While that KRAS mutation was found nowhere in the MEK1-mutated lesion, it was detected in one of the lesions that continued progressing during combination therapy, implying 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," which can be repeated frequently and with little inconvenience to the patient, may be better for treatment monitoring than biopsies of single lesions.

"Overall, our study shows how distinct resistance mechanisms evolving in different metastases in the same patient can drive differential responses to subsequent therapy between individual tumor metastases," says Corcoran, who is an assistant professor of Medicine at Harvard Medical School. "These results highlight the possible pitfalls of selecting therapy based on molecular testing of a single tumor biopsy when resistance develops, but they also illustrate the potential promise of integrating liquid biopsy into clinical decision making in oncology."


He adds, "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."

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Co-lead authors of the Cancer Discovery paper are Mariangela Russo and Giulia Siravegna of the University of Torino, and Lawrence S. Blaszkowsky, MD, MGH Cancer Center. John Iafrate, MD, PhD, MGH Molecular Pathology was also a key contributor to the study. Grants to the MGH Cancer Center that supported this study include National Cancer Institute SPORE Program grant P50 CA127003 and grant 1K08CA166510, and a Damon Runyon Foundation Clinical Investigator Award.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $800 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2015, MGH returned into the number one spot on the 2015-16 U.S. News & World Report list of "America's Best Hospitals."

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