Chip measures breast estrogen with just a poke

By AP Medical Writer Lauran Neergaard – Wed Oct 7, 3:36 pm ET WASHINGTON – Estrogen fuels breast cancer yet doctors can't measure how much of the hormone is in a woman's breast without cutting into it. A Canadian invention might change that: A lab-on-a-chip that can do the work quickly with just the poke of a small needle.

Several years of study are needed before the experimental device could hit doctors' offices, but the research published Wednesday opens the tantalizing possibility of easy, routine monitoring of various hormones. Doctors could use it to see if breast cancer therapy is working, tell who's at high risk, or for other problems, such as infertility — maybe even prostate cancer.

"It's thought-provoking to think, 'What could I do with a tool like this?'" said Dr. Kelly Marcom, breast oncology chief at Duke University Medical Center, who wasn't involved with the new invention. "It opens up an avenue of investigation that without tools like this, you couldn't explore."

The University of Toronto researchers used a powerful new technology to measure tiny droplets of estrogen from samples at least 1,000 times smaller than today's testing requires. Called digital microfluidics, it uses electricity to separate and purify droplets of the hormone from a mix of other cells — all on the surface of a chip no bigger than a credit card.

"Droplets essentially can be made to dance across the surface," said University of Toronto engineer Aaron Wheeler, who co-invented the device and calls the project "the most fun I've had in science."

The research was published in a new journal, Science Translational Medicine.

Here's the problem: Scientists have long known that estrogen plays a role in many breast cancers. While hormone tests traditionally are done with blood, estrogen is particularly concentrated in breast tissue and breast cancer patients have much higher levels than other women. But measuring breast estrogen requires a fairly substantial biopsy, a painful and invasive procedure with its own risks. Then come hours of intense laboratory work to extract and purify the estrogen from the mishmash of other cells. So that breast-testing is hardly ever done.

If doctors had a way to easily monitor breast estrogen levels, they could track which cancer survivors are responding to widely used estrogen-blocking therapies — tamoxifen or drugs known as aromatase inhibitors — that aim to avoid a recurrence. They might even shed light on who's at high risk for developing cancer.

"The breast makes its own estrogen," explained Toronto gynecology specialist Dr. Noha Mousa. "We have solid evidence that measuring estrogen inside the breast is important. No. 1 is to see if these medications are working."

The Toronto team put the multi-step lab processing onto the surface of the new chip. Electrical currents move droplets around the chip, allowing solvents and other chemicals to dissolve a dried tissue sample and remove other biological substances until just droplets of estrogen are left. The team took small breast tissue samples — the amount pulled from a needle instead of an open biopsy — plus blood samples from two breast cancer patients, and reported that the chip allowed accurate estrogen measurement.

Next up: Mousa will use the technique to measure estrogen levels in a soon-to-start study of more than 200 Canadian women at high risk of getting breast cancer, who are testing whether taking those estrogen-blocking aromatase inhibitors for a year lowers their risk.

But the technology is applicable to more than breast cancer. Mousa points to infertile women who have large amounts of blood drawn several times a month to see if treatment is sparking ovulation, saying she's also testing whether the chip might substitute pinpricks of blood.

A healthy diet may trim breast cancer risk

2010-03-25By Lynne Peeples

NEW YORK (Reuters Health) - A woman may not be able to change her family history of breast cancer, but she can typically control what she eats and drinks. And consuming more vegetables and whole grains -- and less alcohol -- just might trim her chances of getting the disease, according to an analysis of published studies.

"As the incidence of breast cancer continues to rise, with many of the risk factors for the disease non-modifiable, potentially modifiable risk factors such as diet are of interest," Dr. Sarah Brennan of Queen's University Belfast in Northern Ireland, who led the analysis, noted in an email to Reuters Health.

It's estimated that more than 120 out of every 100,000 American women are diagnosed with breast cancer each year, yielding a lifetime risk of about 1 in 8. The idea that diet might influence these numbers is not new; yet solid evidence for such a link has remained elusive.

"Even though we have hypothesized a relationship between diet and the risk of breast cancer, showing it has been very hard to do," Dr. Michelle Holmes, an epidemiologist at Harvard Medical School in Boston who was not involved in the study, told Reuters Health. Individual studies are often too small to uncover modest relationships; combining them, however, offers a better chance of detecting a diet's true effects.

After carefully reviewing the relevant research to date, Brennan and her colleagues pooled the results of 18 studies that enrolled a total of more than 400,000 people. Each study aimed to associate breast cancer risks with at least one common dietary pattern: the "unhealthy" Western diet (high in red meats and refined grains), a more prudent "healthy" diet (high in fruits, vegetables and whole grains), or varying levels of alcohol drinking.

Since foods and beverages are never consumed in isolation, this more holistic view of intake better reflects a person's diet than looking at particular nutrients, Brennan and her colleagues explain in the American Journal of Clinical Nutrition.

The team found an 11 percent lower risk of breast cancer among women in the highest versus lowest categories of the prudent diet, while those consuming larger amounts of wine, beer and spirits had a 21 percent increased risk -- a relationship that has been highlighted in many previous studies. Surprisingly, no overall risk difference was seen between high and low categories of the Western diet.

Just how a healthy diet might lower breast cancer risk is not well understood. Alcohol's link, on the other hand, is generally known: Estrogen levels are higher in postmenopausal women who drink alcohol, noted Holmes. And a higher lifetime exposure to estrogen has been tentatively linked to the disease.

Brennan stressed that these findings need to be interpreted cautiously, noting that there are inherent statistical problems in combining the results of multiple studies, in addition to the limitations of each included study, such as recall bias. She pointed to the need for more carefully designed studies in the future to further examine the diet-breast cancer link.

In the meantime, Holmes said: "Consuming a prudent, healthy diet that includes lots of fruits, vegetables and whole grains is a wise idea, because there is lots of scientific evidence that it prevents heart disease and diabetes. This study shows that an additional benefit might be a small decrease in breast cancer risk."

SOURCE: American Journal of Clinical Nutrition, March 10, 2010

How Synthetic Progestin in HRT and the Pill Can Lead to Breast Cancer

ScienceDaily (Oct. 1, 2010) — Breast cancer is one of the most common cancers, affecting up to one in eight women during their lives in Europe, the UK and USA. Large population studies such as the Women's Health Initiative and the Million Women Study have shown that synthetic sex hormones called progestins used in hormone replacement therapy, HRT, and in contraceptives can increase the risk of breast cancers. Now medical researchers at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences in Vienna have identified a key mechanism which allows these synthetic sex hormones to directly affect mammary cells.

The research builds on previous work by Prof Josef Penninger, the IMBA director, who found the first genetic evidence that a protein called RANKL is the master regulator of healthy bones. In a complex system that regulates bone mass, RANKL activates the cells that break down bone material when it needs to be replaced. When the system goes wrong and we make too much of the protein it triggers bone loss, leading to osteoporosis in millions of patients around the world every year. Finding exactly the same molecule in breast tissues led the scientists to the new link between sex hormones and breast cancer.

In a scientific article published in the journal Nature, the research team show that a synthetic female sex hormone used in HRT and contraceptive pills can trigger RANKL in breast cells of mice. As a consequence, these mammary cells start to divide and multiply and fail to die when they should. Moreover, stem cells in the breast become able to renew themselves, ultimately resulting in breast cancer.

In a different set of mouse treatment tests, reported in a second Nature article, researchers at Amgen have found that pharmacologic blocking of the RANKL system significantly delays mammary tumor formation leading to significantly fewer breast cancers in mice. In another mouse model, RANKL inhibition not only decreased breast tumor formation but also reduced lung metastasis.

"Ten years ago we formulated the hypothesis that RANKL might be involved in breast cancer and it took us a long time to develop systems to prove this idea," says Prof Josef Penninger. " I have to admit it completely surprised me just how massive the effects of the system were. Millions of women take progesterone derivatives in contraceptives and for hormonal replacement therapy. Since our results show that the RANKL system is an important molecular link between a synthetic sex hormone and breast tumors, one day women may be able to reduce their risk by taking blocking medicines in advance to prevent breast cancer."

A monoclonal antibody, denosumab, that blocks RANKL has been recently approved in the US and the EU for the treatment of osteoporosis, and is currently under review for the treatment of bone metastases in patients with advanced cancer. "Further studies will be needed to prove the principle of our findings," says Dr Daniel Schramek, who carried out the studies with Prof Josef Penninger at the Institute of Molecular Biotechnology in Vienna. "But we hope that medical trials using denosumab can be started in the near future to test whether the mouse studies can be directly translated to human breast cancer." Scientists have uncovered how hormone replacement therapy can increase the risk of breast cancer, according to new research published on Nature’s website today (Wednesday 29 September, 2010). They found that the link is a protein molecule RANKL, which is essential to regulate bone mass and which is also involved in milk production. The Austrian researchers have shown that a synthetic progesterone, frequently used in HRT and hormonal contraception, can switch on the activity of RANKL within breast cells, causing them to divide and multiply and preventing them from dying when they should. Moreover, stem cells in the breast become able to renew themselves, ultimately resulting in breast cancer. (Credit: Copyright IMBA)

This work was an international collaboration between lead researchers at IMBA and scientists at the Medical University of Vienna; the Garvan Institute of Medical Research, Sydney, Australia; the Ontario Cancer Institute, University of Toronto, Toronto, Canada; Harvard School of Public Health, Harvard Medical School and the Ragon Institute of MGH/MIT and Harvard, Boston, USA; the Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster (CECAD), University of Cologne, Germany; University College London, UK; and the University of Erlangen-Nuremberg, Germany.

High Dietary Fat, Cholesterol Linked to Increased Risk of Breast Cancer and Prostate Cancer

ScienceDaily (Jan. 7, 2011) — Elevated fat and cholesterol levels found in a typical American-style diet play an important role in the growth and spread of breast cancer, say researchers at the Kimmel Cancer Center at Jefferson. The study, published in the January issue of The American Journal of Pathology, examines the role of fat and cholesterol in breast cancer development using a mouse model. The results show that mice fed a Western diet and predisposed to develop mammary tumors, can develop larger tumors that are faster growing and metastasize more easily, compared to animals eating a control diet.

The research team led by cancer biologist Philippe G. Frank, Ph.D., Assistant Professor in the Department of Stem Cell Biology and Regenerative Medicine at Thomas Jefferson University, was interested in learning about the link between diet and breast cancer. The incidence rate of this cancer is five times higher in Western countries than in other developed countries. Moreover, studies have shown an increase in breast cancer incidence in immigrant populations that relocate from a region with low incidence. "These facts suggest strong environmental influence on breast cancer development," says Dr. Frank.

Dietary fat and cholesterol have been shown to be important risk factors in the development and progression of a number of tumor types, but diet-based studies in humans have reached contradictory conclusions. This has led Dr. Frank to turn to animal models of human cancer to examine links between cholesterol, diet, and cancer.

The research team turned to the PyMT mouse model to determine the role of dietary fat and cholesterol in tumor development. This mouse model is believed to closely parallel the pathogenesis of human breast cancer. PyMT mice were placed on a diet that contained 21.2 percent fat and 0.2 percent cholesterol, reflective of a typical Western diet. A control group of PyMT mice was fed a normal chow that had only 4.5 percent fat and negligible amounts of cholesterol.

The researchers found that tumors began to develop quickly in mice fed the fat/cholesterol-enriched chow. In this group, the number of tumors was almost doubled, and they were 50 percent larger than those observed in mice that ate a normal diet. "The consumption of a Western diet resulted in accelerated tumor onset and increased tumor incidences, multiplicity, and burden, suggesting an important role for dietary cholesterol in tumor formation," Dr. Frank says. There was also a trend towards an increased number of lung metastasis in mice fed the fatty diet, he adds.

To confirm the aggressive nature of the cancer in animals fed a cholesterol-rich diet, the researchers examined the levels of several biomarkers of tumor progression and found a signature of a more advanced cancer stage, compared to tumors that developed in the control group.

The researchers also showed that plasma cholesterol levels in experimental mice that developed tumors were significantly reduced compared to a group of "wild-type" mice -- animals with no predisposition to develop tumors -- that was also fed a cholesterol-rich diet. "This suggests that tumor formation was responsible for the reduction in blood cholesterol levels observed in our animals," indicates Dr. Frank.

Dr. Frank explains the use of cholesterol in breast tumors this way: "In a neighborhood, if you want to build more houses, you need more bricks. In tumors, cholesterol provides the bricks that are the foundation for further growth, and this cholesterol comes from the blood. A drop in blood cholesterol may signify that some tumors are growing as cholesterol provides support for breast cancer growth."

"These data provide new evidence for an increase in cholesterol utilization by breast tumors and thus provides many new avenues for prevention, screening, and treatment," indicates Dr. Frank. These findings suggest that use of cholesterol-lowering drugs, such as statins, may both protect against breast cancer as well as treat patients carrying tumors. Since researchers also found that blood cholesterol levels dropped significantly as tumors began to develop, the study indicates measuring blood cholesterol levels may also be an effective method of screening cancer development.

This research team also discovered the same association between cholesterol and growth of prostate cancer in mice in a study published in the December issue of The American Journal of Pathology. The results of these two new studies indicate, according to Dr. Frank that, "Cholesterol does indeed seem to be an important factor in the regulation of tumor formation in several cancer types."

DCIS Patients Who Get Invasive Breast Cancer Have Higher Mortality, Study Finds

ScienceDaily (June 20, 2011) — Women with ductal carcinoma in situ -- DCIS -- who later develop invasive breast cancer in the same breast are at higher risk of dying from breast cancer than those who do not develop invasive disease, according to a study published online March 11 in the Journal of the National Cancer Institute. Retrospective studies of women with DCIS have compared breast conserving surgery (lumpectomy) to mastectomy and found that survival rates are similar. However, women who have lumpectomy alone, without further treatment, are at higher risk of developing invasive breast cancer in the same breast. Whether women who develop invasive breast tumors after DCIS are also at higher risk of dying of breast cancer has not been clear.

To explore this question as well as the long-term effects of treatments aimed at avoiding invasive recurrence after lumpectomy, Irene Wapnir, M.D., of Stanford University School of Medicine, and James Dignam, PhD of University of Chicago looked at the long-term outcomes of patients with localized DCIS who took part in two large randomized trials, both carried out by the National Surgical Adjuvant Breast and Bowel Project (NSABP). The B-17 trial compared lumpectomy alone to lumpectomy plus radiation therapy in women with DCIS. The B-24 trial compared lumpectomy plus radiation in combination with either tamoxifen or placebo.

Wapnir and colleagues analyzed data on outcomes in both trials after 15 years, including overall and breast cancer-specific survival and survival after development of invasive breast cancer in the same, or ipsilateral, breast.

They found that the development of invasive ipsilateral breast cancer was associated with death rates that were statistically significantly higher than those in women who did not develop an invasive ipsilateral breast cancer. Recurrence of DCIS was not associated with higher mortality. Radiation treatment after lumpectomy reduced the risk of ipsilateral invasive breast cancer compared to lumpectomy alone, and treatment with radiation and tamoxifen reduced the risk compared to radiation only. The reductions in risk were statistically significant.

Among all patients in the trials, the 15-year cumulative incidence of death from breast cancer was 4.7% or less for all treatment groups. Some of these events could be attributed to new invasive contralateral breast cancers.

The authors conclude that, regardless of treatment, women with DCIS have an excellent overall prognosis "despite persistent risks of breast cancer in the same or contralateral breast." They note that three other NSABP trials now in progress will provide more information on other treatment options following lumpectomy.

Journal Reference:

Irene L. Wapnir, James J. Dignam, Bernard Fisher, Eleftherios P. Mamounas, Stewart J. Anderson, Thomas B. Julian, Stephanie R. Land, Richard G. Margolese, Sandra M. Swain, Joseph P. Costantino, Norman Wolmark. Long-Term Outcomes of Invasive Ipsilateral Breast Tumor Recurrences After Lumpectomy in NSABP B-17 and B-24 Randomized Clinical Trials for DCIS. Journal of the National Cancer Institute, 2011; DOI: 10.1093/jnci/djr027