamically monitor treatment response and detect MRD earlier than scans, allowing for earlier intervention and improved patient outcomes. While challenges remain, ctDNA holds immense promise for ushering in an era of precision IO with personalized treatment selection and better patient outcomes.

Impact on Blood Cancers

While ctDNA shows promise for early detection of solid tumors, its role in blood cancers is less established. Because blood cancers often shed less ctDNA compared with solid tumors, early detection is more challenging.

Ann LaCasce, MD, MMSc

However, the true strength of ctDNA for blood cancers, such as leukemia, multiple myeloma, and lymphoma, lies in monitoring disease and treatment response.⁷ According to Ann LaCasce, MD, MMSc, director of the Dana-Farber/Massachusetts General Brigham Fellowship in Hematology/Oncology, the role of ctDNA along with PET scans to predict outcomes and guide treatment decisions is growing.

"We are moving forward rapidly in using ctDNA for predicting patient outcomes and refining treatment plans," stated LaCasce.

By tracking ctDNA levels after therapy starts, it is possible to determine the effectiveness of a therapy. A significant decrease in ctDNA indicates a positive response and that the treatment is working effectively. Conversely, stable or rising levels suggest resistance or recurrence, which allows for quick changes in therapy that can facilitate improved patient outcomes.

As previously noted, ctDNA sheds light on MRD and can help identify patients who may be at higher risk of relapse. With MRD information, tailoring of posttreatment strategies can be made easier when trying to decide if a patient needs extra therapy or when determining the intensity of follow-up monitoring.

Recent findings presented at the 2023 American Society of Hematology Annual Meeting showed ctDNA’s potential in managing blood cancers, including that higher baseline ctDNA levels were linked with poorer outcomes in both aggressive non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. This can act as an early warning sign for oncologists, allowing them to adjust treatment plans if required.

Additionally, failure of ctDNA to become undetectable during and following therapy for aggressive NHL and Hodgkin lymphoma can predict a higher risk of relapse. Early detection through ctDNA allows for more proactive intervention. Another presentation showed that PhasED-Seq, a specific ctDNA test, was superior compared with PET/CT scans in a study of patients with aggressive lymphoma at the end of treatment, suggesting that ctDNA could become the preferred method for assessing therapy response due to its potentially greater accuracy.

Clinical Trials and Guidelines

Despite the increasing evidence of ctDNA’s utility, there are obstacles to its integration into clinical practice. According to Kasi, there are polarized opinions within the medical community regarding ctDNA adoption.

"Some institutions pride themselves on not using ctDNA, while others are early adopters. It is important to recognize the value of ctDNA as another tool in our toolbox," he explained.

Clinical trials such as BESPOKE (NCT04264702), GALAXY (NCT05986500), and DYNAMIC (ACTRN12615000381583) are just a few of the many studies aiming to provide new and valuable data on the clinical utility of ctDNA in cancer. Still, Kasi stressed the need for guidelines to ensure the best use of ctDNA, enhancing its role from an exploratory to an integral marker in ongoing studies.

"Guidelines would provide stronger utility and guidance, preventing the misuse of ctDNA without proper direction," Kasi added.

Desai also pointed out the sensitivity issues that have been seen with current ctDNA tests.

“We are still not there yet in terms of the sensitivity of the tests. Especially in the early stage, we still are looking for the ideal test that would give us a good amount of confidence in terms of whether we should base our decision on this or not. I think we will get more data, because again, everyone realizes it is an important tool,” Desai said.

Future Directions

The future of ctDNA in GI, blood, and other cancers is promising. As noted by LaCasce, ctDNA could even become mainstream in both NHL and Hodgkin lymphoma management.

"Circulating tumor DNA is one of the big emerging technologies. It is important for predicting outcomes and potentially reducing treatment," explained LaCasce.

Lewis added that ctDNA is here to stay, emphasizing the need to understand its appropriate use and limitations. "We need to figure out how to use ctDNA effectively. It will not be a one-size-fits-all approach, but it is the next great frontier in understanding and treating cancer."

The role of ctDNA across cancer types is expanding, offering hope for clinicians. As research continues and clinical trials provide more data, ctDNA is on its way to become a key part of oncology practice.

Still, it is important to remember that collaboration among clinicians, researchers, and patients will be crucial to realizing the full potential of this promising technology.

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