The mammography dilemma: 50 years of analysis

A comprehensive review of 50 year’s worth of international studies assessing the benefits and harms of mammography screening suggests that the benefits of the screening are often overestimated, while harms are underestimated. And, since the relative benefits and harms of screening are related to a complex array of clinical factors and personal preferences, physicians and patients need more guidance on how best to individualize their approach to breast cancer screening.The results of the review by researchers at Harvard Medical School’s Department of Health Care Policy and Brigham and Women’s Hospital are published today in JAMA.The American Cancer Society estimates that about 40,000 U.S. women will die of breast cancer this year. In 2009, based on evidence that the benefit-risk ratio for mammography screening is higher among women over 50 and with less frequent screening, the U.S. Preventive Services Task Force (USPSTF) reversed its previous recommendation of mammography every one to two years beginning at age 40, and recommended routine screening every two years starting at age 50, the researchers noted. The recommendations remain controversial among the general public and the medical community. Recent evidence suggests that use of mammography in the U.S. has not changed following the updated recommendations.”What I tell my patients is that the mammogram is not a perfect test,” said Nancy Keating, co-author of the report, associate professor of Health Care Policy at HMS and associate professor of medicine at Brigham and Women’s. “Some cancers will be missed, some people will die of breast cancer regardless of whether they have a mammogram, and a small number of people that might have died of breast cancer without screening will have their lives saved.”The authors report that the best estimate of the reduction in mortality from breast cancer due to annual screening for women overall is about 19 percent. For women in their 40s, the reduction in risk was about 15 percent, and for women in their 60s, about 32 percent. …

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Can vitamin A turn back the clock on breast cancer?

A derivative of vitamin A, known as retinoic acid, found abundantly in sweet potato and carrots, helps turn pre-cancer cells back to normal healthy breast cells, according to research published this month in the International Journal of Oncology. The research could help explain why some clinical studies have been unable to see a benefit of vitamin A on cancer: the vitamin doesn’t appear to change the course of full-blown cancer, only pre-cancerous cells, and only works at a very narrow dose.Because cells undergo many changes before they become fully aggressive and metastatic, Sandra V. Fernandez, Ph.D., Assistant Research Professor of Medical Oncology at Thomas Jefferson University, and colleagues, used a model of breast cancer progression composed of four types of cells each one representing a different stage of breast cancer: normal, pre-cancerous, cancerous and a fully aggressive model.When the researchers exposed the four breast cell types to different concentrations of retinoic acid – one of the chemicals that the body converts vitamin A into – they noticed a strong change in the pre-cancerous cells. Not only did the pre-cancerous cells begin to look more like normal cells in terms of their shape, they also changed their genetic signature back to normal. Dr. Fernandez’s pre-cancerous cells had 443 genes that were either up or downregulated on their way to becoming cancerous. All of these genes returned to normal levels after treatment with retinoic acid. “It looks like retinoic acid exerts effects on cancer cells in part via the modulation of the epigenome,” says Fernandez.“We were able to see this effect of retinoic acid because we were looking at four distinct stages of breast cancer,” says Dr. Fernandez. “It will be interesting to see if these results can be applied to patients.”Interestingly, the cells that were considered fully cancerous did not respond at all to retinoic acid, suggesting that there may be a small window of opportunity for retinoic acid to be helpful in preventing cancer progression. …

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Natural plant compounds may assist chemotherapy

Researchers at Plant & Food Research have identified plant compounds present in carrots and parsley that may one day support more effective delivery of chemotherapy treatments.Scientists at Plant & Food Research, working together with researchers at The University of Auckland and the National Cancer Institute of The Netherlands, have discovered specific plant compounds able to inhibit transport mechanisms in the body that select what compounds are absorbed into the body, and eventually into cells. These same transport mechanisms are known to interfere with cancer chemotherapy treatment.The teams’ research, recently published in the European Journal of Pharmacology, showed that falcarinol type compounds such as those found in carrots and parsley may support the delivery of drug compounds which fight breast cancer by addressing the over-expression of Breast Cancer Resistance Protein (BCRP/ABCG2), a protein that leads to some malignant tissues ability to become resistant to chemotherapy.”It’s very exciting work,” says Plant & Food Research Senior Scientist, Dr Arjan Scheepens. “Our work is uncovering new means to alter how the body absorbs specific chemical and natural compounds. Ultimately we are interested in how food could be used to complement conventional treatments to potentially deliver better results for patients.”Story Source:The above story is based on materials provided by New Zealand Institute for Plant and Food Research. Note: Materials may be edited for content and length.

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Regular physical activity reduces breast cancer risk irrespective of age

Practising sport for more than an hour day reduces the risk of contracting breast cancer, and this applies to women of any age and any weight, and also unaffected by geographical location, according to research presented to the 9th European Breast Cancer Conference (EBCC-9). Compared with the least active women, those with the highest level of physical activity reduced their risk of breast cancer by 12%, researchers say.Professor Mathieu Boniol, Research Director at the International Prevention Research Institute, Lyon, France, recently reported the results of a meta-analysis of 37 studies published between 1987 and 2013, representing over four million women. “These are all the studies looking at the relationship between physical exercise and breast cancer risk that have been published to date, so we are confident that the results of our analysis are robust,” he said.Although the results varied according to tumour type, the overall message was encouraging, the researchers say. However, in women taking hormone replacement therapy (HRT), the protective effect of exercise seemed to be cancelled out. But increased awareness of the side effects of HRT means that its use is decreasing in a number of countries, and this means that the beneficial effects of activity will most likely grow in the years to come. “Whether or not this will be the case is an interesting question and deserves to be followed up at a later date,” Prof Boniol said.Physical activity is known to have a protective role in other cancers, as well as in disorders such as cardiovascular disease. Although the mechanisms for its effect are unclear, the results are largely independent of body mass index (BMI), so the effect must be due to more than weight control. And the age at which sporting activity starts also appears to be immaterial; the researchers found no indication that breast cancer risk would decrease only when physical activity started at a young age.”Adding breast cancer, including its aggressive types, to the list of diseases that can be prevented by physical activity should encourage the development of cities that foster sport by becoming bike and walk-friendly, the creation of new sports facilities, and the promotion of exercise through education campaigns,” said Prof Boniol. “This is a low cost, simple strategy to reduce the risk of a disease that currently has a very high cost, both to healthcare systems and to patients and their families. It is good news both for individuals and for policy makers.”Dr Hilary Dobson, chair of EBCC-9’s national organising committee and who is Clinical Lead of the West of Scotland Breast Screening Service and the Lead Clinician of the West of Scotland Cancer Advisory Network (WoSCAN), commented: “These findings are important for all women, irrespective of their age and weight. …

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Double mastectomy halves death risk for women with BRCA-related breast cancer

Women with BRCA-related breast cancer who have a double mastectomy are nearly 50 per cent less likely to die of breast cancer within 20 years of diagnosis compared to women who have a single mastectomy, according to a new study led by Women’s College Hospital’s Kelly Metcalfe.The findings, published in the British Medical Journal, suggest a double mastectomy may be an effective first-line treatment for women with early-stage breast cancer who carry a BRCA1 or BRCA2 genetic mutation. The BRCA1/2 genes belong to a class of genes that typically act to protect individuals from acquiring cancer, yet women who inherit a mutated form of the genes have a high risk of developing breast and ovarian cancers.”Women with a BRCA mutation have a 60 to 70 per cent chance of developing breast cancer in their lifetime, and once diagnosed, a further 34 per cent chance of developing breast cancer in the opposite breast within 15 years,” said Kelly Metcalfe, an adjunct scientist at Women’s College Research Institute and professor at the University of Toronto. “For these women, we need to think about treating the first breast cancer, but also about preventing a second breast cancer.”To compare the survival rates of women with BRCA-related breast cancers, researchers assessed the medical records of 390 women with stage one or two breast cancer and a BRCA1 or BRCA2 mutation. The women were required to have been initially treated with a single or double mastectomy. The researchers found:Women who had a double mastectomy had a 48% greater likelihood of surviving compared to women with a single mastectomy For women who developed a new breast cancer in the opposite breast, the risk of dying of breast cancer was doubled At twenty years, the survival rate was 88% for women with a double mastectomy and 66% for women with a single mastectomy “Our study’s results provide evidence that in order to improve survival in women with BRCA-associated breast cancer, we need to prevent new breast cancers from developing after an initial diagnosis,” said Dr. Steven Narod, a co-author of the study and a senior scientist at Women’s College Research Institute. “This study highlights the importance of providing genetic testing for BRCA1 and BRCA2 at the time of breast cancer diagnosis if appropriate. This genetic information could help women make decisions that ultimately may increase their chance of surviving breast cancer.”Last year, Hollywood actress Angelina Jolie, publicly announced her decision to opt for a double mastectomy and breast reconstruction surgery after discovering she had the BRCA1 gene. The then 37 year-old actress said doctors estimated she had a 50 per cent risk of developing ovarian cancer and an 87 per cent risk of breast cancer.While existing research widely supports the benefit of a double mastectomy in preventing breast cancer in women with the gene mutation, the study’s researchers caution more research is necessary to confirm the benefit of a double mastectomy in reducing the risk of death in women diagnosed with BRCA-related breast cancer.Story Source:The above story is based on materials provided by Women’s College Hospital. Note: Materials may be edited for content and length.

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Radiotherapy in girls and the risk of breast cancer later in life

Sep. 11, 2013 — Exposing young women and girls under the age of 20 to ionizing radiation can substantially raise the risk of their developing breast cancer later in life. Scientists may now know why. A collaborative study, in which Berkeley Lab researchers played a pivotal role, points to increased stem cell self-renewal and subsequent mammary stem cell enrichment as the culprits. Breasts enriched with mammary stem cells as a result of ionizing irradiation during puberty show a later-in-life propensity for developing ER negative tumors — cells that do not have the estrogen receptor. Estrogen receptors — proteins activated by the estrogen hormone — are critical to the normal development of the breast and other female sexual characteristics during puberty.”Our results are in agreement with epidemiology studies showing that radiation-induced human breast cancers are more likely to be ER negative than are spontaneous breast cancers,” says Sylvain Costes, a biophysicist with Berkeley Lab’s Life Sciences Division. “This is important because ER negative breast cancers are less differentiated, more aggressive, and often have a poor prognosis compared to the other breast cancer subtypes.”Costes and Jonathan Tang, also with Berkeley Lab’s Life Sciences Division, were part of a collaboration led by Mary Helen Barcellos-Hoff, formerly with Berkeley Lab and now at the New York University School of Medicine, that investigated the so-called “window of susceptibility” known to exist between radiation treatments at puberty and breast cancer risk in later adulthood. The key to their success were two mammary lineage agent-based models (ABMs) they developed in which a system is modeled as a collection of autonomous decision-making entities called agents. One ABM simulated the effects of radiation on the mammary gland during either the developmental stages or during adulthood. The other simulated the growth dynamics of human mammary epithelial cells in culture after irradiation.”Our mammary gland ABM consisted of millions of agents, with each agent representing either a mammary stem cell, a progenitor cell or a differentiated cell in the breast,” says Tang. …

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Bad to the bone: Some breast cancer cells are primed to thrive

Aug. 29, 2013 — When a cancer cell sloughs off the edge of a tumor in the breast, it faces a tough road to survive. The cell must not only remain physically intact as it rushes through blood vessels, but it also must find a new organ to lodge itself in, take in enough nutrients and oxygen to stay alive, and begin dividing, all while escaping notice by the body’s immune system.A team of Howard Hughes Medical Institute (HHMI) scientists has discovered that some loose breast cancer cells, have a leg up on survival — the genes they express make them more likely to prosper in bone tissue. The team also found that whether or not cancer cells turn on those genes depends on what their surroundings were like in the primary breast tumor. If the breast tumor had molecular patterns similar to those found in bone, the tumor is more likely to spread to bone later.”It’s like in society — who you hang out with shapes who you are,” says HHMI investigator Joan Massagué of Memorial Sloan-Kettering Cancer Center. “And that might make you better or worse equipped to handle situations you’ll encounter.”The new findings, published August 29, 2013 in the journal Cell, could eventually lead to new drugs that block cancers from spreading to bone or other organs, he says.When cells from a primary tumor circulate through the body and begin growing in a new organ, a metastatic tumor is formed. Such metastases are often harder to treat than primary tumors; the vast majority of people who die of cancer have not only a primary tumor but also metastatic disease. So a major goal of cancer researchers is to not only find ways to treat primary tumors, but stop cancer from metastasizing.Massagué’s lab group discovered in 2009 that by looking at the genetics of breast cancer cells, they could predict which were most likely to spread to bone. A set of genes dubbed the Src response signature (SRS) was more often turned on in the cells that metastasized to the bone. But the researchers didn’t know why.”What was really a conundrum was how this pathway got turned on in the first place,” says Massagué. …

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School-age drinking increases breast cancer risk​​​​​​

Aug. 28, 2013 — Here’s a sobering fact for millions of young women heading back to school: The more alcohol they drink before motherhood, the greater their risk of future breast cancer.That’s according to new research from Washington University School of Medicine in St. Louis that, for the first time, links increased breast cancer risk to drinking between early adolescence and first full-term pregnancy. Previous studies have looked at breast cancer risk and alcohol consumption later in life or at the effect of adolescent drinking on noncancerous breast disease.”More and more heavy drinking is occurring on college campuses and during adolescence, and not enough people are considering future risk. But, according to our research, the lesson is clear: If a female averages a drink per day between her first period and her first full-term pregnancy, she increases her risk of breast cancer by 13 percent,” said co-author Graham Colditz, MD, DrPH, associate director for cancer prevention and control at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.The study is published online Aug. 28 in the Journal of the National Cancer Institute.Colditz also is the Niess-Gain Professor of Surgery at Washington University School of Medicine. He worked on the study with first author Ying Liu, MD, PhD, a School of Medicine instructor in the Division of Public Health Sciences, and colleagues from Brigham and Women’s Hospital, Harvard Medical School, Beth Israel Deaconess Medical Center and Harvard School of Public Health.The researchers also found that for every bottle of beer, glass of wine or shot of liquor consumed daily, a young woman increases her risk of proliferative benign breast disease by 15 percent. Although such lesions are noncancerous, their presence increases breast cancer risk by as much as 500 percent, Liu said.”Parents should educate their daughters about the link between drinking and risk of breast cancer and breast disease,” she said. “That’s very important because this time period is very critical.”The findings are based on a review of the health histories of 91,005 mothers enrolled in the Nurses’ Health Study II from 1989 to 2009. Colditz was key to the development and administration of that and similar studies that track disease risk in female nurses.Colditz and Liu didn’t consider the effects of adolescent and early adulthood drinking on women who didn’t have a full-term pregnancy because not enough were represented among those studied, Liu said.Breast tissue cells are particularly susceptible to cancer-causing substances as they undergo rapid proliferation during adolescence and later. …

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New implanted defibrillator works well without touching heart

Aug. 26, 2013 — A new type of defibrillator implanted under the skin can detect dangerously abnormal heart rhythms and deliver shocks to restore a normal heartbeat without wires touching the heart, according to research in the American Heart Association journal, Circulation.The subcutaneous implantable cardiac defibrillator (S-ICD®) includes a lead placed under the skin along the left side of the breast bone. Traditional implantable cardiac defibrillators (ICDs) include electrical conducting wires inserted into blood vessels that touch the heart.ICDs can greatly reduce the risk of death in patients at high risk for sudden cardiac arrest.Physicians insert the new device without X-ray guidance, and have reduced concerns about broken lead wires, vessel damage, vessel infection and scarring that make traditional device removal difficult.”Defibrillation has repeatedly proven to be a great asset in prolonging the lives of cardiac patients, but there are still some risks to address,” said Martin C. Burke, D.O., senior author of the study and a professor of medicine and director of the Heart Rhythm Center at the University of Chicago. “This new system was developed over a dozen years to combine some of the best aspects of traditional implanted ICDs and external defibrillators.”In the 33-site study, 314 of 330 patients (average age 52) evaluated had the S-ICD® implanted. During an average 11-month follow-up, 21 patients spontaneously developed 38 episodes of ventricular fibrillation or ventricular tachycardia. All were successfully restored to a normal heart rhythm. In addition, 41 patients (13.1 percent) received shocks that were inappropriate because they weren’t preceded by a dangerous heart rhythm.The study surpassed goals set by the U.S. Food and Drug Administration for evaluating the safety and effectiveness of the new device:Ninety-nine percent of the S-ICD® patients remained free of complications 180 days following implantation, compared with a 79 percent goal. When tested by a purposely-induced abnormal rhythm following implantation, the S-ICD® was 100 percent effective at consistently detecting and reversing ventricular fibrillation. …

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The stress and cancer link: ‘Master-switch’ stress gene enables cancer’s spread

Aug. 22, 2013 — In an unexpected finding, scientists have linked the activation of a stress gene in immune-system cells to the spread of breast cancer to other parts of the body.Researchers say the study suggests this gene, called ATF3, may be the crucial link between stress and cancer, including the major cause of cancer death — its spread, or metastasis. Previous public health studies have shown that stress is a risk factor for cancer.Researchers already know that ATF3 is activated, or expressed, in response to stressful conditions in all types of cells. Under typical circumstances, turning on ATF3 can actually cause normal and benign cells to commit suicide if the cells decide that the stressors, such as irradiation and a lack of oxygen, have irrevocably damaged the cells.This research suggests, however, that cancer cells somehow coax immune-system cells that have been recruited to the site of a tumor to express ATF3. Though it’s still unclear how, ATF3 promotes the immune cells to act erratically and give cancer an escape route from a tumor to other areas of the body.”It’s like what Pogo said: ‘We have met the enemy, and he is us,'” said Tsonwin Hai, professor of molecular and cellular biochemistry at The Ohio State University and senior author of the study. “If your body does not help cancer cells, they cannot spread as far. So really, the rest of the cells in the body help cancer cells to move, to set up shop at distant sites. And one of the unifying themes here is stress.”Hai and colleagues first linked the expression of the ATF3 gene in immune-system cells to worse outcomes among a sample of almost 300 breast-cancer patients. They followed with animal studies and found that mice lacking the ATF3 gene had less extensive metastasis of breast cancer to their lungs than did normal mice that could activate ATF3.This stress gene could one day function as a drug target to combat cancer metastasis if additional studies bear out these results, Hai said. In the meantime, she said the results provide important insights into how cells in a tumor use their signaling power to coopt the rest of the body into aiding cancer’s survival and movement to distant organs.The research is published in a recent issue of the Journal of Clinical Investigation.Hai, a member in the Ohio State University Comprehensive Cancer Center, has studied ATF3 in cancer cells for years. …

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Sexual health for postmenopausal women improved by hypnotic relaxation therapy

Aug. 15, 2013 — Hypnotic relaxation therapy improves sexual health in postmenopausal women who have moderate to severe hot flashes, according to Baylor University researchers who presented their findings at the American Psychological Association’s recent annual meeting.The study, which examined sexual comfort, sexual satisfaction and sexual pleasure, is a first step toward a safe and effective alternative toward hormone replacement therapy, which carries associated risks of cancer and heart disease, said Gary Elkins, Ph.D., director of Baylor’s Mind-Body Medicine Research Laboratory and a professor of psychology and neuroscience in Baylor’s College of Arts & Sciences.The conclusion was based on a study funded by the National Institutes of Health. For the study, 187 women were randomly assigned to receive either five weekly sessions of hypnotic relaxation therapy or supportive counseling, said lead researcher Aimee Johnson, a doctoral student in psychology and neuroscience at Baylor University.Led by researchers at Baylor’s Mind-Body Medicine Research Laboratory, all study sessions were conducted by master’s-level therapists trained in clinical hypnosis. Participants in the hypnotic relaxation therapy group received a hypnotic induction followed by suggestions for relaxation, coolness and mental imagery. Participants who received sessions of supportive counseling discussed their symptoms with a trained therapist but did not receive any hypnosis.Women completed questionnaires at the beginning of the study, at the end of treatment and at a 12-week follow-up. They also were asked to complete a self-report questionnaire assessing the extent to which hot flashes interfered with sexual intimacy. The decrease in estrogen that accompanies menopause is associated with hot flashes, night sweats, weight gain and vaginal dryness, discomfort or pain.”The most common complaints are being too tired, anxiety, depression, hot flashes and the fear of close contact,” Elkins said. Because warmth that comes from closeness can trigger a hot flash, some women grow to fear intimacy, he said.At treatment’s end, women who had received hypnotic relaxation therapy reported significantly higher sexual satisfaction and pleasure, as well as less discomfort. This improvement also was seen at the 12-week follow-up assessment.”Women’s sexual health improved, whether because of sleeping better, less stress or fewer hot flashes, or perhaps other unknown mechanisms,” Elkins said.Researchers noted that postmenopausal sexual health can be affected by factors other than hot flashes, among them fatigue, self-esteem, a partner’s health, relationship quality and a lack of interest by either or both partners.For many women — among them those who have had breast cancer — hormone replacement therapy is not an option for menopause-related symptoms. Estrogen, for example, has been associated with more rapid growth of breast cancer.

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Successful treatment of triple negative breast cancer by modulation of the OGF-OGFr axis

Aug. 10, 2013 — Researchers at The Pennsylvania State University College of Medicine, led by Dr. Ian S. Zagon, have discovered that a novel biological pathway, the OGF-OGFr axis, can be modulated in human triple-negative breast cancer cells to inhibit proliferation. According to BreastCancer.org 1 in 8 women in the U.S. will develop invasive breast cancer and more than 39,000 deaths occur annually. Approximately 15 to 20% of all breast cancers are designated as triple-negative meaning that the cancer cells lack estrogen and progesterone receptors, and do not overexpress human epidermal growth factor receptor (HER-2), thereby limiting responsiveness to approved therapy.Share This:In the June 2013 issue of Experimental Biology and Medicine, Zagon and colleagues demonstrate that exposure of human breast cancer cell lines to OGF in vitro repressed growth within 24 hr in a receptor-mediated and reversible manner. Treatment with low dosages of the opioid antagonist naltrexone (LDN) provoked a compensatory elevation in endogenous opioids (i.e., OGF) and receptors that interact for 18-20 hr daily following receptor blockade to elicit a robust inhibition of cell proliferation. Because OGF is an endogenous neuropeptide, there are minimal or no side effects. The mechanism of action for OGF is upregulation of the p21 cyclin-dependent inhibitory kinase pathway that delays passage through the cell cycle. …

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New role for Tamoxifen in saving high-risk breast cancer patients

Aug. 7, 2013 — The global study was led by University of Melbourne and the Peter MacCallum Cancer Centre and published in the Journal of Clinical Oncology today.The study involved about 2,500 women from Europe, North America and Australia who have inherited mutations in BRCA1 or BRCA2, the breast cancer susceptibility genes, and who had been diagnosed with breast cancer. About one-third of these women were placed on tamoxifen.Tamoxifen has been used for decades to treat breast cancer and has recently been shown to prevent breast cancers in many women.Until now, there has been limited information about whether it reduces breast cancer risk for women who are at the very highest level of risk with BRCA1 or BRCA2.Lead author, Professor Kelly-Anne Phillips says this study, the largest to date, suggests that it could work for these high-risk women by halving their breast cancer risk.”In the past, the only way of reducing breast cancer risk for these high-risk women was to do invasive surgery to remove their breasts and/or ovaries. For women who choose not to undergo such surgery, or who would prefer to delay surgery until they are older, tamoxifen could now be a viable alternative.”Such was the case for US actress Angelina Jolie who was found to carry a mutation in one of these genes.Previous research led by Professor Phillips revealed that only 1 in 5 Australian women with a mutation in BRCA1 or BRCA2 choose to undergo bilateral mastectomy to prevent cancer.Professor John Hopper, co-author from the School of Population and Global Health at the University of Melbourne, says “In light of our findings, it is clear that women who have a mutation in BRCA1 or BRCA2 should review their management plan with their specialist and re-discuss the options available to them to lower that risk.”This important finding has come from more than 20 years of research involving breast cancer families recruited from cancer registries and clinics across the country.”Without the generous contributions of those families we would not be able to make such discoveries which help future generations fight breast cancer,” he says.

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Why tumors become drug-resistant

Aug. 6, 2013 — Cancer drugs known as ErbB inhibitors have shown great success in treating many patients with lung, breast, colon and other types of cancer. However, ErbB drug resistance means that many other patients do not respond, and even among those who do, tumors commonly come back.A new study from MIT reveals that much of this resistance develops because a protein called AXL helps cancer cells to circumvent the effects of ErbB inhibitors, allowing them to grow unchecked. The findings suggest that combining drugs that target AXL and ErbB receptors could offer a better way to fight tumors, says Doug Lauffenburger, the Ford Professor of Bioengineering, head of MIT’s Department of Biological Engineering and an affiliate member of MIT’s Koch Institute for Integrative Cancer Research.”Drug resistance is the major challenge in cancer these days. People are coming up with a lot of targeted therapies for particular genes and identifying drugs that work against them, but resistance is just invariably the issue,” says Lauffenburger, the senior author of a paper describing the findings in the Aug. 6 issue of Science Signaling.ErbBs, a family of epithelial growth factor receptors (EGFRs), are proteins that are often overactive in cancer cells, causing them to grow and divide uncontrollably. The drug Iressa is used to treat lung cancer patients whose tumors overexpress one type of ErbB mutant, and Herceptin targets another ErbB family member that is found in certain types of breast cancer.”There are a lot of excellent drugs that target EGFR itself or other members of that family, yet they have these limitations,” Lauffenburger says.Systems analysisIn the new study, Lauffenburger and colleagues set out to identify factors that help tumor cells become resistant to EGFR and other ErbB inhibitors. To do this, they developed a new computer model and applied it to a large dataset called the Cancer Cell Line Encyclopedia, which includes information on about 1,000 human cancer lines and their responses to different drugs.Led by biological engineering graduate student Aaron Meyer, lead author of the paper, the researchers created a machine learning program that can sift through the data and look for pairs of overexpressed proteins that make tumor cells resistant to EGFR inhibitors. In this case, they searched for the EGFR protein in combination with every other possible protein in the database, one pair at a time.Through this analysis, the researchers found that EGFR paired with the AXL receptor appears to be the strongest marker for EGFR inhibitor resistance. They found this pattern across many types of cancer, including lung, breast and pancreatic.A few previous studies have shown that overexpression of AXL is associated with resistance to EGFR inhibitors in a particular tumor, but this is the first systematic study to demonstrate the correlation, Lauffenburger says. …

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Hot flashes? Thank evolution

July 29, 2013 — A study of mortality and fertility patterns among seven species of wild apes and monkeys and their relatives, compared with similar data from hunter-gatherer humans, shows that menopause sets humans apart from other primates.Nonhuman primates aren’t immune to the fading female fertility that comes with age, the researchers say. But human females are unique in living well beyond their childbearing years.”Unlike other primates women tend to have a long post-reproductive life. Even before modern medicine, many women lived for 30 to 35 years after their last child was born,” said co-author Susan Alberts of Duke University and the National Evolutionary Synthesis Center.In a study appearing the week of July 29 in the Proceedings of the National Academy of Sciences, Alberts and colleagues compared mortality and fertility data for seven species of wild primates to similar data for the !Kung people of Southern Africa, a human population of hunter-gatherers with limited access to modern medicine or birth control.The nonhuman primate data were based on long-term observations of 700 adult females, including capuchins in Costa Rica, muriqui monkeys in Brazil, baboons and blue monkeys in Kenya, chimpanzees in Tanzania, gorillas in Rwanda and sifakas in Madagascar.This is the first study to compare humans with multiple primate species living in the wild.For each species, the researchers estimated the pace of reproductive decline — measured as the probability, at each age, that a female’s childbirth will be her last — and compared it with the rate of decline in overall health, measured as the odds of dying with each passing birthday. “This way we were able to compare the rate of aging in the reproductive system with the rate of aging in the rest of the body,’ Alberts said.The results suggest that in nonhuman primates, reproductive decline is surpassed by declines in survival, so that very few females run out of reproductive steam before they die. A female baboon, for example, may live to age 19, and continues to reproduce to the end.But in human females the reproductive system shuts down much more rapidly than the rest of the body. “Half of women experience menopause by the age of 50, and fertility starts to decline about two decades before that,” Alberts said.What distinguishes a human female from her primate cousins is not that the human biological clock ticks faster, but that mortality is so much lower in humans than in other primates, according to work done by University of Utah anthropologist Kristen Hawkes, who was not an author of this study.This study supports that idea, the researchers say. In both humans and chimpanzees, for example, female fertility starts to decline in the late 30s and early 40s. “[But] even in human populations with little access to modern medicine, like the !Kung [hunter-gatherers in this study], most women survive for decades after their last child is born. Nonhuman primates rarely do that,” Alberts said.If evolution has given us longer lifespans than our primate cousins, why hasn’t female reproduction kept pace? And in a world where individuals with more offspring tend to win the evolutionary contest, why shut down reproduction with decades of survival still ahead?It may be that older females who forego future breeding to invest in the survival of their existing children and grandchildren gain a greater evolutionary edge than those who continue to reproduce. …

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Common autism supplement affects endocrine system

July 15, 2013 — Plant-based diets are healthy. Plants are high in flavonoids. So flavonoids are healthy. At least that’s the reasoning of many manufacturers of flavonoid-based nutritional supplements. But a University of Colorado Cancer Center study published this week in the journal Hormones & Cancer shows that may not be the case. Flavonoids tested in the study affected the endocrine system in ways that in one case promoted cancer and in another repressed it.”Even outside these specific findings with cancer, what we’re saying is that flavonoids are active and not always in good or even predictable ways,” says Steven K. Nordeen, PhD, investigator at the CU Cancer Center and professor emeritus in the Department of Pathology at the CU School of Medicine.His study explored the effects of the flavonoids luteolin and quercetin on cell models of breast and endometrial cancer. In over-the-counter supplement form, the first compound, luteolin, is commonly recommended for the treatment of pediatric autism spectrum disorders.Nordeen and colleagues show that luteolin blocks some of the endocrine effects of the hormone progesterone. Work from another CU Cancer Center investigator, Carol Sartorius, PhD, had previously shown that progesterone expands a population of therapy-resistant, stem cell-like cells in some breast cancers. In the present work, Nordeen showed that luteolin blocked this increase — a beneficial effect. …

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Women who give birth to multiple babies after IVF are at higher risk of breast cancer

July 9, 2013 — Women who give birth to multiple babies following IVF treatment are at a higher risk of breast cancer than those giving birth to singletons or who remain childless. Dutch investigators from the Omega study group said the explanation may not be the multiple pregnancy per se but a maternal trait related to a higher implantation potential and to breast cancer itself.Although the results were derived from a large nationwide cohort study, the investigators emphasise that the findings should next be replicated in further studies and that presently there is no reason for earlier breast cancer screening than is recommended for the general population.The study, presented today at the annual meeting of ESHRE by Dr Els Groeneveld from the VU University Medical Centre of Amsterdam, the Netherlands, analysed data from the Omega study, a large Dutch nationwide cohort of 19,861 women who received IVF or ICSI treatment between 1983 and 1995. Between 1997 and 1999 all patients were questioned (by questionnaire) about their treatment and its outcome. Those who completed the questionnaire (12,589 women) were cross-referred to the Netherlands Cancer Registry.Cohort analysis showed that over a median 16.7 years of follow-up 1688 women in the study gave birth to multiples (13%), 6027 delivered singletons (48%), and 4874 remained childless (39%). Among these women there were 317 confirmed diagnoses of breast cancer, of whom 57 gave birth to multiples, 155 to singletons, and 105 remained childless. When these findings were analysed statistically, results showed that mothers of multiples had a (44%) higher breast cancer risk than the mothers of singletons (hazard ratio 1.44, statistically significant) when adjusted for year of IVF treatment, number of IVF cycles, height and age at first birth. Nulliparous women were at no increased risk of breast cancer.Remarkably, only multiple pregnancies conceived after the complete implantation of all transferred embryos were associated with an increased breast cancer risk (HR 1.86), whereas multiple pregnancies conceived after incomplete implantation were not (HR 1.31, not statistically significant). This finding, says Dr Groeneveld, supports the hypothesis of a link between high embryo implantation potential and breast cancer risk.She explained: “It has been generally assumed that increased levels of estrogen and progesterone in multiple pregnancies stimulate cellular proliferation in the breast, which increases accumulation of somatic mutations during cell division and leads to the development of breast cancer. Thus, breast cancer could be seen as a consequence of the multiple pregnancy itself. However, we also hypothesise that an additional maternal trait might be associated with an increased breast cancer risk in these women.”Such a trait could be maternal serum concentrations of vascular endothelial growth factor (VEGF), a known protein involved in breast cancer progression and which Dr Groeneveld’s group in Amsterdam has recently found associated with improved embryo implantation potential.”In our study women who developed a multiple pregnancy from all transferred embryos represent women with high embryo implantation potential, possibly through increased levels of VEGF,” said Dr Groeneveld. …

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Long term night shifts linked to doubling of breast cancer risk

July 1, 2013 — Working night shifts for 30 or more years doubles the risk of developing breast cancer, and is not confined to nurses as previous research has indicated, finds a study published online in Occupational and Environmental Medicine.Shift work has been suggested as a risk factor for breast cancer, but there has been some doubt about the strength of the findings, largely because of issues around the assessment of exposure and the failure to capture the diversity of shift work patterns. Several previous studies have also been confined to nurses rather than the general population.In this study, the researchers assessed whether night shifts were linked to an increased risk of breast cancer among 1134 women with breast cancer and 1179 women without the disease, but of the same age, in Vancouver, British Columbia, and Kingston, Ontario.The women, who had done various different jobs, were asked about their shift work patterns over their entire work history; hospital records were used to determine tumour type.This may be important, say the authors, because risk factors vary according to hormone sensitivity, and the sleep hormone melatonin, disruption to which has been implicated in higher breast cancer risk among night shift workers, may boost oestrogen production.Around one in three women in both groups had worked night shifts. There was no evidence that those who had worked nights for up to 14 years or between 15 and 29 years had any increased risk of developing breast cancer.But those who had worked nights for 30 or more years were twice as likely to have developed the disease, after taking account of potentially influential factors, although the numbers in this group were comparatively small.The associations were similar among those who worked in healthcare and those who did not. Risk was also higher among those whose tumours were sensitive to oestrogen and progesterone.The suggested link between breast cancer and shift work has been put down to melatonin, but sleep disturbances, upset body rhythms, vitamin D or lifestyle differences may also play their part, say the authors.”As shift work is necessary for many occupations, understanding which specific shift patterns increase breast cancer risk, and how night shift work influences the pathway to breast cancer, is needed for the development of healthy workplace policy,” conclude the authors.

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Too much of a good thing? Too many ‘healing’ cells delay wound healing

July 1, 2013 — Like most other things, you can have too much of a good thing when it comes to wound healing, and new research proves it. According to an article published in the July 2013 issue of the Journal of Leukocyte Biology, wound healing can be delayed because the body produces too many mast cells, which normally promote healing. An overabundance of these cells, however, also causes harm by leading to the overproduction of IL-10, which prevents certain white blood cells from reaching the wounded area. The work was conducted in mice with lymphedematous skin, and may one day provide better treatments for elderly individuals with skin ulcers in the lower extremities, for women with upper-extremity wounds following breast cancer surgery, and skin wounds of any type that are not healing as they should.Share This:”Improvement of lymphedema is important for treatment of skin ulcers,” said Makoto Sugaya, M.D., Ph.D., a researcher involved in the work from the Department of Dermatology at the University of Tokyo in Tokyo, Japan. “It is not just fluid retention, but inflammatory cells and cytokines that cause delayed wound healing.”To make this discovery, scientists used two groups of mice. The first group showed severe lymphatic dysfunction. The second group was normal. Researchers administered skin wounds and found that the mice with lymphatic dysfunction showed delayed would healing as compared to the normal mice. Analysis showed that the delayed would healing in the lymphedematous skin is the result of too many mast cells and elevated IL-10 expression, both of which can now be therapeutic targets for future drug development.”Wound healing is something most people take for granted until there’s a problem,” said John Wherry, Ph.D., Deputy Editor of the Journal of Leukocyte Biology. “However, wound healing is a complex process involving immune as well as non-immune cells and problems that arise can be very serious, even if it started as a minor wound. …

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