Mitigating Colorectal Cancer Treatment Risks Through ctDNA Testing

January 09, 2023 - Colorectal cancer affects thousands of patients each year. Although colorectal cancer is typically a disease associated with older patient populations, recent data have suggested rising rates of illness in younger patients. With this in mind, many providers are increasingly concerned about the associated risk of treatment, such as infertility, and how it may impact these younger populations differently. In the search for risk reduction strategies, clinicians and researchers have begun to look at ctDNA testing as a way to mitigate risks.

Colorectal Cancer

According to the American Cancer Society (ACS), in 2022, there were approximately 106,180 new cases of colon cancer and 44,850 new cases of rectal cancer, amounting to a lifetime colorectal cancer risk of 4–4.3%, with variations based on biological and lifestyle factors. The ACS also notes that colorectal cancer is the third deadliest cancer across all genders.

Rising Rates and Attributed Factors

Mohamedtaki Tejani, MD, oncologist, and director of GI Oncology at Advent Health, told LifeSciencesIntelligence that despite a slight decrease in colorectal cancer rates among older patients — patients in their 60s and older — colorectal cancer rates in younger patients (50s and younger) have been increasing.

Tejani notes that much research has gone into determining what has contributed to these rising rates; however, there has yet to be a clear answer. Early hypotheses postulated that the rise in cancer rates in younger populations might be due to genetic or hereditary reasons. Despite this theory, Tejani and other healthcare professionals have noticed, through screenings, that most colorectal cancers in younger patients are not linked to genetic causes. The ACS notes that only about 5% of colorectal cancer cases are due to inherited genes.

“The other observation is that younger patients tend to get colorectal cancer more on the left side or in the rectum, which is the end of the colorectal tract. This lends credibility to the theory that it relates to dietary patterns, such as less dietary fiber and more processed food consumption,” explained Tejani.

He clarified that this upward trend of colorectal cancer cases in younger patients — called early-onset colorectal cancer — is a western phenomenon, mainly affecting those in North America and western Europe. Tejani also suggests that increased inflammatory states in the body may contribute to rising rates of early-onset colorectal cancer. He notes that altering a sedentary lifestyle and managing stress levels may contribute to improved cancer outcomes, suggesting that the majority of cases are associated with lifestyle factors.

Impact on Younger Patient Populations

While the disease presents similarly in younger and older patients, younger patients are often misdiagnosed because colorectal cancer is not on their radar. Unfortunately, these patient populations are often seen in the later stages of disease progression.

Tejani notes that treatments and their concurrent side effects or toxicities disproportionately impact younger patients. For example, a common side effect of chemotherapy and radiation is infertility. While older patients may still struggle to deal with this outcome, they are more likely to have already conceived and not need to plan for post-treatment fertility.

ctDNA Testing

Clinicians’ understanding of the toxicities and impacts of chemotherapy across all patient populations — especially younger patients — has led them to look for tools to de-escalate or focus treatment to mitigate risks. One of the tools being explored is ctDNA testing.

“Currently approved applications of ctDNA testing have primarily been in early-stage colorectal cancer — stage II and stage III,” revealed Tejani. “These patients typically get surgery, then meet with medical oncology after surgery.”

At this point, common questions arise. Is there any microscopic cancer left behind that could then relapse later? Do these patients benefit from chemotherapy?

To alleviate some of these concerns, oncologists would rely on statistics to recommend chemotherapy. Patients with stage III colorectal cancers, having lymph node involvement, would be advised to get chemotherapy. Meanwhile, patients with stage II colorectal cancer — negative lymph nodes — would be steered away from chemotherapy.

Despite being the standard of care, this method of deciding treatment is notoriously unreliable as many stage III patients do not have microscopic cancer left, and many stage II patients have cancer recurrence. According to an article published by Medstar Health, stage II colon cancer has a recurrence rate of 10–12%.

ctDNA testing presents an alternative way for providers to determine whether a patient would benefit from chemotherapy. “ctDNA is a blood test that attempts to measure microscopic cancer DNA in the blood,” stated Tejani.

ctDNA Testing Approaches

Tejani explained that there are multiple approaches and platforms used in ctDNA testing. “One is what we call a tumor-informed approach. That's what is used in a lot of ongoing trials. The tumor-informed approach is when providers take the patient's tumor, sequence it, and know exactly what its genome is. Then they look for it in the blood. It's a longer turnaround, but when providers get the results, they are confident that they are measuring the DNA that the patient's tumor has,” explained Tejani.

The other approach is referred to as the tumor-agnostic approach, which doesn’t require sequencing the tumor sample. Instead, this approach uses common mutations in colorectal cancer and screens for them in the blood. According to Tejani, there are roughly 100 common genes that clinicians can screen for. The benefit of this approach is that it is faster; however, its results are less reliable.

ctDNA Testing Clinical Trials

Current studies are exploring the use of ctDNA testing in determining whether a patient needs chemotherapy. Tejani provided an example of a stage III colorectal cancer patient having a negative ctDNA test, indicating no remaining cancer DNA. Tejani notes that, in this case, some clinical trials would randomize this patient not to receive chemotherapy when traditional approaches would recommend chemotherapy. Conversely, a stage II patient with a positive ctDNA test may be randomized to get chemotherapy when they otherwise wouldn’t.

BESPOKE Trial

Tejani shared information on multiple recent or ongoing clinical trials to test the efficacy and impacts of ctDNA testing in clinical settings. The BESPOKE trial was done in partnership with a testing company, Natera.

“Essentially, it was an observational trial where all patients with stage II and stage III colorectal cancer had the ctDNA testing done, and then they would leave it to the provider to decide whether to give chemotherapy. The study followed the patients longitudinally,” explained Tejani. “Early results from the BESPOKE clinical trial showed that it performed well in predicting which patients would ultimately have a relapse and patients who would not.”

NCI Trials

Based on data from the BESPOKE trial, among other clinical trials, the National Cancer Institute (NCI) launched two additional trials. The first trial is focused on patients with stage III colon cancer, which means positive lymph nodes. These patients, by traditional guidelines, would be advised to get six months of chemotherapy.

Rather than automatically being designated to receive chemotherapy, patients in this trial would get ctDNA testing. Patients with negative ctDNA tests are randomized to receive no chemotherapy or the standard six months of chemotherapy.

Additionally, ctDNA-positive patients are randomized to doublet chemotherapy or escalated triplet chemotherapy. 

“So, on the one hand, researchers are trying to pull back on the patients who don't need it, and surgery was sufficient. But for those who are positive after surgery, we are trying to give them more to see if we can get them to that ctDNA negative state or a cure,” emphasized Tejani.

The other ongoing study is meant for stage II patients with negative lymph nodes. These patients would typically be advised not to get chemotherapy. However, in this study, if their ctDNA test is positive, they would be advised to get chemotherapy.

“After they finish their treatment, clinicians like me follow these patients for five years with scans. We're doing ctDNA testing at regular intervals. So even during the surveillance period, it can be helpful because, often, by the time the scan picks up a recurrence, it is too late for a cure since they typically have multiple liver or lung lesions. In this case, the minute we see the ctDNA blip into positive, we do a scan right away. And hopefully, by catching the recurrence early, we can give them a better outcome.”