Advances hit cancer where it hurts

Access to international trials, new tests and treatments spell better care for the cancer patient in Ireland, writes CLAIRE O'CONNELL

‘I WAS like a rabbit caught in the headlights.” That’s how Sandra Higgins felt when she heard she had breast cancer.

A few weeks earlier, a tennis partner had told Higgins about a friend who was diagnosed with the condition, so when Higgins, then aged 45, found a lump in her breast she decided to get it checked out straight away.

“I went to the GP the next day, and the GP said, ‘It’s probably nothing, but we will get it seen to.’”

Even after the mammogram and biopsy, the mother of three didn’t feel particularly alarmed about the situation.

But when she got the diagnosis that the lump was cancerous, she was glad her husband, John, had come with her to meet the doctor in Cork that day.

“I was reeling,” she says, recalling how they went back to break the news to family members.

Following the surgery, Higgins was waiting to find out what further treatment she would need when John came across details of a test that could help predict whether women with certain forms of breast cancer would likely benefit from chemotherapy after surgery.

“He was looking at this on the internet, on reputable sites like Johns Hopkins, and they kept mentioning this ‘oncotype score’, so he Googled it,” says Higgins.

What he found was Oncotype DX, a test that measures the expression of a suite of genes. The resulting signature, given as a score, can help in the decision about whether to undergo chemotherapy.

The nature of her cancer meant Higgins could not join a clinical trial in Ireland to assess the approach, but she was still eligible to purchase the test. At almost €4,000 it wasn’t cheap, but she considered it worth the investment.

“The hospital sent the tissue samples off for it, I had nothing further to do,” she says.

And she got welcome news back: her score was low, meaning her cancer was unlikely to recur and she was unlikely to benefit from chemotherapy.

“That sorted it for me,” she says. “Because you are there wondering whether or not you need chemotherapy – you obviously don’t want to pump all this poison into your body if you don’t need it – but at the same time I would probably have had it because I would have been afraid not to.”

Higgins is now being refunded the cost of the test through her health insurer – and she considers that the information it provided spared the health service the cost of chemotherapy, as well as avoiding the burden on herself and her family: “To me it was money well spent.”

So how does it work? The Oncotype DX test analyses a suite of genes in the tumour to see how active they are, explains Dr Maccon Keane, a consultant medical oncologist at Galway University Hospital, who describes how the approach was pioneered by the National Surgical Adjuvant Breast and Bowel Project (NSABP) in the US.

“They looked at genes that were known to be important in breast cancer, known to be involved in the proliferation and control of cells,” he says.

“They looked at those genes retrospectively in studies they had already done in women with early stage breast cancer that was oestrogen or progesterone positive, and they were able to say there’s a level at which we believe women won’t benefit from chemotherapy – in fact, they may benefit more from hormone therapy.”

Further studies confirmed that the test could distinguish between women who would benefit from chemotherapy and those who would not, but there was a middle zone where the answer still wasn’t clear, explains Keane.

To help get more clarity on those borderline cases, the TailorX study was set up, an international trial on which all the women are “oncotyped” with the test and receive hormone therapy for oestrogen- or progesterone-positive breast tumours, and some also undergo chemotherapy while others don’t.

Because the trial is looking at the recurrence of cancers over time, the results will not be known for several years, but patients on the trial in Ireland have had access to the oncotype test ahead of its wider use, explains Keane, who leads the clinical trial here.

The test would probably be of benefit in about 30 per cent of breast cancer cases, he notes.

“It would prevent about one-third of those being offered chemotherapy, then for another third it would say they would need chemotherapy. Then the middle 10 per cent are still under investigation with the TailorX study.”

Outside the trial, patients with suitable clinical cases may be able to access the test through one of the health insurance companies, and it is currently undergoing technology assessment with the National Cancer Control Programme, according to Keane. “It has gone quite a long way to going into standard, routine practice in Ireland,” he says.

PICKING UP ON CANCER’S SIGNATURE IN BLOOD

A blood test to identify whether a person needs further tests for colon cancer sounds like a simple step, but figuring out what “biomarkers” to look for has involved complex research.

Currently, patients with symptoms such as weight loss and a change in bowel habits may visit their physician, explains Dermot Kenny, professor of molecular and cellular therapeutics at the Royal College of Surgeons in Ireland (RCSI).

“It can be difficult for a physician at that stage to know what to do next,” he says.

“The blood tests that we have currently are very non-specific. And you can take stool samples and look at them for occult blood, but again they are very non-specific.”

The gold standard for diagnosing colon cancer is a colonoscopy, using a camera to view the inside of the colon, but costs and logistics make it impractical to screen everyone all the time, notes Kenny.

That’s why he has been involved in developing a test to look at signatures of proteins called antibodies in the blood that could indicate whether the person with symptoms should go on for a colonoscopy.

“If we can give a clinician an indication of whether there’s a high probability or low probability of cancer, we can direct someone towards colonoscopy,” he says.

“Cancer is a very complex process and colon cancer is not the same in everybody. So we looked in patients who had symptoms and we did a pretty exhaustive analysis of all the antibodies they were producing.

“We also had a control group who had symptoms but didn’t have cancer, and we were able to show in this relatively small group of patients, that there’s a different profile.”

The Science Foundation Ireland-funded project, which involves researchers at the RCSI, Beaumont Hospital and the Biomedical Diagnostics Institute at Dublin City University, is now looking to engineer the technology so it could be used more widely, explains Kenny.

“Those initial investigations required very complex systems, so we are now trying to get this down to small chips and volumes of blood so we can move to the next stage of clinical trials.”

MOBILISING THE BODY’S DEFENCES AGAINST CANCER

Your body is endowed with a complex immune system to fight off disease, but tumours may create blind spots that hide the errant cells from those defences.

Now researchers at University College Cork are developing a way to put a tumour back on the map by stimulating the immune response to it directly.

The approach uses a vector to deliver DNA sequences directly into the solid tumour, explains Dr Declan Soden, general manager of the Cork Cancer Research Centre.

The cancer cells that take up the DNA start to express molecules called cytokines, which help stimulate the body’s immune response to the cancer.

“The tumour becomes a mini-protein factory producing the cytokines,” says Soden.

“But it produces so many of them that it causes the cells to die. So it’s the combination not only of just expressing the cytokines and recruiting the immune response but killing the cancer cells in the process – it’s a double whammy.”

So far, pre-clinical tests on solid tumours have proven effective and the hope is to transition the approach into clinical trials, according to Soden.

CANCER TREATMENTS ON TRIAL

In medicine, clinical trials are a big deal – they form a key route through which new treatments and approaches are initially brought to patients.

Recent years have seen the cancer clinical trial landscape transform in Ireland, with patients here getting greater access to international trials and the novel treatments they involve.

The main driver behind the change has been the All-Ireland Cooperative Oncology Research Group (Icorg), which was set up by John Crown and John Armstrong in 1997 and now involves clinicians and groups around the country.

“It’s an organisation designed to improve cancer care by bringing clinical trials of newer cancer therapies,” explains Dr Seamus O’Reilly, a consultant medical oncologist at Cork University Hospital.

Through Icorg, which is supported by the Health Research Board and the Irish Cancer Society, thousands of patients in Ireland have participated in trials of new treatment regimes, including the targeted therapy herceptin for breast cancer.

“There are collaborations with European and US clinical trials organisations, which allow us access to their trial portfolios,” says O’Reilly, and he notes the importance of supporting innovations coming from within Ireland too.

“What you really want is not just an organisation where we collaborate with other groups and their trials, but also where the ideas come from the medical and scientific communities in Ireland.

“That’s what you really want in a knowledge-based economy, that the ideas come from within and then the clinical infrastructure to implement these trials is there.”

Running clinical trials helps to raise the standard generally for the care of cancer patients, adds O’Reilly.

“It’s a rising tide – patients have access to treatments earlier, there’s closer supervision of care in patients on clinical trials and it fosters a more academic environment within our hospitals,” he says.

“Hospitals compete in Ireland for patients and resources and staff. Competition is bad for patients, and collaboration is good – and this is one venture where hospitals collaborate.

“But I would be concerned that what has been built up over the last 15 years in Ireland could be in jeopardy now that we have less funding around.”

MICRO BUT MIGHTY

One of the hottest topics to emerge in biomedicine in recent years is microRNA. Don’t be put off by its diminutive-sounding name though: microRNA (or miRNA) is a powerful agent within cells that can fine-tune how genes work.

Levels of miRNAs are altered in many disease states, including cancer, and many researchers are now looking at ways to detect particular miRNAs to help in diagnosis, or even to block them if it could be of benefit.

The discovery of miRNA has been hailed as one of the most exciting in two decades, says Ray Stallings, professor of Cancer Genetics at the Royal College of Surgeons in Ireland.

His team at the College and Our Lady’s Children’s Hospital in Crumlin is analysing signatures of miRNAs in a type of childhood cancer called paediatric neuroblastoma, with the aim of looking for signals about how a tumour is likely to progress.

Another aspect of that work is to boost particular miRNAs within tumours to try to kill them, and Stallings is working with researchers at Dublin City University to develop nanoparticles that can deliver miRNA molecules into tumours in this way.

Meanwhile, miRNAs in the blood could offer a way of detecting cancer elsewhere in the body.

A group led by Prof Michael Kerin in NUI Galway recently announced it had identified specific miRNAs circulating in the blood that are associated with breast cancer. The findings could pave the way for non-invasive blood tests that look for the markers.

And while miRNAs hold promise for new diagnostics and therapies, there’s still a huge amount to understand about their underlying biology.

So a new project led by Prof Luke O’Neill in Trinity College Dublin is to look at how miRNAs fine-tune the immune system and also how they may be disrupted in cancer.

O’Neill recently secured funding for the study, which will start this summer, from the European Research Council.