OHSU scientists develop MRI approach to improve breast cancer detection

Researchers at Oregon Health & Science University's Advanced Imaging Research Center (AIRC) are developing a new imaging method that may provide a clearer diagnosis of breast cancer. The research is published in the latest issue of the journal Magnetic Resonance in Medicine. AIRC Director Charles Springer, Ph.D., is senior author, and AIRC Manager, Xin Li, Ph.D., is first author of the new paper, along with William Rooney, Ph.D., AIRC faculty. Professor Springer also holds appointments in OHSU's Cancer Institute and Department of Biomedical Engineering.



"This technique involves a new method for interpreting information gathered through MRI," explained Springer. "The technique involves recognizing that certain properties of MRI signals can change during the examination, much like the changing of a camera's shutter speed. On a camera, a fast shutter speed can make a speeding car look as if it is standing still. A slower shutter speed may result in a photo showing the car blurring past the camera. This principle, when correctly applied to MRI imaging, can provide more accurate information. In the case of MRI, the blurring is not of the actual image, but of the time courses of the MRI signals."



Magnetic resonance imaging technology combines the use of powerful magnets and radio wave pulses. The magnet influences the magnetization of the body's water molecules. The radio signals that are received from this can be converted into a visual representation.



The shutter speed concept allows researchers to adjust the mathematics of the computer program analyzing the signals to account for the movement of water molecules in and out of cellular compartments in diseased and healthy tissue. When the MR shutter speed increases, this movement appears to slow. In the case of tumors, using shutter speed analysis not only more clearly indicates the locations of tumors, it also allows researchers to distinguish between malignant tumors and benign tumors.



To conduct this research project, the scientists analyzed data from six patients identified as having breast tumors with mammograms (X-rays.) In procedures conducted by New York research collaborators Drs. Wei Huang, Alina Tudorica, and Thomas Yankeelov of Stony Brook University and Brookhaven National Laboratory, the patients were injected with a contrast agent, which acts like an MRI dye and provides clearer images. The patients received MRI scans as the dye passed through the tumors. The time courses of the MRI signals were analyzed with the shutter speed model. The results showed hot spots only in images of malignant tumors but not in the benign tumors (three of the cases). This complete distinction was not the case using the standard MRI technique, and there was no distinction using mammography. Pathology results on these tumors confirmed the accuracy of the new MRI testing.



"While continued research is required, we believe shutter speed analyzed MRI could become a powerful tool for the diagnosis and treatment of breast cancer and almost any other form of cancer, as well as many other pathologies," explained Springer. "The shutter speed is a very general concept and applies to a great many different MRI techniques."



"We are fortunate to have recruited Dr. Springer and his team to lead the imaging research activities at OHSU and the OHSU Cancer Institute." said Grover C. Bagby Jr., M.D., Director of the OHSU Cancer Institute. "His 'shutter-speed' model has the potential of changing our approach to cancer screening in general and may also play a role in determining the early effects of treatment. The findings also provide a unique opportunity for cancer researchers to unravel the basic molecular causes of the different image signatures."



Contact: Jim Newman

newmanjohsu

Oregon Health & Science University

Rate Of Breast Cancer In Italy Significantly Higher Than Previously Reported

A new analysis of the incidence of breast cancer in Italy per 100,000 women between the ages of 0 to 84 from 2000 to 2005 shows a 72 percent spike above official estimates issued by the Ministry of Health, with the sharpest uptick of +28.6 percent found in the youngest group studied (ages 25 to 44).


The new results, which rely on hospitalization databases that track major breast surgeries rather than official estimations computed using statistical models, appear in The Journal of Experimental & Clinical Cancer Research.


"Our findings show that women under 45 who are not currently enrolled in secondary prevention programs, should be considered for receiving regular mammograms," says Prisco Piscitelli, Ph.D., of the CROM (Cancer Research Center) in Mercogliano, Italy, one of the study's authors. "The results also strongly suggests that measures for adopting primary preventative measures to investigate and eliminate dietary, behavioral and environmental causes of breast cancer, such as estrogen in food, hormone pills, smoking, dioxin and pollution."


The study was done by a multidisciplinary team of researchers (epidemiologists, oncologists, radiologists and surgeons) Antonio Giordano, M.D., Ph.D., Director of the Sbarro Institute for Cancer Research and Molecular Medicine and Director of the Center for Biotechnology at Temple University in Philadelphia, PA and 'Chiara fama' Professor in the Department of Human Pathology & Oncology, University of Siena, Siena, Italy.


Overall, the incidence of breast cancer from 2000 to 2005 among all age groups was 26.5 percent higher than official estimations. The incidence of breast cancer per 100,000 women aged 0 to 84 years was 141.80 in the year 2000 and 160.85 in 2005, a 13.4 percent increase. This is 72 percent higher than that provided by official estimations of the Ministry of Health (93 per 100,000 women aged 0 to 84). There was an increase among all groups studied: +9.4 percent in people aged 45 to 64; +11.7 percent in people aged 64 to 75 and +15.7% over 75 years old.


But the most important finding of the study reveals that the highest increase in the incidence rate per 100,000 was observed among women below 45: +28.6 percent in people 25 to 44.


The new analysis examines the number of major surgeries (mastectomies and quadrantectomies) attributed to breast cancer over six years and by age group. Their results show that over that period, 100,745 mastectomies and 168,147 quadrantectomies were performed. A total of 41,608 major surgeries due to breast cancer were performed in the year 2000, a figure that rose to 47,200 in 2005, signifying a 13.8 percent rise over the six years.


By comparison, official estimations from the Italian Ministry of Health tallied only 37,300 cases in the year 2005.


Until now, official epidemiological data concerning the incidence of breast cancer in Italy has been computed using a statistical model (MIAMOD --Morality-Incidence Analysis MODel) based on mortality and survival data. The newly published analysis relies on hospitalization databases that track major breast surgeries.


The current study notes that while use of MIAMOD may be justified in light of the need to evaluate the incidence of all tumors, the figures may underestimate the number of breast cancers, since many deaths that occur at home or in hospital settings might be attributed to cardiovascular causes on the statistical form filled out by physicians.


Source

Sbarro Health Research Organization

New Law Requires Hospitals To Inform Breast Cancer Patients Of Breast Reconstruction Options

While breast reconstruction after a mastectomy is covered by insurers in New York, many poor, minority, and less educated women do not seek out the procedure. Now, NY Gov. David A. Paterson has signed into law a bill that is aimed at reversing this trend.


"A disproportionate number of women who are at a socioeconomic disadvantage do not get breast reconstruction surgery after a mastectomy for one of several reasons. Either they are unaware of it as an option, they do not know it is covered by Medicaid and Medicare insurance programs, they do not know where to gain access to the procedures, or it is never mentioned to them by their other doctors," said Evan Garfein, MD, the plastic and reconstructive surgeon at Montefiore Medical Center who authored the Bill.


He hopes that the new law (A10094B/S6993-B/Information and Access to Breast Reconstruction Surgery) will correct this disparity. It requires hospitals in New York to inform breast cancer patients about the availability of, and insurance coverage for, breast reconstruction before they undergo "mastectomy surgery, lymph node dissection or a lumpectomy."


While Congress passed the Women's Health and Cancer Rights Act in 1998, which guaranteed universal coverage for reconstruction after surgery, and New York soon passed comparable provisions into its laws, disparities in access remain.


"Breast reconstruction has been repeatedly shown to improve the quality of life and overall well-being of women who have been treated for breast cancer," said Dr. Garfein. "This new law will ensure that breast cancer patients from all socioeconomic groups are informed about their options regarding breast reconstruction and about where to get the procedure."


Why the Bill is Needed: Letitia Was Never Told About Reconstruction


Letitia M., a 39-year-old single mom of two who lives in the Bronx, was diagnosed with breast cancer in 2006. She had felt a lump in her left breast and her primary care physician confirmed her suspicions of cancer after he referred her for a mammogram and sonogram. Even though she consulted with three different doctors while planning her treatment, none of them mentioned reconstruction as an option.


Letitia first had a lumpectomy and then a full mastectomy. It was only later in the treatment process, while she was receiving radiation therapy at a Manhattan hospital, that she learned about reconstruction. It was at this time that she was referred to Dr. Garfein at Montefiore, who subsequently performed reconstruction two years after her cancer surgery. When Letitia was asked why she did not undergo reconstruction at the time of her mastectomy, she replied that no one had mentioned that it was an option.















Letitia is doing well and is on the road to recovery. While it is possible that she would have chosen to delay her reconstruction until after her cancer surgery and radiation therapy were complete, the standard of care in 2010 is to at least offer her the option of immediate reconstruction at the time of her mastectomy. The purpose of the Bill is to make sure that no woman ever says, "I didn't get reconstructed because no one mentioned it to me."


One-Third of Women With Breast Cancer Choose Reconstruction


Breast reconstruction is not for everyone. Each year, a quarter of a million women are diagnosed with breast cancer, according to the American Cancer Society. Of those who undergo mastectomy, 30-40 percent, depending on the study, receive breast reconstruction, according to Dr. Garfein.


"This percentage is much lower among poor, minority and less educated women. One reason for this disparity is that their breast surgeons are less likely to discuss it with them and they are less likely to receive treatment at a dedicated cancer center where reconstruction procedures are more readily available," said Dr. Garfein. "We feel strongly that all breast cancer patients, wherever they live and whatever their knowledge level should be informed that reconstruction may be an option and that, if it is, it will be covered."


Discussing Reconstruction Before a Mastectomy is Key


Today, there are many reconstruction options for patients who have breast surgery, including saline and silicone gel implants, and several types of reconstruction using the patient's own tissues from the abdomen, thigh, back or buttocks.


The new law underscores that patients should discuss this range of reconstruction choices before deciding between a mastectomy (the total removal of the cancerous breast) or a lumpectomy (removal of part of the breast), and that the discussion involve both the cancer surgeon, who removes the cancer from the breast, and the plastic surgeon, who would perform the breast reconstruction. The surgical team and the patient can then decide if reconstruction should be performed at all, and if so, whether that should happen at the same time as the cancer surgery (as is now the standard), or at a later date.


Many women who choose not to have reconstruction do so because of personal preferences, their overall health, the stage of their breast cancer, or to avoid the risks of additional surgery. Some women, however, don't receive reconstruction because it wasn't offered to them and they didn't know to ask about it. It is this group that the legislation targets.


Montefiore Medical Center encompasses 126 years of outstanding patient care, innovative medical "firsts," pioneering clinical research, dedicated community service and ground-breaking social activism. A full-service, integrated delivery system caring for patients in the New York metropolitan region and beyond, Montefiore is a 1,491-bed medical center that includes: four hospitals -- the Henry and Lucy Moses Division, the Jack D. Weiler Division, the North Division and The Children's Hospital at Montefiore; a large home healthcare agency; the largest school health program in the US; a 22-site medical group practice integrated throughout the Bronx and Westchester; and, a care management organization providing services to 179,000 health plan members.


Montefiore has been ranked by U.S. News & World Report as among the top 50 hospitals in the country in Geriatrics, Diabetes and Endocrinology, and Neurology and Neurosurgery. The Children's Hospital at Montefiore has been consistently ranked in the magazine's Best Children's Hospitals editions, and in 2010-2011, ranked among the top 10 in the nation in Kidney Disorders and among the top 25 in the nation in Neurology and Neurosurgery.


The Leapfrog Group lists Montefiore among the top one percent of all U.S. hospitals based on its strategic investments in sophisticated and integrated healthcare technology.


Montefiore is committed to meeting the healthcare needs of the future through medical education and manages one of the largest residency programs in the country. Montefiore is The University Hospital and Academic Medical Center for Albert Einstein College of Medicine and has an affiliation with New York Medical College for residency programs at the North Division.


Distinguished centers of excellence at Montefiore include cardiology and cardiac surgery, cancer care, tissue and organ transplantation, children's health, women's health, surgery and the surgical subspecialties. Montefiore is a national leader in the research and treatment of diabetes, headaches, obesity, cough and sleep disorders, geriatrics and geriatric psychiatry, neurology and neurosurgery, adolescent and family medicine, HIV/AIDS and social and environmental medicine, among many other specialties.


Source: Montefiore Medical Center

U.S. State Department Partners With Saudi Arabia, U.A.E., Other Countries For Breast Cancer Awareness, Research, First Lady Says

The U.S. State Department has collaborated with Saudi Arabia, the United Arab Emirates and other partners to expand breast cancer education and research in the Middle East, first lady Laura Bush said Monday, the AP/Forbes reports (Pickler, AP/Forbes, 6/12). As part of the U.S.-Middle East Partnership for Breast Cancer Awareness and Research, Johns Hopkins University researchers are helping the U.A.E. establish a breast cancer center, and the Houston-based MD Anderson Cancer Center plans to share information with the breast cancer unit at King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia. The Susan G. Komen Breast Cancer Foundation also plans to partner in the program (Hoover, Washington Times, 6/13). "This is the first major women's health campaign in the Middle East, and the [U.S.] is proud to be a part of it," Bush said during a speech at the Komen Foundation's 2006 Mission Conference, adding, "Together, these partners will develop awareness campaigns suited to each country; they'll increase research, training and community-outreach efforts; and [they will] help women build the knowledge and the confidence they need to be in charge of their own health" (White House release, 6/12). Bush also said, "By confronting the challenge of breast cancer together, this partnership, which represents the very best kind of public diplomacy, will also help build lasting friendships between our countries" (AP/Forbes, 6/12) Morocco and Jordan are involved in discussions to expand the program, which is organized by the State Department's public diplomacy office and the Middle East Partnership Initiative (Austein, Washington File, 6/12)


"Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Computer Software Less Reliable Than Radiologists' Eyes In Detecting Cancerous Tumors Shown By Mammograms, Study Says

Radiologists using computer-aided detection software for mammograms are more likely to interpret a benign growth as potentially cancerous than "human reviewers using their eyes and experience," and CAD systems do not help detect more cancers, according to a study published in Thursday's New England Journal of Medicine, the Los Angeles Times reports (Gellene, Los Angeles Times, 4/5). CAD systems use complex algorithms to identify "suspicious" areas of a mammogram for a radiologist to review, according to the Wall Street Journal (Armstrong, Wall Street Journal, 4/5). The systems, which cost $50,000 to $175,000, were approved by FDA in 1998 and are sold by several companies, the New York Times reports. Medicare gives providers extra $20 more for administering mammograms that use CAD, and the systems are used in 30% of mammography centers, according to the National Cancer Institute. For the study, Joshua Fenton of the University of California-Davis and colleagues examined 429,345 mammograms performed at 43 medical centers from 1998 to 2002. During the study period, seven of the centers began using CAD (Kolata, New York Times, 4/5). The study found standard mammography detected 4.15 cases of cancer per 1,000 women screened, compared with 4.2 cases of cancer per 1,000 women screened using CAD (Wall Street Journal, 4/5). According to the study, CAD systems correctly identified which women had tumors and which did not 87.2% of the time, compared with 90.2% for standard screening. CAD systems also led to 31% more women being called back for more tests and 20% more biopsies, the study found. The researchers estimate that for every additional woman who was diagnosed with breast cancer using CAD, 156 had unnecessary additional tests and 14 had unnecessary biopsies. The researchers said that CAD systems did find more of a type cancer known as ductal carcinoma in situ, which tends to be less dangerous, the Washington Post reports. Wide use of the systems also would raise annual cost of mammography by 18%, or about $550 million, the study found.

Comments, Reaction
According to Fenton, the "goal of [CAD] systems was to make mammography better." He added, "Our study suggests that, if anything, they appear to be doing more harm than good" (Stein, Washington Post, 4/5). Suzanne Fletcher, an emerita professor of ambulatory care and prevention at Harvard Medical School, said, "With mammography, we have multiple studies showing what happens to mortality rates if you get [the screening] versus if you don't. With [CAD systems] we don't" (New York Times, 4/5). Some radiologists expressed caution about the study -- funded by NCI and the American Cancer Society -- saying that the technology continues to evolve and that larger studies are needed to confirm and expand upon the results. According to some radiologists, the performance of CAD also could be improved with better training of physicians using the technology. "We have a tool that helps us find smaller abnormalities and earlier indications of the disease," Rob Cascella -- president of Hologic, the maker of the best-selling CAD system, which was used in the study -- said (Wall Street Journal, 4/5). Ferris Hall -- a radiologist at Beth Israel Deaconess Medical Center in Boston who wrote an accompanying NEJM editorial -- said some mistakes might have been a result of inexperience with CAD because it takes radiologists several years to learn the technology. Nonetheless, the study is a setback for the technology, Hall said, adding, "This will have a major impact on radiology" (Los Angeles Times, 4/5).















The study is available online.


CBS' "Evening News" on Wednesday reported on the study. The segment includes comments from Katherine Lee of the Cleveland Clinic Breast Center and study co-author Joanne Elmore of the University of Washington (LaPook, "Evening News," CBS, 4/5). Video of the segment is available online.


NPR's "All Things Considered" on Wednesday also reported on the study. The segment includes comments from Elmore and Hall (Knox, "All Things Considered," NPR, 4/5). Audio and a partial transcript of the segment are available online.


"Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Breast Density, No Lobular Involution Increase Breast Cancer Risk

Women with dense breasts and no lobular involution were at a higher risk for developing breast cancer than those with non-dense breasts and complete involution, according to a study published online in The Journal of the National Cancer Institute.



Apart from age, family history, and age at menarche, two additional factors associated with breast cancer risk include mammographic breast density and extent of lobular involution. Lobular involution is the physiological atrophy of the breast epithelium and is known to increase with increasing age.



To determine whether these two factors are independently associated with breast cancer risk, Karthik Ghosh, M.D., of the Mayo Clinic, and colleagues investigated the factors' association with breast cancer risk in a cohort of 2666 women with benign breast disease, followed for a mean of 13.3 years; 172 (6.5%) women subsequently developed breast cancer.



The researchers took their cohort from the larger Mayo Breast Disease cohort, which included 9376 women between the ages of 18 and 85, with no history of breast cancer, who were diagnosed with benign breast disease between 1967 and the end of 1991.



The researchers found that breast density and extent of lobular involution were independent risk factors for breast cancer, and that combined, they pose an even greater risk. The authors write: "Our findings also reveal that having a combination of dense breasts and no lobular involution was associated with higher breast cancer risk than having non-dense or fatty breasts and complete involution."



The researchers write that one of the study's strengths is that it was conducted in a large, well-organized cohort of women; however, limitations include the fact that the study population was predominantly white and representative of the upper Midwest, pointing to the need to conduct research in diverse populations.



In an accompanying editorial, Gretchen L. Gierach, Ph.D., of the National Cancer Institute, and colleagues, describe lobular involution and mammographic breast density as factors that "hold promise for improving risk prediction, particularly because they reflect the cumulative interplay of numerous genetic and environmental breast cancer risk factors over time."



Future studies, they write, should include larger numbers of patients from diverse racial and ethnic backgrounds and aim to understand the relationship between involution and epidemiological risk factors such as body mass index. Furthermore, since neither lobular involution nor mammographic breast density are static processes, evaluating changes over time may improve their predictive value.



Source:

Kristine Crane

Journal of the National Cancer Institute

Breast Cancer And Hormone Therapy - New Study Examines Whether Trends In Breast Cancer Incidence And Use Of HT May Be Directly Linked

The medical community has been debating for many years whether, and to what extent, postmenopausal hormone therapy (HT) use is associated with a higher risk of breast cancer, says Professor Amos Pines, President of the International Menopause Society. Although it is agreed that long-term HT slightly increases that risk, the definition of long-term use is still unclear, particularly in view of data showing that it may vary significantly by type of HT (estrogen-alone vs. estrogen-progestin, brand of progestin, dosage). A new study from the Kaiser Permanente health plan[1] raises the question whether trends in breast cancer incidence and use of HT over the past 25 years may be directly linked.



The Women's Health Initiative (WHI) trial was a landmark in menopause medicine since it provided information based on the best available study methodology[2]. By adopting its results as the ultimate source of information, many organizations, medical societies and health authorities actually declared that data derived from observations in the postmenopausal population are less valuable. Nevertheless, during the past few months, several studies have used databases on the incidence of breast cancer, on the one hand, and sales of HT on the other hand, in order to suggest a direct link between trends of hormone use and the number of newly diagnosed breast cancer patients. While such information, by itself, is very important and interesting, conclusions must be drawn with great caution. It is tempting to simplify the observed year-by-year figures on HT use and breast cancer incidence and establish a 'mirror glass' equation: the more postmenopausal hormone use, the more breast cancer, and vice versa. But human biology is far too complicated and the pathophysiology of breast cancer is far too complex to adopt such a mechanistic approach, as the authors of those studies and related Editorials rightly say.



The mere fact that the incidence of lung cancer is higher among people carrying a lighter in their pocket does not mean that lighters cause lung cancer. Thus, having two parallel time trends, for breast cancer incidence and for hormone use, still makes it necessary to investigate further in order to better understand if and how those trends could be linked. For example, a third important player has now been added, namely the rate of mammography screening, which has proved to have similar fluctuations as HT use and breast cancer incidence1. According to the Kaiser Permanente registry[1], the rate of women aged 45-59 undergoing screening mammography in 2002-2004 (post-WHI period) decreased from 48% to 44%. Thus, awareness of the need for periodic breast examinations may ease, and the likelihood of women coming to be examined may decrease in a population that uses HT less frequently, which could lead to under-diagnosis of breast cancer.
















On the other hand, the 28% increase in breast cancer incidence between the early 1980s and the early 1990s observed in the Kaiser Permanente cohort probably reflects the outcome of implementation of the mammography screening program during that period. The largest group among HT users in most of the countries (excluding the USA) has always been women younger than 60 years. The Kaiser Permanente data show that, for women aged 45-59, the 70% drop in HT use (defined as dispensation of at least one hormonal prescription) in the year 2006 (post-WHI period) as compared to the year 2000 (pre-WHI period) was associated with a non-significant decrease of 4.9% in breast cancer incidence, which translates into a reduction of less than one case of breast cancer per 10,000 women per year. Furthermore, a welcome but unexplained fact is that, in younger women (age groups < 45 years and 45-59 years), the incidence of invasive breast cancer started to decrease before the year 2000 (see Figure 1 in Glass et al.[1]). The same has been shown for the incidence of localized cancers (Figure 2[1]) and the age-adjusted annual incidence rate of both estrogen receptor-positive and -negative breast cancers (Figure 3[1]). Therefore, the decrease of breast cancer incidence analyzed from different angles by Glass and colleagues cannot be attributed simply to the drop in HT use, which started after the publication of the WHI study. There must be another, non-hormonal and still unknown factor explaining, at least in part, these changes in incidence since 1998.



Professor Pines concludes that the new epidemiological data coming from the Kaiser Permanente study do have scientific merits, but may be confusing when interpreted for the lay public. Health-care providers should stay with the first-grade information coming from the WHI study when discussing this issue with their patients: breast-wise, in women younger than 60, HT (particularly estrogen-alone) is safe. Long-term use may be associated with a small increased risk, in the order of one extra case per 1000 women per year. Discontinuation of HT brings this risk back to the values for age-matched non-users after 3-5 years. Weighing the overall benefits and risks of HT in the younger postmenopausal population clearly favors the use of HT for symptomatic women.







References



1. Glass AG, Lacey JV Jr, Carreon D, Hoover RN. Breast cancer incidence, 1980-2006: combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst 2007;99:1152-61



2. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-33



THE INTERNATIONAL MENOPAUSE SOCIETY



The aims of the Society (IMS) are to promote knowledge, study and research on all aspects of aging in men and women; to organize, prepare, hold and participate in international meetings and congresses on menopause and climacteric; and to encourage the interchange of research plans and experience between individual members. The Society is a non-profit association, within the meaning of the Swiss Civil Code. It was created in 1978 during the first World Congress on the Menopause. In addition to organizing congresses, symposia, and workshops, the IMS owns its own journal: Climacteric.



For further information please go to: imsociety



Source: Jean Wright

International Menopause Society

Protein From Pregnancy Hormone May Prevent Breast Cancer

Researchers have found that hormones produced during pregnancy induce a protein that directly inhibits the growth of breast cancer. This protein, alpha-fetoprotein (AFP), may serve as a viable, well-tolerated agent for the treatment and prevention of breast cancer, according to findings published in Cancer Prevention Research, a journal of the American Association for Cancer Research.


"Hormones in pregnancy, such as estrogen, all induce AFP, which directly inhibits the growth of breast cancer," said lead researcher Herbert Jacobson, Ph.D., who is a basic breast cancer researcher in the Center for Immunology and Microbial Diseases and in the Department of Obstetrics, Gynecology and Reproductive Sciences at Albany Medical College, N.Y.


"The body has a natural defense system against breast cancer," he added. "AFP needs to be safely harnessed and developed into a drug that can be used to protect women from breast cancer."


Recent studies have shown that hormones released during pregnancy, such as estrogen, progesterone and human chorionic gonadotropin, reduce a women's risk for breast cancer. AFP is a protein normally produced by the liver and yolk sac of a fetus. Jacobson and colleagues sought to determine whether administering pregnancy hormones to carcinogen-exposed rats led them to produce AFP, which in turn produces the protective effect of pregnancy in the absence of pregnancy.


Results from this study showed that treatment with estrogen plus progesterone, estrogen alone or human chorionic gonadotropin reduced the incidence of mammary cancers in rats. Furthermore, the researchers noted that each of these treatments elevated the serum level of AFP and that AFP directly inhibited the growth of breast cancer cells growing in culture, suggesting that these hormones of pregnancy are preventing breast cancer through their induction of AFP.


Cancer Prevention Research Editorial Board Member Powel Brown, M.D., Ph.D., said while these preclinical findings are important and suggest a role of AFP in breast cancer prevention, they are not yet ready to be used in the clinic.


"The researchers have not directly demonstrated the cancer preventive activity of AFP, instead they found an association of these hormones preventing mammary tumors. None of these treatments prevented mammary tumors in 100 percent of the rats, it appears to delay mammary tumor formation and prevent breast cancer development in approximately 30 to 50 percent of the rats," said Brown, professor of medicine and cancer prevention and clinical cancer prevention department chairman at the University of Texas M. D. Anderson Cancer Center.


"This study is promising and suggests that additional animal studies need to be done before translation to humans," he said. "We may want to further test AFP for its cancer prevention activity."


Jacobson and colleagues are currently conducting studies in which they have isolated a small piece of AFP molecule and are working to convert it into a breast cancer preventative agent.


Source
American Association for Cancer Research (AACR)

Targeted Immunotherapy: Metastatic Breast, Pancreatic Cancers

Early trials using targeted monoclonal antibodies in combination with existing therapies show promise in treating pancreatic cancer and metastatic breast cancer, according to research that will be presented by investigators from the University of Pennsylvania's Abramson Cancer Center at the 2010 meeting of the American Society of Clinical Oncology June 4 through 8. One study uses an antibody to enhance the effectiveness of a breast cancer vaccine developed at Penn to treat women with advanced breast cancer, while a pancreatic cancer trial uses an immune-enhancing antibody to increase the effectiveness of a current standard drug used to treat pancreatic cancer.


In the first new study, investigators used an antibody previously approved by the FDA to enhance the effectiveness of a therapeutic vaccine for women with advanced breast cancers. ("Phase I study of anti-CD25 mAb daclizumab to deplete regulatory T cells prior to telomerase/survivin peptide vaccination in patients with metastatic breast cancer" -- Oral Abstract #2508) The antibody, known as anti-CD25 mAb dacluzimab, targets T regulatory cells (Tregs), naturally occurring cells which tumors harness to dampen the body's normal immune response. Until now, these cells have represented an obstacle to cancer immunotherapy. The Penn Medicine team's approach uses the antibody to turn off the Treg cells' function in the immune system and boosting the effectiveness of a telomerase/survivin peptide vaccine made to tackle the cancer.


The study demonstrated that a single infusion of the antibody given a week before patients received the vaccine results in "rapid, marked and prolonged" loss of Tregs without toxicity in patients with metastatic breast cancer. Six of the 10 patients who received the treatment exhibited a stabilization of their disease. Data for overall survival is not yet available, but the Penn researchers say the results represent significant promise for treating the patient population that does not respond to standard therapies.


"Many of these women have already been treated with and failed several chemotherapy regimens, but using this approach they were able to receive multiple doses of the vaccine without experiencing any of the toxicities that often accompany chemotherapy," says senior author Robert H. Vonderheide, MD, DPhil, an associate professor in the division of Hematology/Oncology. "For this group of patients, an extended period of stable disease represents an encouraging result." He and his team plan to begin much larger studies in the near future, and ultimately, to expand the new combined approach to women who are currently in remission but at very high risk of relapse.


Tregs play an important role in the body's normal immune response. When they are absent or severely depleted, the result is autoimmune problems. To date, however, research has not shown any long-term effects of this targeted immune suppression in the treated patients, which is an important consideration in expanding the trials to women without known active disease.















"Ten years ago, we didn't even know Tregs existed," Vonderheide says. "Our lack of knowledge about the intricacies of the normal immune system and the ways in which tumors can exploit the immune response severely limited the success of previous attempts at cancer immunotherapy. The early results were quite modest and very transient. It has taken five years to develop an understanding of how these cells work, but we have now reached the point where we are on the cusp of a whole new era in cancer immunotherapy."


In second immunotherapy-related study, Penn researchers utilized CP-870,893, a CD40 agonist monoclonal antibody produced by Pfizer that enhances anti-tumor cellular immunity by activating tumor antigens and triggering the release of inflammatory cytokines. ("Phase I study of CD40 agonist monoclonal antibody (CP-870,893) with gemcitabine in pancreatic cancer" -- Poster Presentation #2539). The antibody was combined with the chemotherapy agent gemcitabine to treat pancreatic cancer patients who had not received any previous chemotherapy. The Phase I study demonstrated that the combined therapy produced promising results without causing any significant toxicity. Three of the first 21 patients treated experienced partial regressions of their tumors, and 11 patients' diseases stabilized, with the positive effects of the treatment observed in both the primary and metastatic tumors. Additional studies are underway to evaluate this treatment approach in larger groups of patients.


"The model for this research moves from the lab to the clinic and then back to the lab," says Hematology/Oncology physician Gregory Beatty, MD, who led the study with Peter O'Dwyer, MD, a professor of Hematology/Oncology. "With this approach, we cannot only measure the effects of the treatment, but also understand exactly what is going on at the cellular level and then use that information to develop our next generation of clinical interventions. Our goal is to re-educate the immune system to mount a specific inflammatory response to the tumor. By killing the cancer cells, the chemotherapy in effect alerts the immune system to the location of the tumor and provokes an immune response aimed at the cancer cells."


Currently, fewer than 10 percent of pancreatic cancer patients respond to gemcitabine alone, and most combination therapies studied have not produced more encouraging results - responses, when they do occur, generally only last for about two months. The new combination therapy, however, appears to produce a significantly higher response rate, with an average duration of five to six months.


"This is an encouraging result against a cancer for which the outlook has been so grim for so long," says Vonderheide, who is also a co-author of the pancreatic cancer study. "We can honestly say now that the prospects for patients with pancreatic cancer are beginning to improve. What we are seeing, though, is just the tip of the iceberg. Patients and their families need to know this is no longer a disease against which we are helpless, and physicians must help their patients to seek clinical trials at the earliest point."


The breast cancer study will be presented as an oral abstract at the Developmental Therapeutics Clinical Pharmacology and Immunotherapy session on June 8 from 9:30 to 12:30 p.m. The pancreatic cancer study will be presented at the poster session on Developmental Therapeutics on June 7 from 8 a.m. to 12 p.m.


Source
University of Pennsylvania School of Medicine

Identification Of New Genes Will Help Predict Breast Cancer Patient Outcome

Not a day goes by without a new story about the environment. Although we often consider the environment on a global scale, cells in our body also have to contend with environmental factors. New studies from a team of researchers from the Research Institute of the MUHC and McGill University show that the environment surrounding breast cancer cells plays a crucial role in determining whether tumor cells grow and migrate or whether they fade away. Their study is the first to identify the genes behind this environmental control and correlate them with patient outcome. Their findings are published in this week's issue of Nature Medicine.



"A tumour can not exist on its own. It has to be supported and nourished by the cell types around it, the microenvironment," says senior author Dr Morag Park, Director of the molecular oncology group at the Research institute if the MUHC. "When we began this study there was little known about the importance of this microenvironment on cancer initiation and progression. We now know that this environment is pivotal; different patients have distinct tumour microenvironments at a gene level. Our findings show that the gene profile of these distinct microenvironments can be used to determine clinical outcome - who will fare well and who will not."



Dr Park, a professor of oncology, biochemistry, and medicine at McGill University, and her team analyzed tissue from 53 breast cancer patients. They used a unique technique, laser capture microdissection (LCM), to separate tumour cells from microenvironment tissue. They compared the gene expression between the microenvironment tissue and controls using micro-array analysis. From thousands of genes they identified 163, which correlated with patient outcome. A good outcome was defined as having no tumour metastasis and tumour migration and non-responsiveness to therapy was considered poor outcome.



From the original 163 genes, the team further identified a panel of 26 specific genes that could be used to accurately predict clinical outcome. This 26 gene-profile, called the stromal derived prognostic predictor (SDPP), was used to predict outcome from a second set of beast cancer patients.



"We were able to show that the SDPP effectively predicts outcome in a second group of patients," says Dr Park, "This panel accurately forecasted patient status, suggesting that this may be a promising diagnostic tool.



"Our next steps are to develop this 26-gene predictor into a functional test. We are currently working on this and we anticipate a product for clinical trials within a year," adds Park.



"This work takes tremendous dedication and collaboration from a number of people including pathologists, surgeons, oncologists as well as researchers. I would like to thank the outstanding work done by G. Finak from the laboratory of Dr M. Hallett of McGill's Computer Science Department, the breast surgeons of the MUHC, including Dr S. Meterissian, and by the Department of Pathology at McGill, where Dr A. Omeroglu works."


















This release is also available in French.



This research was funded by from the Quebec Breast Cancer Foundation, Genome Canada-Genome Quebec, Quebec Valorisation-Recherche Quebec, Fonds de la Recherche en Sante du Quebec, Canadian Institutes for Health Research Team Grant, and the National Science and Engineering Research Council of Canada Discovery Grant.



The Research Institute of the McGill University Health Centre (RI MUHC) is a world-renowned biomedical and health-care hospital research centre. Located in Montreal, Quebec, the institute is the research arm of the MUHC, the university health center affiliated with the Faculty of Medicine at McGill University. The institute supports over 600 researchers, nearly 1200 graduate and post-doctoral students and operates more than 300 laboratories devoted to a broad spectrum of fundamental and clinical research. The Research Institute operates at the forefront of knowledge, innovation and technology and is inextricably linked to the clinical programs of the MUHC, ensuring that patients benefit directly from the latest research-based knowledge.



The Research Institute of the MUHC is supported in part by the Fonds de la recherche en santГ© du QuГ©bec. For further details visit: muhc.ca/research.



About McGill University



McGill University is Canada's leading research-intensive university and has earned an international reputation for scholarly achievement and scientific discovery. Founded in 1821, McGill has 21 faculties and professional schools, which offer more than 300 programs from the undergraduate to the doctoral level. McGill attracts renowned professors and researchers from around the world and top students from more than 150 countries, creating one of the most dynamic and diverse education environments in North America. There are approximately 23,000 undergraduate students and 7,000 graduate students. It is one of two Canadian members of the American Association of Universities. McGill's two campuses are located in Montreal, Canada.mcgill.ca/



For more information please contact:



Isabelle Kling

Communications Coordinator (research)

MUHC Public Relations and Communications



Mark Shainblum

Media Relations Officer (Research)

McGill University



Source: Isabelle Kling


McGill University Health Centre

NICE Upholds GlaxoSmithKline Appeal For Advanced Breast Cancer Treatment, Tyverb(R)(lapatinib)

The National Institute for Health and Clinical Excellence (NICE) announced that, following GlaxoSmithKline's (GSK) appeal, it will reconsider the submission for Tyverb (lapatinib), a treatment for an aggressive form of advanced breast cancer (ErbB2-positive).1 GSK is pleased that NICE's appeal panel agreed that the draft negative guidance should be reviewed, providing fresh hope for up to 2,000 women in the UK who could benefit from this effective treatment on the NHS.


Dr Alison Jones, Medical Oncologist at the University College London Hospital and the Royal Free Hospital commented: "It is great that NICE will reconsider the evidence supporting the use of lapatinib as there is a significant unmet medical need for women with this aggressive form of advanced breast cancer. These women have very few treatment options left available to them and lapatinib, when combined with capecitabine, offers a chance of additional time without their disease progressing."


The appeal has been upheld in light of new supplementary NICE advice for the assessment of treatments in small patient populations with a short life expectancy, issued in January this year.2 The appeal panel agreed that GSK and other consultees should be given the opportunity to make a full submission under these new 'end of life' criteria.1


Simon Jose, General Manager, GSK UK commented: "We welcome the decision of the appeal panel and the opportunity to make a full submission to NICE under the end of life criteria. We appreciate that NICE has some very tough decisions to make, especially in this end of life setting, but given the considerable survival benefits that Tyverb offers these women, we believe it deserves full and thorough consideration."


In line with previous commitments, GSK UK will continue to offer the Tyverb Patient Access Programme to both NICE and individual NHS Trusts. Under this scheme GSK bears the cost of lapatinib for up to the first 12 weeks of treatment,


Safety Information


Lapatinib plus capecitabine is generally well tolerated. The most common adverse events associated with lapatinib plus capecitabine were diarrhoea, rash, nausea, vomiting, fatigue and hand-foot syndrome.3,4 Diarrhoea and rash were more common with the combination whilst the incidence of hand-foot syndrome was similar between the two treatment groups.3 A decrease in left ventricular ejection fraction (LVEF) was reported by 2.5% of patients receiving lapatinib plus capecitabine vs. 1% of patients on capecitabine alone.3 Hepatobiliary events (mainly raised liver enzymes and/or bilirubin levels) have been reported commonly in association with lapatinib plus capecitabine therapy.3 Lapatinib has also been associated with reports of pulmonary toxicity.

















About Tyverb


• Tyverb received a conditional marketing authorisation in Europe, June 2008.3


• Tyverb, in combination with capecitabine, is indicated for the treatment of patients with advanced or metastatic breast cancer whose tumours overexpress ErbB2 (HER2). Patients should have progressive disease following prior therapy which must include anthracyclines and taxanes and therapy with trastuzumab in the metastatic setting.3


• Healthcare professionals should refer to the Tyverb Summary of Characteristics (SPC) for full prescribing information, including warnings and precautions.3


GlaxoSmithKline - one of the world's leading research-based pharmaceutical and healthcare companies - is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information please visit gsk


Tyverb® is a registered trademark of the GlaxoSmithKline group of companies.


References


1. Lapatinib for the treatment of women with previously treated advanced or metastatic breast cancer. NICE Appeal Panel's decision, 9 July 2009
guidance.nice.uk/TA/Wave13/1


2. Appraising life extending end of life treatments. January 2009. nice.uk/media/88A/F2/SupplementaryAdviceTACEoL.pdfAccessed 8 July 2009


3. Tyverb® (lapatinib) Summary of Product Characteristics. emc.medicines.uk/medicine/20929/SPC/Tyverb Last accessed 05 June 2009


4. Cameron D, Casey M, Press M, et al. A phase III randomised comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008; 112:533-543


Source
GlaxoSmithKline

Tamoxifen Yields Long-term Reduction In Breast Cancer Risk

Tamoxifen offers long-term benefits for breast cancer prevention among women at high risk of the disease, according to two randomized, blinded clinical trials in the Journal of the National Cancer Institute. The trials found that the breast cancer risk reduction persists long after women stop taking tamoxifen.



Tamoxifen is used both to treat breast cancer and to prevent it among women at high risk of breast cancer. However, most of the data on tamoxifen for breast cancer prevention comes from the period when women were still taking tamoxifen, usually a period of five years. There is little information about breast cancer risk after tamoxifen use is stopped. Tamoxifen, an antiestrogen drug, is only active on estrogen receptor (ER)-positive breast cancer, which is dependent on estrogen to grow.



In the International Breast Cancer Intervention Study (IBIS-I), 7,145 women ages 35 to 70 who were at an increased risk of breast cancer were randomly assigned to receive either 20 milligrams per day of tamoxifen or a placebo for 5 years. Initial study results reported in 2002 - about 4 years into the trial - showed that tamoxifen reduced the incidence of breast cancer by 32 percent. The risk reduction was only for ER-positive breast cancer; ER-negative breast cancer rates were similar in both groups.



In the updated report of the first study, Jack Cuzick, Ph.D., of the Wolfson Institute of Preventive Medicine in London, and colleagues report breast cancer rates on women about 8 years after they were enrolled in IBIS-I. Tamoxifen reduced the incidence of breast cancer by about 27 percent; this amounts to 4.97 breast cancer cases per 1,000 women in the tamoxifen group compared with 6.82 cases per 1,000 women in the placebo group. This reduction was restricted to ER-positive breast cancers. They note that, although the breast cancer reduction remained similar from the earlier report to the current one, side effects decreased after active treatment was stopped. For example, during the 5 years of tamoxifen (or placebo) treatment, women in the tamoxifen group experienced higher rates of deep-vein thrombosis and pulmonary embolism, but this difference disappeared after tamoxifen was stopped.



"These updated results from the IBIS-I trial provide further confirmation that tamoxifen reduces the risk of ER-positive breast cancers in high-risk women," the authors write. "More importantly, they provide the first randomized evidence that the benefits of tamoxifen extend beyond the active treatment period, but the side effects largely do not."



In the second study, Trevor J. Powles, Ph.D., of The Royal Marsden Hospital in London, and colleagues analyzed more than 13 years of data from 2,471 women enrolled in a clinical trial at the hospital. The women were randomly assigned to take 20 mg/day of tamoxifen or a placebo daily for 8 years. In their initial analysis in 1998, the researchers reported that there was no difference in breast cancer rates between the two groups, when using about 6 years of follow-up data.
















In the new analysis with a 20 year follow-up, the researchers again found that overall invasive breast cancer rates were not statistically different (82 breast cancer cases among 1,238 women on tamoxifen, and 104 cases among 1,233 women on placebo). However, when the researchers looked specifically at ER-positive breast cancers, they found that tamoxifen reduced the risk of ER-positive breast cancer by 39 percent. This reduction occurred for the most part in the later follow-up period.



"We found that…a highly statistically significant risk reduction was found that could be attributed principally to a reduction in the risk of ER-positive breast cancers," the authors write. "This reduced risk appears to be increasing with longer follow-up."



In an editorial, Umberto Veronesi, M.D., of the European Institute of Oncology in Milan, Italy, and colleagues put the new results in context with other long-term studies of tamoxifen for breast cancer prevention. They note that, because both trials find that tamoxifen reduced the risk of only ER-positive cancers, it's important to identify specific risk factors for these cancers so tamoxifen use can be appropriately guided. "The results of these two trials … convincingly move tamoxifen beyond the proof-of-principle stage and underscore its worth as a viable standard option for preventing ER-positive breast cancer in high-risk women," the editorialists write.






Contact: Articles:



* Nicola Brebner, press office, Cancer Research UK


* Naomi Wright, press office, Royal Marsden Hospital



Editorial:



* Donata Francese, European Institute of Oncology



Citations:



Articles:



* Cuzick J, Forbes JF, Sestak I, Cawthorn S, Hamed H, Holli K, et al. Long-Term Results of Tamoxifen Prophylaxis for Breast Cancer - 96-Month Follow-up of the Randomized IBIS-I Trial. J Natl Cancer Inst 2007;99:272-282.


* Powles TJ, Ashley S, Tidy A, Smith IE, Dowsett M. Twenty-Year Follow-up of the Royal Marsden Randomized, Double-Blinded Tamoxifen Breast Cancer Prevention Trial. J Natl Cancer Inst 2007;99:283-290.


*
Editorial: Veronesi U, Maisonneuve P, Decensi A. Tamoxifen: An Enduring Star. J Natl Cancer Inst 2007;99:258-260.



Note: The Journal of the National Cancer Institute is published by Oxford University Press and is not affiliated with the National Cancer Institute. Attribution to the Journal of the National Cancer Institute is requested in all news coverage. Visit the Journal online at jnci.oxfordjournals/.



Contact: Liz Savage


Journal of the National Cancer Institute

Breast Cancer Detection: Mathematical Models With Microwave Tomography Are Cheaper And Less Risky

The most popular method of breast cancer detection today is X-ray mammography, which takes images of a compressed breast by low-dose ionizing radiation. However, there are several disadvantages to using X-rays for breast cancer screening, chief among them being the invasivity of radiation and the high costs, which limit their wide use and can deter women from getting them. In addition, depending on the age of the patient and tissue density, X-ray mammograms often result in false positives and negatives.



Microwave tomography can provide a cheaper and less risky alternative to X-ray mammography. In a paper published in the SIAM Journal on Applied Mathematics, the authors describe a mathematical model for imaging tumors in the breast using microwave tomography. Microwave tomography detects cancers by measuring inhomogeneities in the electrical conductivity of breast tissue. An array of low-power microwaves are transmitted into the breast from different positions and the resulting scattered signals are collected by antennas surrounding it. The malignant-to-normal tissue contrast arises because cancerous cells have higher water content, and are hence stronger scatterers than normal tissue.



The electrical properties measured by microwaves are sensitive to physiological parameters such as water content, temperature and vascularization. In addition, they can give an estimate of mammographic breast density, which is a crucial factor in evaluating a patient's risk of breast cancer. The distribution of these electrical parameters in space is used to reconstruct the image of the breast with the help of carefully designed algorithms.



There is room for improvement in the mathematical method that currently exists for image reconstruction in microwave tomography. The problem to be solved is an inverse scattering problem. At microwave frequencies, the inverse problem is difficult to solve accurately because it is highly nonlinear. In addition, it is an ill-posed problem, which means that it does not have a solution in the strict sense, the solutions are not usually unique, and may not depend continuously on the data.



Different approaches have been used to circumvent these. One involves linearizing the problem, but this can result in significant loss of accuracy. A second approach uses nonlinear optimization and relies on initial apriori information on object shape and electric properties. While this yields more accurate results, its reliability depends on the accuracy of the initial information and is computationally expensive.



A more recent approach uses a qualitative method utilizing "sets" of linear integral equations of the first kind. While these are faster and don't require apriori information, they can only provide estimates for sets of points. In this paper, the authors use a linear sampling method in combination with a gap functional to take into account near fields instead of far fields. This results in higher accuracy.



Source:

Karthika Muthukumaraswamy

Society for Industrial and Applied Mathematics

What Is Paget's Disease Of The Breast (nipple)? What Causes Paget's Disease Of The Breast?

Paget's disease of the nipple or breast is a rare type of breast cancer, which can occur in women and men. It shows up in and around the nipple, and usually signals the presence of breast cancer beneath the skin.


Most cases are found in menopausal women, but can also appear in women that are as young as 20.


The disease is named for Sir James Paget. He reported on the link between changes in the nipple and the underlying breast cancer. Although Paget believed the affected cells were not cancerous, it was later proved that the cells were themselves malignant, in addition to indicating underlying breast cancer. Since the condition is often innocuous and limited to a surface appearance, it is sometimes dismissed, despite the fact that it is indicative of breast cancer that may prove fatal if left untreated.


More than 95 percent of people with Paget's disease of the nipple also have underlying breast cancer; however, Paget's disease of the nipple accounts for less than 5 percent of all breast cancers.


Most patients diagnosed with Paget's disease of the nipple are over age 50, but rare cases have been diagnosed in patients in their 20s. The average age at diagnosis is 62 for women and 69 for men. The disease is rare among both women and men.


In an interesting note, retired Boston Red Sox center fielder Dom DiMaggio suffered from Paget's disease and served as a member of the board of directors of the Paget Foundation.
What are the symptoms of Paget's disease?
A symptom is something the patient senses and describes, while a sign is something other people, such as the doctor notice. For example, drowsiness may be a symptom while dilated pupils may be a sign.


On average, a woman may experience signs and symptoms for six to eight months before a diagnosis is made.


Paget's disease's symptoms may vary based on the stage of the disease. However, the main symptoms that can occur in Paget's disease include flaky or scaly skin on the nipple, straw-colored or bloody nipple discharge, skin and nipple changes in only one breast or the flattened nipples.


The first symptom is usually an eczema-like rash, usually only affecting one nipple. The skin of the nipple and areola may be red, itchy and inflamed. Some women have an itching or burning sensation. Fluid discharge may leak from the abnormal area of cells. The nipple may turn inwards. There may or may not be a lump in the breast, and there may be redness, oozing and crusting, and a sore that does not heal.


The symptoms usually affect the nipple and then spread to the areola and then the breast. It is common that the symptoms disappear for a while and this may be tricky as the patient takes it as a sign that the disease has cured, which is not true.















Most women do not visit the doctor because they mistake it as contact dermatitis or eczema. Women who feel a lump or notice skin irritation that does not seem to heal for over a month are recommended to seek the opinion of a specialist.


Patients may also experience crusty, oozing or hardened skin resembling eczema, on the nipple, areola or both and fluctuating skin changes early on, making it appear as if the skin is healing on its own. Some patients complain of burning sensations on the nipples or breasts. These symptoms usually occur in more advanced stages, when serious destruction of the skin often prompts the patient to consult.


Lumps or masses in the breast occur in 50% of the patients. In more advanced stages, the disease may cause tingling, increased sensitivity and pain.
What are the causes of Paget's disease?
If invasive breast cancer or ductal carcinoma in situ (DCIS) is already present in the breast as a tumor, cells might drift off from the tumor and float up through the milk ducts, where they enter the nipple and areola.


In a few cases of Paget's disease, there is no underlying breast cancer, or if a tumor is present, it is unrelated to the disease in the nipple. Researchers suggest that in those cases, nipple skin cells may spontaneously change into cancer cells.
h2 class="blue_sea_paddingtop">Diagnosing Paget's disease
Recommended tests are a mammogram and a biopsy to confirm the diagnosis, and cytopathology may also be helpful.


Paget's disease is difficult to diagnose due to its resemblance to dermatitis and eczema. The difference between these two types of conditions consists of the detail that the latter, unlike Paget's disease, rather affect the areola first and then the nipple.


During a physical examination the doctor examines the unusual areas of the breast, especially the appearance of the skin on and around the nipples and feeling for any lumps or areas of thickening.


The most commonly tests used to diagnose Paget's disease is the biopsy. A biopsy consists in the removal of a tissue sample from the affected area which is after looked at under the microscope by a pathologist. The pathologist may use a technique called immunohistochemistry (staining tissues to identify specific cells) to differentiate Paget cells from other cell types.


Samples of nipple discharge may also be examined under the microscope to check if Paget cells are present.


Imprint or scrape cytology may be useful. They consist in scraping cells from the affected area, or pressing them onto a glass slide to be examined under the microscope.
What are the treatment options for Paget's disease?
Surgery is the most common treatment for Paget disease of the nipple. The specific treatment often depends on the characteristics of the underlying breast cancer.


A modified radical mastectomy may be recommended when invasive cancer or extensive DCIS has been diagnosed. In this operation, a surgeon removes the breast, the lining over the chest muscles, and some of the lymph nodes under the arm. In cases where underlying breast cancer is not invasive, the surgeon may perform a simple mastectomy to remove only the breast and the lining over the chest muscles.


Alternatively, patients whose disease is confined to the nipple and the surrounding area may undergo breast-conserving surgery or lumpectomy followed by radiation therapy. During breast-conserving surgery, a surgeon removes the nipple, areola, and the entire portion of the breast believed to contain the cancer. In most cases, radiation therapy is also used to help prevent recurrence.
Preventing Paget's disease
Paget's disease cannot be prevented. However, one may prevent complications of Paget's disease, such as osteoarthritis, by taking medicine, staying at a healthy weight, and regularly doing gentle exercise that does not cause stress to the bone.


Written by Sy Kraft (B.A.)

Similarities Found In Dog And Human Breast Cancer Pre-Malignant Lesions

Pre-malignant mammary lesions in dogs and humans display many of the same characteristics, a discovery that could lead to better understanding of breast cancer progression and prevention for people and pets, said a Purdue University scientist from the School of Veterinary Medicine.



A group of scientists including Sulma Mohammed have found similarities between benign lesions that are considered to carry risk for developing breast cancer in both canines and humans. Breast cancer is the second leading cause of cancer deaths in women.



"Dogs develop these lesions spontaneously in contrast to other available models and are exposed to the same environmental risk factors as humans," said Mohammed, an associate professor in comparative pathobiology. "These shared features make the dog an ideal model to compare the breast lesions that will progress to cancer and those that will regress. Such a model will facilitate customized treatment and prevention strategies."



Due to the success of mammographic screening and awareness by women, abnormal cell growth within breast tissues is frequently diagnosed, Mohammed said. These intraepithelial lesions are recognized risk factors for invasive cancer, and their presence affects patient management decisions.



"Once a lesion is identified, it can be treated with hormonal therapy if it is estrogen receptor (ER)-positive, but for low-risk and ER-negative lesions, we can't do anything but wait and watch to see if it grows into a tumor," Mohammed said. "With a dog model, we could study these lesions and test different prevention modalities before it becomes a cancer."



The research appears in this month's issue of the Journal of Cancer Epidemiology, Biomarkers, and Prevention. Mohammed's co-authors include Sunil Badve from Indiana University; Margaret (Peg) Miller, Jun Xie and Elisabetta Antuofermo from Purdue; and Salvatore Pirino from the Sassari University School of Veterinary Medicine in Sardinia, Italy.



The scientists studied 212 tissue biopsies from 200 female dogs with tumors that were retrieved from the archives of the Purdue Animal Disease Diagnostic Laboratory and the Veterinary Teaching Hospital as well as from the Institute of General Pathology and Anatomical Pathology at Sassari University.



The canine slides were compared to human specimens collected from the Department of Pathology at the IU School of Medicine. Mohammed said the focus of the study was not on the tumor but on the precancerous, or preneoplasia, lesions in tissue around the tumor.



"We found that preneoplasia lesions are virtually identical, microscopically, in dogs and women," she said. "In fact, many of the slides were so similar it was often difficult to determine if they were from dogs or people without looking at the label."
















In particular, Mohammed said, they wanted to examine each type of mammary intraepithelial lesion for estrogen receptors expression. Recently, scientists have concluded that breast cancer is not a single disease, but a group of malignancies.



"Establishing an animal model is paramount for testing new treatment and prevention modalities, especially for lesions that express none of the targeted receptors, such as triple-negative types, before human clinical trials," Mohammed said.



The team determined that because of the frequency of lesions, their association with spontaneous mammary cancer and the resemblance to human lesions, dogs may be the ideal model to study human breast cancer progression as well as prevention and treatment. Mohammed emphasized that the research results would benefit both dogs and humans.



According to the American Cancer Society, 62,030 cases of precancerous malignant lesions and 178,480 new cases of breast cancer will be diagnosed. There will be 70,880 women who die from breast cancer this year.



Much of the difficulty in research on dogs with breast cancer is that the data is outdated, Mohammed said. According to a 1969 study of female dogs over 4 years old that were not spayed, one out of four were expected to develop mammary neoplasia, or abnormal cell growth that may progress to cancer. Thirty percent to 50 percent of canine mammary tumors were malignant, and 50 percent to 75 percent of these recurred or metastasized within one to two years.



"Women have become more aware and conscientious of conducting their own breast self-exams, and pet owners also are more aware to check their animals," Mohammed said. "With better diagnostic tools and early detection, we are able to give dogs the same treatment that we give humans."



Mohammed said the dogs provide a more realistic comparison to humans than the mice and rat models, in part because the tumors developed spontaneously, just as in humans. Dogs have been evaluated in a few studies, but rodent research is more common, she said.



"This is a very large, untapped resource for comparative oncology research," Mohammed said. "Unlike laboratory rodents, dogs share a common environment with people and, therefore, may be exposed to some of the same carcinogens. Also, because dogs have a shorter life span than people, it is possible to study mammary lesions and invasive tumors that develop after a few years instead of decades."



Miller, a veterinary pathologist in the Animal Disease Diagnostic Laboratory, said that mammary cancer in dogs is one of the most common forms of cancer studied at the Animal Disease Diagnostic Laboratory.



"We already had hundreds of mammary tumor specimens archived in the diagnostic laboratory," Miller said. "It's a wonderful thing when we're able to collaborate with other departments at Purdue and Indiana University with these specimens. There's so much to be learned from these types of studies."



Tissue samples are kept indefinitely at the Animal Disease Diagnostic Laboratory, but most of the samples in this study were less than a year old, she said. The records kept for each sample provide opportunities for follow up if necessary in future studies.



"Diseases such as this are important to a diagnostic laboratory," Miller said. "Through diagnostic pathology, we gain knowledge that's useful for veterinarians and animals, as well as collecting information that's helpful for people."



The main form of treatment of breast cancer tumors has been surgical removal. Both Mohammed and Miller would like to find out if there is a way to identify the lesion early with noninvasive screening, such as ultrasound or magnetic resonance imaging.



As a next step, Mohammed will determine the prevalence of lesions in dogs with no tumors. In addition, she and Miller are looking at cats, which have a 90 percent malignancy rate when they are diagnosed with breast cancer.







This research was funded by the U.S. Department of Defense.



Writer: Maggie Morris



Related Web site:


School of Veterinary Medicine: vet.purdue/



Click here to access abstract on the research in this release.



Source:

Sulma Mohammed

Maggie Morris


Purdue University

Node Negative Early Stage Breast Cancer Patients Benefit From Taxotere(R)-Based Chemotherapy

Sanofi-aventis and
GEICAM (Grupo Espanol de Investigacion en Cancer de Mama) announced
that for women with high-risk node-negative early stage breast cancer
adjuvant treatment (post surgery) with Taxotere(R) (docetaxel) Injection
Concentrate as part of the TAC regimen (Taxotere(R), doxorubicin,
cyclophosphamide) was associated with a significant improvement in Disease
Free Survival (DFS) compared to a standard FAC regimen (5-Fluorouracil,
doxorubicin, cyclophosphamide) in the GEICAM 9805/Target-0 study.


The results will be presented at the 2008 annual meeting of the
American Society of Clinical Oncology, ASCO, in Chicago (Monday June 2,
2008, 2-6 pm, poster number 1D, abstract 542).



In Europe and North America, most breast cancer patients are diagnosed
at an early stage, before the tumor has spread to the lymph nodes. However,
few clinical trials in the past were dedicated exclusively to this
population of patients. GEICAM 9805/Target-0 is the first taxane-based
study to exclusively enroll women with node-negative early stage breast
cancer considered to be at high risk for recurrence. High risk patients
were defined as having at least one of the following St Gallen 1998
criteria: patient's age 2 cm, or hormone-receptor (estrogen and/or progesterone receptor)
negative tumor.



The 1059 women enrolled in this multicenter, phase III study were
randomized to receive either TAC (n=539) or FAC (n=520) after surgical
resection of their tumor. Therapy was given every three weeks for a total
of 6 cycles. The primary end point was Disease Free Survival (DFS) and
secondary end points included overall survival (OS), safety, and quality of
life.



Analysis of efficacy, determined by DFS, was performed after a minimum
of 5-years of follow up. The study showed a significant improvement in
5-year DFS that was demonstrated in the TAC arm over the FAC arm, with 91%
and 86% patients, respectively, alive and disease free (HR 0.66, 95% CI
0.46-0.94, p=0.0202). The OS data are immature; estimated 5-year OS is 97%
for TAC and 95% for FAC (HR 0.72, 95% CI 0.40-1.30, p=0.2677). The safety
results have been already published (Martin et al (2006), Ann Oncol 17:
1205-12) TAC produced significantly more hematological adverse reactions
than FAC. Primary prophylaxis with G-CSF reduced the rate of neutropenic
fever. No toxic deaths were reported.



"First of all, I would like to congratulate the patients and my fellow
investigators for having the courage to participate in this innovative
trial in a purely node-negative patient population. This study showed that
the TAC regimen improves Disease Free Survival in women with high risk
node-negative breast cancer," said GEICAM Chair and principal investigator
of the 9805 study, Prof. Miguel Martin.
















About the Study



The GEICAM 9805/Target-0 trial was initiated as a complementary study
to BCIRG 001/TAX 316, a study that enrolled women with node-positive early
stage breast cancer.


b

From December 2001 to March 2003, 1059 patients aged 18-71, with T1-T3,
N0, M0 operable breast cancer and at least one high-risk St Gallen 1998
criterion (patient age 2 cm, or
hormone-receptor negative tumor) were enrolled in the study; 1047 patients
were eligible. Patients from Spain as well as Germany and Poland were
stratified by institution and menopausal status and randomized after
surgery to receive either TAC (docetaxel 75 mg/m2, doxorubicin 50 mg/m2,
cyclophosphamide 500 mg/m2) or FAC (5-fluorouracil 500 mg/m2, doxorubicin
50 mg/m2, cyclophosphamide 500 mg/m2) every 3 weeks for 6 cycles.
Radiotherapy was mandatory after conservative surgery and recommended for
patients with tumors > 5 cm; tamoxifen was given for 5 years to all
patients with endocrine responsive tumors. A study amendment initiated
during enrollment mandated the use of G-CSF with the first cycle of TAC, in
order to reduce the incidence and severity of hematological toxicities and
febrile neutropenia.



The primary end-point was DFS with analysis planned after a minimum
follow-up of 5 years.



The full safety analysis has previously been published (Martin et al
(2006), Ann Oncol 17: 1205-12). The analysis demonstrated that febrile
neutropenia (grade 4) was the most common and clinically severe event
(24.6%) reported with the TAC regimen. The incidence of febrile neutropenia
decreased to 6.5% with the use of G-CSF from the first cycle of TAC. The
incidence of febrile neutropenia among patients treated with FAC was 2.3%.
Grade 2-4 anemia was higher in the TAC regimen (47.4%) vs FAC (7.5%). The
incidence of anemia TAC decreased (27.5%) with the use of G-CSF. No toxic
deaths were reported.



About Breast Cancer



According to the American Cancer Society, worldwide, breast cancer is
the most common cancer in women and the second most common after lung
cancer in both genders. More than one million new cases of breast cancer
are reported worldwide annually and more than 400,000 women die each year
from the disease.



In Europe, breast cancer is recsponsible for 27.3% of all new cancer
cases among women and 20.22% of cancer deaths. The International Agency for
Research in Cancer estimates that in 2004 there were 360,749 new breast
cancer cases diagnosed while the number of deaths was 129,013.



According to the American Cancer Society, in general, breast cancer
rates have risen about 30% in the past 25 years in western countries. In
addition, the incidence is highest in western countries. This appears to be
due to increased screening which detects breast cancer in earlier stages.



About GEICAM



GEICAM (Grupo Espanol de Investigacion en Cancer de Mama) is a Spanish
non-profit scientific cooperative group fully devoted to breast cancer.
GEICAM is comprised of oncologists who belong to the Spanish Society of
Medical Oncology (SEOM) and of other health professionals related to breast
cancer research and treatment. The main GEICAM objectives are to promote
basic, epidemiological and clinical research, and to provide education to
doctors and patients and dissemination of information in the field of
breast cancer to the Spanish general population.



About Sanofi Aventis



Sanofi-aventis, a leading global pharmaceutical company, discovers,
develops and distributes therapeutic solutions to improve the lives of
everyone. Sanofi-aventis is listed in Paris (EURONEXT PARIS: SAN) and in
New York (NYSE: SNY).



Forward Looking Statements



This press release contains forward-looking statements as defined in
the Private Securities Litigation Reform Act of 1995, as amended.
Forward-looking statements are statements that are not historical facts.
These statements include financial projections and estimates and their
underlying assumptions, statements regarding plans, objectives, intentions
and expectations with respect to future events, operations, products and
services, and statements regarding future performance. Forward-looking
statements are generally identified by the words "expects," "anticipates,"
"believes," "intends," "estimates," "plans" and similar expressions.
Although sanofi-aventis' management believes that the expectations
reflected in such forward-looking statements are reasonable, investors are
cautioned that forward-looking information and statements are subject to
various risks and uncertainties, many of which are difficult to predict and
generally beyond the control of sanofi-aventis, that could cause actual
results and developments to differ materially from those expressed in, or
implied or projected by, the forward-looking information and statements.
These risks and uncertainties include those discussed or identified in the
public filings with the SEC and the AMF made by sanofi-aventis, including
those listed under "Risk Factors" and "Cautionary Statement Regarding
Forward-Looking Statements" in sanofi-aventis' annual report on Form 20-F
for the year ended December 31, 2007. Other than as required by applicable
law, sanofi-aventis does not undertake any obligation to update or revise
any forward-looking information or statements.


Sanofi Aventis

sanofi-aventis

Large Study Documents How P53 Mutations Link To High-Grade Breast Cancer, Poor Outcomes

In what is believed to be the largest study of its kind in the US, researchers have found that almost 26 percent of women studied who have breast cancer have mutations in a gene important in controlling cell growth and death, and that patients with mutations in this gene - known as p53 - had poorer outcomes including a significantly increased risk of death from the cancer.



Researchers say their study, presented at the Annual Meeting of the American Association for Cancer Research (AACR), confirm the findings of other smaller studies, and is an important step forward in understanding risk factors that lead to development of breast cancer.



For example, the investigators have found that postmenopausal women with high body weight were more likely to have a particular kind of p53 mutation, but they say this link needs to be studied further.



"The p53 gene is the guardian of the genome because it signals the cell to repair DNA damage when that occurs. If we can find genetic or environmental risk factors that lead to damage of p53 or stress on the gene, we may be able to help prevent development of breast cancer as well as other cancers," says the study's lead investigator, Catalin Marian, MD, PhD, a research instructor of cancer genetics and epidemiology at the Lombardi Comprehensive Cancer Center at Georgetown University Medical Center (GUMC).



The work was conducted by research groups led by Peter Shields, MD, professor of medicine and oncology at Lombardi, and Jo Freudenheim, PhD, chair of social and preventive medicine at the State University of New York at Buffalo.



Scientists from both institutions are evaluating data from a population-based case-control study of breast cancer in New York. The Western New York Exposure and Breast Cancer (WEB) Study included 1,170 women diagnosed with breast cancer between 1996 and 2001 as well as 2,116 women without cancer, and is an effort to link lifestyle and environmental exposures to gene changes and development of breast cancer. In this part of the study, GUMC researchers isolated DNA from 803 breast cancer tumor samples, and screened them for DNA mutations in the p53 gene. They found the p53 mutation frequency among the cases to be 25.6 percent, and 95 percent of those were point mutations - a change in a single base nucleotide with another nucleotide.



They determined that a p53 mutation was most commonly associated with ER-/PR- tumors in premenopausal women, but among postmenopausal women with breast cancer, the presence of a p53 mutation was most commonly associated with higher body mass index (BMI), and higher-grade, poorly differentiated tumors. Women with these tumors as well as p53 mutations had a 2.4-fold increased risk of dying from their disease, Marian says.



The researchers then dug a little deeper to see if tumor status was related to the type of point mutation found in the p53 gene. There are four nucleotides in the genome and they come in two complementary pairings пїЅ- A and G are purines and C and G are pyrimidines. A transition mutation occurs when one purine is replaced by the other purine or when pyrimidines are switched. A transversion mutation is replacement of a purine with a pyrimidine or vice versa and is considered to be "more dangerous, with a higher chance of negatively affecting the function of the p53 protein," Marian says.



While either transition or transversion mutations were found in premenopausal with hormone receptor-negative cancer, only transition mutations (A or G replaced by each other) were positively associated in postmenopausal women with hormone receptor-negative cancers that were higher-grade and had a poorer outcome. Transversion mutations (A or G replaced by C or G or vice versa) in postmenopausal women with breast cancer were associated with a higher BMI.



"The association between transversions and BMI is particularly interesting, because excess body weight is already known to be a risk factor for breast cancer," Marian says.



"We are laying the groundwork for future studies that look at gene-gene and gene-environmental interactions with p53," he says. "If we can document such effects, it may be possible to test patients for these factors in advance and tailor treatment appropriately."



Marian and his co-authors report no potential financial conflicts. This work was funded by the Department of Defense Breast Cancer Research Program and the National Institutes of Health.



Source:
Karen Mallet


Georgetown University Medical Center

Lack Of Care For Older Breast Cancer Patients

Older women with breast cancer get a lower level of care than younger women, researchers at The University of Manchester have found.


Compared to younger women, older women with breast cancer are less likely to be diagnosed via needle biopsy and triple assessment, less likely to undergo surgery and less likely to receive radiotherapy, the researchers report in this week's British Journal of Cancer.


Such management of older women is likely to lead to higher rates of local recurrence of the disease and higher than necessary mortality.


Dr Katrina Lavelle, who led the study at the University's School of Nursing, Midwifery and Social Work, explains: "We have found that older women from aged 70 and over are less likely to receive the same breast cancer care as younger women and that this is related to their age rather than differences in the biology of their tumour."


The highest incidence of breast cancer in England occurs in women aged 70 years and older. Older women also experience the worst survival women aged 70-79 have a 76% five-year relative survival compared to 80% for all ages, and for women aged 80 plus this drops considerably to 61%, beyond what might be expected owing to an increase in age.


The team carried out a retrospective cohort study involving case note review based on the North Western Cancer Registry database of women aged 65 and over, resident in Greater Manchester with invasive breast cancer registered over a one year period. The results of the study, funded by an NHS R&D Training Fellowship, may be generalized nationally as variation in survival between regions is lower for breast cancer compared to other cancers.


The they found that, compared to women aged 65-69 years, women aged 80 plus with operable breast cancer have increased odds of not receiving triple assessment, not receiving primary surgery, not undergoing axillary node surgery and not undergoing steroid receptor tests (which indicate suitability for hormone therapy). Compared with her 65-69-year-old counterpart, the odds of a woman aged 80 or older not receiving triple assessment for operable breast cancer are five-and-a-half times higher, and the odds of her not receiving surgery are more than 40 times higher. Even women as young as 70-74 have over 7 times the odds of not receiving radiotherapy following breast conservation surgery compared to women aged 65-69 years.


In addition, the team discovered that the overall percentage of women in all the age groups not receiving steroid receptor tests was high at 41%, which resulted in treatment decisions being taken without this fundamental information. Three quarters of the patients who did not receive steroid receptor tests were given the hormone therapy, tamoxifen: that is, prescribed a treatment without evidence that it would work.


In a survey of UK breast cancer surgeons in 2004, 75% reported that they would treat older breast cancer patients in a similar way to younger patients and 98% responded that the cut off point for breast cancer surgery was not age related.


Dr Lavelle says: "Clearly there is a difference in clinicians' perceptions of how older breast cancer patients should be treated and their actual practice.


"Standard management of breast cancer was infrequent in older women in Greater Manchester. The lack of diagnostic and steroid receptor testing resulted in older cancer patients having no effective treatment with 41% not undergoing a steroid receptor test, 32% of whom received tamoxifen as their sole form of treatment.


"Mortality of elderly breast cancer patients is unlikely to improve where this pattern of management persists."


Research lead for the School of Nursing, Midwifery and Social Work, Professor Chris Todd, commented: "It would be wrong to conclude that ageism is to be found in the NHS on the basis of these results alone, as this study has not been able to take the preferences of older women themselves into account. This is something we intend to investigate in the next phase of our research."


MANCHESTER UNIVERSITY

Oxford Road

Manchester

M13 9PL

manchester.ac.uk

Device Promising For Detecting Metastatic Breast Cancer Cells

Research by engineers and cancer biologists at Virginia Tech indicate that using specific silicon microdevices might provide a new way to screen breast cancer cells' ability to metastasize.
An image of their work provided to Biomaterials was selected as one of the 12 best biomaterials-related images published in the journal's 2010 catalogue.


The Virginia Tech researchers are: Masoud Agah, director of Virginia Tech's Microelectromechanical Systems Laboratory (MEMS) Laboratory in the Bradley Department of Electrical and Computer Engineering; Jeannine Strobl, a research professor in the Bradley Department of Electrical and Computer Engineering; Mehdi Nikkhah of mechanical engineering; and Raffaella DeVita of engineering science and mechanics and the director of the soft biological systems laboratory. Nikkhah was Virginia Tech's Outstanding Doctoral Student in the College of Engineering for 2009.


Their work appeared in two journal articles they authored in 2010 issues of Biomaterials, titled "Actions of the anti-cancer drug suberoylanilide hydroaxamic acid (SAHA) on human breast cancer cytoarchitecture in silicon microstructures," and "The cytoskeletal organization of breast carcinoma and fibroblast cells inside three dimensional isotropic microstructures."


Cell cytoskeleton refers to the cell's shape and its mechanical properties, Agah explained. "Any change in the cytoskeletal structure can affect the interaction of cells with their surrounding microenvironments. Biological events in normal cells such as embryonic development, tissue growth and repair, and immune responses, as well as cancer cell motility and invasiveness are dependent upon cytoskeletal reorganization," the electrical engineer added.


Understanding how the cell interacts with the contents of its surrounding environment inside the human body, including the introduction of a drug, is a fundamental biological question. The answers have implications in cancer diagnosis and therapy, as well as tissue engineering, Agah said.


In previous experimentation by others in the field, researchers have exposed cells to mechanical, chemical and three-dimensional topographical stimuli. They recorded the cells' various responses in terms of migration, growth, and ability to adhere. Also, in the past, researchers have created substrates of precise micro- and nano-topographical and chemical patterns to mimic in vivo microenvironments for biological and medical applications.


What distinguishes the work of Agah, a National Science Foundation (NSF) CAREER Award recipient, and his colleagues, is they developed a specific three-dimensional silicon microstructure for their work. Due to its curved isotropic surfaces, they were able to characterize and compare the growth and adhesion behavior of normal fibroblast and metastatic human beast cancer cells, they reported in Biomaterials.















"In invasive breast carcinoma, tumor cells will fill a milk duct, and the basement membrane," they wrote. This action allows the carcinoma cells and the fibroblast cells of the breast tissue to be in close proximity, constituting "a critical pathobiological transition that leads to the progression of the disease," Strobl said.


Using their uniquely designed three-dimensional silicon microstructure, they were able to incorporate three key cellular components found in any breast tumor microenvironment. Additionally, they were able to determine the detailed interaction of the cells within this environment, including the normal breast cells, the metastatic breast cancer cells, and the fibroblast cells.


Their understanding of the behavior of the cells within the microstructures is what leads them to believe their research could "provide important diagnostic and prognostic markers unique to the tumor, which could ultimately be used to develop new tools for the detection and treatment of cancer."


Following their initial findings, Strobl, Nikkhah and Agah identified a unique application of the experimental anti-cancer drug SAHA in their studies with the silicon microstructure. SAHA, also known as Vorinostat, is the first drug of its type to receive Food and Drug Administration approval for clinical use in cancer treatment.


Unlike many of the conventional cytotoxic chemotherapy agents that target DNA to kill cancer cells, SAHA's unique properties include its ability to inhibit a family of enzymes referred to medically as "histone deacetylases." These enzymes are known to "increase levels of acetylation of many proteins, including beta-actin, alpha-, and beta-tubulin, and additional actin binding proteins comprising the cytoskeleton.


"The role of drugs such as SAHA in the control of cancer cell metastasis is only beginning to be understood," explained Strobl, "however our work shows that SAHA elicits a very characteristic cytoskeletal alteration specifically in metastatic breast cells that provides a handle for predicting which breast cells in a cell mixture might have the ability to metastasize."


Cell motility is "one hallmark of metastatic cancer cells involving the coordinated actions of actin and other cytoskeleton proteins," Agah explained. When metastatic disease develops, it is usually fatal.


They found SAHA caused cancer cells to stretch and attach to the microstructures through actin-rich cell extensions. By contrast, control cells conformed to the microstructures. This result allowed them to "conclude that isotropically etched silicon microstructures comprise microenvironments that discriminate metastatic mammary cancer cells in which cytoskeletal elements reorganized in response to the anti-cancer agent SAHA."


The Virginia Tech work in this area "is the first to address the use of microdevices to study this emerging class of anti-cancer agents," Agah said.


Source:

Virginia Tech (Virginia Polytechnic Institute and State University)