SUPER-NEXT brings together a multidisciplinary team of Australia’s leading cancer experts to improve the diagnosis, care and treatment of people with Cancer of Unknown Primary (CUP).
SUPER-NEXT uses state-of-the-art genomics approaches to interrogate the molecular landscape of CUPs. These studies aim to help resolve the cancer tissues of origin, as well as identify potential targeted treatment approaches, providing valuable new information to clinicians to help guide best cancer care.
The study will assess how best to integrate comprehensive real-time genomic profiling into current standard clinical assessment and decision making processes for CUP. Emphasis will be on timely delivery of clinically-relevant genomics insights to clinicians to improve clinical management and outcomes for patients.
To do this, SUPER-NEXT will systematically determine best practices by comparing different sequencing approaches, as well as developing novel assays to overcome common issues around tissue availability, including sequencing of genetic material from blood (ctDNA) and archived tissue (FFPE).
The use of genomic precision-based medicine has the potential to improve the duration and quality of life of CUP patients. SUPER-NEXT will also formally assess the societal and health economic benefits of utilising genomics in the clinical management of CUP.
What is CUP?
A diagnosis of CUP is made when a patient presents with metastatic (spread) cancer for which no primary cancer can be identified, despite extensive clinical assessment, imaging and pathological evaluation.
Since current cancer medicine is based largely on anatomical location, CUP significantly challenges established care paradigms. With no known tumour origin, CUPs are treated mostly with non-targeted chemotherapies, with very limited success.
New approaches that provide critical information to clinicians that can help guide diagnostic, treatment, or supportive care practices for people with CUP are therefore urgently needed.
What is genomics?
DNA is made up of building blocks (nucleotides) that string together to form a unique genetic sequence. The DNA inside our cells is organised into coding and non-coding regions. Coding regions are also known as ‘genes’, which encode for proteins.
Genomics is the study of DNA and genes, and of the changes that can occur to the genome during disease development, such as cancer.
DNA sequencing provides a molecular ‘fingerprint’ of the changes that have occurred within cancer cells. These changes are unique to each and every person and their cancer, however there are identifiable patterns that are recurrently seen in specific cancer types that arise from different organs or tissues.
Genomics can therefore provide important clues about where a cancer has come from, what is driving it’s growth and whether it may respond to different forms of therapy.
What types of sequencing will be performed in SUPER-NEXT?
Different genomics technologies reveal different aspects of a cancer, that may be assessed independently, or in combination, to provide a comprehensive understanding of a cancer’s makeup.
Depending on a range of parameters, such as how much tumour tissue is available to analyse, different sequencing approaches may be employed.
Targeted gene sequencing (Illumina TSO500)
Targeted gene sequencing panels analyse DNA samples for specific gene mutations. The TSO500 panel from our industry partner Illumina 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.
The TSO500 panel can also provide information on whether the genome is unstable (microsatellite instability) and the overall number of mutations present across the genome (tumour mutation burden), both of which are biomarkers of potential response to immune-based therapies.
Whole genome sequencing (WGS)
Unlike targeted gene sequencing, WGS analyses all of the genome, including both genes and non-coding regions. Therefore, WGS provides a deeper understanding of the genomic landscape and reveals extra details not covered by targeted sequencing.
In particular, WGS can reveal genome-wide mutational signatures that may provide clues for diagnosing a tissue of origin (ToO) of a cancer (for example, a ‘UV signature’ may indicate sun exposure and a skin origin).
Mutational signatures can also reveal the presence of particular driver mutations or processes that could indicate potential responses to certain types of therapy.
Whole transcriptome sequencing (WTS)
During the process of making proteins, genes are ‘transcribed’ into intermediate molecules, called mRNA transcripts. Collectively, the transcripts contained within a cell or tissue are called the ‘transcriptome’.
WTS measures the activity of all call genes and this type of analysis provides a detailed insight into the cancer cell “program”. Cancer cells in fact often retain a program that is somewhat reminiscent of the original tissue or cell type from which the tumour arose.
For example, metastatic breast cancer will often retain the activity of breast-related genes despite it spreading to distant sites such as the liver or bone. This information can be harnessed so that unknown primary cancers can be matched to tumours of known origin.
Gene activity can also indicate potential response to certain therapies, confirm different types of genetic mutations and fusions found in the DNA, or confirm evidence of prior exposure to viral infections (eg. HPV) that could also give clues into the tumour tissue of origin.
How does SUPER-NEXT work?
SUPER-NEXT brings together leading cancer scientists and clinicians from across Australia to deliver real-time molecular insights, leading to improved cancer care.
CUP patients are recruited to participate in SUPER-NEXT via SUPER – an established prospective clinical study involving more than 10 sites nationally. Patients are consented, and diagnostic tissues sourced from pathology archives. Blood is also taken. Depending on the sample size and type, DNA and RNA is extracted and subjected to different types of sequencing. Bioinformaticians and curation scientists scour through the data to find cancer-specific genetic variants to identify the most clinically relevant genomic features.
Personalised recommendations for diagnosis (eg. tissue of origin prediction), as well as treatment and clinical trial options, are finalised through a series of round-table discussions between curators, scientists, expert pathologists and clinicians, before being presented back to the patient’s own treating clinician to help guide patient management.
Patients are recruited via SUPER, sponsored by Peter MacCallum Cancer Centre. Further information on patient referrals can be found on the SUPER website.
SUPER-NEXT Study details
Associate Professor Richard Tothill – University of Melbourne Centre for Cancer Research
Professor Linda Mileshkin – Peter MacCallum Cancer Centre
Professor Penelope Schofield – Peter MacCallum Cancer Centre
SUPER-NEXT is supported by the Australian Federal Government’s Medical Research Future Fund (MRFF).
Richard Rebello – Cancer Genomics Post-Doctoral Scientist
- Useful links
Associate Professor Richard Tothill's Rare Disease Oncogenomics lab
Dr Richard Tothill's Rare Disease Oncogenomics (RADIO) laboratory is dedicated to translational research of rare and less common cancers. The lab's research uses advanced genomic and histology (cell-based) methods to comprehensively analyse tissues and blood samples taken from cancer patients.