BIO 2008 - Cancer detection by a hair's breadth

In the 1990s, Australian physicist Professor Veronica James and colleagues were studying the structure of hair, and particularly its chief protein component, keratin, using x-ray diffraction. In 1997, she published a study on the unusual change she saw in the structure of the hair from monkeys with diabetes.

In 1999, she and other Australian researchers published a paper in Nature which showed discernable changes in the diffraction pattern of hair from women with breast cancer. A ring was noticeable in the pattern in the breast cancer samples that was absent in healthy women. This was followed by a 2005 paper in the International Journal of Cancer confirming the result.

The science was so intriguing, that when Sydney investment banker Leon Carr and cell biologist Dr Peter French came across the published hair studies, they immediately began investigating their scientific and commercial potential. ,. The science was particularly interesting to French, whose PhD is in the use of monoclonal antibodies in determining the structure of keratin in wool

Carr decided to set up a company to commercialise the potential of the technique, with French and Gary Corino, one of the authors on the 2005 paper, as scientific advisors and businessman David Young as managing director.

Their new company, Fermiscan, was listed in October 2006 and is about to finalise a validation study of the technology in 2000 women in Australia. The idea is to have a diagnostic test for breast cancer that is far less invasive than current screening techniques like mammography but which has a comparable or better outcome.

The science behind the test is reasonably straightforward even if the actual reason these changes can be seen in hair is still not fully understood. Samples of hair are collected from close to the scalp, thus avoiding the problems that are caused by chemical treatments such as dyeing, perming and straightening, which can penetrate the hair and break down its proteins.

The samples are loaded onto specially designed holders and shipped to Chicago, where Fermiscan has a group based at that city's synchrotron, and placed into the centre of an x-ray beam. "The hair is exposed for less than 30 seconds - we are doing multiple hairs per person - and the time to run a sample is about two to three minutes," French says. "The result is then transferred to a PC where image processing occurs to enhance the features we are looking for."

The x-rays penetrate the hair and diffract off its molecular structure, he says. "There is a standard, well-known alpha keratin pattern of hair that has been looked at by x-ray diffraction for more than 50 years - it's not a new technique. But with the synchrotron there is much greater flux than can be achieved by standard x-ray sources and as a result very subtle, fine features can be seen. It is one of these that is associated with the presence of breast cancer."

What the data shows is a peculiar ring at a specific position or spacing in the diffraction pattern, he says. Normally the pattern shows a series of black arcs on a white background, but in samples from women with breast cancer, a circular feature is frequently observable.

"What causes that ring is not yet known. We have a few theories and what we think happens is the breast cancer secretes a range of molecules like growth factors and cytokines into the bloodstream. Some of those can interact with the hair follicle.

"It is possible that what we are seeing is a slight disturbance of the normal filament arrangement that causes the arcs to become rings. Whether this distubance is due to something that the cancer secretes that is taken up by the follicle and is put into the fibre, or whether the factor itself alters the way the hair follicle functions so that it lays down filaments slightly differently, is still open to debate. We have a research program in place to look at those sorts of issues but it's at a fairly early stage."

---PB--- Further potential

Fermiscan - named in honour of one of the founders of synchrotron technology, the great Italian particle physicist Enrico Fermi - will be exhibiting on the Australian pavilion at BIO in San Diego in June. The company hopes not only to raise awareness of the test but also to meet other people doing biomarker research into breast cancer.

By then the company will be close to releasing the results of the validation trial it is running in several clinics in NSW, the ACT and Victoria. The company aims to have its diagnostic test available through women's health clinics in both the developed and developing world.

It is not necessarily the women in the current target group for mammography screening that the test is aimed at, David Young says. Women who are ineligible for mammography, and also those who refuse to be screened for whatever reason, are a potential market.

"From our perspective the real benefit is probably for women that are of an age that aren't eligible for mammography," Young says. "Despite the fact that the medical community has promoted self-breast examination and clinical breast examination, the sensitivity and specificity of that is proven to be very low.

"In reality there is a whole population base today that does not access mammographic screening, either because they are too young, or actually won't go and have a mammogram. Forty per cent of the target population don't have a mammogram, some due to embarrassment, pain or they don't want to know. The reality is that there is an enormous potential exclusion of patients from current screening. That in the long run will be our greatest benefit, to provide an alternative."

Women in developing countries are also potential targets, although not the prime one at the moment. Young points out that global statistics show that developing nations have the biggest fatality rates from breast cancer, predominantly because of a lack of screening. "We started from a more commercial, paying patient type of approach and therefore those countries weren't our original target, but from both an ethical perspective that is a significant opportunity," he says.

And while it is a long way down the track, breast cancer is potentially not the only disease category that could be diagnosed with x-ray diffraction of hair. The Company's patents also cover the use of the technology to potentially diagnose prostate cancer and Alzheimer's disease, which the company will explore, in addition to colon cancer, French says.

"The theory that links breast, prostate and colon cancer is that all of those cancers are adenocarcinomas - epithelial cancers that secrete factors that may have effects on other epithelial tissues, including skin and hair follicles," he says. "There is an overlying theory about this and it is more complex than it initially was foreseen.

"Some of the things that women do to their hair can significantly alter the diffraction pattern. We did look at pubic hair but that's thrown up too many false positives so we have decided not to pursue that. There's something odd about pubic hair that is unhelpful for this particular application."

---PB--- Trial results

Fermiscan released early results from its Australian trial in December 2007, which was designed with the assistance of a biostatistician to ensure a statistically significant result. From those 800 women tested, the company ended up with a sensitivity and specificity of around 80 per cent.

Young says that is comparable with other diagnostic tests such as mammography and is probably an advance on most countries' mammography standard.

In May, the validation trial was completed with an accuracy of 69 per cent, which grew to 75 per cent once samples from patients who had chemically treated their hair were excluded.

The company is also conducting a trial in Singapore as a way into the vast Asian market. The Singapore trial, at the KK Women's and Children's Hospital, is a 200-patient, controlled clinical trial designed to compare results of the Fermiscan test with the current gold standard breast screening methods of mammography and ultrasound, with follow-up biopsy and pathology.

Fermiscan licensed six countries in south-east Asia early in its development process, Young says. He has more than a decade of experience working in Taiwan, Hong Kong and Singapore and felt that a licensing model was the best entry platform to the market.

"The trial in Singapore is a population specific trial to get the engagement of the medical community and clinical acceptance in Singapore and therefore by default it flows to most other parts of south Asia," he says.

All trials will follow the processes developed in Australia. The samples are collected and sent to Fermiscan, who arranges for them to be tested at the synchrotron beamline in Chicago, which is managed by US chief scientist Gary Corino.

"At the moment we are using the synchrotron in Chicago for the trial but we have agreements in place with the Australian Synchrotron, which would be the logical place for Australia, but their development timelines are still a little further away," Young says.

"In its implementation phase as a diagnostic test, the hairs would be collected and sent to us, we would load them and run them through our diagnostic process on a synchrotron beamline, and electronically communicate the records back. Our estimate is that that would take somewhere between a week and 10 days in the initial stages."