Liquid Biopsies Identify Distinct Genomic Profiles With Potentially Targetable Alterations in Carcinoma of Unknown Primary

Key Points

  • Using next-generation sequencing, researchers found a total of 66% of patients had at least one characterized genetic mutation, and 43.9% harbored two or more.
  • The most prevalent variants were found in the genes TP53, KRAS, PIK3CA, BRAF, and MYC.
  • Among patients with cancer of unknown primary found to have at least one characterized alteration, 99.7% of patients had theoretically actionable genetic mutations.

Next-generation sequencing of circulating tumor DNA (ctDNA) identified distinct genomic profiles with potentially targetable alterations in 99.7% of patients with carcinoma of unknown primary (CUP) who have detectable alterations, according to results published by Kato et al in Cancer Research.

“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 senior study author 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. “This is important because, with [carcinoma of unknown primary], it has been problematic to determine how to treat patients.”

This rare metastatic disease—cancer with no identifiable primary tumor—has an incidence of 7 to 12 cases per 100,000 per year.

“There is a large unmet need in the [carcinoma of unknown primary] patient population. Response to standard platinum-based combination chemotherapy is modest at best, and overall median survival is poor—about 6 to 8 months,” said first author 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.

Study Findings

Using liquid biopsies from 442 patients with [carcinoma of unknown primary], the researchers interrogated 54 to 70 genes in ctDNA using next-generation sequencing. They found that a total of 66% of patients had at least one characterized genetic mutation, and 43.9% harbored two or more.

The most prevalent variants were found in the genes TP53, KRAS, PIK3CA, BRAF, and MYC. Among [carcinoma of unknown primary] patients found to have at least one characterized alteration, 99.7% of patients had theoretically actionable genetic mutations, either with off-label use of U.S. Food and Drug Administration–approved agents or agents currently under investigation.

Case Studies

Next, the researchers conducted two case studies to demonstrate the clinical relevance of their findings. In the first case, which was evaluated by Brian Leyland-Jones, MD, PhD, and colleagues collaborating from Avera Cancer Institute, they analyzed a series of five liquid biopsies from a woman with metastatic [carcinoma of unknown primary] 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,” Dr. 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–programmed cell death protein 1 (PD-1) checkpoint inhibitor. Within 8 weeks, the patient had a partial response (36.4% tumor reduction) and a rapid decline in tumor marker CA-19-9, an antigen used to monitor treatment response.

“Our results show that ctDNA evaluation is feasible in [carcinoma of unknown primary] and that most patients have a unique somatic profile with pharmacologically actionable mutations,” Dr. Kurzrock said. “Liquid biopsies can be used to guide and evaluate treatment response in patients with [carcinoma of unknown primary] and should be included in next-generation clinical trials.”

Limitations of the study included that the [carcinoma of unknown primary] diagnosis was reported by referring physicians and the database was deidentified, so it was not possible to evaluate clinical characteristics and outcomes.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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