Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary
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Updated: Aug 12, 2025
Predictive Immune Modeling of Solid Tumors
Published on: February 25, 2020
Atara Posner1, Tharani Sivakumaran2,3, Andrew Pattison1
1Department of Clinical Pathology and Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia.
Background:
Cancer 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.
Methods:
Patients 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.
Results:
A 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.
Conclusions:
A 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.
Insights
Identifying biomarkers for cancer of unknown primary (CUP) is crucial for effective treatment. Gene expression profiling revealed a high immunotherapy response (IR) score as a sensitive predictor of response to immune checkpoint inhibitors (ICIs) in CUP patients.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Cancer of unknown primary (CUP) presents a significant clinical challenge due to its heterogeneity and limited treatment options.
- Optimal predictive biomarkers for immunotherapy response in CUP remain largely unknown.
- Immune checkpoint inhibitors (ICIs) show potential efficacy in a subset of CUP patients.
Purpose of the Study:
- To assess immune and genomic biomarkers for predicting immunotherapy response in cancer of unknown primary (CUP).
- To determine the tissue of origin (TOO) using gene-expression profiling (GEP) and DNA sequencing.
- To evaluate the efficacy of ICIs in CUP patients with identified biomarkers.
Main Methods:
- Gene-expression profiling (GEP) and DNA panel sequencing were performed on CUP patient samples.
- Immune and stromal gene expression, including immunotherapy response (IR) genes, were analyzed.
- Tumor mutation burden (TMB), gene mutations, and predicted tissue of origin (TOO) were assessed.
Main Results:
- 33% of CUP cases exhibited a high IR gene-expression score, and 16% had high tumor mutation burden (TMB).
- 47% of CUPs with a determined or suspected TOO belonged to ICI-responsive cancer types.
- Among CUP patients treated with ICIs, 29% responded, with responders frequently showing a high IR score and/or high TMB.
Conclusions:
- CUP tumors frequently possess genomic features associated with immunotherapy response.
- A high IR gene-expression score emerged as the most sensitive predictive biomarker for ICI response in CUP.
- Further validation in larger cohorts is warranted to confirm the predictive value of the IR score.
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