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Liquid biopsies may help predict response to immune checkpoint inhibitors

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Bottom Line: The number of alterations detected in the DNA collected from blood samples (liquid biopsies) of cancer patients treated with immune checkpoint inhibitors was associated with response to the treatment.

Journal in Which the Study was Published: Clinical Cancer Research, a journal of the American Association for Cancer Research.

Authors: Senior author: Razelle Kurzrock, MD, director of the Center for Personalized Cancer Therapy at the University of California San Diego Moores Cancer Center; Lead author: Yulian Khagi, MD, a Hematology-Oncology fellow at the University of California San Diego Moores Cancer Center.

Background: "Immune checkpoint inhibitors, a class of immunotherapy, are transforming cancer treatment; however, overall only about 20 percent of patients respond to these drugs, and the drugs sometimes have significant side effects," said Kurzrock. "Therefore, it is important to have biomarkers that can help predict response to these relatively new drugs.

Most biomarkers used to predict response to checkpoint inhibitors are measured on tumor biopsy specimens and have limitations, said Khagi. "Biopsies can be painful, expensive, risky, and not always representative of the tumor characteristics overall," he said. "We wanted to identify an easily obtainable and easily interpretable biomarker that can predict response to checkpoint inhibitor therapy utilizing genomic sequencing of DNA that is shed from cancer cells into the bloodstream."

How the Study Was Conducted and Results: Using blood samples from 69 patients with different types of cancer treated with immune checkpoint inhibitor therapy, the investigators analyzed the ctDNA by next-generation sequencing (Guardant360 assay). Specifically, they counted the number of variants of unknown significance (VUS, alterations/mutations in the DNA whose association with disease risk is unknown).

Of the 69 patients, 29 percent had more than three VUS alterations and 71 percent had three or fewer VUS in their ctDNA.

After being treated with an immune checkpoint inhibitor, patients with more than three VUS in their ctDNA had significantly higher response rates (45 percent) compared with those who had three or fewer VUS (15 percent).

Among patients who had higher numbers of alterations of the VUS type, the median survival was not reached while those who had lower numbers of alterations of the VUS type had a median survival of only about 11 months.

Authors' Comments: "Our study demonstrated that high circulating tumor DNA [ctDNA, tumor DNA derived from a blood sample] alteration number was associated with response to checkpoint inhibitor therapy," Kurzrock said.

"Though the study was small, a significant difference could also be identified for a longer survival without progression of cancer and even a longer overall survival in the high versus low VUS alteration group," noted Khagi. "It is likely that, with larger studies, this difference will become more significant."

"Mutations lead to the production of abnormal proteins; the more mutations and abnormal proteins the tumors produce, the better the chance that one or more of these proteins will be 'detected' by the immune system," explained Kurzrock. "We showed that counting the mutations in the DNA floating in the bloodstream could help predict response to these new and exciting drugs that boost the immune system to attack cancer."

Khagi noted, "If verified by further studies, clinicians will be able to utilize the objective results of this simple blood test to make determinations about whether to use checkpoint inhibitor-based immune therapy in a variety of tumor types. It should also be noted that the cutoff points might be different as these blood tests evolve to detect more mutations in more genes."

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Limitations: The researchers noted that the study's retrospective nature and small sample size are key limitations.

Disclosures: This study was funded by the Joan and Irwin Jacobs Fund and the National Cancer Institute. Khagi has no significant conflicts of interest. Kurzrock receives consulting fees from XBiotech, Loxo, and Actuate Therapeutics; has an ownership interest in CureMatch Inc; receives speaker fees from Roche; and has research funds from Incyte, Genentech, Pfizer, Sequenom, Guardant Health Inc., Foundation Medicine, and Merck Serono.

To interview Yulian Khagi or Razelle Kurzrock, contact Julia Gunther at [email protected] or 215-446-6896.

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About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 37,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and patient advocates residing in 108 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 30 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 21,900 attendees. In addition, the AACR publishes eight prestigious, peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the Scientific Partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual investigator grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and other policy makers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit http://www.AACR.org.

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