This Physician's View opinion piece is written by Mohamedtaki Tejani, MD, FACS, medical director of gastrointestinal oncology program at the AdventHealth Cancer Institute.
With the exception of some types of skin cancer, colorectal cancer is the fourth most common cancer diagnosed in the United States and the second leading cause of cancer-related deaths. While the overall death rate has dropped in recent years, both incidence and deaths among younger adults has been on the rise with cases among those under age 55 nearly doubling since the 1990s according to the National Cancer Institute. Great efforts are being made to understand why this is happening, and the medical community is also focused on identifying new and better ways to catch colorectal cancer early and more effectively treat it.
For decades, stage II/III colorectal cancer treatment has pretty much been a “one-size-fits-all” approach: surgery followed by adjuvant radiation or adjuvant chemotherapy to eliminate any microscopic residual tumor. We know that approximately 30 to 40 percent of colorectal cancer patients relapse after resection, and adjuvant chemotherapy can delay recurrence or be curative for some patients. However, we also know that chemotherapy comes with its own set of risks and toxic side effects. Unfortunately, the biomarkers that have historically been available to us are not very effective in determining if and when chemotherapy should be administered for an individual patient. In addition, while early detection of colorectal cancer relapse can improve outcomes, the only way we have been able to monitor patients for recurrence is with radiographic imaging.
A Revolutionary New Approach to Managing Colorectal Cancer Treatment and Improving Patient Outcomes
The fields of medical genetics and technology have advanced significantly in recent years, giving rise to personalized medicine and more customized approaches to cancer treatment. Some of these new developments hold great promise for improving the care and outcomes of our colorectal patients. One of the most exciting developments to emerge is a sequencing technology that can detect very small amounts of tumor DNA. Called circulating tumor DNA (ctDNA), this cell-free DNA can now be detected and measured in the body’s circulatory system using a blood draw and specialized assay.
Accurate identification of ctDNA can indicate the presence of molecular residual disease (MRD) after surgery. A positive assay indicates the need for additional treatment, and a negative assay could actually eliminate the need for some patients to undergo adjuvant chemotherapy.
In addition, for those patients with MRD who require chemotherapy, regular ctDNA testing could help inform when to intensify or reduce treatment. This new testing technology also holds promise for surveillance of colorectal cancer patients, allowing us to identify MRD more accurately and earlier than radiological findings, increasing the likelihood of detecting recurrence while it is still resectable.
There are currently two different approaches to ctDNA testing available:
- Tumor-informed — This type sequences a patient’s tumor and creates a customized assay (personalized genetic test) for that patient based on the unique mutation signature of their tumor. While extremely precise, there is a longer turnaround time to receive the initial assay results, and it is expensive.
- Tumor-agnostic — This is an assay based on the most common colorectal cancer tumor mutations. It is not as precise but is quicker to secure results and less expensive since a patient tumor sample is not needed.
Current Research Studies Underway to Evaluate ctDNA Testing
The AdventHealth Research Institute is actively participating in clinical trials to evaluate the effectiveness and impact of different types of ctDNA testing for colorectal cancer patients:
- AdventHealth is the only Central Florida hospital participating in the BESPOKE Study of ctDNA Guided Therapy in Colorectal Cancer and is one of the leading sites nationally for accruals under the leadership of Principal Investigator Ahmed Zakari, MD. This is a multi-center, prospective, observational study that is enrolling a total of 2,000 patients who have undergone surgery for stage I-IV colorectal cancer. Patients will receive tumor-informed ctDNA test results and may be recommended for post-operative systemic therapy or observation by their treating clinician. They will be followed for up to 2 years with serial ctDNA analysis, timed with standard-of-care visits. The study’s control arm includes matched Stage I to IV colorectal cancer cases that have a minimum of least 2 years of clinical follow-up data. The primary endpoints include the impact of ctDNA testing on adjuvant treatment decisions and recurrence rates while asymptomatic and without correlate imaging.
- A National Cancer Institute trial, the Circulating Tumor DNA Testing in Predicting Treatment for Patients With Stage IIA Colon Cancer After Surgery, is a Phase II/III trial investigating how well ctDNA testing in the blood works in predicting treatment for patients with stage IIA colon cancer after surgery. I am serving as Principal Investigator, and this study aims to enroll over 1,400 participants. After completion of the study treatment, patients will be followed up at 12 months and then every 6 months for 2 years. Primary outcome measures include clearance of ctDNA (to undetectable levels) for patients who had baseline ctDNA detected as well as recurrence-free survival for the same group.
- A National Cancer Institute trial, Colon Adjuvant Chemotherapy Based on Evaluation of Residual Disease (CIRCULATE-US), is a Phase II/III trial evaluating what kind of chemotherapy to recommend to patients based on the presence or absence of ctDNA after surgery for colon cancer. I will also serve as Principal Investigator for this study, and primary outcome measures will include time from randomization to the first ctDNA positive status and time from randomization to disease-free survival.
In addition to these studies, a multi-center, randomized, controlled Phase II trial out of Melbourne, Australia, called DYNAMIC was recently presented at the American Society of Clinical Oncology meeting in Chicago. This study was designed to assess if a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. A total of 455 patients with stage II colon cancer who were suitable for adjuvant chemotherapy were enrolled and randomly assigned 2:1 to ctDNA-guided management or standard management. The DYNAMIC study found that the ctDNA-guided approach reduced adjuvant chemotherapy use without compromising recurrence-free survival, meaning that ctDNA-negative patients were unlikely to benefit from chemotherapy.
Researchers are also beginning to explore the application of ctDNA testing to improve care and management of other cancers, including gynecologic and hepatobiliary/pancreatic malignancies.
A Brighter Future for Colorectal Cancer Patients
As a scientist, I love contributing to the development and advancement of innovation. As a physician, however, improving patients’ lives has always been my greatest motivation and reward. One of my current patients, Mark Deloach, was shocked by his colorectal cancer diagnosis in early 2021 at age 56. A financial analyst accustomed to conducting thorough research for his clients, he applied that same investigative approach to his treatment plan, eventually seeking out AdventHealth for ctDNA testing after completing his initial resection and chemotherapy treatments at another institution. We continued Mark on a chemotherapy regimen, and his first ctDNA test came back negative. Like many patients, he was experiencing fatigue from the chemotherapy and also began to develop some mild neuropathy in his feet. After his second negative ctDNA test result a few months later along with clean CT scans, we decided it was safe for Mark to stop chemotherapy altogether -- two months early! He remains cancer free today and just returned from enjoying a full month of European travel.
We still have a lot to learn about ctDNA testing but are excited about the potential it holds. Every cancer is different, and this technology could enable us to take a more effective and more personalized approach to managing each individual patient’s cancer— reducing unnecessary treatment and detecting changes earlier so that we can make prompt adjustments to treatment. More importantly, it could be a game changer for our patients like Mark, keeping them better informed and improving their quality of life throughout their cancer care journey.
If you have patients who could benefit from participation in any of our current ctDNA studies, please contact us.