News Release

Liquid biopsies find distinct genomic profiles in most patients with carcinoma of unknown primary

Peer-Reviewed Publication

American Association for Cancer Research

Bottom Line: Next-generation sequencing of circulating tumor DNA (ctDNA) identified distinct genomic profiles with potentially targetable alterations in 99.7 percent of patients with carcinoma of unknown primary (CUP) who have detectable alterations.

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

Authors: Shumei Kato, MD, a medical oncologist and assistant clinical professor in experimental therapeutics in the Division of Hematology and Oncology and Center for Personalized Cancer Therapy at Moores Cancer Center; Razelle Kurzrock, MD, chief of the Division of Hematology and Oncology at the University of California San Diego School of Medicine and Director of the Center for Personalized Cancer Therapy at UC San Diego Moores Cancer Center in San Diego, California.

Background: CUP is a rare metastatic disease with no identifiable primary tumor with an incidence of 7 to12 cases per 100,000 per year. "There is a large unmet need in the CUP patient population. Response to standard platinum-based combination chemotherapy is modest at best and overall median survival is poor, about six to eight months," said Kato.

How the Study Was Conducted and Results: Using liquid biopsies from 442 patients with CUP, the researchers interrogated 54 to 70 genes in ctDNA using next-generation sequencing. They found that a total of 66 percent of patients had at least one characterized genetic mutation and 43.9 percent harbored two or more. The most prevalent variants were found in the genes TP53, KRAS, PIK3CA, BRAF and MYC. Among CUP patients found to have at least one characterized alteration, 99.7 percent of patients had theoretically actionable genetic mutations, either with off-label use of FDA-approved agents or agents currently under investigation.

Next, the researchers conducted two case studies to demonstrate the clinical relevance of their findings. In the first case, which was evaluated by Dr. Brian Leyland-Jones and colleagues who collaborated from Avera Cancer Institute, they analyzed a series of five liquid biopsies from a woman with metastatic CUP and identified dynamic changes in ctDNA that corresponded to therapeutic interventions. "This case demonstrated that cancer can change dramatically during treatment and the changes can be identified using simple blood tests to allow for customizing therapies," Kato explained.

In the second case, the investigators matched a patient, with adenocarcinoma of unknown primary with liver and abdominal lymph node metastases harboring KRAS and MLH1 mutations, to combination treatment with trametinib (Mekinist), a MEK inhibitor targeting downstream KRAS mutation, and nivolumab (Opdivo), an anti-PD1 checkpoint inhibitor. Within eight weeks, the patient had a partial response (36.4 percent tumor reduction) and a rapid decline in tumor marker CA-19-9, an antigen used to monitor treatment response.

Authors' Comments: "Our research is the first to show that we can use a simple blood test to evaluate ctDNA effectively in this difficult to diagnose patient population," said Kurzrock. "This is important because, with CUP, it has been problematic to determine how to treat patients."

"Our results show that ctDNA evaluation is feasible in CUP and that most patients have a unique somatic profile with pharmacologically actionable mutations," she added. "Liquid biopsies can be used to guide and evaluate treatment response in patients with CUP and should be included in next-generation clinical trials."

Study Limitations: CUP diagnosis was reported by referring physicians and the database was de-identified, so it was not possible to evaluate clinical characteristics and outcomes.


Funding & Disclosures: This study was supported by funds from the Joan and Irwin Jacobs Fund and by the National Cancer Institute. Kurzrock receives consulting fees from Xbiotech, Roche, and Actuate Therapeutics; has an ownership interest in CureMatch Inc.; and has research funds from Incyte, Genentech, Pfizer, Sequenom, Guardant Health Inc., Foundation Medicine, and Merck Serono. Kato declares no conflict of interest.

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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 policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit

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