Sunday, 16 June 2013

Clinical Sequencing Technology Identifies New Targets in Diverse Cancers

June 7, 2013 — Novel abnormalities in the FGFR gene, called FGFR fusions, were identified in a spectrum of cancers, and preliminary results with cancer cells harboring FGFR fusions suggested that some patients with these cancers may benefit from treatment with FGFR inhibitor drugs, according to data published in Cancer Discovery, a journal of the American Association for Cancer Research.

FGFR genes are receptors that bind to members of the fibroblast growth factor family of proteins and play a role in key biological processes of a human cell. Because of a chromosomal abnormality, this gene sometimes fuses with another gene and forms a hybrid, or a gene fusion, resulting in a gene product with an entirely different function, causing cancers.
"We found targetable FGFR gene fusions across a diverse array of cancer types. Although rare for any individual cancer type, if found in an individual patient, these fusions are likely a major driver of that patient's cancer," said Arul M. Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology at the University of Michigan in Ann Arbor. "We were surprised to find so many different FGFR fusions in so many different cancers.
"This study demonstrates the benefit of broad-based sequencing efforts in personalized oncology. It has the potential to identify novel, rare mutations that are 'actionable' therapeutic targets," Chinnaiyan added. "Such advances in sequencing technology facilitate rational precision therapies for individuals with late-stage cancer."
The Michigan Oncology Sequencing Program (MI-ONCOSEQ) facilitates integrative sequencing analysis of tumors from patients with advanced cancers. More than 100 patients have been enrolled since 2011. Through the project, researchers analyze the mutational landscape of each patient's tumor and suggest clinical trials or approved drugs that might be appropriate for that patient, according to Chinnaiyan.
He and his colleagues identified novel fusions of the gene FGFR2 in the tumors of four patients recruited to MI-ONCOSEQ. Of these four patients, two had metastatic tumors of the bile duct; the third had metastatic breast cancer and the fourth had metastatic prostate cancer.
To further analyze whether FGFR fusions are present across different types of cancers, the researchers extended their assessment and analyzed data generated from an internal cohort of 322 patients, as well as from a large cohort of 2,053 patients recruited to The Cancer Genome Atlas. They identified several distinct FGFR fusions in nine different types of cancers, including bladder cancer, brain cancer and lung cancer.
Chinnaiyan and colleagues then conducted studies using cancer cells and found that the different FGFR fusion proteins all seemed to drive cancer cell proliferation by activating FGFR signaling. The researchers were able to inhibit proliferation of the cells in vitro using the FGFR inhibitors PD173074 and pazopanib. In addition, they injected mice with human cancer cells and found that the tumors grown in mice could be inhibited with PD173074.
One of the four patients whose metastatic bile duct tumor failed to respond to conventional chemotherapy was recruited to an FGFR inhibitor trial, and he is currently undergoing treatment, according to Chinnaiyan.

Menopause May Be an Unintended Outcome of Men's Preference for Younger Mates

Singh, an evolutionary geneticist, backed by computer models developed by colleagues Jonathan Stone and Richard Morton, has determined that menopause is actually an unintended outcome of natural selection -- the result of its effects having become relaxed in older women.
Over time, human males have shown a preference for younger women in selecting mates, stacking the Darwinian deck against continued fertility in older women, the researchers have found.
"In a sense it is like aging, but it is different because it is an all-or-nothing process that has been accelerated because of preferential mating," says Singh, a professor in McMaster's Department of Biology whose research specialties include the evolution of human diversity.
Stone is an associate professor in the Department of Biology and associate director of McMaster's Origins Institute, whose themes include the origins of humanity, while Morton is a professor emeritus in Biology.
While conventional thinking has held that menopause prevents older women from continuing to reproduce, in fact, the researchers' new theory says it is the lack of reproduction that has given rise to menopause.
Their work appears in the online, open-access journal PLOS Computational Biology.
Menopause is believed to be unique to humans, but no one had yet been able to offer a satisfactory explanation for why it occurs, Singh says.
The prevailing "grandmother theory" holds that women have evolved to become infertile after a certain age to allow them to assist with rearing grandchildren, thus improving the survival of kin. Singh says that does not add up from an evolutionary perspective.
"How do you evolve infertility? It is contrary to the whole notion of natural selection. Natural selection selects for fertility, for reproduction -- not for stopping it," he says.
The new theory holds that, over time, competition among men of all ages for younger mates has left older females with much less chance of reproducing. The forces of natural selection, Singh says, are concerned only with the survival of the species through individual fitness, so they protect fertility in women while they are most likely to reproduce.
After that period, natural selection ceases to quell the genetic mutations that ultimately bring on menopause, leaving women not only infertile, but also vulnerable to a host of health problems.
"This theory says that natural selection doesn't have to do anything," Singh says. "If women were reproducing all along, and there were no preference against older women, women would be reproducing like men are for their whole lives."
The development of menopause, then, was not a change that improved the survival of the species, but one that merely recognized that fertility did not serve any ongoing purpose beyond a certain age.
For the vast majority of other animals, fertility continues until death, Singh explains, but women continue to live past their fertility because men remain fertile throughout their lives, and longevity is not inherited by gender.
Singh points out that if women had historically been the ones to select younger mates, the situation would have been reversed, with men losing fertility.
The consequence of menopause, however, is not only lost fertility for women, but an increased risk of illness and death that arises with hormonal changes that occur with menopause. Singh says a benefit of the new research could be to suggest that if menopause developed over time, that ultimately it could also be reversed.

Gene Variant May Provide Novel Therapy for Several Cancer Types

June 6, 2013 — A novel gene variant found in human and animal tissue may be a promising treatment for cancer, including breast and brain cancer, according to scientists from the Icahn School of Medicine at Mount Sinai. The variant, called PTEN-long, may contribute to a cell's healthy function and also suppress tumor cell development.

This landmark study is published in the June 6, 2013 issue of the journal Science.
Ramon Parsons, MD, PhD, Professor and Chair of Oncological Sciences led the team that discovered a mutation in the tumor suppressor gene PTEN, which has subsequently been recognized as the second most common mutation in cancer, especially in breast, prostate, and brain cancers. PTEN encodes a 403 amino acid lipid phosphatase protein that is critical to cellular growth, proliferation, and survival. Genetic inactivation of PTEN causes tumor development.
In the current study, Dr. Parsons and his team analyzed human cells and discovered a PTEN variant that has an additional protein sequence and is 43 percent longer than normal PTEN. They called this new variant PTEN-Long. Like PTEN, the long form has the same enzymatic activity, but unlike PTEN, it is secreted by the cell and can enter other cells, indicating that the added protein sequence acts as a delivery system for the tumor suppressor gene.
"This study culminates more than a decade of research that began soon after we learned the therapeutic potential of PTEN and the PI3K pathway," said Dr. Parsons. "We are excited about the potential of PTEN-Long as a therapy for multiple cancer types."
Using human breast and brain tumor cells that lacked PTEN and PTEN-Long, the research team introduced and overexpressed PTEN-Long and PTEN into the cells. They found that, similar to PTEN, PTEN-Long decreased the signaling activity on the PI3K pathway, thus reducing cellular proliferation. They also found that PTEN-Long was reduced in breast tumor tissue compared to healthy breast tissue.
To test the therapeutic potential of PTEN-Long, Dr. Parsons and his team injected mice with tumor cells, then administered PTEN-Long or a control preparation to the mice. For one of their tumor models, after five days of treatment, the tumors disappeared completely. The authors conclude that PTEN-Long alters signaling on the PI3K pathway to inhibit tumor growth and that its ability to enter other cells is critical to this process. As insulin operates on the PI3K pathway as well, the research team also noticed a brief increase in glucose concentration in the PTEN-Long treated mice.
"These findings indicate that PTEN-Long may contribute to cell homeostasis and suppression of cancer," said Dr. Parsons. "This gene variant has significant potential as a protein-based therapy to treat cancer, and may have implications in diseases such as diabetes."
Next, Dr. Parsons plans to study the normal functions of PTEN-Long, how tumors become resistant to it, what happens when it is missing, and how it can be used as a tool for therapy.
The work was funded by the NCI, The Octoberwoman Foundation, and the Avon Foundation.
Dr. Parsons is a named inventor of a pending patent filed by Columbia Technology Ventures related to the use of PTEN-Long for the treatment of cancer and may benefit financially from this patent.

Significant Under-Use of Genetic Testing for Inherited Cancers Puts Health of Entire Families at Risk

A new study of the use of genetic testing for cancer-causing mutations in affected families in France has found that its take-up is very low. Professor Pascal Pujol, Head of the Cancer Genetics Department, Montpellier University Hospital, Montpellier, France will tell the annual conference of the European Society of Human Genetics on June 9 that analysis of data from the French National Cancer Institute covering the years 2003 to 2011 showed that, although there had been a steady increase in tests performed for the breast and ovarian cancer-causing mutations BRCA1 and BRCA2, this was not the case with the MMR mutation, implicated in Lynch syndrome (a form of colorectal cancer). Only a third of relatives of individuals with either mutation underwent genetic testing themselves.

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"Given that such testing can provide many options to enable individuals to manage their cancer risk, it is vital to encourage awareness and acceptance among both the public and medical professionals," he will say. "For example, removal of the ovaries in women over 40 years old who carry a BRCA mutation decreases their overall cancer mortality by 20% and prophylactic mastectomy can reduce the chances of breast cancer in women carrying such a mutation by around 90%. Those who are unwilling to undergo prophylactic surgery can benefit from increased surveillance, with regular MRI (magnetic resonance imaging) scans. For familial colon cancer, screening by colonoscopy has been shown to decrease mortality. It is therefore regrettable that so few people seem to be aware of the benefits of genetic testing in families with a history of breast, ovarian, or colorectal cancer."
Professor Pujol and colleagues from cancer centres across France analysed 240134 consultations and 134652 genetic tests from patients referred for a predisposition to breast or colorectal cancer. They found a substantial increase in tests for BRCA1/2 - from 2095 a year in 2003 to 7393 in 2011 -- but for MMR mutations the increase was tiny -- from 1144 to 1635 a year over the same period.
Mutations in BRCA1/2 genes are thought to be responsible for about 5% of all cases of breast and ovarian cancer. A woman with such a mutation has a risk of up to 87% of having breast cancer before she reaches the age of 80, as opposed to a risk of 8% in the general population. Such cancers are diagnosed at an average age of 43, as opposed to 60 in the general population, and are often more aggressive. In the case of ovarian cancer, a woman carrying a BRCA1 mutation has a risk of ovarian cancer of up to 63%.
Individuals with Lynch syndrome, or hereditary nonpolyposis colorectal cancer, have a 45% risk of developing colorectal cancer by the age of 70, and women with the syndrome are at increased risk of endometrial and ovarian cancers.
"While the increase in BRCA testing is encouraging, it is far from optimal. And the uptake of MMR testing for Lynch syndrome -- responsible for 5% of all colorectal cancers -- is frankly disappointing," says Professor Pujol. "And of course, positive test results may have implications for other family members.
"While we have only studied the situation in France, we believe that our findings would be likely to be replicated in many other countries across the world. It is extremely worrying that such a simple test, which has the potential to spare whole families from devastating illness, is being so under-used. We urgently need a major programme of awareness among all those concerned, involving medical education and training, information programmes for patients and their families, public health campaigning, and improved genetic counselling," he will conclude.

Screening Fails to Affect Breast Cancer Mortality Statistics, UK Study Finds

New research analysing breast cancer mortality data spanning almost 40 years concludes that breast cancer screening does not yet show an effect on mortality statistics. The research, published in the Journal of the Royal Society of Medicine, analysed mortality trends before and after the introduction of the National Health Service Breast Screening Programme in 1988. The research was based on an analysis of mortality statistics in the Oxford region because, unlike the rest of England, all causes of death on the death certificate, not just the underlying cause, are available prior to the commencement of the National Health Service breast cancer screening programme. In addition, mortality statistics for the whole of England, where death is recorded as an underlying cause, were analysed.

Researchers from the Department of Public Health at the University of Oxford sought evidence of a decline in population-based breast cancer mortality that could be attributed to the implementation of mammographic screening programmes. They concluded that population-based mortality statistics for England do not show a past benefit of breast cancer screening.
The new research contrasts with the findings of an independent review commissioned by the Department of Health published in 2012 which concluded that there was a 20% relative reduction in mortality from breast cancer in women invited to screening. The review also found that for each breast cancer death prevented, about three over-diagnosed cases will be identified and treated.
Lead researcher, Ms Toqir Mukhtar, says that while the new results do not rule out a benefit of breast cancer screening at the level of individual women, "the effects are not large enough to be detected at the population level." The results were unaltered by an analysis with the enhancement of using all certified causes of death.
Ms Mukhtar describes the evaluation of the effectiveness of mammographic screening programmes as problematic, saying that the effect of screening on mortality needs to be considered in light of improvements in treatment, and technological advancements made in mammographic screening, during the past 20 years.
She concludes: "Measuring the effectiveness of mammography screening is a fundamental area of concern in countries which have established mammography screening programmes. Clinical trials have indicated that several years have to elapse between the start of screening and the emergence of a reduction in mortality. Yet our data shows that there is no evidence of an effect of mammographic screening on breast cancer mortality at the population level over an observation period of almost 40 years."

New Layer In Human Eye Discovered

A new layer in the front layer of the human eye has been discovered by researchers at The University of Nottingham.

The findings, published in the journal Ophthalmology, could significantly help doctors carry out corneal grafts or transplants.

The layer has been called the "Dua's Layer", named after the researcher who led the study, Professor Harminder Dua.

Harminder Dua, Professor of Ophthalmology and Visual Sciences, said that the discovery means that ophthalmology textbooks will literally have to be re-written.

He added:

"Having identified this new and distinct layer deep in the tissue of the cornea, we can now exploit its presence to make operations much safer and simpler for patients."

Clinicians across the world are starting to relate the tear or absence in this layer to diseases at the back of the cornea.

The cornea is located on the front of the eye and allows light to enter. Previously believed for made up of five different layers:

Bowman's layer
The corneal epithelium
The corneal stroma
Descemet's membrane
The cornel endothelium

The Dua's layer is located in the back of the cornea between the corneal stroma and Descemet's membrane. It is extremely tough and strong despite being only 15 microns thick, it also impervious to air.

The newly discovered layer of the cornea is a significant advancement in our understanding of the human eye.

The new layer was discovered by simulating human corneal transplants on eyes collected from donors across the UK - given recent success in cultivated stem cells on human corneas, there might not be a need for donors in the future.

Small air bubbles were injected into the cornea of the eye to separate it into different layers. The researchers were able to study the layers a thousand times their actual size with electron microscopy.

Surgeons will benefit considerably by understanding more about the new Dua's layer, which will improve outcomes for patients undergoing corneal grafts and transplants. There are over 65,000 penetrating corneal graft procedures being carried out worldwide each year, according to Eye Journal.

During corneal surgery, a method called the "big bubble technique" is used, whih involves injecting tiny air bubbles into the corneal stroma. Sometimes these bubbles burst, leaving the patient's eye severely damaged.

However, now that doctors know they can inject the bubbles under the Dua's layer instead of above it, the chances of tearing during surgery are significantly reduced.

The researchers say that corneal hydrops, a condition that occurs when water from inside the eye rushes in and leads to a fluid buildup in the cornea, is likely caused by a tear in the Dua layer.

Dua concluded:

"From a clinical perspective, there are many diseases that affect the back of the cornea, which clinicians across the world are already beginning to relate to the presence, absence, or tear in this layer."

Eyeball Licking (Oculolinctus) Can Be Dangerous, Doctors Warn

Eyeball-licking fetishism, also known as "oculolinctus" or "worming", has become a popular way of expressing affection or inciting sexual arousal in Japan. Doctors warn that it is linked to a serious risk of virus conjunctivitis, other eye infections, and even blindness

According to the Japanese website Naver Matome, the oculolinctus craze in the country among young lovers has resulted in a significant increase in eye-infection cases.

Naver Matome first reported on eyeball-licking when a Japanese school noticed that children were coming into class wearing eye patches. Apparently, one third of all the twelve-year-old children at the school had engaged in oculolinctus.

Eyeball licking is dangerous

Pink eye - a case of viral conjunctivitis caused by eyeball licking

When the tongue makes contact with the eye, it is exposed to all kinds of infections and eye damage.

In an interview with the Huffington Post, David Granet, M.D., an ophthalmologist said "Nothing good can come of this. There are ridges on the tongue that can cause a corneal abrasion. And if a person hasn't washed out their mouth, they might put acid from citrus products or spices into the eye."

There is a serious risk of passing on viruses. If somebody who does the licking has herpes and a cold sore, there is a risk of human transmission via oculolinctus.

The International Science Times quoted Dr. Phillip Rizzuto, a spokesman for the American Academy of Ophthalmology, who said there is a risk of eventual blindness. "The bacteria in the mouth are nothing like the bacteria in the eyeball, which is why we no longer recommend people lick contact lenses to moisten them.," Rizzuto added.

If the person doing the licking suffers from halitosis (bad breath), they are likely to have a huge number of harmful bacteria. Allow them to lick your eyeball, which has an absorbing membrane, and your risk of infection is considerable.

Animals use their tongues for personal hygiene (watch a cat cleaning itself), to a certain extent humans do the same. However, the tongue and mouth are designed to deal with a much wider variety of pathogens than our eyeballs are. Who knows what would be passed on to somebody's eye when the licker had just licked his/her hands, especially if that hand has not been washed in a while.

South Asian Women Have Higher Breast Cancer Risk Than White Women, UK

South Asian women in Britain have an 8% higher risk of developing breast cancer than British white women, compared to a 45% lower risk ten years ago, researchers from the University of Sheffield reported at the National Cancer Intelligence Network Conference in Brighton on Friday, June 14th.

Study leader, Dr. Matthew Day and team are not sure why breast cancer incidence has increased so rapidly among British South Asian females. They suggest that possibly some lifestyle factors, like having fewer children today, getting pregnant later in life, an increase in screening uptake, oral contraceptive usage, alcohol consumption, and possibly smoking may have had an impact.

Dr. Day and team said, however, that after carrying out their study in Leicester, the evidence is compelling that breast cancer risk for South Asian women in Britain has increased considerably over the last decade.

The researchers had gathered and examined data on 135,000 adult females from a range of ethnic backgrounds from 2000 to 2009. They found that:

During the period 2000-2004, South Asian women's risk of developing breast cancer was 45% lower than it was for white women

By the end of the 2005-2009 period, South Asian women were 8% more likely to develop breast cancer compared to white women

The greatest increase in breast cancer risk was seen among South Asian women aged 65+ years, who by the end of 2009 were found to be 37% more likely to develop breast cancer compared to white women in the same age group.

The study did not examine diabetes prevalence among older South Asian women during the nine-year period to determine whether this might have explained the dramatic increase in breast cancer rates. Post-menopausal women with type 2 diabetes have a 27% higher risk of breast cancer.

The impact of socioeconomic deprivation - during the 2000-2004 period, socioeconomic deprivation was not seen as a risk factor for breast cancer risk, but it was by 2009. This surprised the researchers, because the trend in the rest of the female population was the other way round.

From 2000 to 2009, breast cancer rates for white women remained fairly constant.

Dr. Day said:

"Historically South Asian women, and women in lower socio-economic groups, have been considered at lower risk of developing breast cancer. Based on our study in Leicester, this should no longer be considered the case.

The exact causes behind this change are not clear cut, they could relate to increases in screening uptake among these groups of women, which have in the past been shown to be lower than in other groups . . . . . Or they could be due to changes in lifestyle factors, like having fewer children and having them later in life, increased use of oral contraceptives, and increased smoking and alcohol intake - factors linked to increased breast cancer risk across the board."

Clinical Lead at Public Health England's National Cancer Intelligence Network, Dr Mick Peake, said "The results of the Leicester study should assist public health services to both plan for, and respond to, the changing risk profile of breast cancer in the population, particularly with regards Asian women who for a long time have been another group whose attendance rate for screening has been low. At the individual level, if women are concerned about breast cancer, they should speak to their GP."

Low Asian breast cancer risk? Is it a myth?

Several studies over the last ten years have challenged the belief that breast cancer incidence in Asia is very low and that female Asian immigrants or female descendants of Asian immigrants have lower breast cancer risks. Others have shown that Asian immigrants' breast cancer risk rises after they have settled in their adopted country.

Asia is an enormous continent. Breast cancer rates vary enormously from Japan to China, Indonesia, the Philippines, India, Pakistan, Bangladesh, etc.

A team of scientists from the Cancer Prevention Institute of California (CPIC) released their findings from a study that challenged the notion that breast cancer rates are uniformly low across the population of Asian women.

Researchers at West Virginia University reported in the journal Cancer (September 2008 issue) that immigrants from Pakistan and India have higher risks of breast and prostate cancer after entering the USA. Study leader, Jame Abraham, M.D., said "Breast cancer and prostate cancer develop due to many reasons, but environmental factors and lifestyle play a major role in these cancers. When men and women from India and Pakistan migrate to the United States, their disease profiles change, mirroring the American risk."

Scientists Make Breast Cancer Advance That Turns Previous Thinking On Its Head

New research published today in the Journal of Biological Chemistry reveals that an enzyme called MMP-8 (matrix metalloproteinase-8) could be acting as a locator to the immune system, which then becomes activated to attack tumours. It was originally thought that the production of MMPs by breast cancer cells worked to promote cancer growth.
Lead researcher Prof Dylan Edwards from UEA's School of Biological Sciences said: "MMPs are a family of enzymes that are released from cancer cells. They were once thought to act like 'molecular scissors' to snip away at the scaffolding structures outside cells and clear a path for the cancer cells to invade and spread to other organs.
"Drugs that target this broad family of enzymes were trialled to treat cancer in the 1990s but largely failed. This led us to think that not all of these enzymes were bad guys that promoted tumour growth and spread."
Scientists from UEA worked with clinicians at the Norfolk and Norwich University Hospital to look in detail at the patterns of MMPs in breast tumours from patients. Previous research published in 2008 revealed that one of these enzymes, known as MMP-8, has a protective role which holds tumours in check. And patients whose breast tumours have more of this particular enzyme seemed to have better outcomes.
The latest research was funded by cancer charity the Big C and carried out by PhD student Sally Thirkettle. Prof Edwards said: "She has shown that if she makes breast cancer cells produce MMP-8, it causes them to produce two other inflammatory factors (IL-6 and IL-8) that have previously been shown to promote cancer. However, breast tumour cells that over-produce MMP-8 don't survive long-term -- the enzyme stops them growing."
"We now think that in tumours, MMP-8 acts as a sort of 'find me' signal to the immune system, which then becomes activated to attack the tumour, which may help to explain its protective function.
"The fact that a protective enzyme such as MMP-8 was also blocked by the first generation anti-MMP drugs used in the 1990s also partly explains why these drugs failed in the clinic," he added.
It is still unknown exactly how MMP-8 causes IL-6 and IL-8 to be activated -- but the findings are an important step forward which will help direct further research.

Chemotherapy: Greater Potential Benefit in Overall Survival for Eribulin Compared With Capecitabine

The specific patient populations who appeared to benefit from eribulin, in comparison to capecitabine, are as follows:

Patients with more than two organs involved with metastatic breast cancer
Patients who had not received chemotherapy for six months or longer
Patients who had received anthracycline and/or a taxane therapies in the metastatic setting

Previous pre-specified exploratory analysis of overall survival and progression-free survival showed women with triple-negative, ER-negative, HER2-negative also had a greater relative benefit in overall survival with eribulin over capecitabine.
"These exploratory analyses suggest that other patient subgroups may benefit from eribulin and further studies are warranted," said Peter A. Kaufman, MD, associate professor of medicine at the Geisel School of Medicine at Dartmouth, and oncologist at Dartmouth-Hitchcock and Norris Cotton Cancer Center in Lebanon, N.H.
In 2010, the FDA approved eribulin for the treatment of patients with metastatic breast cancer who had previously received an anthracycline and a taxane and at least two cytotoxic chemotherapy treatment regimens for metastatic breast cancer. The FDA granted approval based on data showing a statistically significant improvement in overall survival compared with current treatments.
Kaufman and colleagues are still compiling data from the quality-of-life analysis, which according to Kaufman, will help guide their next steps in further studying eribulin in this patient population.

Chemotherapy: Greater Potential Benefit in Overall Survival for Eribulin Compared With Capecitabine

The specific patient populations who appeared to benefit from eribulin, in comparison to capecitabine, are as follows:

Patients with more than two organs involved with metastatic breast cancer
Patients who had not received chemotherapy for six months or longer
Patients who had received anthracycline and/or a taxane therapies in the metastatic setting

Gene Variants May Predict Who Will Benefit from Breast Cancer Prevention Drugs

The work represents a major step toward truly individualized breast cancer prevention in women at high risk for the disease based on their age, family history of breast cancer, and personal medical history.
"Our study reveals the first known genetic factors that can help predict which high-risk women should be offered breast cancer prevention treatment and which women should be spared any unnecessary expense and risk from taking these medications," said the study's lead scientist, James N. Ingle, M.D., professor of oncology at the Mayo Clinic in Rochester, Minn. "We also discovered new information about how the drugs tamoxifen and raloxifene work to prevent breast cancer."
Ingle and Mayo-based colleagues in the NIH Pharmacogenomics Research Network (PGRN) conducted the study in collaboration with PGRN-affiliated researchers at the RIKEN Center for Genomic Medicine in Tokyo. Data and patient DNA came from the long-running National Surgical Adjuvant Breast and Bowel Project (NSABP), supported by the National Cancer Institute.
"This innovative, PGRN-enabled international research partnership has produced the first gene-based method to identify which women are likely to benefit from a readily available preventive therapy," said PGRN director Rochelle Long, Ph.D., of the NIH's National Institute of General Medical Sciences. "Because the disease affects so many women worldwide, this work will have a significant impact."
The research, which shows nearly a six-fold difference in disease risk depending on a woman's genetic makeup, appears in the June 13, 2013, issue of Cancer Discovery.
Women undergoing breast cancer preventive treatment take tamoxifen or raloxifene for five years. In rare cases, the drugs can cause dangerous side effects, including blood clots, strokes and endometrial cancer.
Many women never try the therapy because the chance of success seems small (about 50 women in the NSABP trials needed to be treated to prevent one case of breast cancer) compared to the perceived risk of side effects. More women might benefit from the potentially life-saving strategy if doctors could better predict whether the therapy was highly likely to work. That's what the current study begins to do.
The investigators leveraged data from past NSABP breast cancer prevention trials that involved a total of more than 33,000 high-risk women -- the largest sets of such data in the world. Women in the trials gave scientists permission to use their genomic and other information for research purposes.
The scientists analyzed the genomic data by focusing on more than 500,000 genetic markers called single nucleotide polymorphisms (SNPs). Each SNP represents a single variation in the DNA sequence at a particular location within the genome.
To determine whether any SNPs were associated with breast cancer risk, the researchers computationally searched for SNPs that occurred more commonly in women who developed breast cancer during the trial than in women who remained free of the disease. The analysis identified two such SNPs -- one in a gene called ZNF423 and the other near a gene called CTSO.
Neither ZNF423 nor CTSO -- nor any SNPs related to these genes -- had previously been associated with breast cancer or response to the preventive drugs. The scientists' work revealed that women with the beneficial version of the two SNPs were 5.71 times less likely to develop breast cancer while taking preventive drugs than were women with neither advantageous SNP.
Using a variety of biochemical studies, the scientists learned that ZNF423 and CTSO act by affecting the activity of BRCA1, a known breast cancer risk gene. Healthy versions of BRCA1 reduce disease by repairing a serious form of genetic damage. Harmful versions of BRCA1 dramatically increase a woman's chance of developing breast cancer.
"The results of our collaborative research bring us a major step toward the goal of truly individualized prevention of breast cancer," said Ingle. "Our findings also underscore the value of studying the influence of gene variations on drug responses."
NIH's National Institute of General Medical Sciences and National Cancer Institute funded this research through grants U19GM61388, P50CA116201, U10CA37377, U10CA69974, U24CA114732 and U01GM63173.

Osteoporosis Drug Stops Growth of Breast Cancer Cells, Even in Resistant Tumors, Study Suggests

The findings, presented June 15, 2013, at the annual Endocrine Society meeting in San Francisco, indicate that the drug bazedoxifene packs a powerful one-two punch that not only prevents estrogen from fueling breast cancer cell growth, but also flags the estrogen receptor for destruction.
"We found bazedoxifene binds to the estrogen receptor and interferes with its activity, but the surprising thing we then found was that it also degrades the receptor; it gets rid of it," said senior author Donald McDonnell, PhD, chair of Duke's Department of Pharmacology and Cancer Biology.
In animal and cell culture studies, the drug inhibited growth both in estrogen-dependent breast cancer cells and in cells that had developed resistance to the anti-estrogen tamoxifen and/or to the aromatase inhibitors, two of the most widely used types of drugs to prevent and treat estrogen-dependent breast cancer. Currently, if breast cancer cells develop resistance to these therapies, patients are usually treated with toxic chemotherapy agents that have significant side effects.
Bazedoxifene is a pill that, like tamoxifen, belongs to a class of drugs known as specific estrogen receptor modulators (SERMs). These drugs are distinguished by their ability to behave like estrogen in some tissues, while significantly blocking estrogen action in other tissues. But unlike tamoxifen, bazedoxifene has some of the properties of a newer group of drugs, known as selective estrogen receptor degraders, or SERDs, which can target the estrogen receptor for destruction.
"Because the drug is removing the estrogen receptor as a target by degradation, it is less likely the cancer cell can develop a resistance mechanism because you are removing the target," said lead author Suzanne Wardell, PhD, a research scientist working in McDonnell's lab.
Many investigators had assumed that once breast cancer cells developed resistance to tamoxifen, they would be resistant to all drugs that target the estrogen receptor, McDonnell explained.
"We discovered that the estrogen receptor is still a good target, even after it resistance to tamoxifen has developed," he said.
The investigators tested a variety of breast cancer cell types, including tamoxifen-sensitive cells that are resistant to the drug lapatinib, another targeted therapy that is used to treat patients with advanced breast cancer whose tumors contain the mutant HER2 gene. These cells had previously been shown to reactivate estrogen signaling in order to acquire drug resistance. In this cell type, bazedoxifene also potently inhibited cell growth.
Paradoxically, in bone tissue, bazedoxifene mimics the action of estrogen, helping protect it from destruction. Because bazedoxifene has already undergone safety and efficacy studies as a treatment for osteoporosis, it may be a viable near-term option for patients with advanced breast cancer whose tumors have become resistant to other treatment options, Wardell reported. In clinical trials, the most often reported side effect was hot flashes in the bazedoxifene treatment groups.
The study was funded by a research grant from Pfizer Pharmaceuticals, maker of bazedoxifene.
In addition to Wardell and McDonnell, Erik Nelson and Christina Chao of the Department of Pharmacology and Cancer Biology, Duke University School of Medicine, contributed to the research.

Health Affairs, the leading journal of health policy thought and research, is published by Project HOPE. The peer-reviewed journal appears monthly in print, online, and via iPad with additional online Web First articles appearing online ahead of print. Published since 1981, The Washington Post, has called Health Affairs the bible of health policy.
John Iglehart, Founding Editor of Health Affairs, serves as the journal's Editor-in-Chief. All submitted papers undergo external peer review and are authored by leading academics from fields that intersect with health policy such as economics, public health, sociology, political science, medicine and nursing, to name a few. Government policymakers and health industry decision makers from the U.S. and around the globe also write for and read the journal.

Health Affairs is available via subscription and all articles ever published by the journal are available online at healthaffairs.org. All abstracts, tables of contents and many articles are free to access online, and all content is free online to readers from the lowest income nations. Health Affairs Blog offers an inclusive and interactive dimension to the journal’s timely commentary and analysis of health policy dialog. Health Policy Briefs provide a short history of a current health policy issue, an exploration of opposing views, an explanation of what is at stake and what the research says.

- See more at: http://www.projecthope.org/what-we-do/health-affairs/?gclid=COuime7I6LcCFWlS4godjm8ApQ#sthash.PdeSbb06.dpuf

There’s Never a Wrong Time to Start Making Lifestyle Changes

A Look at Hypertension During National Women’s Health Week

Jennifer Wider, MD
SWHR, Contributing Writer
May 2013

Each year, the US Department of Health and Human Services’ Office on Women’s Health promotes the health of women and its importance during a weeklong health observance called National Women’s Health Week. The purpose is to empower women to take charge of their own health and to make it a priority.
One important step in taking care of your health is visiting a health care professional on a regular basis for checkups and preventive screenings. These guidelines may vary by age and your own medical profile, so it’s important to speak with your health care provider to see what’s right for you.
“The most important screenings are the basic ones,” says Nina Karol, MD a physician at Internal Medicine Associates of Westport, CT. “Blood pressure, cholesterol, weight, and waist circumference; and make sure that you discuss the overall quality of your diet with your doctor: calcium intake, fruit/vegetable intake.” Karol also recommends diabetes screening, mammogram and colonoscopy when they are age appropriate. “Everyone should be screened for skin cancer,” she adds. “A melanoma that is diagnosed early is completely curable.”
One issue that some women don’t pay close attention to is high blood pressure. Oftentimes, people mistakenly believe that high blood pressure, or hypertension, is more common among men. But according to statistics from the American Heart Association, nearly half of all adults with high blood pressure are women. And beginning at age 65, post-menopausal women are actually more likely to have hypertension than men.
“High blood pressure is more common in women than people realize,” says Karol. “This is one of the risk factors for cardiovascular disease and stroke that people can control, and it’s easy to treat.” People need to be aware of their risk factors, which include: age, family history, weight, sedentary lifestyle, stress, tobacco use and poor diet. “Even if you have had normal blood pressure your whole life, it can come on at any time,” adds Karol.
High blood pressure can damage a person’s blood vessels and their vital organs. The extra pressure on the artery walls can wreak havoc, especially over time. The longer a person suffers from high blood pressure the worse the damage. Uncontrolled hypertension can lead to: a stroke, heart failure, heart attack and an aneurysm. It can also affect a person’s ability to think and remember things.
Making lifestyle changes can make a huge difference in controlling a person’s blood pressure. “Weight loss, regular exercise and eating a diet lower in processed foods and higher in fresh fruits, vegetables and low fat dairy can go a long way,” says Karol. But sometimes lifestyle modifications aren’t enough. There are a host of medications available to treat hypertension including: diuretics, beta-blockers, ACE inhibitors, calcium-channel blockers, among many others. If you have hypertension, it’s important to speak with your doctor to choose the right plan for you.
All too often, women deprioritize their own health because they are busy taking care of other family members. National Women’s Health Week is a great time to highlight how important it is to take steps to prioritize the health of women everywhere. Getting active, eating healthy, making regular checkup and screening appointments, paying attention to mental health and avoiding unhealthy behaviors such as smoking, drinking, seatbelts and cellphone texting or talking while driving are among the steps women can take to ensure better health for themselves throughout the year.

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For more information on the Society for Women’s Health Research please contact Dimetrius Simon at 202-496-5067 or dimetrius@swhr.org.

Jennifer Wider, M.D., is a medical advisor for the Society for Women’s Health Research (SWHR), a national non-profit organization based in Washington D.C., widely recognized as the thought leader in research on sex differences and dedicated to improving women’s health through advocacy, education, and research.

Dr. Wider is a graduate of Princeton University and received her medical degree in 1999 from the Mount Sinai School of Medicine in New York City. She is frequently published in newspapers, magazines, and websites and has been a guest on the Today Show, CBS News, Fox News, Good Day New York, and a variety of cable channels. Dr. Wider hosts “Paging Dr. Wider,” a weekly segment on Sirius satellite radio for the Cosmopolitan magazine channel.

Dr. Wider is a past managing editor of the health channel at iVillage.com. She writes a monthly news service article for SWHR and is the author of the consumer health booklet “Just the Facts: What Women Need to Know about Sex Differences in Health” and the book “The Doctor’s Complete College Girls’ Health Guide: From Sex to Drugs to the Freshman Fifteen.”

Osteoporosis Drug Stops Growth of Breast Cancer Cells, Even in Resistant Tumors, Study Suggests

June 15, 2013 — A drug approved in Europe to treat osteoporosis has now been shown to stop the growth of breast cancer cells, even in cancers that have become resistant to current targeted therapies, according to a Duke Cancer Institute study.