DNA released from colon cancers into the bloodstream successfully guides chemotherapy after surgery: helps clarify the benefits of chemotherapy in stage II cancers

The international, multi-institutional study, led by researchers at Johns Hopkins Kimmel Cancer Center and WEHI in Melbourne, Australia, found that cDNA screening after surgery and administration of chemotherapy to patients positive for cDNA overall reduced the use of chemotherapy without compromising recurrence. free survival.

There are several previous research studies demonstrating that circulating tumor DNA can be detected in the blood and that the presence of ctDNA after surgery predicts a risk of cancer recurrence. However, this is believed to be the first clinical study to show that measuring circulating tumor DNA before treatment can benefit patients.

These conclusions will be published in the New England Journal of Medicine and presented at the American Society of Clinical Oncology Annual Meeting on June 4.

“Previous studies have hypothesized that ctDNA measurements might be useful in guiding patient management, and this study provides real-world clinical evidence that supports these theories,” says Bert Vogelstein, MD, Clayton Professor of oncology, co-director of the Ludwig Center at Johns Hopkins and an investigator at the Howard Hughes Medical Institute. Vogelstein and his group were the first to show that colon cancer is caused by a sequence of genetic mutations and showed that DNA released by tumors could be detected in blood, stool and other bodily fluids.

Currently, the use of chemotherapy in stage II colon cancer, which is defined as colon cancer that has grown through the wall of the colon but has not spread to the lymph nodes or other organs, is controversial. There is no consensus among cancer experts on its benefit. This study aimed to help resolve the controversy by evaluating whether ctDNA could be used to provide a more accurate prediction of recurrence risk after surgery. Patients who were ctDNA negative could be spared the toxicities of chemotherapy, and those with remaining cancer could receive chemotherapy to attack persistent malignant cells.

In the study, 455 patients with stage II colon cancer were randomized after surgery in a 2:1 ratio to receive standard treatment or ctDNA-guided management. Among these patients, 153 received standard care, which includes monitoring over time for recurrence or chemotherapy. An additional 302 patients underwent blood tests within seven weeks of surgery to look for ctDNA. If ctDNA was detected, patients received chemotherapy with fluoropyrimidine or oxaliplatin. If ctDNA was not detected, patients did not receive chemotherapy.

The ctDNA-guided approach reduced the use of chemotherapy compared to the standard management group (15.3% of patients in the ctDNA-guided group received chemotherapy compared to 27.9% in the standard management group). Cancer recurrence-free survival at two and three years was similar between the ctDNA-guided group and the standard management group.

“Stage II colon cancer presents a unique challenge,” says Anne Marie Lennon, MBBCh., Ph.D., professor of medicine and director of the division of gastroenterology and hepatology. “In stage I colon cancer, patients do not receive chemotherapy because their survival prognosis is greater than 90%. The risk of discomfort and toxicity from the therapy outweighs the benefits it may bring. On the other hand, every patient with stage III colon cancer currently receives chemotherapy because the risk of relapse is high.”

The goal of chemotherapy in colon cancer is to eradicate micrometastases, cancer cells not yet visible on X-ray images that travel through the bloodstream and cause the cancer to come back or spread to other parts of the body. . Using ctDNA to detect these invisible cells can now identify patients most likely to have micrometastases and, therefore, most likely to benefit from chemotherapy.

“Using ctDNA to guide treatment, a patient with stage II cDNA negative colon cancer has a lower risk of cancer recurrence than an average patient with colon cancer. stage I. So we have the opportunity to change clinical practice,” says Joshua Cohen, a lead author of the study and MD/Ph.D. candidate at 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, researchers will explore patients with early-stage pancreatic cancer and stage III colon cancer to see if ctDNA can similarly identify patients most likely to benefit. more aggressive chemotherapy than currently used. They also plan to explore whether the presence of residual cDNA can be used to help optimize the management of individual patients after surgery or other forms of therapy.

Using ctDNA to stratify treatments among patients is part of the movement toward precision medicine – individualized care that tailors therapies to the unique characteristics of a cancer.

The researchers also believe the results will provide opportunities to test promising new drugs in early-stage cancer patients.

“All drugs work best 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,” says Vogelstein. “We hope that ctDNA analysis will help test new drugs in patients with early-stage cancers and micrometastases, when new drugs are most likely to save lives.”

In addition to Vogelstein, Cohen, Lennon, other researchers were Kamel Lahouel, Ph.D., Yuxuan Wang, MD, Ph.D., Janine Ptak, MS, Natalie Silliman, BS, Lisa Dobbyn, BA, Maria Popoli, MS, Ralph Hruban, MD, Nicholas Papadopoulos, Ph.D., Kenneth Kinzler, Ph.D., and Cristian Tomasetti of Johns Hopkins, and Jeanne Tie, MD, Serigne Lo, Ph.D., Suzanne Kosmider, MBBS, Jeremy Shapiro, MBBS, Margaret Lee, MBBS, Sam Harris, MBBS, Adnan Khattak, MBBS, Matthew Burge, MBBS Marion Harris, MBBS, James Lynam, MBBS, Louise Nott, MBBS, Fiona Day, Ph.D., Theresa Hayes, MBBS , Sue -Anne McLachlan, MBBS, Belinda Lee, MBBS, and Peter Gibbs, MD, of the Walter and Eliza Hall Institute of Medical Research, the Peter MacCallum Cancer Center, or the University of Melbourne in Melbourne, Australia.

This research was supported by the Australian National Health and Medical Research Council, Marcus Foundation, Virginia and DK Ludwig Fund for Cancer Research, Lustgarten Foundation, Conrad R. Hilton Foundation, Sol Goldman Charitable Trust, John Templeton Foundation, the National Institutes of Health (CA62924, CA009071, GM136577, CA06973), and the Eastern Health Research Foundation Linda Williams Memorial Fellowship.

Bert Vogelstein, Kenneth Kinzler and Nickolas Papadopoulos are the founders and owners of Thrive Early Detection, an exact science company. Kenneth Kinzler and Nickolas Papadopoulos are consultants for Thrive Early Detection, an exact science company. Bert Vogelstein, Kenneth Kinzler, Nickolas Papadopoulos and Joshua Cohen are consultants and own shares in Haystack Oncology. Nickolas Papadopoulos and Kenneth Kinzler serve on the Haystack Oncology Board of Directors. The companies named above have licensed previously described technologies related to the work described in this article from Johns Hopkins University. Bert Vogelstein, Kenneth Kinzler, Nickolas Papadopoulos and Joshua Cohen are the inventors of some of these technologies. The licenses of these technologies are or will be associated with royalty payments to the inventors as well as to Johns Hopkins University.