Single-Lesion Biopsies Miss Targetable Mutations in Patients With Colorectal Cancer

Single-lesion biopsy may be insufficient to identify resistance mutations for targeted therapy selection, according to investigators at Massachusetts General Hospital (MGH) Cancer Center and the University of Torino in Italy. They have found that a single-lesion biopsy may miss additional targetable mutations that arise in different metastases. 

In the February issue of Cancer Discovery, the researchers report that analyzing tumor DNA fragments in the bloodstream may give a more complete picture of the molecular basis of a patient’s cancer. They report that molecular analysis of a single-lesion biopsy, which is currently the diagnostic standard for targeted therapy trials, may regularly fail to detect clinically relevant molecular alterations. In addition, these mixed molecular alterations may be responsible for lesion-specific or even subclone-specific clinical response and consequent treatment failure.

“We found that the molecular mechanism of resistance that emerges in one metastatic lesion while on a given therapy can be totally different from the mechanism driving resistance in a neighboring lesion in the same patient,” said co-study author Ryan Corcoran, MD, PhD, who is translational research director for the Center for Gastrointestinal Cancers at the MGH Cancer Center, in a news release. “Our conclusion is that the standard practice of performing molecular testing on a biopsy from a single metastatic lesion may be inadequate and that circulating tumor DNA testing may better capture the molecular diversity in a patient’s tumor.”

Dr. Corcoran and colleagues report on a patient with colorectal cancer metastatic to the liver, who responded to the EGFR antibody drug cetuximab (Erbitux) for 15 months. When the patient’s disease became resistant to therapy, a biopsy of a single liver metastasis was performed to analyze for new mutations.

The specimen was found to have an MEK1 mutation that had not been present before cetuximab treatment. The researchers also found that the MEK1 mutation could drive resistance to EGFR antibodies in laboratory models of colorectal cancer. Based on those findings, the patient was treated with a combination of the MEK inhibitor trametinib (Mekinist) and another EGFR antibody panitumumab (Vectibix)--the metastatic liver lesion regressed upon treatment with this combination therapy.

An analysis of circulating tumor DNA showed that in addition to the MEK1 mutation, a previously undetected KRAS mutation was present in blood samples taken at the start of treatment. During combination therapy with trametinib and panitumumab, levels of the MEK1 mutation detectable in the blood declined, but levels of the KRAS mutation increased despite therapy and continued progressing during combination therapy. This implied that separate resistance mutations had developed and were driving the growth of different metastases.

Noting the ability of circulating tumor DNA analysis to identify both resistance mutations, the authors emphasize that such “liquid biopsies,” may be better for treatment monitoring than biopsies of single lesions. 

“There has been dramatic progress in our ability to analyze circulating tumor DNA in recent years, and the technology continues to evolve. But while some assays are currently available for clinical use, we are not at a point where these liquid biopsies can replace tumor biopsies entirely. We need to learn how best to exploit the potential of liquid biopsies to provide real-time monitoring of a patient’s tumor as it develops resistance to therapy, allowing us to anticipate both the timing and the cause of resistance and modify treatment accordingly,” said Dr. Corcoran.