Researchers make important discovery

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Amadeo Parissenti and a team of researchers at Sudbury Regional Hospital's Regional Cancer Program have discovered a method of determining tumour responsiveness to chemotherapy agents midway through a chemotherapy treatment plan.

Currently, the effectiveness of a chemotherapy drug is determined by measuring the size of a tumour using magnetic resonance imaging.

"An MRI tells you if the tumour is shrinking, but you want to know more because you get shrinkage even with tumours that ultimately become resistant," said Parissenti. "Sometimes it will shrink by half, but you don't know if you have a dead carcass or if you have an active core of resistant tumour cells."

PET scans can also be used to determine if tumours are actively growing, but with only 23 to 25 per cent accuracy for tumours smaller than 10 mm.

Researchers at Sudbury's Regional Cancer Program have discovered what promises to be a more accurate method of determining the effectiveness of a chemotherapy treatment after one or two cycles have been administered, allowing physicians to proceed immediately to surgery or try something else if it's not working.

The team made the discovery while doing genome profiling of tumor samples as part of a National Cancer Institute of Canada clinical trial focusing on patients with locally advanced inflammatory breast cancer.

"We decided to profile the genomes of the tumours before treatment, but we also decided we would profile what was happening within the tumour mid-treatment and post-treatment," said Parissenti. "We were one of the first trials in Canada that went into tumours mid-treatment and post-treatment."

Biopsies

Patients participating in the trial consented to a series of biopsies, knowing there was a risk of infection and that there was no benefit to them.

The Sudbury research team isolated RNA from the tumour cells.
RNA, explained Parissenti, is a product of DNA and is the active component of our genes,  "so you know which genes are active and which are not by looking at the RNA."

As the samples were coming in, senior researcher Baoqing Guo, approached Parissenti with the news that the RNA isolated from some of the tumours was very low quality.

"We had isolated RNA from tumours before and we never had this problem," said Parissenti. "We were all a bit nervous because there was a lot of confidence being placed on us to do this genome profiling, and here we were unable to isolate good RNA from the tumours...but it wasn't in all patients. It was only in about half of the patients that the RNA was very low quality."

The team then looked at the pre-treatment samples and discovered that the RNA was fine.

"We started thinking that (the RNA degradation) could be a consequence of the chemotherapy," said Parissenti. "No one was too shocked that this was the case, but no one had ever reported this finding before."

The results also correlated with the dose levels administered, "so the more drug, the greater the magnitude of the drop in RNA quality. That made it even more compelling.

"Often, in science, you end up discovering something unintentionally. This was one of those unintentional discoveries."

Not one disease

According to Parissenti, researchers have come to the conclusion that breast cancer isn't one disease.

Five different types of breast cancer have been identified and they all behave quite differently.

"What this tells us is that we're going to have to do a better job of tailoring therapies to cancer patients and that the idea of a standard therapy that works for the majority of the population is not good enough."

As a result, researchers around the world have been relying more and more on the power of genetics to better understand and characterize cancers and determine differences in response to various chemotherapy drugs.

"Typically, a patient will go through the full eight cycles of chemotherapy," said Parissenti. "That's a long time to be on a drug that's giving you very little benefit. After treatment, you follow up with the patient and look for evidence of disease, but it's not ideal because by the time you recognize that you have a recurrence, the tumour is already fairly large."

There's no point in waiting six months to remove a tumour that isn't responding to chemotherapy and continuing to grow or spread.

Parissenti presented the findings of the research at the San Antonio Breast Cancer Symposium and published a paper in Breast Cancer Treatment and Research this fall. An application has also been filed for patent protection.

Funding

The team has applied for funding to learn how soon after treatment RNA quality is affected, which chemotherapy agents induce degradation and whether degradation occurs in some types of breast cancer and not in others.

Getting approval for a diagnostic test could take several years, said Parissenti, but talks with diagnostic companies interested in investing in the discovery are already underway.

Ironically, Cancer Care Ontario funding for the research component of Sudbury's Regional Cancer Program comes to an end in July, following a five-year period of 50 per cent funding. From July onwards, research will be funded by the Northern Ontario School of Medicine, dedicated hospital reserves, donations to the Northern Cancer Research Foundation and contracts with pharmaceutical companies.

The team is comprised of three career scientists, an epidemiologist and some 30 post docs, graduate students, research associates and technicians.

Copies of the article in Breast Cancer Research and Treatment can be ordered from http://springerlink.com


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