Study: Liquid biopsies personalize early-stage colon cancer treatment

Contents

STUDY AT A GLANCE

What is this study about?

This study is about whether liquid biopsies can be used to personalize treatment for stage 2 colon cancer.

Why is this study important?

After a diagnosis of colon cancer, surgery is performed to remove all visible cancerous tissue. Chemotherapy is often used to destroy any remaining cancer cells in the body that can’t be detected through imaging but could cause recurrence.

Current guidelines recommend chemotherapy for stage 2 colon cancers with features that increase the risk for recurrence and spread. However, this approach is not ideal for predicting who will most likely have a  recurrence. Surgery alone can cure up to 80 percent of patients with stage 2 colon cancers, but some will experience recurrence.

It’s important to better understand which people with stage 2 colon cancer may benefit from chemotherapy.

Circulating tumor DNA (ctDNA) is fragmented DNA that is released from cancer cells and floats freely in the blood. Blood tests called “liquid biopsies” can detect very small amounts of ctDNA, which has been linked to a risk for recurrence in some cancers.  Notably, ctDNA tests are not ready for early detection of undiagnosed cancer (see this XRAY review for more information). However, for people diagnosed with cancer, the information provided by ctDNA tests may help doctors select treatments, predict outcomes or find and treat recurrence earlier.

Researchers wanted to know whether using liquid biopsy to detect circulating tumor DNA could reduce the overall use of chemotherapy without compromising recurrence-free survival in people with stage 2 colon cancer.

Study findings

The DYNAMIC study enrolled people with stage 2 colon cancer from healthcare centers in Australia and New Zealand between 2015 and 2019. Participants were randomly assigned to the liquid biopsy group (302 people) or the standard of care group (153 people).

The liquid biopsy-guided group was tested for ctDNA in their blood at four and seven weeks after surgery. People with a positive ctDNA test underwent up to six months of chemotherapy, and people with negative ctDNA tests underwent surveillance only.

Participants in the standard care group received chemotherapy only if their cancers were determined to be high-risk based on tumor features (higher T stage, difficult lymph node retrieval, presence of cancer invasion into blood vessels, bowel obstruction or bowel perforation, and irregular cells when viewed under the microscope) at the time of surgery. They did not have a ctDNA test.  The median follow-up time for participants was about three years.

Can ctDNA testing identify people with stage 2 colon cancer who should receive adjuvant chemotherapy?

• Using a liquid biopsy-guided strategy roughly halved the use of chemotherapy without affecting recurrence-free survival, with 15% of participants in the liquid biopsy group receiving chemotherapy vs 28 percent in the standard management group.
• At 2 years of follow-up, 93.5% of participants in the liquid biopsy group had no disease recurrence, compared to 92.4% of participants in the standard management group.
• At 3 years of follow-up, 91% of the participants in the liquid biopsy group had no disease recurrence compared to 92.4% of the standard management group.
• Within the liquid biopsy group, 3-year recurrence-free survival was 86.4% among ctDNA-positive people who received adjuvant chemotherapy and 92.5% among ctDNA-negative people who did not. These results were similar for those who received standard of care.
• Previously, researchers observed a high risk for recurrence (more than 80%) in people with stage 2 colon cancer who tested positive for ctDNA after surgery but did not undergo adjuvant chemotherapy. In this study, only 14% of ctDNA-positive people who received adjuvant treatment had a recurrence within 3 years, suggesting that chemotherapy is beneficial for this group.

Can ctDNA testing find people who do not need adjuvant chemotherapy therapy?

This is less clear. Patients whose ctDNA was negative after surgery had fewer recurrences than individuals whose ctDNA was positive. However people with no ctDNA detected and high-risk tumor features had more recurrences than if they had low-risk tumor features. This suggests that tumor features may also be needed to identify those without ctDNA who would still benefit from adjuvant chemotherapy.

• People with no ctDNA detected and low-risk clinical tumor features are less likely to have a recurrence and can likely omit adjuvant chemotherapy.
• People with no ctDNA detected and high-risk clinical tumor features may need to consider adjuvant chemotherapy. More research is needed to clarify this group.

Strengths and limitations

Strengths

• This type of study, known as a randomized controlled trial, tends to provide answers that are more conclusive than other kinds of studies. The goal of a randomized controlled trial is to identify the difference between treatments.  In this study, a ctDNA-guided approach to chemotherapy was compared to the standard of care. 
• This is the first clinical trial to show that liquid biopsies can guide chemotherapy decisions and benefit people by decreasing the need for chemotherapy without increasing cancer recurrence.

Limitations

• A longer follow-up time is needed to determine whether chemotherapy prevents or only delays recurrence.
• This research did not specifically look at outcomes of people with inherited mutations linked to colorectal cancer, including people with Lynch syndrome.
• This trial was smaller than most randomized trials. The number of trial participants was too small to draw conclusions about the best treatment for different subgroups of people. For example, more research is needed to determine which type of chemotherapy works best for ctDNA-positive people and whether ctDNA-negative people with high-risk tumor features could benefit from chemotherapy.
• This study only looked at individuals with resected  (cancer removed by surgery) stage 2 colon cancer. Individuals with other stages of colon cancer and individuals with rectal cancer were not analyzed in this study.
• It remains unclear what the optimal type of chemotherapy is for patients with resected stage 2 colon cancer patients who are ctDNA positive after surgery. In this study the ctDNA positive group received two chemotherapy drugs fluoropyrimidine and oxaliplatin. Typically people with stage 2 colon cancer are given only one, fluoropyrimidine. This may account for the low rate of recurrence in this group. It is also possible that group was overtreated. Because these drugs can have significant side effects, finding the optimal treatment is important. More research is needed to understand the most beneficial approach for people with stage 2 colon cancer who are positive for ctDNA.
• Recurrence-free survival at 3 years in both the liquid biopsy group and the standard of care group was higher than typically seen. It suggests that additional research is needed to understand why this is and whether the overall results are repeatable.
• The specific ctDNA test used in this study was not indicated. There are large differences between the reliability and variability of different types of ctDNA tests for different cancers and stages. It is not clear how generalizable these findings are.

Context

Circulating tumor DNA testing, or liquid biopsy, is a promising tool to improve clinical decision-making, especially for advanced cancers. It also has been shown to predict which people are most likely to have a cancer recurrence. Previous studies have shown a high risk for recurrence (more than 80 percent) in people with stage 2 colon cancer who test positive for ctDNA after surgery but do not undergo adjuvant chemotherapy. However, among people in this study who had a positive ctDNA test and received adjuvant therapy, only 14 percent had a recurrence.

It is still important to note that a prior study conducted on people with early-stage breast cancer showed that ctDNA-positive people had the highest probability of recurrent disease (see this XRAY review for more information). This confirms that adjuvant therapy is beneficial when ctDNA is present. Whether adjuvant therapy can be omitted for ctDNA-negative patients is less clear.

This study is the first to show that liquid biopsy can help guide chemotherapy decisions for people with early-stage colon cancer. Yet, questions remain about how to best treat ctDNA-positive people and whether ctDNA-negative people with high-risk tumors might still benefit from chemotherapy. In addition, longer follow-up is needed to determine whether chemotherapy prevents or only delays recurrence in ctDNA-positive people. The results of the DYNAMIC trial provide a basis for additional research that will improve and refine liquid biopsy in the context of personalized adjuvant therapy. Two clinical trials are currently recruiting people with stage 3 (NCT03803553) and nonmetastatic (NCT03832569) colon cancer to build on the DYNAMIC results. Similar studies are also being conducted in breast cancer.

It is not yet known how the results of this study apply to people with Lynch syndrome or other inherited mutations that are linked to colorectal cancer.

Conclusions

The results of this study support the emerging body of evidence showing that liquid biopsy can be used to predict cancer recurrence. This is also the first study to indicate that liquid biopsy can be used to guide chemotherapy decisions without sacrificing recurrence-free survival for people with stage 2 colon cancer. Using a ctDNA-guided approach resulted in fewer people requiring adjuvant treatment, sparing many others from the side effects of unnecessary chemotherapy. On the other hand, those with positive ctDNA findings ended up receiving more aggressive chemotherapy than is typically used for most patients with stage 2 colon cancers in current practice. The results of the DYNAMIC trial suggest that ctDNA may be a useful addition to personalize adjuvant chemotherapy in colon cancer.

Ongoing studies are looking at ctDNA for treatment decision-making in other settings.

What does this mean for me?

If you have stage 2 colon cancer, this study suggests that liquid biopsies could help determine if you need chemotherapy. However, it is not yet known how the results of this study apply to people with Lynch syndrome or other inherited mutations that are linked to colorectal cancer.

Currently, most healthcare providers base their treatment recommendations for people with stage 2 colon cancer on high-risk tumor features. This study shows that adding ctDNA tests to make decisions about chemotherapy could prevent unnecessary treatment. Some doctors are beginning to include liquid biopsy in their decision-making for people with stage 2 colon cancer. More research is needed to determine if this is useful for people with all types of stage 2 colon cancer.

Reference

Tie J, Cohen JD, Lahouel K, et al., Circulating tumor DNA analysis guiding adjuvant therapy in stage II colon cancer. The New England Journal of Medicine; 2022; 386: Article number 24. Published online June 4, 2022.

Disclosure: FORCE receives funding from industry sponsors, including companies that manufacture cancer drugs, tests and devices. All XRAYS articles are written independently of any sponsor and are reviewed by members of our Scientific Advisory Board prior to publication to assure scientific integrity.

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posted 11/22/22