Category Archives: Breast Cancer

Marijuana component could ease pain from chemotherapy drugs

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A chemical component of the marijuana plant could prevent the onset of pain associated with drugs used in chemo therapy, particularly in breast cancer patients, according to researchers at Temple University’s School of Pharmacy.

The researchers published their findings, “Cannabidiol Prevents the Development of Cold and Mechanical Allodynia in Paclitaxel-Treated Female C57Bl6 Mice,” in the journal Anesthesia and Analgesia.

The researchers developed animal models and tested the ability of the compound cannabidiol, which is the second most abundant chemical found in the marijuana plant, to relieve chemo-induced neuropathic pain, said Sara Jane Ward, research assistant professor of pharmaceutical sciences in Temple’s School of Pharmacy and the study’s lead author.

“We found that cannabidiol completely prevented the onset of the neuropathic, or nerve pain caused by the chemo drug Paclitaxel, which is used to treat breast cancer,” said Ward, who is also a research associate professor in Temple’s Center for Substance Abuse Research.

Ward said that one of cannabidiol’s major benefits is that, unlike other chemicals found in marijuana such as THC, it does not produce psycho-active effects such as euphoria, increased appetite or cognitive deficits. “Cannabidiol has the therapeutic qualities of marijuana but not the side effects,” she said.

Ward’s research has long focused on systems in the brain that are impacted by marijuana and whether those systems could be targeted in the treatment of various disorders. “Marijuana binds to the cannabinoid receptors in the body and researchers have long been interested in whether there is therapeutic potential for targeting this receptor system,” she said.

Ward became interested in this current study after attending a conference in which she learned about a pain state that is induced by chemo-therapeutic agents, especially those used to treat breast cancer, which can produce really debilitating neuropathic pain.

Cannabidiol has also demonstrated the ability to decrease tumor activity in animal models, said Ward, which could make it an effective therapeutic for breast cancer, especially if you “combined it with a chemo agent like Paclitaxel, which we already know works well.”

According to Ward, there are currently about 10 clinical trials underway in the United States for cannabidiol on a range of different disorders, including cannabis dependence, eating disorders and schizophrenia. Because of this, she believes it will be easier to establish a clinical trial for cannabidiol as a therapeutic against neuropathic pain associated with chemo drugs.

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In addition to Ward, Temple researchers involved in the study included Michael David Ramirez, Harshini Neelakantan and Ellen Ann Walker. The study was supported by grants from the National Institutes of Health and the Peter F. McManus Charitable Trust.

Temple University October 6 2011

Survival increased in early stage breast cancer after treatment with herceptin and chemo

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Treating women with early stage breast cancer with a combination of chemotherapy and the molecularly targeted drug Herceptin significantly increases survival in patients with a specific genetic mutation that results in very aggressive disease, a researcher with UCLA’s Jonsson Comprehensive Cancer Center reported Wednesday.

The study also found that a regimen without the drug Adriamycin, an anthracycline commonly used as a mainstay to treat breast cancer but one that, especially when paired with Herceptin, can cause permanent heart damage, was comparable to a regimen with Adriamycin. The data shows that anthracyclines aren’t necessary to treat early stage breast cancer effectively, and that the cardiac and other associated toxicities can and should be avoided, said study lead author Dr. Dennis Slamon, whose basic laboratory and clinical research led to the development of Herceptin.

“We’re encouraged that the survival advantages found in this study have been maintained and continue to be significant,” said Slamon, director of clinical/translational research at UCLA’s Jonsson Comprehensive Cancer Center. “I believe there’s room for even further improvement.”

The study appears Oct. 6, 2011 in the peer-reviewed New England Journal of Medicine.

The three-armed study compared the standard therapy of Adriamycin and Carboplatin followed by Taxotere (ACT), the same regimen plus one year of Herceptin (ACTH), and a regimen of Taxotere and Carboplatin with one year of Herceptin (TCH).

Slamon said this is the first time that overall survival has been measured this far out — a little more than five years — in this population of breast cancer patients.

The study shows a survival advantage for patients in the Herceptin-containing arms, with 92 percent of patients on ACTH and 91 percent of patients on TCH still alive at five years, compared to 87 percent in the ACT arm. Estimated disease-free survival, or the time from treatment to recurrence, was 75 percent the ACT arm, 84 percent among those receiving ACTH and 81 percent in the TCH arm.

The study set out to specifically test Herceptin with and without anthracylines to determine whether oncologists could provide a therapy as effective as ACTH without the resulting toxicities, including congestive heart failure and other cardiac problems. The study, Slamon said, showed that the women who did not receive Adriamycin had outcomes similar to those who did, but had much less heart toxicity.

The women who did receive Adriamycin and Herceptin had a five-fold greater increase of experiencing congestive heart failure and a two-fold increase of sustained cardiac dysfunction without symptoms. The women getting Adriamycin and Herceptin also experienced worse “acute” toxicities, such as nausea, diarrhea, vomiting, neuropathy, fatigue and falling white blood counts, Slamon said. Additionally, seven women in the anthracycline arms developed acute leukemia, a rare and deadly side effect of Adriamycin. One woman in the non-Adriamycin arm did develop an acute leukemia after receiving an anthracyline outside the study, Slamon said.

“Given the data in this study, it makes one really question what role Adriamycin should play in the treatment of HER-2 positive early breast cancer, or in the treatment of early breast cancer at all,” Slamon said. “This trial should impact the way these breast cancers are treated, with a non-anthracycline regimen being our preferred option. I think this is a change that is going to be slow in coming, unfortunately, as many of our adjuvant treatments for breast cancer are built on the backbone of anthracyclines. While they’re effective, whatever gain patients may receive is more than made up for in the serious and chronic long-term side effects.”

Herceptin is effective in women with HER-2 positive breast cancer, about 20 to 25 percent of those diagnosed with the disease every year or 200,000 to 250,000 women annually worldwide. HER-2 positive breast cancer is more aggressive and results in a poorer prognosis and shorter survival times, said Slamon, who discovered the link between HER-2 positivity and aggressive breast cancer in 1987.

Conducted by the Breast Cancer International Research Group (BCIRG), the study enrolled 3,222 women with early stage breast cancer between April 2001 and March 2004. Patients were randomized to one of the three arms.

The study’s primary endpoint was disease-free survival, but it also measured overall survival, safety, including cardiac toxicities, pathologic and molecular markers and quality of life.

“An improved understanding of the molecular basis of malignant disease is allowing the development of rational treatment strategies that are more effective and less toxic than traditional empiric regimens,” the study states. “The identification and characterization of the HER-2 alteration in a subset of human breast cancers and the subsequent development of Herceptin represent the practical realization of this translational ideal. Our findings show that we can further exploit this new and translational knowledge to optimize efficacy while simultaneously minimizing acute and chronic toxic effects.”

An editorial that accompanies the article states that the data in the study “suggest that a non-anthracycline regimen is an acceptable standard of care. The present is clearly brighter for patients with HER-2 positive breast cancer and the future promises to shine even more.”

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The study was sponsored by Sanofi-Aventis and Genentech and was funded in part by the Department of Defense, the Revlon/UCLA Women’s Cancer Program, the U.S. Army Medical Research and Development Command, the National Cancer Institute, the California Breast Cancer Research Program and the Peter and Denise Wittich Family Project for Emerging Therapies in Breast Cancer.

Tyk2 protein potential new Breast Cancer Therapy Target

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New Rochelle, NY, October 5, 2011 — A possible new target for breast cancer therapy comes from the discovery that the Tyk2 protein helps suppress the growth and metastasis of breast tumors, as reported in Journal of Interferon & Cytokine Research, a peer-reviewed journal published by Mary Ann Liebert, Inc.

Qifang Zhang and Andrew Larner, Virginia Commonwealth University (Richmond, VA), and colleagues from VCU, Temple University School of Medicine (Philadelphia, PA), Jagiellonian University (Krakow, Poland), and Miyazaki University (Japan), present data demonstrating that mice lacking Tyk2 tyrosine kinase that are injected with breast cancer cells exhibit enhanced breast tumor growth and metastasis compared to mice with normal Tyk2 protein expression.

The authors conclude that altered Tyk2 expression affects the ability of the animals’ immune systems to respond to the tumor challenge. They present the evidence in the article entitled, “The Role of Tyk2 in Regulation of Breast Cancer Growth,” and they describe the role of Tyk2 in immunity-related biochemical signaling pathways.

“This study suggests that boosting Tyk2 activity may be beneficial for arresting breast tumor growth,” says Ganes C. Sen, PhD, Chairman, Department of Molecular Genetics, Cleveland Clinic Foundation and Co-Editor-in-Chief of Journal of Interferon & Cytokine Research.

Cellular origin of a rare form of breast cancer identified

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BOSTON (September 22, 2011) — Identifying the cellular origins of breast cancer might lead to earlier diagnosis and more efficient management of the disease. New research led by Charlotte Kuperwasser of Tufts University School of Medicine (TUSM) has determined that common forms of breast cancer originate from breast cells known as luminal epithelial cells while rarer forms of breast cancer, such as metaplastic carcinomas, originate from basal epithelial cell types. The study was published online ahead of print this week in PNAS Early Edition as part of its breast cancer special feature.

Clinicians and researchers classify breast cancers into subtypes based on both clinical features and molecular features, including expression of certain genes and proteins. These classifications help determine diagnosis, treatment decisions, and patient prognosis. The most common form of breast cancer, called invasive ductal carcinoma, is classified broadly into two types based on molecular features of the tumor cells: luminal-like cancers, which are sensitive to hormones, and the more aggressive basal-like cancers, which are not sensitive to hormones and tend to have a poorer prognosis.

However, there are also rare forms of breast cancer, some of which are called metaplastic carcinomas, where the cancer cells no longer resemble cells of the breast. Scientists do not yet fully understand how and why these different types of breast cancers form but one theory is that they originate from adult breast tissue stem cells.

“For the past several decades, most research efforts have been focused on discovering cancer-causing genes in hope that this information might help us discover better treatments for breast cancer. While these efforts have led to successes in treating some common forms of breast cancer, they have not provided us with information regarding where breast cancer originates and in particular, the origins of rare forms of metaplastic breast cancers for which the best course of treatment has not yet been determined,” said Kuperwasser, PhD, associate professor in the department of anatomy and cellular biology, Tufts University School of Medicine, and a member of the genetics and cell, molecular & developmental program faculties at the Sackler School of Graduate Biomedical Sciences at Tufts and the Molecular Oncology Research Institute (MORI) at Tufts Medical Center.

In light of this, the research team chose to study the two major types of cells in the human breast, those that line the ducts and produce milk (luminal cells) and those that surround the ductal cells and contract to move the milk from the ducts (basal/myoepithelial cells) to determine whether they might form different types of breast cancers.

“We found that when basal/myoepithelial breast cells become cancerous they no longer resemble breast tissue; instead they look more like cells of the skin and form rare metaplastic breast cancers. In contrast, when luminal breast cells become cancerous, they retain the structure and molecular features of more common types of breast cancers,” said first author Patricia Keller, PhD, post-doctoral associate in the anatomy and cellular biology department at TUSM and a member of the Kuperwasser lab and MORI.

The researchers introduced cancer-causing genes into healthy breast cells obtained from breast reduction surgeries. Using specialized markers, they were able to isolate different types of normal breast cells and evaluate how they behaved as they became cancerous in a mouse model.

“By understanding more about the cellular beginnings of cancer, we can direct our research toward investigating preventive methods and possibly even developing new therapies,” said Kuperwasser.

This study adds to Kuperwasser’s growing body of work in breast cancer research. Earlier work identified a mechanism behind the preferential formation of aggressive breast cancers in people carrying a mutated BRCA1 gene. A team co-led by Kuperwasser and Philip Hinds, of Tufts Medical Center, also proposed and supported a model for breast cell differentiation that identified two distinct populations of progenitor cells for breast cancer. Her work has been published in Cell Stem Cell, Breast Cancer Research, Cancer Cell, and Nature Protocols.

Keller PJ, Arendt LM, Skibinski A, Logvinenko T, Klebba I, Dong S, Smith AE, Prat A, Perou CM, Gilmore H, Schnitt S, Naber SP, Garlick JA, Kuperwasser C. PNAS Early Edition, “Defining the cellular precursors to human breast cancer.” Published ahead of print, September 21, 2011, doi:10.1073/pnas.1017626108

Studying how to stop breast cancers from coming back

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Medical researchers at the University of Leeds have come a step closer to understanding how to stop breast cancers from coming back.

Their findings, published in the International Journal of Cancer, suggest that some novel drugs that are being developed to tackle other cancers should be considered as a future treatment for breast cancer too.

Hormone therapies, such as tamoxifen, that target a protein responsible for tumour growth, have dramatically improved the treatment of breast cancer. Survival rates have improved considerably for patients whose breast cancer is spotted at an early stage and many patients with advanced disease can now have a much better quality of life.

But hormone therapies do not work in all patients and the tumours continue to grow and spread. In other patients, the hormone therapies work well at first but then their cancer often develops resistance and the tumour starts to grow again.

Leeds researchers have now pointed the finger at a key protein that they believe helps breast cancer to become resistant to hormone treatments. Laboratory studies on breast cancer tissue revealed that resistant tumours contained excessive levels of a protein known as FGFR3. Levels of this protein were much, much lower in tumours that had responded to hormone treatment. This suggests an important link between FGFR3 and resistance to hormone treatment.

“The options available for treating breast cancers that return are relatively limited at the moment. It is therefore of utmost importance to identify the factors that cause this resistance to help promote the development of novel drugs that can be used to target recurrent breast cancers,” said Dr Darren Tomlinson, lead author of the research.

“Drugs are currently being made to target this protein – FGFR3 – in other types of cancers. Our work suggests that these drugs could potentially be made available to treat some breast cancers too and help tackle this problem of resistance.

“Similar work has already been done on different proteins that belong to the same family. We’ve added to this research by identifying a further family member. If drugs could be developed to target these different family members, then in the future, patients could be given a personalised treatment programme, depending on how their particular cancer was trying to evade the hormone therapy,” he said.

The work is very encouraging. We know that resistance to breast cancer is complex, so identifying the proteins involved brings us closer to understanding how to prevent breast cancer from coming back,” said Dr Valerie Speirs, the study’s principal investigator.

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The work was funded by the Association for International Cancer Research.

1. The paper: Mechanisms of FGFR3 actions in endocrine resistant breast cancer, Tomlinson D, Knowles M, Speirs V, is published in the International Journal of Cancer [doi: 10.1002/ijc.26304].

More immigrant women are getting mammograms now than a decade ago.

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Fewer immigrant women receive mammograms than native-born American women, according to Penn State researchers, who note that more immigrant women are getting mammograms now than a decade ago.

“Lack of access to health care persistently contributes to mammography screening disparities among immigrants,” said Nengliang Aaron Yao, graduate student in health policy and administration.

Yao, working with Marianne Hillemeier, associate professor of health policy and administration, reviewed data on women over 40 who received mammograms in the United States from the years 2000 and 2008. He reported these statistics to attendees at the American Association for Cancer Research conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved today (Sept. 19) in Washington, D.C. The data came from the National Health Interview Survey.

“More recent immigrants, those with poor access to health care, and those who were younger and less educated had lower mammography rates at both time points,” said Yao.

Yao found the number of immigrant women who received mammograms rose by almost 10 percent from 2000 to 2008. While the percentage of immigrant women receiving mammograms is less than U.S.-born women, the gap has shrunk. In 2000, the gap between immigrants and U.S.-born women was 11.2 percent, while in 2008 the gap was only 3.4 percent. In 2000 60.2 percent of immigrant women over 40 received mammograms while in 2008, 65.5 percent received them.

“Mammography rates among immigrant women remain lower than the native-born,” Yao said. “Increasing access to health insurance and a usual source of care will further diminish disparities in mammography receipt.”

Depression and pain increase fatigue in breast cancer survivors

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In Spain, 5-year survival following breast cancer diagnosis is more than 83%. Around 66% suffer fatigue following treatment. A Spanish research establishes the factors associated with tiredness in cancer survivors to improve their quality of life and rehabilitation.

“Cancer-related fatigue is the symptom that most limits quality of life and is most common in patients that survive cancerous processes,” explained Manuel Arroyo, researcher from the University of Granada and lead author of a study that links psychological disorders and physical pain episodes with fatigue after treating a breast tumour.

More than 66% of breast cancer survivors suffer tiredness following recovery, caused directly by the disease, physical deterioration or the treatment received. Therefore, understanding the factors related with fatigue and how they can be alleviated optimises survivors’ recovery.

Fifty-nine female patients treated for breast cancer were followed-up one year after having clinically overcome the disease. The researchers assessed their psychological and physical condition as well as different aspects linked to the typical medical symptoms following a cancerous process (tiredness, pain, limited movement, depression, etc.).

A statistical procedure (resampling) allowed inferences to be made similar to those that would be obtained from larger samples. “This method means that the data were more reliable and eliminated the problem of having a reduced sample size,” explained Arroyo. “It is difficult to find volunteers because patients are not often very willing to participate in research after having been through such harsh treatment.”

The results show that the patients most affected by tiredness following treatment also suffer episodes of depression and body image deterioration, neck and shoulder pain, and limited arm movement, possibly due to the surgical intervention.

Effects of survival

Following breast cancer treatment, patients present with physical and psychological symptoms that influence their health.

Previous studies have already observed self-esteem- and body image-related disorders following the cancerous process. But for the first time, a team of researchers has associated sensory hypersensitivity, limited movement and certain psychological conditions with fatigue observed following cancer treatment.

“These findings should motivate patient support programmes which improve their psychological condition and offer resources that can reduce pain,” pointed out Arroyo, who further stressed that “if fatigue is not treated, patients can suffer it for years, having a serious physical, emotional, social and economic impact.”

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References: Cantarero Villanueva, Antarero Villanueva, C- Fernández Lao, C. Fernández de las Peñas, L. Díaz Rodríguez, E. Sánchez Cantalejo, M. Arroyo Morales. “Associations among musculoskeletal impairments, depression, body image and fatigue in breast cancer survivors within the first year after treatment”. European Journal of Cancer Care 20 (2011): 632-636, 11th Septembre 2011.

Study: Gene therapy causes breast cancer stem cells to self-destruct

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Targeted agent avoids healthy cells, blocks proteins that prevent cell death in tumors

HOUSTON — Gene therapy delivered directly to a particularly stubborn type of breast cancer cell causes the cells to self-destruct, lowers chance of recurrence and helps increase the effectiveness of some types of chemotherapy, researchers at The University of Texas MD Anderson Cancer Center reported in the Sept. 13 edition of Cancer Cell.

In cellular and mouse studies, scientists found the gene mutation BikDD significantly reduced treatment-resistant breast-cancer initiating cells (BCICs), also known as breast cancer stem cells, by blocking the activity of three proteins in the Bcl-2 family. This genetic approach increased the benefits of lapatinib, one of the most common chemotherapy drugs for breast cancer.

“There are no effective methods to target BCICs, and they’re urgently needed, especially for relapsed breast cancer patients,” said senior author Mien-Chie Hung, Ph.D., vice president for basic research, professor and chair of MD Anderson’s Department of Molecular and Cellular Oncology. “This research suggests a potential therapeutic approach to breast cancer stem cells that will minimize recurrence and drug resistance.”

Special delivery system targets cells

Gene therapy was deposited directly into breast cancer cells with an innovative delivery system called VISA, short for versatile expression vector, which was developed at MD Anderson. It includes a targeting agent, also called a promoter, two components that boost gene expression in the target tissue and a payload — a Bik mutant gene called BikDD known to kill cancer cells. It’s all packaged in a fatty ball called a liposome and delivered intravenously.

This system has been successfully applied in pancreatic, lung, liver and ovarian cancer preclinical models. MD Anderson clinical researchers are preparing a phase I clinical trial for pancreatic cancer.

Stem cells frequently stymie treatment

Breast cancer stem cells, often resistant to chemotherapy and radiotherapy, are a major obstacle for breast cancer treatment, Hung said. If any of these cells remain after treatment, a new tumor often forms. Although lapatinib, known commercially as Tykerb®, can stabilize the level of these cells, no drugs are available to reduce them.

The Bcl-2 family of proteins – especially the subtypes Bcl-2, Bcl-xL and Mcl-1 — is essential for breast cancer tumor growth and treatment resistance. If too many of these three proteins are present, they can cause poor prognosis and resistance to chemotherapy drugs including lapatinib, as well as paclitaxel, doxorubicin and cisplatin.

This study shows that Bcl-2 proteins help breast cancer stem cells survive, causing resistance to treatment and likelihood of recurrence. However, using VISA to deliver BikDD can block the three key Bcl-2 proteins, eliminating the stem cells.

VISA-claudin4-BikDD cuts tumor burden

The researchers engineered a VISA that contained claudin4, a protein over-expressed in breast cancer, as a targeting agent to preferentially express BikDD in breast cancer cells. This process silenced the three Bcl-2 proteins and caused the cancer cells to self-destruct. Since the VISA focused the BikDD on cancer cells, normal cells were not affected.

Treating mice with the VISA-claudin4-BikDD therapy reduced tumor volume by 75 percent compared to control mice.

They also compared VISA-claudin4-BikDD therapy to BikDD packaged with a non-specific strong promoter from cytomegalovirus. Both versions reduced tumor burden and extended survival of mice, but tumor volume in mice treated with VISA-claudin4-BikDD was half that of the CMV-BikDD-treated mice. In a safety study using an unusually high dose, 60 percent of mice treated with CMV-BikDD survived after three days; all mice treated with VISA-Claudin4-BikDD survived for the duration of the 14-day safety profile study.

In cell line experiments, the CMV-BikDD also invaded and destroyed normal cells, while the VISA-Claudin4-BikDD did not.

Agent energizes lapatinib, other drugs

BikDD made HER2-positive breast cancer cells more sensitive to lapatinib when all three Bcl-2 proteins were inhibited but not when they were inhibited separately. HER2-positive breast cancer is a particularly aggressive type that makes too much human epidermal growth factor 2; it accounts for about 20 percent of breast cancers. BikDD also sensitized EGFR+ (epidermal growth factor positive) breast cancer cells to lapatinib and several other breast cancer cells lines to paclitaxel.

Moving discovery forward

Hung said this approach is promising for breast cancer treatment, especially recurrent disease.

“VISA-claudin4-BikDD gene therapy may provide an effective strategy to inhibit breast tumor growth,” he said. “It demonstrates virtually no toxicity in normal cells and produces a profound killing effect in multiple breast cancer cell lines and synergy with other agents.”

Hung said the next step is to move VISA-claudin4-BikDD into a Phase I clinical trial to test its effect on patients with breast cancer.

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This work was supported by grants from the National Cancer Institute, including MD Anderson’s Specialized Program in Research Excellence grant, the MD Anderson/China Medical University Hospital Sister Institution Fund, the Breast Cancer Research Foundation, National Breast Cancer Foundation, Inc., Patel Memorial Breast Cancer Research Fund, MD Anderson’s Center for Biological Pathways and NCI Cancer Center Support Grant, and the Taiwan Department of Health Cancer Center Research of Excellence Grant.

In addition to Hung, MD Anderson researchers include first author Jing-Yu Lang, Ph.D., first author, Jennifer Hsu, Ph.D., Chun-Ju Chang, Ph.D., Qingfei Wang, Ph.D., Xiaoming Xie, Ph.D., Yi Bao, Ph.D., Hirohito Yamaguchi, Ph.D. and Dihua Yu, M.D., Ph.D., Department of Molecular and Cellular Oncology; Funda Meric-Bernstam, M.D., Department of Surgical Oncology; Wendy Woodward, M.D., Ph.D., Department of Radiation Oncology; and Gabriel Hortobagyi, M.D., Department of Breast Medical Oncology.

Hung and Hsu hold joint appointments at China Medical University and Asia University, Taichung, Taiwan. Xie holds an appointment at Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China.

Study: Chemotherapy is as effective before breast cancer surgery as after

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Approach may help some women avoid mastectomy

San Francisco, CA – Whether chemotherapy is given before or after breast-conserving therapy (BCT) does not have an impact on long-term local-regional outcomes, suggesting treatment success is due more to biologic factors than chemotherapy timing, according to a study by researchers at The University of Texas MD Anderson Cancer Center.

Presented today at the 2011 Breast Cancer Symposium, the study also found that neoadjuvant chemotherapy (given before surgery), often shrinks breast cancer tumors, making them more likely to be treatable with BCT, or a lumpectomy to remove a portion of the breast followed by radiation.

“Even women who present with clinical Stage 2 or 3 breast cancer may have good results with BCT after chemotherapy and not need a mastectomy,” said Elizabeth Ann Mittendorf, M.D., assistant professor in the Department of Surgical Oncology and lead author of the study. “The molecular characteristics of the tumor and other factors have an impact on treatment success, but not the order in which chemotherapy and surgery are given.”

The retrospective study of almost 3,000 women treated for breast cancer at MD Anderson from 1987 to 2005 also confirmed several prior studies showing BCT offers high rates of cancer control for certain patients.

Approaches have similar outcomes

Of the patients surveyed, 78 percent had surgery before chemotherapy and 22 percent received chemotherapy first. Overall, women with more cancers that had more adverse prognostic factors tended to be treated with chemotherapy first.

Five and 10-year local-regional recurrence-free survival rates were excellent for both groups: 97 percent and 94 percent respectively for those who had surgery before chemotherapy, 93 percent and 90 percent for patients who received chemotherapy first.

Mittendorf said that if adverse features, such as stage and grade of the cancer, age of the patient and tumor hormone expression, were factored in, survival rates were essentially the same for both groups of women.

Neoadjuvant chemotherapy resulted in complete pathologic response in 20 percent of patients and lowered cancer stage in almost half of patients who had Stage 2 or 3 cancer before chemotherapy, increasing the likelihood that BCT may be effective for many women after chemotherapy.

Carrying results forward

“This study shows that women appropriately selected for BCT, even some women with Stage 3 breast cancer, can have excellent rates of local-regional control,” Mittendorf said. “The most important thing is putting all the factors together to determine who can most benefit from this approach.”

The group plans to extend the study into MD Anderson patients treated after 2005.

“Since 2005, treatment techniques have improved, including the ability to add targeted therapies to chemotherapy,” she said. “In the future we will look at the effects of newer agents, and we anticipate the results will be even more favorable for women who received these treatments before surgery.”

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Other MD Anderson team members included Thomas Buchholz, M.D., Department of Radiation Oncology; Susan Tucker, Ph.D., Department of Bioinformatics and Computational Biology; Funda Meric-Bernstam, M.D., Henry Kuerer, M.D., Ph.D., Isabelle Bedrosian, M.D., Gildy Babiera M.D., Merrick Ross, M.D. and Kelly Hunt, M.D., Min Yi, M.D., Ph.D., Department of Surgical Oncology; Ana Gonzalez-Angulo, M.D. and Gabriel Hortobagyi M.D., Department of Breast Medical Oncology.

Key function of mutation in BRCA1 gene discovered

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Richmond, Va. (September 1, 2011) –It is widely known that mutations in the breast cancer susceptibility 1 (BRCA1) gene significantly increase the chance of developing breast and ovarian cancers, but the mechanisms at play are not fully understood. Now, researchers at Virginia Commonwealth University Massey Cancer Center have shown that certain BRCA1 mutations result in excessive, uncontrolled DNA repair, which challenges the prior assumption that mutations in BRCA1 only contribute to breast cancer through a reduction in function.

Recently published in the journal Aging, the study led by Kristoffer Valerie, Ph.D., discovered that certain BRCA1 mutations affecting the BRCA1 C-terminal (BRCT) binding site resulted in excessive DNA repair, or hyper-recombination, which may contribute to the development of breast and ovarian cancers. The BRCT domain is a protein binding site typically found on DNA repair proteins like BRCA1 that are responsible for maintaining genomic stability and facilitating DNA repair. This study has implications for the treatment, diagnosis and development of therapies for patients with breast and ovarian cancer.

“Our findings suggest that caution should be exercised when targeting BRCA1 for breast and ovarian cancer therapies,” says Valerie, co-leader of the Radiation Biology and Oncology program and a professor in the Department of Radiation Oncology at VCU Massey Cancer Center. “We need to better understand the biological mechanisms that lead to the development of breast and ovarian cancer before we attempt to attack it through targeted therapies aimed at causing DNA damage.”

When DNA damage occurs, various forms of BASC (BRCA1-associated genome surveillance complex) bind to the BRCT domain on BRCA1. BASC is a protein complex that in part binds to the BRCT domain and serves as a “docking site” for other proteins and enzymes to come in, effectively repair the DNA damage and leave when repair is completed. However, certain BRCT mutants unable to bind to BASC disrupt the delicate DNA repair process. Previously, it was assumed this meant that BRCA1 was unable to assist with the repair process and, thus, recombination did not occur.

Valerie and his colleagues showed through experiments with cultured breast cancer cells and tissue samples from breast cancer patients that BRCT mutants increased ubiquination of BASC, which, in turn, increased recombination several-fold over normal levels. Ubiquitin is a small protein in all living organisms that “marks” other proteins for degradation or, as more recently discovered, the participation in specific cellular processes such as recombination. The researchers proposed that the hyper-recombination resulting from increased ubiquination of the BASC might result in improperly repaired DNA and increased genomic instability, which could lead to the development and aggressive progression of breast and ovarian cancers.

“Our results point to ubiquitination as a potential therapeutic target,” says Valerie. “By disrupting ubiquitination we may be able to prevent hyper-recombination and stop the growth of cancer cells with these BRCT mutations. This might sensitize the cancer cells to radiation therapy while having little effect on cells with normal BRCA1 function.”

The researchers hope to continue studying the role of BRCA1 in DNA double-strand break repair in order to determine whether the mutations they examined are important for the onset of cancer and whether targeted therapies can be developed.

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The full manuscript of this study is available online at: http://www.impactaging.com/papers/v3/n5/abs/100325a.html.

Valerie collaborated on this study with Seth M. Dever, Ph.D., Sarah E. Golding, Ph.D., Elizabeth Rosenberg, M.S., Bret R. Adams, Michael O. Idowu, M.D., M.P.H., John M. Quillin, Ph.D., C.G.C., Nicholas Valerie, and Lawrence F. Povirk, Ph.D., from Virginia Commonwealth University, and Bo Xu, M.D., Ph.D., from The Methodist Hospital in Houston, Texas.

Funding for this study was provided by the National Institutes of Health.