Poster Presentation 32nd Lorne Cancer 2020

Identifying biomarkers to guide immunotherapy treatment of cancer of unknown primary (#332)

Atara Posner 1 , Andrew Pattison 1 , Shiva Balachander 1 , Colin Wood 2 , Krista Fisher 2 , Andrew Fellowes 2 , Dariush Etemadmoghadam 2 , HuiLi Wong 2 , Eryn Dow 2 , Anna DeFazio 3 , Nicholas Wilcken 4 , Bo Gao 4 , Chris Karapetis 5 , Madhu Singh 6 , Ian Collins 7 , Gary Richardson 8 , Christopher Steer 9 , Mark Warren 10 , Narayan Karanth 11 , Penny Schofield 2 , David Bowtell 2 , Owen Prall 2 , Linda Mileshkin 2 , Richard Tothill 1 2
  1. Rare Disease Oncogenomics Lab, UMCCR, University of Melbourne, Melbourne, VICTORIA, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, Vic, Australia
  3. The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia
  4. Department of Medical Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW, Australia
  5. Department of Medical Oncology, Flinders University and Flinders Medical Centre, Melbourne , Vic, Australia
  6. Department of Medical Oncology, Barwon Health Cancer Services, Melbourne, Vic, Australia
  7. Department of Medical Oncology, South West Regional Cancer Care and Deakin University, Geelong, Vic, Australia
  8. Department of Medical Oncology, Cabrini, Melbourne, Vic, Australia
  9. Border Medical Oncology, Albury Wodonga Regional Cancer Centre, Albury, Vic, Australia
  10. Department of Medical Oncology, Bendigo Health, Bendigo, Vic, Australia
  11. Division of Medicine, Top End Health and Hospital Services, Alan Walker Cancer Centre, Darwin, NT, Australia

Cancer of unknown primary (CUP) is a metastatic cancer where a primary tissue of origin (ToO) evades detection despite extensive clinical investigation. CUP is typically treated with empiric chemotherapy, which provides limited survival benefit for most patients. Recent approaches to the workup and treatment of CUP have involved gene-expression profiling to resolve the likely ToO, enabling site specific therapy, and mutational profiling to identify targeted treatments. Current evidence from our group and others is that both of these methods can have some clinical benefit but only in a minority of cases.

Immunotherapy, which is efficacious across many cancer types, may also be effective in CUP. As part of the Solving Unknown Primary Cancer (SUPER) study we have reviewed the outcomes of 18 CUP patients treated with anti-PD1/PD-L1 immune checkpoint inhibition (ICI) therapy, showing that seven had partial response, five had stable disease and six had progressive disease. As part of SUPER, genomic data is available for 245 patients involving gene-expression profiling by custom Nanostring panel assay and/or cancer panel DNA sequencing.  We used the genomic data from 217 of these patients to explore interdependencies between predicted ToO (based gene-expression testing), immune gene-expression patterns, mutation profile and ICI response.  Tumour mutation burden was weakly correlated with a gene-expression score for adaptive immune response (AIR) based on averaged z-score values of six genes (CD8A, IFNG, PRF1, PD-L1, GZMA, GZMB) (Spearman rho=0.136) with many outliers exhibiting low TMB but high AIR scores. Amongst 18 patients treated with ICIs genomic data was available and we found that an elevated AIR score was more predictive of ICI response than TMB.  All patients with either stable disease or partial response to ICI treatment had positive AIR scores, whereas all patients with progressive disease had negative AIR scores.

Our results demonstrate that ICI therapy may benefit some CUP patients and that an adaptive immune response gene-expression score may be predictive of ICI treatment response.