Comprehensive analysis of cancers of unknown primary for the biomarkers of response to immune checkpoint blockade therapy

Eur J Cancer. 2018 May;94:179-186. doi: 10.1016/j.ejca.2018.02.021. Epub 2018 Mar 20.

Abstract

Background: Cancer of unknown primary (CUP) accounts for approximately 3% of all malignancies. Avoiding immune destruction is a major cancer characteristic and therapies aimed at immune checkpoint blockade are in use for several specific cancer types. A comprehensive survey of predictive biomarkers to immune checkpoint blockade in CUP were explored in this study.

Methods: About 389 cases of CUP were analysed for mutations in 592 genes and 52 gene fusions using a massively parallel DNA sequencing platform (next-generation sequencing [NGS]). Total mutational load (TML) and microsatellite instability (MSI) were calculated from NGS data. PD-L1 expression was explored using immunohistochemistry (with 5% cutoff value).

Results: High TML was seen in 11.8% (46/389) of tumours. MSI-high (MSI-H) was detected in 7/384 (1.8%) of tumours. Tumour PD-L1 expression was detected in 80/362 CUP (22%). A small proportion of CUP cases harboured genetic alterations of negative predictive biomarkers to immune checkpoint inhibitors (predictors to hyperprogression) including MDM2 gene amplification (2%) and loss of function JAK2 gene mutations (1%). Amplifications of CD274 (PD-L1) and PDCD1LG2 (PD-L2) genes were also rare (1.4% and 0.8%, respectively). The most frequently mutated genes were TP53 (54%), KRAS (22%), ARID1A (13%), PIK3CA (9%), CDKN2A (8%), SMARCA4 (7%) and PBRM1, STK11, APC, RB1 (5%, respectively).

Conclusions: Using a multiplex testing approach, 28% of CUP carried one or more predictive biomarkers (MSI-H, PD-L1 and/or TML-H) to the immune checkpoint blockade, providing a novel option for treatment in patients with CUP.

Keywords: Cancer of unknown primary (CUP); Immune checkpoint inhibitors; Targeted therapy.

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Immunological / therapeutic use*
  • B7-H1 Antigen / analysis
  • B7-H1 Antigen / biosynthesis
  • Biomarkers, Tumor / genetics*
  • Female
  • Humans
  • Male
  • Microsatellite Instability
  • Middle Aged
  • Mutation
  • Neoplasms, Unknown Primary / genetics*

Substances

  • Antineoplastic Agents, Immunological
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human