Oral Presentation Clinical Oncology Society of Australia Annual Scientific Meeting 2023

Employing clinical whole-genome sequencing in the diagnostic work-up of cancer of unknown primary (#79)

Richard J Rebello 1 , Tharani Sivakumaran 2 , Clare Fedele 3 , Samantha Webb 2 , Ruining Dong 1 , Aidan Flynn 1 , Wendy Ip 1 , Georgia Scott 2 , Shohei Waller 2 , Owen Prall 2 , Catherine Mitchell 2 , Nadia Traficante 2 , Camilla Mitchell 1 , Joseph Vissers 1 , Huiling Xu 2 , Atara Posner 1 , Alexander Caneborg 1 , Shiva Balachander 1 , Krista Fisher 2 , Hui Li Wong 2 , Ian M Collins 4 , Mark Warren 5 , Bo Gao 6 , Madhu Singh 7 , Christopher Steer 8 , Pei Ding 9 , Stephen Quinn 10 , Narayan Karanth 11 , Anna Kuchel 12 , Rachel Wong 13 , Zhen Siow 13 , Mark Shackleton 14 , Zee Wan Wong 15 , Louise Nott 16 , Shamsudeen Padinharakam 17 , Sarah Jane Dawson 2 , Rodney Hicks 18 , David Bowtell 2 , Andrew Fellowes 2 , Stephen Fox 2 , Louisa Gordon 19 , Oliver Hofman 1 , Sean Grimmond 1 , Penny Schofield 10 , Linda Mileshkin 2 , Richard Tothill 1
  1. University of Melbourne, Melbourne, VICTORIA, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  3. CSL Innovation, Melbourne, VIC, Australia
  4. South West Healthcare, Warrnambool, Victoria, Australia
  5. Bendigo Cancer Centre, Bendigo Health, Bendigo, Victoria, Australia
  6. Westmead Private Hospital, Westmead, New South Wales, Australia
  7. Barwon Health Cancer Services, Barwon, Victoria, Australia
  8. Border Medical Oncology, Albury Wodonga Regional Cancer Centre, New South Wales, Australia
  9. Nepean Cancer Care Centre, Nepean Hospital, Kingswood, New South Wales, Australia
  10. Swinburne University of Technology, Department of Health Science and Biostatistics, Melbourne, Victoria, Australia
  11. Medical Oncology Department, Alan Walker Cancer Centre, Royal Darwin Hospital, ., Darwin, Australia
  12. Department of Medical Oncology, The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
  13. Eastern Health Clinical School, Monash University, Melbourne, Victoria, Australia
  14. Department of Medical Oncology, Alfred Health, Melbourne; Central Clinical School, Monash University, Melbourne, VIC, Melbourne, Victoria, Australia
  15. Oncology Unit, Peninsula Health, Peninsula, Victoria, Australia
  16. Royal Hobart Hospital, Hobart, Tasmania, Australia
  17. Launceston General Hospital, Launceston, Victoria, Australia
  18. Department of Medicine, St. Vincent's Hospital, Melbourne, VIC, Australia
  19. QIMR Berghofer Medical Research Institute, Population Health Department, Brisbane, Queensland, Australia

Introduction: Cancer of unknown primary (CUP) is a metastatic cancer that evades a primary site diagnosis and is the 6th most common cause of cancer-related death in Australia. CUP patients have difficulty in accessing precision treatments given tissue of origin (TOO) is often a prerequisite. Whole genome and transcriptome sequencing (WGTS) can help resolve a TOO and identify precision treatments in CUP, but requires validation in a real-world setting. 

Study design: Molecular testing was applied to CUP patients from 12 Australian sites using gene-panel (Illumina TSO500) and/or WGTS. Patient eligibility included a standardised diagnostic work-up (ESMO guidelines). Patients were excluded if they had a poor ECOG (>2). Curated molecular reports were delivered to the treating physician and pathologists via a molecular tumour board. Diagnostic impact of testing was assessed by surveying pathologists and treating clinicians.

Results: We recruited 203 patients overs 18 months to the SUPER-NEXT study. For molecular testing, 90% of cases involved formalin-fixed paraffin embedded (FFPE) tissues; predominantly core tissue biopsies (81.5%). Fifty-three percent (107/203) were suitable for both WGTS and TSO500 cancer panel. Twenty-six percent (53/203) of cases were suitable for TSO500 only and 18% (36/203) received no test. Additional reportable variants were found by WGTS in 85.7% of cases receiving both tests. An algorithmic TOO classifier (CUPPA) was applied to WGTS data and predicted TOO with high-likelihood in 52% of cases. Based on pathologist surveys, a WGTS+CUPPA result impacted the diagnostic opinion for 80% (86/107) of cases and assisted single site TOO diagnosis in 64% (68/107) that received WGTS+CUPPA compared with only 38% (17/45) of cases receiving TSO500 only.

Conclusion: Clinical WGTS was possible in more than half of patients with CUP despite use of FFPE samples. WGTS was superior to TSO500 panel in resolving a cancer diagnosis. This data supports the utility WGTS as part of a histopathology work up for CUP patients.