Evaluation of Targeted Next-Generation Sequencing for the Management of Patients Diagnosed with a Cancer of Unknown Primary

Abstract

Background: Cancer of unknown primary (CUP) comprises a heterogeneous collection of malignancies that are typically associated with a poor prognosis and a lack of effective treatment options. We retrospectively evaluated the clinical utility of targeted next-generation sequencing (NGS) among CUP patients to assist with diagnosis and identify opportunities for molecularly guided therapy.

Patients and methods: Patients with a CUP at Moffitt Cancer Center who underwent NGS between January 1, 2014 and December 31, 2019, were eligible for study inclusion. Next-generation sequencing results were assessed to determine the frequency of clinically actionable molecular alterations, and chart reviews were performed to ascertain the number of patients receiving molecularly guided therapy.

Results: Ninety-five CUP patients were identified for analysis. Next-generation sequencing testing identified options for molecularly guided therapy for 55% (n = 52) of patients. Among patients with molecularly guided therapy options, 33% (n = 17) were prescribed a molecularly guided therapy. The median overall survival for those receiving molecularly guided therapy was 23.6 months. Among the evaluable patients, the median duration of treatment for CUP patients (n = 7) receiving molecular-guided therapy as a first-line therapy was 39 weeks. The median duration of treatment for CUP patients (n = 8) treated with molecularly guided therapy in the second- or later-line setting was 13 weeks. Next-generation sequencing results were found to be suggestive of a likely primary tumor type for 15% (n = 14) of patients.

Conclusion: Next-generation sequencing results enabled the identification of treatment options in a majority of patients and assisted with the identification of a likely primary tumor type in a clinically meaningful subset of patients.

Keywords: cancer genetics; cancer of unknown primary; next generation sequencing; pharmacogenetics; precision medicine.

Figure 1.

Therapeutic opportunities identified utilizing next-generation sequencing to guide the treatment of cancer of unknown primary.

Figure 2.

Overall survival (OS) Kaplan–Meier curves by therapy (molecularly guided vs standard options).

Figure 3.

Duration of molecularly guided therapy for patients treated in the first line of therapy. (Mutation predicted to cause a loss-of-protein function (‡).).

Figure 4.

Duration of molecularly guided therapy for patients treated in the second line or later. (Loss-of-function mutation (‡), activating mutation (¥)).

Figure 5.

Treatment durations for three cases that received molecularly guided treatments for multiple lines of therapy. (Loss-of-function mutation (‡), activating mutation (¥)).