SUPER Solving Cancer of Unknown Primary

A diagnosis of ‘Cancer of Unknown Primary’ CUP is made when a patient presents with metastatic disease for which no primary cancer can be identified despite extensive clinical assessment, imaging and pathological evaluation. Currently, there is very little information available to clinicians to help guide diagnostic, treatment, or supportive care practices for patients with CUP.

SUPER is a cohort study that was initiated by a multidisciplinary research team to address the difficulties that both clinicians and patients face when dealing with a diagnosis of CUP.

Professor Linda Mileshkin is the clinical lead for the SUPER studies, and works closely with Dr Richard Tothill (genomics lead) from the University of Melbourne and Professor Penelope Schofield (behavioural science lead) from Peter MacCallum Cancer Centre and Swinburne University of Technology

SUPER established a ‘bio and information bank’ which is a national information resource of clinical, molecular and patient questionnaire information that is currently being used to identify the supportive care and psychosocial needs of CUP patients, understand the clinical and molecular characteristics of CUP, as well as improving the diagnostic assessment of CUP patients. 

We have manuscripts in preparation exploring patient experiences throughout their CUP diagnosis and treatment journey. We have identified differences in needs between patients residing in metropolitan versus rural/regional areas and compared the economic, quality of life and psychosocial needs of CUP patients to other patients diagnosed with advanced cancer of a known primary. Some of the work we have already presented/published is listed below.

SUPER recruited patients from 11 metropolitan sites nationally in Victoria, New South Wales, South Australia, Northern Territory and Australian Capital Territory and well exceeded the target recruitment of 300 participants. To our knowledge, we are the only translational, cross-disciplinary research group in Australia investigating CUP.

SUPER-NEXT Complete Whole Genome Sequencing for Cancer of Unknown Primary

SUPER-NEXT is a prospective clinical study involving 16 sites nationally and an extension of the very successful SUPER study. We hope to recruit an additional 200 patients to the study, collect clinical and patient reported outcome data and biospecimens (fresh or archival tumour material and a blood sample).

Our goal is to develop and rapidly deploy genomics and precision medicine for CUP patients. SUPER-NEXT will generate a comprehensive molecular genomics report for individual patients that will be used to make recommendations for molecularly targeted therapy, immunotherapy or site-specific therapy, as well as help to correctly diagnose primary tissue of origin.

Molecular Tests for CUP patients

As part of the SUPER team’s larger body of work, we currently offer participants two molecular tests; a targeted gene sequencing panel (Illumina TSO500) test, as well as whole genome and transcriptome sequencing.

Both test reports are prepared simultaneously at the Peter MacCallum Cancer Centre (PMCC) and University of Melbourne Centre for Cancer Research (UMCCR)and results are fed back to clinicians within 4-6 weeks from receipt of tissue at Peter Mac.

See SUPER-NEXT: Solving Unknown Primary Cancer for more information.

The TSO500 panel is reported by the PeterMac molecular pathology team and contains a select set of genes or gene regions that are implicated in a range of cancer types, some of which may be targets of newer types of precision therapies.

This test can also provide information on whether the genome is unstable (microsatellite instability) and quantify the mutations present across the genome (tumour mutation burden), both of which are biomarkers of potential response to immune-based therapies.

Whole genome sequencingS analyses all of the genome, including both germline and somatic genes and non-coding regions and also measures their complete expression/activity.  This= provides a deeper understanding of the genomic and gene expression landscape and reveals extra details not covered by targeted sequencing. This information can be harnessed so that unknown primary cancers can be matched to tumours of known origin. Whole Genome sequenciung also reveal mutational and gene expression signatures which may suggest the tissue of origin of cancer and response to therapy. For example, a ‘UV signature’ may indicate sun exposure and a likely origin from the skin.

Figure 1. Patients will be consented, diagnostic tissues sourced from pathology archives and blood taken for germline DNA and ctDNA extraction. SUPER-NEXT will incorporate WGS and WTS and comparative targeted gene-panel testing. Targeted DNA sequencing of ctDNA will also be applied. Novel methods for detection of mutational signatures and tissue of origin classification will be developed. Curation of WGS/WTS and ctDNA data will be done through the VCCC Precision Oncology Program at University of Melbourne and Peter Mac. Results including driver gene mutations, mutational signatures, tissue of origin prediction and immune/stromal signatures will be discussed at the VCCC Molecular Tumour Board, together with any additional information from pathology review (including validation IHC stains and FISH

Recruitment sites


Peter MacCallum Cancer Centre
South West Healthcare – Warrnambool
Bendigo Cancer Centre
Alfred Hospital
Box Hill Hospital
Frankston Hospital – Peninsula Health
Geelong Hospital – Barwon Health


Royal Brisbane and Women’s Hospital

New South Wales

Blacktown Mount Druitt Hospital
Border Medical Oncology
Nepean Hospital 
Canberra Hospital

Northern Territory

Royal Darwin Hospital

South Australia

Flinders Medical Centre


Royal Hobart Hospital
Launceston General Hospital 

Primary Objectives

  • Demonstrate that WGS/WTS in CUP can assist diagnosis and provide evidence-based therapeutic leads  superior to current targeted DNA panel testing
  • Demonstrate circulating tumour DNA from CUP patients facilitates rapid mutation testing

Secondary Objectives

This project has two long-term objectives:

  1. To establish a biobank for analysis of CUP patient tumour and blood samples including establishment of organoid and patient-derived xenograft (PDX) models
  2. Describe the clinical characteristics and outcomes of CUP patients receiving genomic testing.


Peter MacCallum Cancer Centre


The project has received 4 sources of grant funding:

  1. ‘SUPER’ was funded by Cancer Australia. This study established a ‘biobank’ of 120 CUP patients, and 120 non-CUP patients which is a resource of clinical, molecular and patient questionnaire information for future studies. The study is based in NSW, SA and Melbourne Victoria.
  2. ‘SUPER plus’ is funded by the Victorian Cancer Agency. This study expanded SUPER by increasing patient numbers, and expanding recruitment sites across regional Victoria. In addition, clinical questionnaires were included here to assess whether receiving timely molecular profiling results would alter patient management and treatment choice.
  3. ‘Recuperate’ is funded by Cancer Australia, and compliments ‘SUPER plus’ by expanding the study nationally to include Northern Territory and the Australia Capital Territory. In addition, Recuperate also is assessing the costs associated with a diagnosis of CUP.
  4. ‘SUPER-NEXT’ is funded by the MRFF Genomics Health Future Mission and extends the very sucessful SUPER study, bringing recent innovations in the use of whole genome (WGS) and whole transcriptome (WTS) sequencing to increase our sensitivity to detect therapeutic targets in CUP patients and also help to correctly diagnose primary tissue of origin.

Principal Investigator/s

  • SUPER - CIA: Prof Penelope Schofield, CIB: Prof David Bowtell, CIC: Prof Linda Mileshkin
  • SUPER plus - CIA: Prof Linda Mileshkin, CIB: Prof Penelope Schofield, CIC: Prof David Bowtell
  • Recuperate - CIA: Prof Linda Mileshkin, CIB: Prof David Bowtell; CIC: Prof Penelope Schofield
  • SUPER-NEXT – Co-le by A/Prof Richard Tothill, CProf Linda Mileshkin, Prof Penelope Schofield

Contact details

Ms Samantha Webb

SUPER Study Coordinator

Email:  [email protected]

Publications & presentations

Moran S, Martínez-Cardús A, Sayols S, Musulén E, Balañá C, Estival-Gonzalez A, Moutinho C, Heyn H, Diaz-Lagares A, de Moura MC, Stella GM, Comoglio PM, Ruiz-Miró M, Matias-Guiu X, Pazo-Cid R, Antón A, Lopez-Lopez R, Soler G, Longo F, Guerra I, Fernandez S, Assenov Y, Plass C, Morales R, Carles J, Bowtell D, Mileshkin L, Sia D, Tothill R, Tabernero J, Llovet JM, Esteller M. Epigenetic profiling to classify cancer of unknown primary: a multicentre, retrospective analysis. Lancet Oncol. 2016 Oct;17(10):1386-1395.

Tothill RW, Shi F, Paiman L, Bedo J, Kowalczyk A, Mileshkin L, Buela E, Klupacs R, Bowtell D, Byron K. Development and validation of a gene expression tumour classifier for cancer of unknown primary. Pathology. 2015 Jan;47(1):7-12

Guccione, L., Mileshkin, L., Schofield, P., Bowtell, D. Carcinoma of unknown primary – rare but ripe for help from genomics? Cancer Forum, 2015; 39(1): 44-46

Tothill, R.W., Li, J., Mileshkin, L., Doig, K., Signakis, T., Cowin, P., Fellowes, A., Semple, T., Fox, S., Byron, K., Kowalczyk, A., Thomas, D., Schofield, P., Bowtell, D. (2013). Massively-parallel sequencing assists the diagnosis and guided treatment of cancers of unknown primary. Journal of Pathology.

Richard Wagland, Mike Bracher, Allison Drosdowsky, Alison Richardson, John Symons, Linda Mileshkin, Penny Schofield. Differences in experiences of care between patients with metastatic cancer of known and unknown primary: mixed method findings from the 2013 Cancer Patient Experience Survey (CPES). BMJ Open 2017 Sep 27;7(9):e017881. doi: 10.1136/bmjopen-2017-017881.

Christos S Karapetis, Lisa Guccione, Martin HN Tattersall,  Helen Gooden, Claire M Vajdic,  Sylvie Lambert,  Monica Robotin, Linda Mileshkin, Penelope Schofield. Perceptions of Cancer of Unknown Primary Site – A National Survey of Australian Medical Oncologists. Internal Medical Journal 2017 Apr;47(4):408-414.

Kamil Wolyniec, Lisa Guccione, Linda Mileshkin, Penelope Schofield: Poor understanding of the diagnosis predicts psychological morbidity in Cancer of Unknown Primary patients. Asia Pacific Journal of Clinical Oncology, 2018; 14: 88-89

Linda Mileshkin, Tharani Sivakumaran, Dariush Etemadmoghadam, Alexandra Murray, Richard Tothill, Lisa Guccione, Alison Freimund, Ellen Shaef, Anna DeFazio, Nicholas Wilcken, Bo Gao, Chris Karapetis, Madhu Singh, Ian Collins, Gary Richardson, Christopher Steer, Mark Warren, Cindy Bryant, Penelope Schofield, David Bowtell. Clinical impact of tissue of origin testing and mutation profiling in the Solving Unknown Primary Cancer (SUPER) national prospective study: Experience of the first two years. Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019) 3072-3072.

Kamil Wolyniec, Jessica Sharp, Smaro Lazarakis, Linda Mileshkin, Penelope Schofield. Understanding, information needs and communication preferences of cancer patients regarding treatment-focused genomic testing: A systematic review. PsychoOncology 2020;29(4):632-638

Arielle van Mourik, Gina Tonkin-Hill, John O’Farrell, Lavinia Tan, Richard Tothill, David Bowtell, Stephen Fox, Andrew Fellowes, Clare Fedele, Penelope Schofield, Tharani Sivakumaran, Hui Li Wong, Linda Mileshkin. A dedicated Carcinoma of Unknown Primary Clinic facilitates Molecular analysis which is associated with improved overall  survival outcomes. COSA Annual Scientific Meeting, Melbourne, Nov 2021 (Virtual rapid fire presentation)

Recent webinars from our team at