MedicalResearch.com Interview with:
Dr. Pentao Liu PhD and Dr. Walid Khaled PhD
Wellcome Trust Sanger InstituteCambridgeshire United Kingdom
Medical Research: What is the background for this study? What are the main findings?
Dr. Pentao Liu: The significance of this research is that it aims to tackle the worst type of breast cancer. Triple Negative Breast Cancer (TNBC) has the poorest patient survival rate compared to other forms of breast cancer. At present there are no targeted therapies available for TNBC, leaving the non-specific chemotherapy as the only treatment option. In this study we identify a new key gene in Triple Negative Breast Cancer which could potentially be inhibited for the targeted treatment of TNBC.
In this study we report the identification of a novel gene for Triple Negative Breast Cancer. By analyzing genomics data from 3,000 patients we find BCL11A to be highly expressed in TNBC. We then demonstrate experimentally that upregulation of BCL11A drives tumour development while its downregulation leads to reduction in tumour size. In the experimental mouse model, inactivation of this gene completely abolishes breast tumour development.
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MedicalResearch.com Interview with: Hazel B. Nichols, PhD
Assistant Professor, Department of Epidemiology
University of North Carolina
Gillings School of Global Public Health
MedicalResearch:What is the background for this study?Dr. Nichols: Tamoxifen, a drug that is often used to treat breast cancer, has also been approved to prevent breast cancer in women who may be at high risk for developing the disease. Taking tamoxifen for 5 years can lower breast cancer risk by up to 48%. The United States Federal Drug Administration (FDA) approved tamoxifen for breast cancer prevention more than 15 years ago (in 1998) for women ages 35 and older who are at high risk of breast cancer and who are at low risk for serious side effects.
National estimates show that <1% of women who are eligible to use tamoxifen actually use it for breast cancer prevention. While tamoxifen lowers breast cancer risk it does cause hot flashes and may lead to serious side effects such as cataract, stroke, and uterine cancer. Women who start taking may also stop taking it before the recommended 5-years due to side effects.
We used a tool developed by scientists at the National Cancer Institute (NCI) to calculate whether the benefits of tamoxifen outweighed the risks for women in the Sister Study, a study of more than 50,000 U.S. and Puerto Rican women with a family history of breast cancer. The tool uses information on a woman’s age, race, breast cancer risk, menopausal status, and whether she had a hysterectomy (surgical removal of the uterus) to estimate whether there is no, moderate or strong evidence that the benefits of tamoxifen will outweigh the risks.
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MedicalResearch.com Interview with:
Dr. Chao Cheng PhD
Department of Genetics
Geisel School of Medicine at Dartmouth
Hanover 03755, NH
MedicalResearch: What is the background for this study? What are the main findings?Dr. Chao Cheng: Cancer survival prognosis—“How long do I have, Dr.?” is a topic of great importance to cancer patients and their families. While clinical and pathological variables, such as cancer type, stage, grade, and patient demographics, have long been used to predict survival outcomes, only recently have molecular signatures become incorporated into survival prediction. A molecular approach holds great promise for improving prediction accuracy and additionally elucidating mechanisms of disease, however it is fraught with difficulty due to assay “noise” and “big data” statistical issues, such as the multiple comparisons problem
In this study, we began by analyzing transcription factor binding profiles across available cell lines. By restricting our analysis to transcription factors, DNA expression regulators known to be involved in tumor genesis, we reasoned that we could avoid many of the “big data” issues and achieve results that would make mechanistic and biological sense. We first employed a statistical method we described previously to calculate which genes were the major downstream targets of our transcription factors. With these targets identified, we then analyzed gene expression data using a bioinformatics method to infer the relative activity of each transcription factor based upon the overall expression levels of their gene targets. From here, we incorporated cancer survival data and examined how each transcription factor’s regulatory activity did, or did not, correlate with survival.
The most prognostic transcription factor was E2F4, a member of the E2F family and a known regulator of the cell cycle. We therefore restricted our analysis to E2F4 and examined how its activity level impacted survival in breast cancer patients.
We found that tumors with high E2F4 regulatory activity as compared to low E2F4 regulatory activity had much worse survival outcomes. These results were stable even after controlling for tumor stage, grade, patient age, and treatment, and were based on data from over 1900 patients across eight independent datasets. These results demonstrate that E2F4 is an independent and enhancing predictor of survival above the currently examined variables.
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MedicalResearch.com Interview with:
Pamela Vacek, PhD
Research Assistant Professor
Department of Pathology
Medical Biostatistics Unit, College of Medicine
University of Vermont, Burlingon, Vermont
Medical Research: What is the background for this study? What are the main findings?
Dr. Vacek: Clinical trials to evaluate the effectiveness of screening mammography have focused primarily on women under age 70 and, consequently, its benefit for older women is uncertain. However, many believe that the benefit of screening mammography diminishes as women age and acquire other health problems, because they are less likely to live long enough for any detected breast cancer to have a clinical impact. To gain insight into this, we followed approximately 20,000 women aged 70 and older for an average of 10 years to examine their mammography use, cancer detection and survival.
We found that screening mammography use declined steadily (9% per year) after age 70, but this was not accompanied by decline in the incidence of invasive breast cancer. Hence, as the women aged breast cancer was more likely to be detected clinically than by screening. The clinically detected tumors were significantly larger and of more advance stage and were associated with poorer overall survival, for all but the oldest and most infirm women. We also found that the use of breast conserving surgery as the only treatment for early stage cancer increased markedly with age and was associated with shorter survival compared to women receiving radiation or mastectomy.
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MedicalResearch.com Interview with:
Dr. Lynn C. Hartmann MD
Professor of Oncology, Mayo Clinic
Associate Director for Education of the Mayo Clinic Cancer Center.
Medical Research: What is the background for this study? What are the main findings?
Dr. Hartmann: Women with atypical hyperplasia of the breast – which is defined via breast biopsy that was done to evaluate findings on a mammogram or a palpable concern – have been considered a “high risk” group of women, but the extent of their risk has not been clearly defined. As a consequence, practice guidelines for high-risk women (eg for screening MRI) do not include them. Mayo Clinic has developed a cohort of women with atypical hyperplasia who have been followed long-term for later breast cancers and we show that their risk of developing breast cancer is about 30% at 25 years of follow-up. This same level of risk was confirmed in the other large cohort of women with atypical hyperplasia, based at Vanderbilt University (Nashville Breast Cohort). This level of risk meets the current criterion for screening MRI and should also encourage the use of anti-estrogen drugs, such as tamoxifen, which have already been shown to be efficacious in this population of women. (more…)
MedicalResearch.com Interview with:
William M. Sikov, MD
Associate Chief of Clinical Research Program in Women's Oncology
Women & Infants Rhode Island
Associate professor of Medicine
The Warren Alpert Medical School of Brown University
Medical Research: What is the background for this study? What are the main findings?Dr. Sikov: The data presented at San Antonio this year are the first results from correlative studies performed on pretreatment tissue samples from patients treated on CALGB 40603, a 2 x 2 factorial randomized phase II study which tested the addition of carboplatin or bevacizumab to a standard neoadjuvant chemotherapy regimen consisting of weekly paclitaxel followed by dose-dense AC in patients with stage II-III triple breast cancer. Last year at San Antonio (and subsequently published in the JCO) we presented the primary endpoint of the study - pathologic complete response (pCR) - and reported that the addition of either carboplatin or bevacizumab significantly increased pCR rates compared to the control regimen. This year we reported results of a preplanned analysis which assessed the impact of intrinsic subtype (based on mRNA expression analysis) - especially the basal-like subtype - on the impact of the two agents on pCR rates. We also reported the effects of a number of previously published mRNA expression signatures on pCR rates and the benefits of adding carboplatin or bevacizumab.
The findings reported were as follows: We had a higher percentage of basal-like cancers than we anticipated when the study was designed (87% vs. 70-80% expected), which we hypothesize is due to improvements in the ways we assess hormone receptor and HER2 status, and thus define triple-negative breast cancer, compared to 10-15 years ago. When we limit our analysis to the subset of patients with basal-like cancers, we continue to see a statistically significant increases in pCR rates with both carboplatin and bevacizumab. However, while the 13% of patients with non-basal-like cancers get essentially the same increase in pCR rates with carboplatin as do the basal-likes, non-basal-likes actually had a reduction in their pCR rates with the addition of bevacizumab - thus, there was a significant interaction between subtype and pCR benefit for bevacizumab but not for carboplatin. Among the mRNA signatures we assessed, higher expression of immune signatures (indicating more tumor-infiltrating lymphocytes) correlated with higher pCR rates, but not greater pCR increments with either carboplatin or bevacizumab. Higher proliferation, lower estrogen, and higher TP53 mutation signaturss also correlated with higher pCR rates overall, and also with greater pCR increments with bevacizumab, but not carboplatin.
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MedicalResearch.com Interview with:
Dr. Judy Karp, Dr. Antonio Wolff and Dr. Kala VisvanathanBreast Cancer Program
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center
Baltimore, MD 21287
Medical Research: What is the background for this study? What are the main findings?
Response: The background for this study was the clinical observation from the Johns Hopkins Leukemia Program that a significant number of women with newly diagnosed acute myeloid leukemia had a personal history for breast and/or ovarian cancers. This observation led to our examination of the large NCCN breast cancer database in a multidisciplinary and multi-institutional study. The overarching finding in our study is that the risk of developing some form of leukemia following chemotherapy with or without radiation therapy, while small, continues to increase over at least 10 years without a plateau and is roughly twice what we thought it to be from previous breast cancer studies.
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MedicalResearch.com Interview with:
Dr Ranjit Manchanda
Consultant Gynaecological Oncologist, St Bartholomew’s Hospital, London, UK
Honorary Sr Lecturer, Women’s Cancer, EGA Institute for Women's Health, University College London, UK and
Professor Ian Jacobs
Vice President, The University of Manchester
Dean & Head School of Medicine
Faculty of Medical & Human Sciences, Director
MAHSC (Manchester Academic Health Science Centre)
Medical Research: What is the background for this study? What are the main findings?
Dr. Jacobs: Background- Women carrying a BRCA1/2 gene alteration have a very high risk of developing breast and ovarian cancer and men carrying this alteration have an increased risk of prostate and breast cancer. Approximately 45-65% women who have this inherited genetic change will develop breast cancer and 15-35% ovarian cancer. They also have a 50% chance of passing these genes on to their children. At risk individuals can access available options of screening and prevention through the National Health Service (NHS). Some population groups across the world are known to have a higher frequency of BRCA 1/2 gene alterations than others. One example is Ashkenazi Jews who have a 1 in 40 likelihood of having a BRCA1/2 gene alteration. This is 10-20 times higher than in the general non-Jewish population.
At present in the UK, genetic testing is available within the NHS to individuals who have a strong family history of cancer. However, many people are not aware of their family history or its significance and do not seek advice. Many other individuals with BRCA1/2 gene alterations do not have a family history at all. The current approach misses a large number of people at risk who could benefit from knowing about their BRCA 1/2 mutation status and the ability to access opportunities for prevention or screening. In order to address this the GCaPPS study has investigated the best method of screening for risk of inherited (familial) cancer by exploring the alternative approach of offering the genetic test to all men and women >18 years in the Ashkenazi Jewish population. It does so by comparing the benefits and disadvantages of: (i) The current system of testing only those with a family history and (ii) The new option of testing everyone in the population.
Main Findings: Over half of the BRCA1/BRCA2 carriers detected did not give a strong family history of cancer and would not have been identified by current family history based testing criteria used in the NHS (National Health Service) in the UK and most health systems internationally. Reassuringly population-based genetic testing in Ashkenazi Jews did not adversely affect short term psychological health or quality-of-life. A health economic analysis indicated that population-based screening for BRCA-mutations in Ashkenazi Jewish women ≥30years would be highly cost-effective compared to the traditional family history based approach. Such an approach if implemented could reduce the incidence of and deaths from breast and ovarian cancer as well as reducing cost and save the NHS funds.
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MedicalResearch.com Interview with:
Thomas Rogers
PhD Candidate- Cancer Biology Graduate Program
Laboratory of Jennifer Richer
Department of Pathology
University of Colorado-Anschutz Medical Campus
Laboratory of CU Cancer Center investigator, Jennifer Richer, PhD.
Medical Research: What is the background for this study? What are the main findings?Response:
Background: Survival while detached from a basement membrane is a critical trait of cancer cells progressing through the metastatic cascade. This is particularly important for the triple-negative breast cancer (TNBC) subtype, which lacks estrogen and progesterone receptors and does not have amplification of HER2, and has a peak risk of recurrence within the first three years post-diagnosis. Triple-negative breast cancer also has the highest mortality rate in the first five years as compared to other breast cancer subtypes. We performed global profiling of TNBC cells in adherent versus forced suspension culture conditions after24 hours. These data revealed that triple-negative breast cancer cells surviving in suspension upregulate multiple genes involved in tryptophan catabolism, also known as the kynurenine pathway, including the rate limiting enzyme tryptophan 2,3,-dioxygenase (TDO2) and kynureninase (KYNU). Kynurenine, a key intermediate metabolite of this pathway activates the aryl hydrocarbon receptor (AhR), which was also up-regulated in TNBC cells grown in forced-suspension culture.
Main Findings: Critical enzymes of the kynurenine pathway, TDO2 and KYNU, are upregulated in triple-negative breast cancer cells grown in forced-suspension culture. Furthermore, secreted kynurenine doubles in TNBC cells in forced-suspension culture as measured by high performance liquid chromatography (HPLC). Kynurenine activates the aryl hydrocarbon receptor in triple-negative breast cancer cells grown in forced-suspension culture. Targeting TDO2 and AhR with small molecule inhibitors or short hairpin RNAs decreased survival in suspension, migration/invasion, and proliferation of TNBC cells. Lastly, TDO2 gene expression is higher in invasive ductal breast carcinoma as compared to normal breast tissue and is significantly higher in estrogen receptor negative tumors as compared to estrogen receptor positive tumors. In addition, patients with higher (above-median) TDO2 expression in their primary tumor had significantly shorter overall survival than those with low TDO2.
Conclusions: The kynurenine pathway is activated in TNBC cells in forced suspension and facilitates the invasive/metastatic phenotype of this aggressive breast cancer subtype. Our findings support further investigations into targeting the enzyme TDO2 in TNBC as a novel therapeutic strategy with potential to reduce TNBC mortality rates. Kynurenine is well-known to suppress immune cell function via activation of AhR. (more…)
MedicalResearch.com Interview with: Dr. Ryan Hartmaier PhD
Postdoctoral Associate
Magee-Womens Research Institute (MWRI)
and the University of Pittsburgh Cancer Institute
Medical Research: What is the background for this study? What are the main findings?Response: The inhibition of signaling through the estrogen receptor is a major target in breast cancer therapy. However, within recurrent disease others have recently identified point mutations within the estrogen receptor as a mechanism of resistance to this therapy.
We undertook a comprehensive study of breast cancer progression by applying many next-generation sequencing technologies to a collection of paired primary-metastasis tissue samples from 6 patients. We placed special emphasis on the identification of structural variants (i.e. translocations, duplications, inversions, and deletions) acquired in metastatic breast cancer. In one patient with recurrent disease while on endocrine therapy, we identified a fusion gene between ESR1 (estrogen receptor alpha) and DAB2 (disabled-2). In vitro functional studies indicate that this fusion is constitutively active and hormone independent.
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MedicalResearch.com Interview with:
Fiona Larner, PhD Postdoctoral Research Associate
Department of Earth Sciences, University of Oxford, South Parks Road, Oxford, UK
Department of Earth Science & Engineering, Imperial College London, Exhibition Road, South Kensington, London, UK
Medical Research: What is the background for this study? What are the main findings?
Response: Zinc has been identified to have a role in breast tissue and breast cancer for over a decade. Zinc has several isotopes (different versions of zinc due to varying numbers of neutrons), which require slightly different amounts of energy to go through biological processes. By measuring the changes in the zinc isotopic signature, we can probe it's behaviour to a greater resolution to that currently available in medical institutions. We looked at the isotopic signatures in different tissues of healthy patients and those with breast cancer in order to understand the mechanisms involved in more detail and in search for a biomarker that uses these signatures to diagnose breast cancer.
We found that preferentially retains the lighter isotopes of zinc to a greater extent than healthy breast tissue. This means that the partnering heavy isotopes must be ejected from the cell, and may provide a biomarker for cancer in the future.
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MedicalResearch.com Interview with:
Prudence A. Francis, M.D
Associate Professor, Peter MacCallum Cancer Centre
Melbourne, Australia
Medical Research: What is the background for this study? What are the main findings?Response: The background for this study was the observation that premenopausal women diagnosed with hormone receptor positive breast cancer under age 35, had an increased risk of recurrence, as compared with older premenopausal women. We postulated that this might be because this age group was less likely to enter menopause after receiving chemotherapy, and so their ovaries were continuing to produce estrogen, which might have the effect of stimulating any remaining cancer cells.
The main findings were that while not all premenopausal women benefit from the addition of treatment with ovarian function suppression to , the women who underwent chemotherapy and remained premenopausal (median age 40) did have improved breast cancer outcomes. This same group of women had even further improvement in recurrence rates if the ovarian suppression was combined with an aromatase inhibitor exemestane, as compared with tamoxifen. The effects of including ovarian suppression were particularly striking in women under 35 years of age. Those premenopausal women who did not receive chemotherapy (median age 46) after discussion with their doctor, did well with tamoxifen alone and do not appear to benefit from ovarian suppression currently.
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MedicalResearch.com Interview with:
Dr. Matthew P. Goetz, MD
Associate Professor of Pncology
Mayo ClinicMedical Research: What is the background for this study? What are the main findings?
Dr. Goetz: There has been conflicting data with regard to the importance of metabolism as measured by CYP2D6 genetic variation. Two large “negative” studies were reported simultaneously in 2012 and these were referenced by guidelines that CYP2D6 should not be used to select hormonal therapy. Our findings demonstrated that these studies were flawed in part based on analytical validity issues. In short, the use of tumor tissue to derive CYP2D6 germline genotype leads to genotyping error in up to 45% of samples.
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MedicalResearch.com Interview with:
Dr. James Yu
Yale School of Medicine
Cancer Outcomes, Public Policy, and Effectiveness Research Center
Yale School of Medicine
Department of Therapeutic Radiology
New Haven, ConnecticutMedical Research: What is the background for this study? What are the main findings?Response: Hypo fractionated radiation has been shown to be safe and effective, and more convenient for women with early stage breast cancer after lumpectomy. It also has been identified by ASTRO as a practice that physicians can adopt to reduce healthcare expenses for patients and for society. We looked at the National Cancer Database, a database created by the American College of Surgeons for trends in the use of hypo fractionated radiation for breast cancer through 2011. We found that the use of hypofractionated radiation had increased to 22.8% in 2011. I found this remarkable as it predated the ASTRO choosing widely guidelines, and indicated to me that physicians were already thinking of ways of making treatment more convenient and affordable for patients and insurers.
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MedicalResearch.com Interview with:
Rachel Blitzblau, M.D., Ph.D.
Butler Harris Assistant Professor
Department of Radiation Oncology
Duke University Medical Center
Durham, NC 27710
Medical Research: What is the background for this study? What are the main findings?
Dr. Blitzblau: Radiation reduces the risk of loco-regional recurrence. Data from the CALGB 9343 study suggests that the local benefit from adjuvant radiation is less in older women with small, . The potential acute and late toxicities of radiotherapy, patient inconvenience and healthcare costs must be considered given the small clinical benefit associated with adjuvant radiotherapy in this patient group. We looked at rates of radiotherapy in women fitting the entry criteria of this trial before and after publication of 5 year results of the CALGB trial. We found an approximately 5% decrease in use of radiotherapy overall, and noted that there seemed to be a small but significant shift in the type of radiotherapy used for these patients. Less patients received standard whole breast radiotherapy, and more received a short course of treatment to just the tumor bed plus margin called accelerated partial breast irradiation. We concluded that the publication of the trial therefore had only a very small impact on practice patterns.
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MedicalResearch.com Interview with:
Tina J Hieken, MD
Department of Surgery Associate Professor of Surgery
Mayo Clinic College of MedicineRochester, MN 55905
MedicalResearch.com: What is the background for this study?Dr. Hieken: Many newly diagnosed breast cancer patients undergo breast MRI; Breast MRI includes a component of axillary imaging. However, there is limited data on MRI staging of axilla.
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MedicalResearch.com Interview with: Brian L. Sprague, PhDOffice of Health Promotion Research,
University of Vermont, Burlington, VT
MedicalResearch: What is the background for this study? Dr. Sprague: Mammographic breast density refers to the appearance of breast tissue on a mammogram. High breast density means that there is a greater amount of glandular tissue and connective tissue, which appears white on a mammogram. It is more difficult to detect breast cancer on a mammogram when there is greater breast density. It has also been shown that women with dense breasts are at a higher risk of developing breast cancer. Because of these two factors, women with dense breasts have a greater chance of developing breast cancer after a normal screening mammogram than women whose breasts are not dense. Many states have now passed laws that require mammography facilities to inform women with dense breasts so that they are aware of this. Similar legislation is now under consideration at the national level. More than 40% of women undergoing mammography screening have dense breasts.
Researchers are trying to determine whether supplemental breast cancer screening with other tools would improve outcomes for women with dense breasts. One possible approach is to use ultrasound imaging to screen for breast cancer in women with dense breasts after they have had a normal mammogram. We wanted to estimate the benefits, harms, and cost-effectiveness of this approach compared to mammography screening only. No randomized trials or observational studies have assessed long term outcomes after ultrasound screening for women with dense breasts, but we have short term data on how often cancer is diagnosed by ultrasound screening and how often false positive exams occur. We used computer simulation modeling to estimate long term outcomes by combining the currently available data on mammography and ultrasound screening with the best available data on breast cancer risk and survival.
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MedicalResearch.com Interview with:
Elissa R. Price, MD
Assistant Professor of Clinical Radiology
Director of Clinical Operations, Breast Imaging
Breast Imaging Fellowship Program Director
Department of Radiology and Biomedical Imaging
University of California, San Francisco San Francisco, CA 94115
MedicalResearch: What is the background for this study? What are the main findings?Dr. Price: Screening mammography recommendations for the 40 - 49 age group is very controversial. 2009 USPTF guidelines emphasized taking patient context into account when making decisions for these young women. Recent publications have suggested risk-based screening strategies. Family history and breast density are important are easily accessible risk factors.
Had we been using this risk-based approach to screening mammography at our institution, we would have missed more than 3Ž4 of the screen detected breast cancers in the 40-49 age group, thereby foregoing most of the survival benefit from screening mammography.
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MedicalResearch.com Interview with:
Ben Ho Park, M.D., Ph.D.
Associate Professor of Oncology, Breast Cancer Program
Associate Director, Hematology/Oncology Fellowship Training Program The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, MD 21287
Medical Research: What is the background for this study? What are the main findings?
Dr. Park: To discover genetic mediators of tamoxifen resistance in breast cancers, we used genetic screening of breast cancer cell line models and patient data to identify a new gene that can mediate drug resistance. We found that amplification and overexpression of this gene in estrogen receptor positive breast cancers results in resistance and is associated with worse outcomes in patients whose tumors demonstrate amplification/overexpression of this gene.
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MedicalResearch.com Interview with
Dr. Jonathan Myles
Centre for Cancer Prevention, Queen Mary, University of London
Wolfson Institute of Preventive Medicine, Charterhouse Square, London
Medical Research: What is the background for this study? What are the main findings?Dr. Myles: Breast cancer screening uptake is low in areas of high social deprivation and large populations of some ethnic groups. The main finding of this study is that an intervention in the form of contacting women by telephone a few days before the date of their screen, reminding them of their appointment and answering any queries they may have, significantly increases uptake.
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MedicalResearch.com Interview with:
Dr. Kristy Lynn Kummerow MD
Division of Surgical Oncology and Endocrine Surgery
Vanderbilt University Medical Center
Tennessee Valley Healthcare System, Veterans Affairs Medical Center
Geriatric Research, Education, and Clinical Center
Nashville, Tenn
Medical Research: What is the background for this study? What are the main findings?Dr. Kummerow: This study looked at how we are currently treating early stage breast cancer in the US – early stage breast cancer includes small cancers with limited or no lymph node involvement and no spread to other body site – it was prompted by something we observed an our own cancer center, which is that more and more women seem to be undergoing more extensive operations than are necessary to treat their cancer. It is helpful to understand the historical context of how we treat early breast cancer. Prior to the 1980s, the standard of care for any breast cancer was a very extensive procedure, which involved removal of the entire breast, as well as underlying and overlying tissues and multiple levels of lymph nodes drained by that area. Informative clinical trials were completed in the 1980s demonstrated that these extensive procedures were unnecessary, and that equivalent survival could be achieved with a much more minimal operation, by removing only the tumor, with a margin of normal breast tissue around it, and performing radiation therapy to the area; this technique is now known as breast conservation surgery, also known as lumpectomy with radiation. In the 1990s, breast conservation was established by the national institutes of health and was embraced as a standard of care for early stage breast cancer; performance of breast conservation surgery also became a quality metric – accredited breast centers in the US are expected to perform breast conservation surgery in the majority of women who they treat for breast cancer. However, what our research team observed at our institution didn’t fit – over time it appears more aggressive surgical approaches are being used for more women. This has been found in other institutions as well, and is supported by smaller national studies. We wanted to understand how surgical management of early breast cancer is changing over time at a national level using the largest data set of cancer patients in the United States.
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MedicalResearch.com: Interview Invitation
Dr. Wenji Guo
University of Oxford
Medical Research: What is the background for this study?Response: Previous studies report increased risk for breast cancer in postmenopausal women who have a higher Body Mass Index (BMI) – a measure of body fat based on height and weight. However, BMI is unable to distinguish between excess weight due to fat rather than muscle. More direct measures of fatness, such as body fat percentage, may be better indicators of disease risk. And although probable evidence for the relationship between physical activity and breast cancer now exists, questions still remain over the role of vigorous compared to lower intensity physical activity.
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MedicalResearch.com Interview with:
Ruth Keri, PhD, Professor and Vice Chair Department of Pharmacology
Case Western Reserve University School of Medicine, and Associate Director for Basic Research in the Case Comprehensive Cancer Center Case Western Reserve University
Medical Research: What is the background for this study? Dr. Keri: Over the last several decades, the discovery of targeted therapies for certain types of breast cancer, and their use in the clinic, have greatly improved the long-term outcome of patients. Yet some breast cancers don’t respond to these therapies, and ones that do often become resistant over time, resulting in patient relapse and metastatic disease. Why does resistance occur? There are many tricks a tumor employs to evade death. When a drug targets a certain protein or pathway the cancer cell relies on for survival, one potential route of resistance is the cancer cell’s ability to adapt and find another pathway to maintain growth. We reasoned that targeting two separate proteins or pathways important for cancer cell growth may be more effective at preventing or delaying this adaptation.
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MedicalResearch.com Interview with:
Antoine E. Karnoub, Ph.D.
Assistant Professor of Pathology
Beth Israel Deaconess Medical Center
Harvard Medical School Center for Life Science 0634
Boston, MA 02215
Medical Research: What are the main findings of the study?Dr. Karnoub:The main findings of the study are:
(1) that the metastatic propensities of cancer cells can be remarkably modulated by otherwise ‘normal’ mesenchymal stem/stromal cells found in their vicinity;
(2) that generation of highly malignant tumor-initiating cells can be significantly triggered by microenvironmental cues;
(3) that repression of the gene FOXP2 by a miR-199a-led microRNA network enables the propagation of cancer stem cell and metastatic traits in otherwise weakly metastatic cancer cells; and
(4) that such a signaling axis appears to forecast poor patient outcome.
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MedicalResearch Interview with:
Melissa Skala, Ph.D.
Assistant Professor of Biomedical Engineering
Assistant Professor of Cancer Biology
Vanderbilt University Nashville, TN 37235
Medical Research: What is the background for this study? What are the main findings?
Dr. Skala: We developed a new metabolic imaging technique that is highly sensitive to tumor cell response to anti-cancer drug treatment. We coupled this imaging technique with new, three-dimensional cultures that can be grown from breast tumor biopsies. Together, our data indicate that this approach could be used to perform rapid, low-cost, and accurate drug screens for individualized treatment of cancer patients.
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MedicalResearch.com Interview with:
Shidong Jiang
Associate professor of Engineering
Thayer School of Engineering at DartmouthMedical Research: What is the background for this study? What are the main findings?
Dr. Jiang: Breast cancer is the most common non-skin cancer in women worldwide, and the second leading cause of women’s cancer mortality in the United States. A common treatment strategy after diagnosis is to shrink breast cancer tumors larger than 3 centimeters with a 6 to 8 month course of Neoadjuvant Chemotherapy prior to surgery. Clinical studies have shown that patients who respond to Neoadjuvant Chemotherapy have longer disease-free survival rates, but only 20 to 30 percent of patients who receive Neoadjuvant Chemotherapy fit this profile.
Our work represents the first clinical evidence that tumor total hemoglobin estimated from DOST images differentiates women with locally advanced breast cancer who have a complete pathological response with Neoadjuvant Chemotherapy from those who do not with predictive significance based on image data acquired before the initiation of therapy. The implication of this prognostic information is that certain tumors are pre-disposed to responding to Neoadjuvant Chemotherapy, and that this predisposition should be known prior to choosing the therapy. The study also demonstrates the potential of dramatically accelerating the validation of optimal Neoadjuvant Chemotherapy regimes through future randomized clinical trials by reducing the number of patients required and the length of time they need to be followed by using a validated imaging surrogate as an outcome measure. (more…)
MedicalResearch.com Interview with:Edith A. Perez, MD
Mayo Clinic
Jacksonville, FL 32224
Medical Research: What are the main findings of the study?Dr. Perez: Our joint analysis of two large prospective trials showed that adding one year of Trastuzumab to otherwise standard adjuvant chemotherapy significantly improved long term survival in women with resected HER2+ breast cancer.
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MedicalResearch.com Interview with:
Professor Xiaodong Zhang
Professor of Macromolecular Structure and FunctionDepartment of Medicine
Imperial College, London, UK
Medical Research: What are the main findings of the study?Prof. Zhang: Since its discovery 20 years ago, the BRCA2 gene and its protein product, BRCA2, have been under intensive investigations. The importance of the BRCA2 protein lies in the central roles it plays in the most faithful DNA damage repair pathway. Mutations in BRCA2 thus can cause defects in this repair pathway, making the repair inefficient or forcing cells to use alternative repair methods that are prone to mistakes, all of which contribute to mutations in the genomic DNA, thus increase the risk of cancer development. Our study aims to understand how BRCA2 works through studying its 3-dimensional structures and its interactions with other key partners in the repair pathway.
Our study provides first 3-dimensional views of BRCA2 and BRCA2-RAD51 and reveals that BRCA2 molecules exist as pairs and a BRCA2 pair recruit two sets of RAD51 molecules arranged in opposite orientations. Our study also shows a single stranded DNA binds across the BRCA2 dimer and that BRCA2 increases the frequency of RAD51 filament formation events, presumably to increase the efficiency of establishing a longer filament required for searching for matching strands of DNA in intact sister chromatin. Our results thus not only define the precise roles of BRCA2 in helping RAD51 filament formation, but how it helps RAD51 loading onto single stranded DNA.
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MedicalResearch.com Interview with: Gary Ulaner, MD, PhD
Assistant Attending Radiologist
Memorial Sloan Kettering Cancer Center
Assistant Professor of Radiology, Weill Cornell Medical School
Chair, Radiology Research Committee
Medical Research: What are the main findings of the study?Dr. Ulaner: FDG PET/CT revealed distant metastases in 17% of asymptomatic stage IIB breast cancer patients below 40 years of age. Although NCCN guidelines recommend against systemic staging in patients with stage II disease, our data suggests that PET/CT might be valuable in younger patients at earlier stages of disease than previously expected.
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MedicalResearch.com Interview with:Professor Usha Menon, Evangelia-Ourania FourkalaPhD
and Matthew Burrell PhD
Gynaecological Cancer Research Centre, Women's Cancer, UCL EGA
Institute for Women's Health, University College London, UK
Medical Research: What are the main findings of the study?Response: Our study has shown that skirt size is a good proxy for central obesity. Each unit increase in UK skirt size every ten years between the age of 20 and 60 was associated with a 33% increase in postmenopausal breast cancer in our cohort.
(more…)
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