Clinical impact of molecular profiling in the national prospective cohort Solving Unknown Primary Cancer (SUPER) study.

person Tharani Sivakumaran Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia info_outline Tharani Sivakumaran, Matthew White, Owen Prall, Catherine Mitchell, Christine Dijkstra, Richard Rebello, Huiling Xu, Joseph Vissers, Sean Grimmond, Hui-Li Wong, Anna DeFazio, Bo Gao, Madhu Sudan Singh, Ian M. Collins, Christopher B. Steer, Mark Andrew Warren, Narayan Vaderahobali Karanth, David Bowtell, Richard W Tothill, Linda R. Mileshkin

Authors person Tharani Sivakumaran Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia info_outline Tharani Sivakumaran, Matthew White, Owen Prall, Catherine Mitchell, Christine Dijkstra, Richard Rebello, Huiling Xu, Joseph Vissers, Sean Grimmond, Hui-Li Wong, Anna DeFazio, Bo Gao, Madhu Sudan Singh, Ian M. Collins, Christopher B. Steer, Mark Andrew Warren, Narayan Vaderahobali Karanth, David Bowtell, Richard W Tothill, Linda R. Mileshkin Organizations Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia, Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia, Department of Pathology, Peter MacCallum Cancer Centre; and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia, University of Melbourne Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Melbourne, Australia, Department of Pathology, Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Australia, Peter MacCallum Cancer Centre, University of Melbourne Centre for Cancer Research and Department of Clinical Pathology, The University of Melbourne, Melbourne, Australia, University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Australia, The University of Sydney, Westmead Institute for Medical Research and Westmead Hospital, Westmead, NSW, Australia, Westmead Hospital, Sydney, NSW, Australia, Andrew Love Cancer Centre, Geelong, Australia, South West Healthcare, Warrnambool, VIC, Australia, Border Medical Oncology, Albury Wodonga Regional Cancer Centre and UNSW School of Clinical Medicine, Rural Clinical Campus, East Albury, NSW, Australia, Bendigo Health Oncology Department, Bendigo, Australia, Royal Darwin Hospital, Tiwi, NT, Australia, Peter MacCallum Cancer Center and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia, Sir Peter MacCallum Department of Oncology, University of Melbourne Centre for Cancer Research, Department of Clinical Pathology, University of Melbourne, Melbourne, Australia, Department of Medical Oncology and the Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre and the University of Melbourne, Melbourne, VIC, Australia Abstract Disclosures Research Funding Cancer Australia Victorian Cancer Agency, Australian Genomics Health Alliance Background: Cancer of unknown primary (CUP) is a common cause of cancer death, with a median survival < 12 months. SUPER is a prospective cohort study designed to create a national information and biobank of patients (pts) with no confirmed primary site following diagnostic work-up. We aimed to determine the impact of tumour molecular profiling on treatment decisions. Methods: 449 pts were recruited (2013-2021) over 3 phases from 12 Australian sites. Clinical information collected over 12 months included: demographics, treatments, investigations and clinico-pathological characteristics. Molecular tests were centrally performed and included comprehensive panel (CCP) sequencing and gene-expression tissue of origin (TOO) assays in Phase 1&2 and CCP and whole genome sequencing (WGS) in Phase 3. The number of genes reported on increased over the 3 phases. Molecular results were discussed in a molecular tumour board. Clinicians completed clinical management questionnaires before and after receiving molecular results. A combined retrospective evaluation of therapeutic actionability was applied to all DNA sequencing data using the TOPOGRAPH database. Results: Median age 63 years [19-86], with 81% ECOG 0-1 and 87% classified as unfavourable CUP subtype. Reporting timelines and rates of successful sequencing improved over time (Table). Clinically actionable genomic abnormalities were detected in 95/331 (29%) pts. Moderate or high match results on TOO assay were consistent with a suspected or later confirmed TOO as reported by clinicians in 81/195 (42%) pts in phase 1 + 2. Germline pathogenic mutations were detected in 34/331 (10%) pts. Molecular tests confirmed clinician’s treatment (started while awaiting results) was consistent with the most likely TOO in 170/331 (51%) pts. Clinicians reported that molecular tests resulted in a change in management in 11/118 pts (9%) in phase 1 and 40/213 (19%) pts in phases 2+3, with 17/51 (33%) pts changed treatment based on potential TOO determination. 11/51 (22%) pts could access treatment via standard pathways given a more specific tumour-type diagnosis and 15/51 (29%) pts were potentially eligible for clinical trials; however, only 7 pts were well enough for referral. Conclusions: The clinical impact of molecular testing in CUP improved over time as testing became more sophisticated and turnaround times improved. Clinicians suspected TOO pre-profiling was consistent with molecular results in half of the pts. Routine access to novel therapies in CUP remains a challenge. Phase 1 (2013-2015) Phase 2 (2017-2020) Phase 3 (2020-2021) Number of genes on CCP (n) 245 462 578 Molecular test successfully completed (n,%) CCP 98/118 (68) TOO 96/118 (81) CCP 111/120 (93) TOO 99/120 (83) CCP 90/93 (97) WGS 44/93 (47) Median turnaround time for reporting (days, range) CCP 186 (94-478) TOO 30 (14-245) CCP 60 (22-339) TOO 58 (13-339) CCP 49 (16-256) WGS 67 (39-221)