Liquid biopsy for colorectal cancer may lead to tumor therapy

A new study from the Washington University School of Medicine in St. Louis shows that a liquid biopsy examining blood or urine can help measure the effectiveness of colorectal cancer therapy that has just begun to spread beyond the original tumor. Such a biopsy can detect long-term illnesses and can serve as a guideline for deciding whether a patient should undergo further treatments due to some tumor cells that evade the initial attempt to eradicate the cancer.

The study appears on February 12 in the Journal of Clinical Oncology Precision Oncology, a journal of the American Society of Clinical Oncology.

Although a few liquid biopsies have been approved by the Food and Drug Administration, mostly for lung, breast, ovarian and prostate cancers, none have been approved for colorectal cancer.

Patients in this study called an oligometastatic colorectal cancer, meaning that each patient’s cancer spread beyond his or her original tumor, but only in a small number of places. Such patients undergo chemotherapy to shrink the tumors before undergoing surgery to remove the remnants of the primary tumor. There are debates in the field as to whether oligometastatic cancer should be treated after initial treatment as metastatic cancer, with more chemotherapy – or as localized cancer, with more surgery plus radiation in those limited areas.

A contribution to the problem is that physicians have a limited ability to predict how patients will respond to early chemotherapy, especially since most patients do not have access to cancer genome sequences to identify the DNA mutations in their original tumors.

“Being able to measure response to early chemotherapy without knowledge of the tumor’s mutations is a new idea and important in determining whether the patient responds well to the therapy,” said senior author Aadel A. Chaudhuri, MD, Ph.D. ., an assistant professor of radiation oncology. “It can provide guidance on the treatment of oligometastatic diseases. For example, if the liquid biopsy indicates that a patient is responding well to early chemotherapy, they may need to be offered the option of having more surgery, which may cure their disease. But if they did not respond well, the cancer is probably too widespread and cannot be eradicated with surgery, so the patients need to receive more chemotherapy to control their disease. ‘

Liquid biopsies for colorectal cancer detect tumor DNA that is free of the cancer and circulates in the blood and collects to a lesser extent in the urine. The biopsies described in this study are unique compared to other liquid biopsies developed in three important ways for colorectal cancer. First, most such biopsies were developed to detect metastatic cancers or to verify that local cancers had not spread. Second, most liquid biopsies for cancer depend on knowledge of the original tumor’s mutations, to see if the mutations still occur in the blood after treatment. But many patients do not get the opportunity to have their original tumors sequenced. Instead, the new biopsies rely on detecting DNA mutations in the blood or urine and comparing them to DNA mutations measured in the treated primary tumor after surgery. And finally, the urine biopsy is unique to colorectal cancer, as most urine biopsies are limited to the use of cancer in the genitals, especially bladder cancer.

“The levels of the circulating tumor DNA that we were able to measure in urine were lower than what we measured in blood, but it is still evidence that it is possible to measure residual diseases in a non-urinary cancer on this totally non-invasive way, “said Chaudhuri, who also treats patients at the Siteman Cancer Center at Barnes-Jewish Hospital and the Washington University School of Medicine. “We will need to develop more sensitive techniques to detect DNA from colorectal tumors in urine to make it a useful clinical test. But it is a promising start.”

The study showed that lower circulating DNA levels of the tumor correlated with better responses to early chemotherapy. Indeed, most patients who had undetectable levels of tumor DNA in blood samples also had no measurable cancer in their surgical samples.

There was also evidence that the residual disease detected in fluid biopsies was more predictable for the outcomes than residual diseases found in surgical samples. The researchers, for example, described the experience of one man who, after early chemotherapy to shrink or eliminate the tumor, still had detectable cancer removed during the operation. But his blood sample taken the same day showed no tumor DNA in circulation. He experienced long-term survival without cancer. On the other hand, a woman with no detectable cancer cells in her surgical sample, which was removed after early chemotherapy, was found to have tumor DNA in her blood sample on the same day. Eight months later, the cancer in her liver returned.

The study suggests that such liquid biopsies may help personalize the treatment of oligometastatic colorectal cancer. In addition to identifying patients at high risk of recurrence and making decisions about which traditional therapies to give, the patient was also identified to be suitable for immunotherapies and other effective treatments.

“Based on mutations in the blood biopsy, we can identify patients who could benefit from a type of immunotherapy called immune-control inhibitors after their initial treatment is completed,” Chaudhuri said. “We have also found mutations that can be targeted with drugs approved for other cancers. Our current study is observational, but it paves the way for the design of future clinical trials that could test some of these potential therapies.”

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More information:
Pellini et al. ctDNA MRD detection and personalized oncogenomic analysis in oligometastatic colorectal cancer of plasma and urine. JCO Precision Oncology. 12 February 2021.