Circulating tumor DNA guides chemotherapy in colon cancer

Researchers from TGen, a part of City of Hope, contribute to study supporting the value of looking at tumor markers in the blood in assessing treatment options

Tumor DNA circulating in the bloodstream can help clinicians decide whether chemotherapy is right for their patients who have undergone surgery for Stage 2 colon cancer, according to a breakthrough study published online in The New England Journal of Medicine and presented at the 2022 American Society of Clinical Oncology annual meeting. An international team that included investigators from the Translational Genomics Research Institute (TGen), part of City of Hope, conducted the study to lend clarity to the role of adjuvant chemotherapy in this setting.

Previous studies suggested that the presence of circulating tumor DNA (ctDNA), the small fragments of a cancer’s genetic material shed into the blood, predicted a recurrence of the cancer after surgery, while the absence of ctDNA predicted a low recurrence risk. The real-world study is thought to be the first to use ctDNA to guide follow-up chemotherapy decisions in Stage 2 colon cancer patients after surgery to determine if certain patients can be spared from this form of treatment.

A total of 455 patients in Australian centers were assigned to either ctDNA-guided care or standard care following their surgeries. Standard care follows traditional guidelines based on clinicopathological features that are associated with higher cancer risk. If patients in the study’s guided group still had ctDNA present in their blood samples four to seven weeks after surgery, they received one of two kinds of chemotherapy. If tumor DNA was not found, then those patients in the ctDNA-guided group were not treated with chemotherapy. 

Of those receiving ctDNA-guided care, physicians were able to not only inform treatment, but actually reduce the number of patients who were treated with chemotherapy without compromising their recurrence-free survival.

Avoiding Unnecessary Chemo 

“The study’s findings suggest a way to identify which patients can avoid unnecessary chemotherapy, with its potentially serious side effects and its expense. And for those who have undergone chemotherapy or know someone who has, and know what it means, I think this is really great news,” said Cristian Tomasetti, Ph.D., the newly appointed director of the Center for Cancer Prevention and Early Detection at City of Hope and TGen.  

ctDNA can be a useful addition to traditional tissue-based features — like a tumor’s size — to determine risk of recurrence, since tumors themselves are so different from one another.

Kamel Lahouel, Ph.D.

“For instance, sometimes the potential of a large tumor to be dangerous and invade tissues can actually be lower than a smaller cancer with the right combination of mutations,” TGen’s Kamel Lahouel, Ph.D., a first author on the paper, explained.

In the follow-up 37 months later, patients under standard care were almost twice as likely as patients in the ctDNA-guided group to receive chemotherapy: 27.9% compared to 15.3%. Despite the difference in treatment, two-year recurrence-free survival rates were not worse in the guided group (93.5%) compared to the standard care group (92.4%). 

“The goal at the beginning of the study was to prove that ctDNA-guided therapy would not lead to worse outcomes than standard care,” said Lahouel, “and we ended up with an estimate that is even better than the standard of care guidance. I think that is what is really impressive.”

Assessing Therapy

Among the patients in the guided group, those who had the circulating DNA and were treated with chemotherapy had an 86.4% three-year recurrence-free survival rate, compared to 92.5% for those who did not have ctDNA and did not receive chemotherapy

“We wanted to come up with ways to tell whether therapy was needed, and this technology will also help in the future to determine whether a particular therapy isn’t working, or when we should switch to another therapy, or even when it is OK to stop chemotherapy in a patient.  Based on further study, we can think about further personalizing treatment with these technologies,” said Tomasetti.  

Finally, while these findings confirm that certain patients are not likely to need chemotherapy, they also confirm the importance of chemotherapy for those with detectable ctDNA after surgery, Lahouel and Tomasetti noted. In previous studies, scientists found an 80% risk of recurrence in Stage 2 colon cancer patients with detectable ctDNA who did not receive chemotherapy.

These exciting results were achieved thanks to new technologies able to find tumor DNA in the blood. The same technologies are also very promising for detecting cancer much earlier.

This groundbreaking study was led by Bert Vogelstein, M.D., and researchers at the Johns Hopkins Kimmel Cancer Center, Jeanne Tie, M.D., and researchers at the Peter MacCallum Cancer Centre of the University of Melbourne, Australia, and  Lahouel and  Tomasetti of TGen and City of Hope.