Bronwyn Grout, now 42, was given a maximum of five years to live when she was 31. But she's a super responder - someone who responded so well to a treatment that her ovarian cancer virtually disappeared. Credit:Kate Geraghty It has been almost a decade since and it's fair to say Grout has astounded doctors. Not very long ago she might have been called a miracle. But this isn't a story about miracles. It's about how scientists, doctors and patients refused to accept that miracles like Grout's were just freakish one-offs and in so doing may be about to upend conventional thinking about treating cancer. 'It was very unusual' In the early 2000s, a healthcare team at Sydney's Westmead Hospital was discussing ovarian cancer patients when one of the doctors realised aloud that some patients had been returning for check-ups for years. Given most patients relapsed within a year and a half of treatment, "it was very unusual", remembers Professor Anna deFazio, Sydney West Chair of Translational Cancer Research, who was at the meeting.

The team decided to study these "extreme responders" as they called them. To make sure they got only the truly exceptional cases – the Grout-style miracles – they set strict limits. They would look at patients with widespread cancer that couldn't be cleared by surgery but which had apparently responded to chemotherapy. "Patients who should have, in any other circumstances … relapsed early and died," deFazio says. Professor Anna deFazio is part of a team studying exceptional responses to cancer and the genomes that go with them. Credit:Wolter Peeters The ovarian cancer they were studying – high-grade serous – was so lethal that women who didn't relapse within three years were deemed extreme responders. The researchers tested genes they suspected of playing a part in exceptional response, but at that time they could only test those they already knew about. Given there are about 20,000 genes in the human genome it was something of a lucky dip. "We only got a certain way down the track," deFazio says. Professor David Bowtell, the head of Cancer Genomics and Genetics at the Peter MacCallum Cancer Centre, lost his own mother to ovarian cancer in 1996 when far less was known about it. Credit:Justin McManus

But then Whole Genome Sequencing arrived. DeFazio and her colleagues – including experts from across the country who had joined forces to form the Australian Ovarian Cancer Study – knew it was the key to unlocking the secrets of patients like Grout. With Whole Genome Sequencing they would no longer have to guess which genetic mutations were present in the genome of a cancer tumour; they would be able to see the entire genome. If previously they had been looking for needle in a haystack, now they would see the entire stack in such detail it would be like looking through the Hubble telescope at the bruises and bends on each strand of hay. Professor Sean Grimmond, who investigates ovarian and pnacreatic cancer genomes, shows Health Minister Susan Ley, US Vice President Joe Biden and Victorian Premier Daniel Andrews around a research labs at the Victorian Comprehensive Cancer Centre. Credit:Getty Images The new technology was particularly important when it came to exceptional responders because it would allow scientists to identify all the genetic mutations that tumours from these patients had in common. And it would let them see whether the mutations had been inherited – like the BRCA1 mutation that predisposes carriers to breast and ovarian cancer – or had been acquired as the cancer developed. Still, whole genome sequencing was slow and expensive, and the secrets of exceptional responders remained out of reach. The Human Genome Project, completed in 2003, took 13 years and $US2.7 billion ($3.5 billion). But then the cost and time involved plummeted, and over little more than a decade it became possible to sequence a genome in days and for a few thousand dollars. The secrets of the exceptional responders were within reach.

Thanks to egg donors, Bronwyn Grout has had three children since having both her ovaries removed: Emily, Daniel and Thomas. Credit:Kate Geraghty Earlier this year, the Australian Ovarian Cancer Study and its international partners got funding to map the genomes of exceptional responders to ovarian cancer therapy. The US Agency that awarded the funding after a four-year international competition has stipulated that the patients to be studied are those who have survived 10 years or more since therapy. It's a much more ambitious target than the three-years-without-relapse first nominated by deFazio and her colleagues. And it's a target they like. The devil in the detail "If you know the enemy," Sun Tzu writes in The Art of War, "you need not fear the result of a hundred battles." Professor Sean Grimmond is lead investigator for Australia's effort to map ovarian and pancreatic cancer genomes for the International Cancer Genome Consortium. Credit:Justin McManus

It's a quote the head of the Australian Ovarian Cancer Study, Professor David Bowtell, is fond of repeating. When his mother died from ovarian cancer in 1996, four and a half years after being diagnosed, he didn't know the enemy at all. Now Bowtell – also head of Cancer Genomics and Genetics at the Peter MacCallum Cancer Centre – is determined to know all the secret mutations and behaviours of his nemesis. Back in 1996, ovarian cancer was thought of as one disease. It is, in fact, several. Cancer is essentially damage to the genome or operating system of an organism, which causes cells to grow out of control. And whole genome sequencing has revealed just how unique each cancer is. "In each genome there is a certain constellation of mutations," Bowtell says. "It's like being dealt a hand of cards. Two people with a hand may have some cards in common – some mutations in common – but each will be a unique combination." He wonders whether exceptional responders may have an unusual combination of mutations that make their cancer particularly vulnerable to therapy, "which would go to explaining the unusual nature of exceptional responders," he says. In addition to classifying ovarian cancer into several different subtypes, Bowtell and his colleagues have already identified three different kinds of exceptional responder. There are those, like Grout, whose cancer seems to just disappear in response to chemotherapy. "These are the ones whose biomarkers just drop off a cliff to a normal number and then just flatline," Bowtell says.

Then there are patients whose cancer returns following treatment but "for some reason the cancer doesn't learn to recognise the chemotherapy", so it keeps working, once, twice, several times. In a third group, the cancer disappears for longer stretches between chemo. The first kind of responder may have a mutation or cluster of mutations that makes their cancer vulnerable to treatment and Bowtell hopes that studying them might lead to drugs targeting specific mutations, while the other responders may hold the key to finding new ways of triggering the body's own immune system to fight cancer. Bowtell and his colleagues are not the only ones racing to learn out the secrets of the exceptional responder. In 2014, the National Cancer Institute in the United States announced an Exceptional Responders Initiative, which would study responders who had defied the odds in failed clinical trials as well as those who had done particularly well on standard treatments. In Australia, there is a project to sequence the genomes of a small number of patients that responded exceptionally well to therapy for the brain cancer glioblastoma – a therapy that failed clinical trials. (Two of these patients are still alive and receiving the "failed" therapy from the drug company on compassionate grounds even though the trial was closed in 2014). Other researchers have looked at exceptional responders to pancreatic cancer therapy.

Sean Grimmond, lead investigator for Australia's effort to map ovarian and pancreatic cancer genomes for the International Cancer Genome Consortium, remembers sequencing a pancreatic tumour for the consortium as the patient was starting palliative care. Grimmond and his colleagues found a mutation common in other types of cancer – BRCA2, best known for predisposing carriers to breast, ovarian and prostate cancer – that they suspected would make the tumour vulnerable to a certain type of chemotherapy. Their research was not allowed to influence patient care, and in any case sequencing technology was still too slow, but while they were still analysing the tumour they learnt the patient had received the chemotherapy as a palliative measure. It melted the tumour away. The researchers then found another exceptional responder among the patients they had sequenced for the consortium. This second patient also had a BRCA2 mutation and had received the same chemotherapy. And when Grimmond and colleagues reviewed other consortium patients who had responded well to the same chemo, they discovered all had damage to the BRCA2 or related genes, genes that play a crucial role in repairing DNA. The BRCA2 mutation has since been the basis of clinical trials here and overseas. "It's kind of a hackneyed idea, 'the war on cancer'," Bowtell says. "But to me it really feels like that." And with whole genome sequencing, he is finally getting to know his enemy.

Finding the unicorns Miracles tend to upend our basic assumptions about how the world works. Exceptional responders too, are shifting the very foundations of how we treat cancer. Back in 1998, when the Human Genome Project was still five years off completion, US computer scientist Marty Tenenbaum discovered a lump under his arm. It was the metastasis from a primary melanoma that his doctor couldn't find. Tenenbaum went to the payphone in the doctor's lobby and called his wife. "Houston, we have a problem," he said. "I was scared." Tenenbaum consulted as many doctors as he could, including the then head of the National Cancer Institute in Washington, for whom Tenenbaum had been doing pro-bono consulting. "They all agreed on one thing, which was that the prognosis was dire," he remembers. But what Tenenbaum found "intriguing" was that they didn't agree on the "Hail Mary". "Everyone had a different thing that I should try," he says. "I made a vow that if I somehow got through this that I would use my background as a computer scientist to try to solve that problem."

Tenenbaum pinpointed the clinical trial he wanted to be on, the one he thought held the most hope of curing his incurable cancer, only to be told he had the wrong haplotype, a cluster of genes that can determine immune response. Determined not to give up, Tenenbaum enrolled in another trial that combined extensive surgery to remove metastases – an uncommon treatment at the time – with immunotherapy. The trial failed because too few patients responded to the treatment. A few however, responded exceptionally well, including Tenenbaum. What did it mean that he had survived and others hadn't? That he had gotten into the one trial that could have cured him? "If I'd gone into the other study? Died." Grimmond says the existence of exceptional responders like Tenenbaum, "the unicorns", means we have to completely rethink the way cancer is treated. As it is, trials are generally only considered successful if a statistically significant percentage of patients respond to the therapy – even if those who do respond are practically healed. Whole genome sequencing allows researchers to identify identical mutations across different types of cancers and target patients they think will respond, whether they have breast or ovarian cancer or melanoma. They could also exclude those without the susceptible mutation, ensuring a better trial result. That would both lower the cost of trials and ensure many more drugs are kept in use.

UNSW's Associate Professor Kerrie McDonald, principal investigator on the study of exceptional responders to glioblastoma treatment, says "we need to stop ignoring the minority of patients who may actually respond to the drug and study their biology so we can better stratify the trial population leading to success". For Tenenbaum, the existence of exceptional responders and poor responders means "clinical trials in cancer don't make sense anymore" because once you factor in the millions of genetic subtypes and the thousands of possible drug combinations, "there are far too many hypotheses to explore". "People at the cutting edge of oncology are continually experimenting with individual patients … doing molecular profiling, trying to come up with a theory of how to treat this patient or that patient, using a combination of drugs, [but] no one captures that learning." In 2011, Tenenbaum founded Cancer Commons, which has been called the "LinkedIn" for cancer. Patients can post their case online and get a quick expert response recommending a particular trial or treatment, and then that patient can let the Commons know how their treatment went, improving understanding. The Commons is still building its network, but Tenenbaum's dream is that one day it will catalogue millions of individual treatments and outcomes as they occur and feed the results back into the system so that the understanding of what works and what doesn't is continually improving.

"I believe that based on the variation of outcomes, we can significantly extend life," he says. Maybe even downgrade cancer to a chronic disease for "half the people who are now dying". And that's without developing any new drugs. Grout, who with the help of egg donors has had three children following her exceptional response, would like those odds. She hopes that somewhere in her genome or in her cancer's genome there's something that will help the scientists who've turned the miraculous into exceptional turn the exceptional into everyday. "I don't believe it's a miracle," she says. "Because that would mean there can't be an explanation and it can't be benefited from by others." 'Failed drug' keeping two brain cancer patients alive She doesn't even know their names, but Associate Professor Kerrie McDonald hangs out for news of her exceptional responders. "I literally do," she says. Two weeks ago, she heard that both patients were still alive, almost two years after the clinical trial they'd been in was wound up.

"It's fantastic," she says, "completely unexpected." The trial of a combination therapy for recurrent glioblastoma, a type of brain cancer, was deemed a failure because not enough of the 122 patients enrolled responded to the treatment. But about 10 per cent responded exceptionally including McDonald's two responders, who are still receiving the "failed" therapy on compassionate grounds from the drug company. Thanks to whole genome sequencing, McDonald is now comparing the genomes of the 10 patients who best responded to the treatment with the 10 patients who responded worst, "trying to find genes that are specific to each group". It's a big task – each genome takes McDonald between three and six months to sequence. Still, such explorations are only just recently possible, and McDonald says the landscapes they've opened up must change the way we treat cancer. "When you look at one tumour it's completely different to the next patient's tumour, yet we treat everyone the same." McDonald calls for a "more personalised approach", saying we need more biomarkers or "red flags" indicating the presence of a particular gene mutation or protein, for which patients can be tested before they're given a treatment to determine how they're likely to respond.

Not only would that help the patient, it would mean more successful trials and more available treatments, she says.