Stephen Huff was about to get married when he had a scan to investigate why he had been feeling short of breath. He was a fit 29-year-old who had played professional baseball and never smoked, so he wasn’t expecting the diagnosis: stage 4 lung cancer. “I had multiple spots all in my lungs, my neck, my spine, my liver, my brain – just everywhere,” he says. “I put on a brave front, but deep down I was terrified. I didn’t know if I’d be here in six months.”
Luckily for Huff, his mother, a cancer researcher, encouraged him to get a new kind of test that is quietly revolutionising treatment. Rather than focusing on the place in the body where the cancer originated – for example, the lungs, bowel or skin – the new approach focuses on genes. The aim is to pinpoint the exact mutation driving the tumour, so it can be switched off with targeted drugs that act like guided missiles.
Through this fresh approach, Huff “hit the lottery” – as his oncologist told him – because it meant he could be treated with a recently approved drug that specifically targeted the genetic alteration driving his cancer. Within weeks, Huff began to feel better. “My first scan showed that basically every tumour site had either shrunk or gone away completely,” he says.
Now, thanks to this precision oncology method, more and more people like Huff are surviving cancers that were once considered a death sentence, like lung, pancreatic and brain cancer. “Being able to identify exactly what makes a cancer tick is having an incredible impact,” says David Thomas, a pioneer of precision oncology at the University of New South Wales in Sydney. But surprisingly, it has received little fanfare outside of the medical community so far.
In the past, most cancer drugs were discovered by chance. The common chemotherapy drug cisplatin, for example, was stumbled upon by scientists playing around with platinum electrodes and bacteria in the 1960s. Paclitaxel, another widely used drug, was isolated from the bark of the Pacific yew tree and hit on during random screening of plant extracts. Both work by killing rapidly dividing cells, regardless of whether they are in a person’s cancer or elsewhere. This is like dropping a large bomb on the body, inflicting mass damage and causing side effects like fatigue, nausea and hair loss, but often still missing cancer cells hiding inside deep bunkers.
Over time, blind trial and error worked out which of these drugs worked best for each cancer type, based on its anatomical location and appearance under a microscope. The type of lung cancer that Huff had, for example, was non-small cell lung cancer, named for the large size of its cells when viewed under a microscope. Decades of trialling different drugs in this specific cancer type identified that a combination of cisplatin and paclitaxel seemed to treat it best. However, it still gave people an average of only eight months to live.
The new era of precision oncology is instead informed by the exact gene that has gone awry in a person’s cancer, rather than by its broad anatomical location or cellular appearance. “Cancer is fundamentally a genetic disease,” says Thomas. “So, by pinpointing the precise genes responsible for cancer, and rationally designing drugs to target those individual genes, we are making rapid strides.”
The first seeds of precision oncology were planted in the 1990s and early 2000s, when scientists discovered a handful of genes that spurred cancer growth if they became mutated or mixed up. A gene called , for example, was shown to be relevant to the development of some lung cancers, and two others, , to chronic myeloid leukaemia, a blood cancer. These discoveries paved the way for some of the first targeted drugs, including one called imatinib, which blocks an abnormal cancer-promoting protein that is produced when the and genes mistakenly fuse together. Since imatinib was introduced in 2001, the survival rate for chronic myeloid leukaemia eight years after diagnosis has shot up to almost 90 per cent.
The field picked up momentum in the 2010s, when it became possible to rapidly sequence not just one gene in a cancer’s cells, or a small panel of genes, but hundreds in a single test. It became known as comprehensive genomic profiling, or comprehensive biomarker testing.
The test that Huff undertook, for instance, looked at over 300 genes in a biopsy of one of the tumours in his neck. It found that his cancer was being driven by an alteration in a gene called that is involved in cell growth. Identifying the gene meant he could be treated with a drug called alectinib, which specifically targets this alteration.
Thomas oversaw one of the early trials of comprehensive genomic profiling, launched by the Garvan Institute of Medical Research in Sydney in 2016. It enrolled almost 4000 people with advanced cancers like lung, pancreatic, brain, ovarian, bowel and breast cancer who had exhausted all available treatment options. Samples of their tumours were collected by biopsy and sequenced to examine more than 500 cancer-relevant genes. Over a third of participants were found to have telltale changes in at least one gene that meant they could be recommended a targeted drug. They ended up living almost twice as long as those who weren’t matched to a treatment. “It was so successful we had patients flying over from Western Australia so they could take part,” says Thomas.
Based on the trial’s success, the Australian government agreed to fund a nationwide programme, led by Thomas, which launched in 2023. It offers free comprehensive genomic profiling and tailored treatment recommendations to all Australians with cancers that have low survival prospects. So far, over 26,000 people have signed up.
The outlooks for these participants have become increasingly rosy. “Now, about 48.5 per cent are getting a strong recommendation, meaning we know with reasonable confidence that they will live longer if they receive the recommended treatment,” says Thomas.
Targeting the worst cancers
This is even the case for pancreatic cancer, known as the “worst of the worst” cancer, because it is often survived for only a few months. “We’ve found that over 30 per cent of patients with pancreatic cancer who receive a good treatment recommendation are alive past five years, compared to 4 per cent who don’t get a match,” says Thomas. This is mostly because the testing can identify individuals who are likely to respond to immunotherapy drugs called checkpoint inhibitors, which stop cancer cells from disarming the immune system.
Things are set to get even better, now that a drug called daraxonrasib has just been approved in the US. It targets mutations in a gene called that are commonly found in pancreatic cancer and, in the latest clinical trial, it doubled survival time for those with advanced forms of the cancer.
Another of the most feared malignancies is brain cancer, but precision oncology is starting to make inroads here, too. A new drug called vorasidenib targets mutations in genes called and , which often trigger the growth of brain tumours called gliomas. In a clinical trial, people with gliomas caused by these mutations were 61 per cent less likely to experience worsening of their cancer during the study period if they received vorasidenib compared with a placebo.
As the evidence stacks up, countries like Japan, Germany, Norway and Denmark have recently made comprehensive genomic profiling routinely available to all those with advanced cancers as part of their public healthcare systems.
The picture is more complicated in the UK. Most people with advanced cancers are now eligible for comprehensive genomic profiling through National Health Service (NHS) systems across the UK. But despite hundreds of genes being sequenced in each person’s tumour as part of a standard test, the results are reported for only around one to 10 genes based on the cancer type and whether treatments are available on the NHS. For example, gene alterations are reported for lung cancer because alectinib is already available via the UK’s health system.
“This supports optimal treatment for standard care, but there’s untapped potential for identifying people who could be recruited into clinical trials for new treatments,” says Matthew Krebs, an oncologist and researcher at the University of Manchester, UK. To address this, he and his colleagues recently advocated for NHS England to add an extra 30 “research genes” to the small panel currently reported, with the hope of eventually increasing this number.
The US doesn’t have a nationally coordinated precision oncology programme, instead relying on a patchwork of services led by various universities and research institutes. “There’s quite a bit of competition in terms of different academic centres wanting to have programmes like this for their catchment areas,” says Jens Rueter, who runs the Maine Cancer Genomics Initiative at the Jackson Laboratory, an independent research institute. But despite this, only a minority of people with advanced cancer in the US, about 1 in 4, undergo comprehensive genomic profiling. This has been put down to a lack of awareness and socioeconomic and geographic disparities in access.
Tumour-agnostic drugs
As well as improving access to testing, there is a need to improve access to the drugs that are then recommended by that testing. Sometimes, for example, an individual with ovarian cancer is recommended a drug that is currently approved only for breast cancer, meaning they can access it only if they pay for it out of pocket. To address this challenge, some drugs are now being approved as “tumour-agnostic drugs”, meaning that they can be prescribed for any cancer, regardless of where it is.
Another headache for precision oncology is the issue of drug resistance. The ability of new drugs to precisely hit their intended targets is both a strength and a weakness – it maximises efficacy and minimises side effects, but also means that, over time, a person’s cancer can devise workarounds. That means we have to keep building up our arsenal of targeted drugs.
In Huff’s case, alectinib worked for five years, but then his cancer started progressing again. Fortunately, by that time, a new -targeted drug called lorlatinib had been approved. Again, his tumours shrank, and four years on, he says his health is great. He is now married with two children and works in medical technology sales. “Life is really good; I’m just trying to cherish it for as long as I can,” he says.
One of the brightest lights in the world of precision oncology is a programme called Zero Childhood Cancer, which is available to all children in Australia with cancer. It goes beyond what is offered in adult programmes in an effort to meet an ambitious goal of cutting childhood cancer deaths down to zero.
Eliminating childhood cancer
When a child is enrolled in the programme, the whole genome of their cancer is sequenced, not just a few hundred genes. Extra tests, called RNA whole transcriptome sequencing and methylation profiling, are performed on top of this to give an even clearer picture of what is driving their cancer. In addition, the genome that the child was born with in their normal cells is sequenced to try to identify why they developed cancer in the first place. Finally, in some cases, the child’s cancer cells are grown in a lab so that a robot can test over 100 different cancer drugs on them, or are grown in a mouse to test the potential efficacy of a specific drug.
Jack Kennelly is one of Zero’s success stories. He was diagnosed with a fast-growing brain tumour when he was 3 years old, after telling his parents that his head hurt. He was found to have a mutation in a gene called , which had triggered the growth of a rare form of cancer in his brain. normally functions as a tumour-suppressor gene, but certain mutations stop it from working, leading to unchecked cell growth.
No targeted drugs are yet available for -related cancers, but the finding meant that Jack could be given a combination of three chemotherapy drugs that had previously been shown to be most effective for treating his rare form of cancer. This regime, in combination with surgery and radiation, wiped out Jack’s brain tumour. “He went in and had an MRI, and they called us and said, ‘It’s gone’,” says his mother, Kristen. “Words can’t really express how incredible that feeling was.” Jack is now 7, and “just little things like school assemblies are different for us because he’s up there doing his thing, he is full of joy, and we’re so thankful every day that he is still with us”, says Kristen.
The finding that Jack carries a mutation in the genome he was born with also means that his ongoing monitoring can be precisely tailored. Before the age of 8, mutations are most likely to trigger tumour growth in the kidneys, so he currently gets regular scans of this area. “The next thing will be his thyroid,” says Kristen. The worry is endless, but the regular surveillance is designed to detect any new tumours while they are still at an early, treatable stage.
Louis Chesler, the director of Children’s Cancer Institute in Sydney, which coordinates the Zero programme, says he now believes “more than ever” that children dying from cancer will eventually become a thing of the past. “It’s not a matter of if, but when,” he says. “It’s the most empowering time I can ever think of to be a researcher or clinician in medicine.” Emerging technologies like personalised cancer vaccines, blood tests for early detection of cancer recurrences and AI-assisted drug discovery will make precision oncology even more powerful, he says.
For Thomas, precision oncology has become deeply personal. Four years ago, while he was busy setting up Australia’s nationwide programme, he himself was diagnosed with cancer and enrolled in his own programme. “Fortunately, I have a cancer that is responding to some of these brilliant treatments,” he says. “At this point, I don’t think I’m likely to be cured, but I am still able to make a meaningful contribution, both professionally and personally,” he adds. “I’m a poster child of what modern medicine can achieve.”