KEY POINTS:
Scientists hope that unravelling the genetic complexities of cancer will enable them to match exactly the right drug to each patient's unique disease.
Otago University is at the forefront of this research as it applies to bowel cancer. This is highly relevant for New Zealand, which has one
of the world's highest rates of the disease, also called colorectal cancer.
The university's Cancer Genetics Laboratory is about to have published the first of a series of articles on its genetic studies of bowel cancer patients in a leading American scientific journal, Clinical Cancer Research.
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The studies used gene-expression profiling, also called DNA chip analysis, to work out which genes were switched on in tumour samples from 150 patients.
In these tests, genetic material from tumour cells is compared with the 30,000 genes that occur in humans. Fluorescent dyes and computers tell the researchers which genes are turned on. The result is the tumour's genetic signature.
"It allows us to take a snapshot of the workings of the entire cancer gene factory, the cancer genome," said the Otago laboratory's director, Professor Anthony Reeve.
"So instead of looking at the way one gene is functioning aberrantly in the cancer, we can look at 30,000 genes simultaneously, for every cancer that we look at. This is extraordinarily powerful.
"We have identified [bowel cancer] gene expression signatures which will predict whether or not people are going to relapse, or survive for five years.
"The five-year interval for colorectal cancer is quite interesting. If patients survive the five years, their chance of having a further relapse is not great at all."
Professor Reeve said the study's results would need to be repeated in a large trial for gene expression profiling to be deemed clinically useful.
Knowing which cancer patients were going to survive and which were not could help decide whom to treat with expensive medicines.
"This is one of the most pressing needs and the New Zealand population doesn't realise, but there is an avalanche of drugs waiting out there. Herceptin is the tip of the iceberg."
Like Herceptin - and Avastin - they are extremely expensive. Many are a new type of medicine: genetically engineered human antibodies. Each blocks one or more molecular pathways to stop tumours doing the things needed to grow, such as establishing blood vessels.
Otago is planning a study with US partners which Professor Reeve believes will dramatically improve cancer treatment.
"I think it is going to revolutionise oncology. This new approach is to say every cancer is unique."
The study would match each cancer's gene signature - and the knowledge that gives of which pathways are activated - with the most suitable medicine to block it.
"The important thing about this is that it doesn't need new drugs; it needs all the old drugs. I know of one case [in the US] where a woman was treated with all the breast cancer drugs. None of them worked. Then she was tested according to this programme.
"She was found to require Glivec [a breakthrough leukaemia drug also used against stomach cancer]."
Using this drug for breast cancer was considered heretical, he said, but the woman had advanced cancer and it went into remission.
Herceptin had likewise been used against bowel cancer.
When diagnosed, around a quarter of bowel cancer patients have stage 3 disease: it has spread to nearby lymph nodes. Standard treatment comprises surgery plus 5FU chemotherapy, now available as a tablet, Xeloda.
New combinations of chemotherapy are being tried.
The five-year survival rate is lower for the group with more advanced disease and higher for those picked up earlier.
Other chemotherapies like oxiplatin and irinotecan can be used if the cancer has spread widely (metastasised).
Avastin was approved in the US in 2004 for use in combination with 5FU-based chemotherapy for metastatic bowel cancer and this year for one kind of lung cancer.
In a large trial, it extended metastatic bowel cancer patients' median survival by nearly a quarter: to 20.3 months from 15.6. But, like some similar new cancer drugs, it also carries significant risks of serious side-effects.
A British Medical Journal editorial says Avastin heralds a new era in cancer treatment. "Median survivals of over 20 months in patients with metastatic colorectal cancer were unheard of just a few years ago and are now within our grasp."
In New Zealand Avastin, an extremely expensive drug made by Roche, which also makes Herceptin, is not state-funded. Pharmac is still considering an application for health boards to pay for patients to receive it.
Avastin is thought to work mainly by preventing the growth of new blood vessels - by blocking a protein signal sent out of tumours that otherwise stimulates blood vessels to grow towards them.
"This [protein]," explains Michael Findlay, Auckland University's professor of oncology, "can be chucked out of cancer cells when they get stressed because the cancer lump has grown big enough that it can't just absorb local oxygen from the tissue around it.
"Avastin probably also has a role in modifying established blood vessels to make them more orderly and less leaky; therefore we understand that when we give this drug with chemotherapy it can, paradoxically, improve the amount of chemotherapy that gets into the tumours ... "
Two other new drugs, cetuximab and panitumumab, are aimed at blocking cell signalling that spurs tumour growth. Neither is state-funded here.
"We were involved in a clinical trial [of panitumumab] 18 months ago and that trial became positive," said Professor Findlay. "It's probably a little better tolerated than cetuximab, but they haven't been tested head to head."
New combinations of drugs continue to surprise researchers.
Professor Findlay cited a trial among advanced-bowel-cancer patients in which cetuximab generally worked better when given with irinotecan, even though patients' tumours had previously developed resistance to irinotecan.
" ... it means the cetuximab is doing something synergistic with resistance to irinotecan. As the trials evolve from late-stage patients to earlier stage patients, there is an optimism that there might be something interesting happening there that may improve the cancer cure rate when you apply it to the [middle stage patient]. Or it may improve the survival rate when you apply it to patients with incurable disease."
Internationally around 50 potential therapies are being developed which aim to block pathways like the ones Herceptin and cetuximab target.
In June, the Ludwig Institute for Cancer Research said in New York that in a clinical trial, its anti-cancer antibody 806 had targeted certain growth factor protein receptors on the cells of bowel tumours and several other types of cancer. Crucially, however, it did not target normal tissue.
As survival and cure rates edge ahead with new therapies, the Government may be closer to introducing a mass screening programme for bowel cancer.
A Health Ministry advisory group has recommended setting up a pilot screening scheme to test the feasibility of a national programme, but it is understood to have reiterated concerns about whether there will be enough specialists to carry out the extra colonoscopies.
Tumours signals are blocked, and a three-way counter-effect helps chemotherapy get through
For tumours to survive, they need to produce a network of blood vessels that feeds the cancer cells with oxygen and nutrients, enabling these cells to grow, invade nearby tissue and spread to other parts of the body.
Angiogenesis is the process by which new blood vessels are formed. Angiogenesis inhibitors interfere with the development of blood vessels, starving the cancer of nutrients.
Avastin, which is used for treating colorectal cancer, is one example of an angiogenesis inhibitor.
To start angiogenesis, a tumour sends out signals to nearby blood vessels, causing them to grow towards the tumour.
Avastin works by blocking proteins called vascular endothelial growth factors, which are a key signal in angiogenesis. Its effect is threefold - blood vessels shrink away from the tumour, blocking the supply of oxygen and nutrients, the growth of new blood vessels is interrupted, and existing blood vessels are changed in ways that help chemotherapy reach the tumour.
Scientists are studying natural and synthetic angiogenesis inhibitors, and clinical trials are being done in patients with cancers ranging from breast and prostate, to some leukaemias and lymphomas.
- additional reporting: Errol Kiong
