“This is the most exciting time of my professional career,” says Professor David Thomas, “and I’ve been in medicine for 30 years.”
As Director of the Kinghorn Cancer Centre and Head of the Garvan Institute’s Cancer Division, Thomas is optimistic about recent advances in genomic medicine, particularly with regards to rare cancers.
He says understanding the genetic make-up of individuals is providing researchers with a more refined method of determining the cause of cancers, and taking away the presumption that all cancers in the same location – such as in the lung or bowel – have the same cause, and should be treated in the same way.
“It’s replacing old methods, such as a cancer’s appearance under a microscope or its anatomical classification, with molecular testing,” he says. “A sarcoma, a pancreatic cancer, and a lung cancer might all share the same mutation and respond to the same drug.”
The previous generation of genetic testing looked only at specific genes, searching for known causes of cancer. Now, for as little as $1,000, a person’s entire genetic make-up can be explored using an algorithm that hunts for abnormalities.
Research teams around the world can then collaborate to match any genetic abnormalities with those of other patients.
“We can match up an Australian patient with a rare condition to another person with that disease in California or Spain, matching their disease and the gene change,” says Professor Robyn Ward, Executive Director of the Faculty of Medicine and Health at the University of Sydney.
“Once you know that the patients all have the same thing, then you can say that there are three people with this condition, and you can study them together to find ways to treat or prevent the damage caused by the genetic change.”
Another benefit is that genomics gives a name to a disease that didn’t previously have one, allowing scientists to put things together in ways like never before. As Ward puts it, “You study apples, not a fruit salad.”
While important discoveries have been made using genomics, the complexity of interpreting genomic testing has brought with it new challenges.
Given that many diseases are not related to genomic abnormalities, genetic testing doesn’t benefit all patients. The challenge is to understand where genomics is useful and where it does harm.
Thomas mentions three major advances in genomics in the past five years.
Firstly, there has been a massive reduction in cost and an increased efficiency in genetic testing. In other words, you get more bang for your buck.
Secondly, there are many new drugs that specifically counter the effects of particular gene mutations.
“Every year a new drug comes out,” says Thomas. “Each time, the value proposition for performing a test increases.”
Thirdly, research has shown that some mutations are present across several different cancer types, rather than being restricted to one organ. This opens up more treatment options for those with resistant cancers.
“As the landscape of cancer is increasingly filled in, the opportunities for intervention are being recognised more and more in places where we wouldn’t have thought to look,” says Thomas.
For example, NTRK mutations are present in 1% percent of a broad range of cancers.
“It’s a gene that’s involved in nervous system development and is present in a whole range of sarcomas and other cancers, particularly infantile fibrosarcoma,” he says, noting that the new drug larotrectinib has been a “gamechanger” in tackling cancers linked to these mutations.
“There have been a number of children whose lives have been saved in the past 18 months because they have access to this new drug for the first time,” says Thomas.
“And 1% of all cancers is still a sizeable proportion of people: that’s about 1,400 diagnoses a year in this country, contributing to perhaps 500 deaths. That’s a significant number who might benefit from those drugs.”
In November 2018, larotrectinib was approved by the US Food and Drug Administration (FDA) for the treatment of any cancer with an NTRK mutation.
That was the second ever ‘pan-cancer’ approval, following the success of a drug in the US called pembrolizumab in treating multiple cancers on the basis of the presence of a particular mutation. It may be listed on the PBS in Australia in the future.
Drugs are usually only developed for one type of cancer, but with these two new pan-cancer drugs, we’re seeing a move towards more efficient and effective drug design.
“This supports the view that this trend is only set to continue, and is pivotally dependent on access to genomic testing,” says Thomas.
“It’s a massive step forward. It’s opened up the possibility of drug development across multiple cancers for the first time.”
Curing the incurable
Broad-spectrum chemotherapy drugs have been a great success in recent years. They now effectively treat 90% of testicular cancer and Hodgkin’s lymphoma.
What we need now, says Thomas, are new drug therapies for rare and incurable cancers, which kill around 25,000 Australians each year.
He explains that, 20 years ago, lung cancer had a “dreadful, dismal prognosis, without many effective options for therapy”.
Now, there are about a dozen therapies, thanks to a more comprehensive understanding of the genetics underlying the disease.
Another advantage of understanding an individual’s genetic make-up is that fewer patients need to be subjected to the often-damaging side effects of chemotherapy drugs that may not work for them.
“Rather than treating everybody with lung cancer with the same drug, knowing that only a fraction of people will respond, by doing these molecular tests, you are able to identify the individuals within that group who carry the relevant target, and spare all the other patients from futile treatment,” says Thomas.
The Garvan Institute is currently running the Australian Genomic Cancer Medicine Program, providing free molecular testing to all patients who have seemingly incurable cancers.
“Thirty to 60% of those people have something – a mutation – that we find might be useful for getting them onto trials of new drugs, if not actually drugs that are available on the PBS already,” says Thomas.
“We’ve had enormous support from state and federal governments and the pharmaceutical sector. I’m going to be really interested to see over the next five years how these trials create new treatment options for patients with rare cancers.”
By Ken Eastwood
Photo credit: Zita/Shutterstock.com