A new research study led by scientists at the Johns Hopkins Kimmel Cancer Center and WEHI demonstrates that circulating tumor DNA (ctDNA) can identify stage II colon cancer patients who can most benefit from chemotherapy following surgery.
The findings are published in the New England Journal of Medicine in a paper titled “PD-1 Blockade in Mismatch Repair–Deficient, Locally Advanced Rectal Cancer.”
“Neoadjuvant chemotherapy and radiation followed by surgical resection of the rectum is a standard treatment for locally advanced rectal cancer,” wrote the researchers. “A subset of rectal cancer is caused by a deficiency in mismatch repair. Because mismatch repair–deficient colorectal cancer is responsive to programmed death 1 (PD-1) blockade in the context of metastatic disease, it was hypothesized that checkpoint blockade could be effective in patients with mismatch repair–deficient, locally advanced rectal cancer.”
Previous research studies have demonstrated that circulating tumor DNA can be detected in blood and that the presence of ctDNA post-surgery predicts the risk of cancer recurrence. However, this is believed to be the first clinical study showing that the measurement of circulating tumor DNA prior to therapy may benefit patients.
“Previous studies have theorized that ctDNA measurements might be useful in guiding patient management, and this study provides real-world clinical evidence that supports these theories,” said Bert Vogelstein, MD, the Clayton professor of oncology, co-director of the Ludwig Center at Johns Hopkins, and a Howard Hughes Medical Institute investigator. Vogelstein and group were the first to show that colon cancer is caused by a sequence of genetic mutations and showed that DNA shed from tumors could be detected in blood, stool, and other body fluids.
The researchers sought to determine whether ctDNA could be used to provide a more precise prediction of recurrence risk after surgery.
In the study, 455 patients with stage II colon cancer were randomized after surgery 2:1 to standard treatment or ctDNA-guided management. Of these patients, 153 received standard management, which includes monitoring over time for recurrence or chemotherapy. An additional 302 patients underwent blood tests within seven weeks after surgery to search for ctDNA.
The ctDNA-guided approach reduced the use of chemotherapy compared with the standard management group (15.3% of patients in the ctDNA-guided group received chemotherapy versus 27.9% in the standard management group). The two- and three-year survival with no cancer recurrence was similar between the ctDNA-guided group and the standard management group.
“Stage II colon cancer presents a unique challenge,” explained Anne Marie Lennon, PhD, professor of medicine, and director of the division of gastroenterology and hepatology. “In stage I colon cancer, patients do not receive chemotherapy because their prognosis for survival is over 90%. The risk of discomfort and toxicities from the therapy outweigh the benefits it can provide. On the other hand, every stage III colon cancer patient currently receives chemotherapy because the risk of relapse is high.”
“Using ctDNA to guide treatment, a stage II colon cancer patient who is negative for ctDNA has a lower chance of cancer recurrence than the average stage I colon cancer patient, so we have an opportunity to change clinical practice,” explained Joshua Cohen, a lead author of the study and MD/PhD candidate at the Johns Hopkins University School of Medicine.
The researchers hope these findings will stimulate the study of ctDNA in patients with other stages of colon cancer and other types of cancer. In future studies, the researchers will explore patients with early-stage pancreatic cancer and stage III colon cancer to see if ctDNA can similarly identify patients who are most likely to benefit from more aggressive chemotherapy than is currently used. They also plan to explore whether the presence of residual ctDNA can be used to help optimize the management of individual patients following surgery or other forms of therapy.
Using ctDNA to stratify treatments among patients is part of the movement toward precision medicine.
“All drugs work better in patients with cancers that are detected relatively early, before they have given rise to large metastatic masses. However, new drugs are usually first tested in patients whose cancers are very advanced,” said Vogelstein. “We hope that ctDNA analysis will enable testing of new drugs in patients with early-stage cancers and micrometastases, when the new drugs are most likely to save lives.”