Tumor Biopsies with Blood Monitoring Show Lesion-Specific Response

Metastatic tumors driven by drug-targetable genetic mutations become resistant to a targeted therapy drug and the usual practice is to biopsy a single metastatic lesion to test for new mutations that can guide the selection of next-line therapies.

A single-lesion biopsy at disease progression may vastly under represent the molecular heterogeneity of resistant tumor clones in an individual patient and may fail to detect the existence of distinct but important resistance mechanisms that could affect treatment responses.

Scientists at the Massachusetts General Hospital (Boston, MA, USA) and their Italian colleagues collected blood and tumor specimens from a patient with colorectal cancer metastatic to the liver, who responded to an epidermal growth factor receptor (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, resistance-conferring mutations.

The biopsy specimen was found to have a mitogen-activated protein kinase kinase (MEK1) mutation that had not been present before cetuximab treatment, and the authors demonstrated that 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), a combination that had been effective in a cellular model of cetuximab-resistant tumor cells with the same mutation.

Ryan Corcoran, MD, PhD, translational research director, and co-corresponding author of the study, said, “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, enhancing our ability to select effective therapies to overcome resistance.” The study was published on February 1, 2016, in the journal Cancer Discovery.

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