Our sarcoma research

‘My lab focuses on the genetics of sarcomas, as well as cancers more broadly in young adults. We use patient-centred approaches to understanding human disease, complemented with cellular and animal models to explore biological processes relevant to cancer,’ said Professor Thomas.

Because hereditary predisposition is a key risk factor for sarcoma, Professor David Thomas’s team have created a large informative group of patients and families affected by cancer, and are applying state-of-the-art genomic technologies to understand the basic question of ‘Why me?’.

‘Neglected and understudied illnesses, such as sarcoma, have such devastating impacts because not only do they comprise more than 1 in 5 cancers, but they are more lethal than most cancers, representing 1 in 3 cancer deaths. They are neglected because they are individually rare, but taken together they comprise a major health challenge. The good news is that I believe neglected cancers offer the greatest opportunities for breakthroughs, precisely because they have not been studied in as much detail. These approaches offer greater possibilities of early detection and better treatment, as well as novel clinical trials that will increase access by cancer patients to new therapies.’

This is a critical time for the development of personalised medicine and the use of genomics in clinical care.

‘Cancer treatments have traditionally been very toxic and may have life-long consequences. There is no point in using treatments that won’t work and may cause harm,’ said Professor Thomas.

‘And all too often, we detect cancers too late to cure them. It is important that we use the right drug in the right person; and also that we understand who is at risk of cancer, so we can direct our efforts towards early detection in the most effective way, particularly in the young, where cancer is so rarely suspected.’

Unlike the more common and well-studied cancers like breast, bowel, lung or melanoma, rare and neglected cancers, like sarcomas, often don’t have well-defined treatments.

‘Because sarcomas are understudied, there simply isn’t the evidence-base for treatment, which means that we need to tailor treatment for each individual – and if we can’t do this, we are often left without accepted or effective therapeutic options.’

Genomics information can be used to guide treatments, estimate the risk of relapse, make reproductive choices and define surveillance for second cancers. It can also be used to pick up cancers in apparently unaffected family members.

The Molecular Screening and Therapeutic (MoST) program is tailored for people with rare and neglected cancers in general and will benefit people with sarcomas. In the MoST trials, we offer tumour testing and treatments for people with no other options. Using genomics, we test the tumours and target those mutations with drugs and other targeted therapies. The Surveillance in Multi-Organ Cancer (SMOC+) study looks at cancer risks and surveillance, and with MoST we have new clinical treatments.

The MoST program will evaluate the effectiveness of new treatments using an innovative clinical trial design where patients will undergo molecular screening and then be assigned to substudies of targeted therapies based on specific genetic alterations. The program includes an immunotherapy substudy open to patients who cannot be matched with a targeted treatment.

‘It is important to bring genomics into clinical care. We need to translate fundamental scientific knowledge into interventions that help patients – to assess cancer risk or to evaluate molecular targeted therapies.’

The International Sarcoma Kindred Study (ISKS) is an Australian initiative investigating the heritable aspects of adult-onset sarcoma. Recruitment began at six sites in Australia in 2009 and has since expanded to 21 sites globally, including in France, India, New Zealand, USA, UK and Korea, but with the global study centre in Australia as a biospecimen storage facility, laboratory and database repository.

Sarcoma patients and their families are asked to complete a family pedigree and questionnaire and give blood samples. There are more than 1700 families involved worldwide, with recruitment aiming for 3000 families internationally.

To date more than 1000 individuals with sarcoma have been screened and the researchers have uncovered numerous new genetic risk factors for the cancer and, in a world first for any cancer type, they showed how carrying two or more of these rare mutations increases an individual’s cancer risk.

The ISKS team looked at a ‘gene panel’ of 72 genes in each participant, identifying a number of new genes significantly increasing the risk of developing sarcoma, including mutations in the genes ERCC2, ATR, BRCA2 and ATM. Importantly, for individuals carrying mutations in two genes the risk of developing sarcoma was measurably higher than in those with only a single mutation. And in carriers of three or more mutations the risk was greater still.

‘Until now, we’ve been limited to single-gene thinking, so we tell patients, for instance, that carrying a BRCA1 mutation means your breast cancer risk is higher, or that your risk of sarcoma and other cancers is higher because you’ve got a particular p53 mutation.

‘The study shows us that the landscape of cancer risk is far more complex than that. We can now see that the risk for developing sarcoma is equally due to the combined effect of multiple genes, and that the more mutations you carry, the earlier the onset of cancer.

‘These previously invisible effects are at least as large as the impact of a mutation in p53 itself, currently the strongest known genetic cause of sarcoma. Being able to identify these at-risk individuals, and their families, means that we can manage risk better and help those people to get the care they need, when they need it.

‘Understanding the genetic drivers that give a person an increased risk of cancer also helps us understand how best to treat that person’s cancer. And for about a third of the individuals we studied, the gene mutations they carry have implications for how they should be treated.

‘A lot of what we’re doing going forward is looking at how we use genetic information about risk to alter the way we treat people. The more we know, the more precisely we can match individuals with the best possible treatment for them.’

As ionising radiation increases cancer risks, it is important to avoid diagnostic and therapeutic radiation exposure in high-risk individuals where mutations are identified and it is possible to do so without compromising care.

Taken together, the pace of recent developments in genomic screening programs suggests that the issue of genetic testing and management will become an increasingly important area for research.

‘We are moving from the International Sarcoma Kindred Study (ISKS) to a new generation of cancer risk management with the world first Surveillance in Multi-Organ Cancer+ (SMOC+) study that looks at families carrying an excess of genetic risk over an extended period of time'

‘Our goal is to recruit 3000 families with sarcoma to the ISKS and then to undertake whole genome sequencing of these individuals, to map comprehensively the genetic basis of developing these rare diseases of the young.

‘So far, SMOC+ has delivered important information for family members who don’t yet have cancer. In clinical practice, screening BRCA1 carriers reveals a rate of asymptomatic cancer of 2 women for every 100 screened. In the SMOC+ study to date, of 27 at-risk individuals screened, 3 were found to have asymptomatic but curable high-grade cancers. SMOC+ is showing that information about genetic risk can be used to offer personalised surveillance that could save lives.’