Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary

Author:

Posner AtaraORCID,Sivakumaran Tharani,Pattison Andrew,Etemadmoghadam Dariush,Thio Niko,Wood Colin,Fisher Krista,Webb Samantha,DeFazio Anna,Wilcken Nicholas,Gao Bo,Karapetis Christos S,Singh Madhu,Collins Ian MORCID,Richardson Gary,Steer Christopher,Warren Mark,Karanth Narayan,Fellowes Andrew,Fox Stephen B,Hicks Rodney J,Schofield Penelope,Bowtell David,Prall Owen W J,Tothill Richard WilliamORCID,Mileshkin Linda

Abstract

BackgroundCancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs.MethodsPatients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed.ResultsA total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p<0.001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease.ConclusionsA significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series.

Funder

Victorian Cancer Agency

AstraZeneca

Sydney Health Partners

National Health and Medical Research Council

Rivkin Center for Ovarian Cancer

University of Sydney

Medical Research Future Fund

Cancer Australia

U.S. Army Medical Research and Materiel Command

NSW Ministry of Health

Cancer Institute NSW

Publisher

BMJ

Subject

Cancer Research,Pharmacology,Oncology,Molecular Medicine,Immunology,Immunology and Allergy

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