SPORE Newsletter. Specialized Programs of Research Excellence Autumn Issue - 4

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1 SPORE Newsletter Specialized Programs of Research Excellence BREAST DENSITY AND THE FUTURE RISK OF INVASIVE CANCER IN WOMEN TREATED FOR DCIS E. Shelley Hwang E. Shelley Hwang UCSF Breast Surgeon Ductal carcinoma in-situ of the breast, or DCIS, affects over 50,000 women every year in the United States and accounts for more than 20% of malignancies diagnosed by mammogram. By definition, DCIS is thought to have no risk of spreading to other areas of the body and thus has almost no impact on survival. However, without treatment, DCIS can increase the risk of developing invasive cancer. Because of this observation, women diagnosed with DCIS are usually recommended a course of aggressive treatment consisting of a combination of surgery, radiotherapy, and hormonal treatment. Autumn Issue - 4 However, only hormonal therapy reduces the risk of invasive cancer in the opposite breast, which is also elevated with a diagnosis of DCIS. Mammographic breast density has been shown to be an independent risk factor for development of invasive breast cancer, increasing the risk of invasive cancer two to four- times that of women with low breast density. The factors that make up breast density are not well described, but likely include a combination of genetic, dietary, and hormonal factors. The reasons that DCIS is associated with invasive cancer in some women and not in others are largely unknown, but are thought to be related to both tumor and patient characteristics. Aside from genetic factors, breast density has been identified as one of the strongest risk factors for development of invasive breast cancer. Thus, we undertook a study to determine whether women with higher breast density at the time of their DCIS diagnosis were at increased risk for developing future invasive cancer when compared to women with DCIS and low breast density. The 4,200 patients analyzed in this study were diagnosed with DCIS between 1996 and 2004 and were enrolled in the National Cancer Institute Breast Cancer Screening Consortium (BCSC- The BCSC is a national mammography registry designed to study breast cancer screening practices and outcomes in seven geographic regions in the United States. Mammographic breast density has been shown to be an independent risk factor for development of invasive breast cancer One of the most active sites is the San Francisco Mammography Registry, which includes San Francisco and Marin Counties. More than 800,000 women are annually screened at one of the BCSC sites. Breast density is recorded at the time of mammography screening. In this study of 4,200 women with DCIS, 2,728 were treated by lumpectomy alone. All women were followed for an average of 41 months. 115 women from the initial cohort developed invasive breast cancer. The study suggested that the risk of developing invasive breast cancer in the same breast affected by DCIS was reduced among patients that had radiation therapy. However, this risk was not affected by breast density....this data could be used to help determine which women would benefit most from hormonal therapy...

2 Bay Area Breast Cancer Shelly Hwang cont d On the other hand, the risk of developing invasive cancer in the opposite breast was increased almost two-fold in patients with high breast density when compared to similar patients with low breast density. This study suggests that women with increased breast density may be at higher risk for developing invasive cancer in the opposite breast when compared to women with low breast density. If confirmed in other studies, this information could be used to help determine which women would benefit most from hormonal therapy, such as Tamoxifen, or the aromatase inhibitors, such as Arimidex, for reducing risk of invasive breast cancer after surgical treatment for DCIS. Women with high breast density may be the best candidates for such treatment, which could benefit patients by reducing breast cancer risk in both breasts. Our study points to the importance of national registries to track both risk factors for disease and treatment outcomes of disease. Many important questions about breast health could never be answered without the active participation of thousands of women across the United States enrolled in mammography registries. BEING A PATIENT BECOMING AN ADVOCATE Linda Vincent, Breast SPORE Advocacy Core Linda Vincent Patient - Advocate What is an advocate and how does one become one? Good question. There isn't one answer that fits all advocates. For me advocacy began after I was diagnosed with breast cancer. Stunned by my diagnosis in 1996 I went to a drop-in support group at the cancer center in Berkeley. It was a support group for women newly diagnosed with breast cancer but included women who were still receiving chemotherapy. At the meetings women spoke of their diagnoses and treatment decisions and I found their information very helpful. Later, a smaller group of us decided to meet once a month. We met to eat! We were changing our diets to best defend our bodies from breast cancer recurrences. We were very serious about this. Three of us joined the Women's Healthy Eating and Living (WHEL) Study Clinical Trial that had set guidelines for low fat and high fiber in diets. I was jolted when one of my support group friends had a recurrence two years after her treatment. Cancer patients are wary of interacting with cancer researchers because we don't understand science. It is difficult to understand. Fortunately, there are many workshops available for the determined patient advocate to get a basic education in cancer science. Together we searched the internet for more information. We were both scared. I was frustrated with how little I knew about getting good information about cancer. We were hopeful for her chances of beating cancer again, because we knew of women who had many recurrences and had lived a relatively long time. She wasn't to be one of them. From that time I vowed to become better informed. I had heard of Breast Cancer Action (BCA) from another support group friend and attended a BCA task force meeting on cancer therapeutics. It was at one of the task force meetings, I heard about a UCSF Breast SPORE Advocacy Core's (BSAC) Training Day held at the UCSF Cancer Research Building. I attended the March 2000 Training Day and began to attend BSAC meetings. What is BSAC? BSAC is a funded advocacy "Core" and part of the Breast SPORE grant at UCSF. SPORE is an acronym for the National Cancer Institute's Specialized Programs of Research Excellence (SPORE). As members of this advocacy group, we are invited to attend regularly scheduled oncology lectures held on Wednesday mornings, participate on steering committees, give input to clinical trial design, and provide education for both patient and scientific audiences.

3 SPORE Newsletter Linda Vincent cont d The weekly oncology lectures are intimidating for BSAC members, oncology science novices. We are patient advocates at these lectures and may not understand all the science, but we do understand how cancer patients may react to patient participation in trials proposed at these lectures. The responsibility that comes with invitations to attend the meetings is to give voice to patients' concerns and we do. Workshops and conferences Cancer patients are wary of interacting with cancer researchers because we don't understand science. It is difficult to understand! Fortunately, there are many workshops available for the determined patient advocate to get a basic education in cancer science. An excellent workshop is Project LEAD sponsored by National Breast Cancer Coalition Fund (NBCCF) for patient advocates. Women and some men have attended LEAD, without previous science education, and do come away with a basic understanding of cancer and research science. LEAD is 4 days of intense lectures and breakout sessions of cancer biology, clinical cancer care, epidemiology, and statistics. Skills are taught for the novice advocate who wants to participate in advocate reviews in research programs and cancer protocol committees. The responsibility that comes with invitations to attend these meetings is to give voice to patients' concerns and we do. Research programs and advocate reviews Any advocate that wants to be involved with the research grant application process can do so by applying to funding organizations that have an advocate review program. Once accepted as a reviewer they are sent the research projects that are being considered for funding. The researcher outlines his or her plan (a grant application) to carry out a specific project. Scientific reviewers and advocate reviewers evaluate and score them based on criteria established by the funding organization. High scored applications get funded, and science progresses. There are advocate review programs in the Department of Defense breast cancer research program and the Susan G. Komen Foundation. The challenge of reading medical journals I met women in that first support group I attended just after my diagnosis who had researched their diagnoses in the medical literature. I was not one of them. My education in breast cancer took a lot of effort and is one of my continuing education projects. One of my projects with BSAC was designed to help other patients understand medical journals. In September 2005, BSAC sponsored the first workshop called "Understanding Medical Journal Articles and Reports. " I presented information in a lecture format on the access, organization, and evaluation, including statistics, of medical journal articles. Gail Sorrough from the Cancer Center library gave a real time, internet journal search with a computer on site. A journal reading group formed from the workshop participants who met to discuss current and relevant breast cancer articles. If you are interested in this workshop please contact Linda Vincent by lvvincent@earthlink.net or phone (Check out NBCCF's website for more information and applications for Project LEAD). If you are interested in this workshop please contact Linda Vincent by lvvincent@earthlink.net or phone

4 Anjali S. Kumar UCSF Breast Surgeon NOT JUST FOR CHOLESTEROL - STATINS AND BREAST CANCER By Elisabeth Garwood, BS; Juan Lessing, BA and Anjali S. Kumar, MD Statins are widely prescribed medications that lower blood cholesterol and decrease the risk of death and illness from cardiac and vascular causes (heart attacks and stroke). This decreased risk, however, is only partly related to the cholesterol-lowering effect of the drugs. Some of the risk reduction may be related to the effect of statins on a number of different cell pathways, one of which controls inflammation. The mechanism by which statins reduce stroke risk, for example, does not depend on cholesterol, but works through a pathway that is actually active in cancer. In laboratories around the world, the precise link between statins and cancer prevention is being intensely studied. Here at the UCSF Breast Care Center, researchers Laura Esserman, Michael Campbell, and Christopher Benz have made significant progress in determining the molecular pathway by which statins block growth in cancer cells. Our researchers are now discovering whether the molecular pathway that statins block to prevent stroke can explain their effect in breast cancer cells. Our researchers are now discovering whether the molecular pathway that statins block to prevent stroke can explain their effect in breast cancer cells. Some statins work better than others, and some types of breast cancer cells are more strongly affected. What is exciting, however, is that estrogen receptor negative (ER-negative), HER-2-negative cell lines seem to be the most affected. This is important because we can prevent and treat ER-positive breast cancers with hormonal agents, such as Tamoxifen and aromatase inhibitors. But we don t have a drug yet that inhibits the development of ER-negative cancer. In the laboratory, the anti-cancer evidence of statins is strong. However, the epidemiological evidence - cancer riskreduction among a large population of statin users compared to non-statin users - is mixed. Numerous randomized clinical trials of statins have been conducted for heart disease. When these trials are examined specifically to see if the risk of breast cancer is lower in statin users, sometimes the risk seems lower, sometimes not. But we need to keep in mind that these studies were specifically designed to look for a change in the rate of heart disease, not in breast cancer. Recent analyses looking at the results of completed statin trials have concluded that there is no convincing evidence supporting either a cancer promoting or cancer preventing effect for statins. There are many reasons why the overall effect of statins on cancer is still unknown and why these studies have come to very different conclusions. One reason is that there are different classes of statin drugs ( lipophilic versus hydrophilic ) whose effects need to be considered separately in the context of breast cancer. This point is illustrated clearly in a recent study that did look at the different classes of statins and their relationship to breast cancer. This study found that lipophilic statins reduced the risk of breast cancer development by 18% while the other statins had no effect at all. Another reason is that the different types of breast cancers (ER-positive and ER-negative) that need to be considered As we move toward the ultimate goal of preventing breast cancer, we are thrilled to have the opportunity to test a drug that has already been proven to be safe and generally health-promoting to find out if it can help to inhibit the growth of breast cancer. separately when looking at their response to statin treatment. ER positive and ER negative cancers have very different responses when treated with the same drug and may reasonably respond differently to statin treatment. Also the duration of statin use may be a very important factor that has not been considered in all of these studies. In short, we are in need of trials designed to specifically look at the relationship between statin use and cancer before this question can be answered. We have shown, in a large populationbased study using the Kaiser Northern California Cancer Registry (n=2380 cancers) that women on statins develop fewer ER negative cancers. This is consistent with the laboratory data described above. In our study, a significantly lower proportion of patients who had taken lipophilic statins daily for more than a year had ER negative tumors (2% vs. 17%, 36% reduced age-adjusted odds). This data supports our interest in exploring the role of lipophilic statins in breast cancer prevention. Taking the strongly favorable laboratory data in consideration with the mixed, but intriguing population data, Dr. Laura Esserman has spent the last four years carefully designing and gaining support for a clinical trial to investigate a link between statin use and breast cancer prevention.

5 SPORE Newsletter Anjali Kumar cont d We are currently conducting a randomized clinical trial of statins given to patients with DCIS or Stage 1 breast cancer 3-6 weeks prior to their surgery. UCSF is coordinating this trial, which also takes place at three other sites: Memorial Sloan Kettering, University of Chicago, and Dana Farber Cancer Center. Novartis is donating the statin drug fluvastatin (Lescol) for the trial. The trial is exploring the impact of two different doses of statins on tumor cell activity, measured by the rate of tumor cell growth and cell death, as well as a number of exploratory biomarkers (markers of disease) focused around inflammation and immune function. We are performing MRI before and after collecting tissue from the core biopsy and the final surgical specimen, and we are collecting blood after diagnosis and after treatment. The design of this trial, which tests the impact of statins in the perioperative phase in DCIS, sets the stage to move to a neoadjuvant trial design, where statins are tested for a longer period of time prior to, or in lieu of, surgery. As we move toward the ultimate goal of preventing breast cancer, we are thrilled to have the opportunity to test a drug that has already been proven to be safe and generally health-promoting to find out if it can help to inhibit the growth of breast cancer. Editor s note: Dr. Kumar gives credit to Peggy Devine, a UCSF s Breast SPORE Advocate who initially reviewed the trial protocol and helped with the consent form for this trial. Elad Ziv Primary Care Physician Study of Tamoxifen Response Elad Ziv Dr. Ziv and his colleagues have been conducting a study of factors that predict response to Tamoxifen. Specifically, the investigators would like to identify factors that may increase the effectiveness of Tamoxifen or factors that may increase the risk of side effects. They are evaluating a wide range of factors from clinical factors (such as age, body mass index, history of medication use) to variations in genes. Some of you may have been asked to participate in this study by donating a blood sample and by completing a questionnaire. So far the study has been able to evaluate the prevalence of side effects and identify some predictors of these side effects. Among the most common side effects were hot flashes, vaginal dryness and sleep problems. Approximately 50% of women reported hot flashes on Tamoxifen. Vaginal dryness was reported by 25 %, and sleep problems were reported by 16%. One interesting initial result emerging from preliminary analyses is an association between women who have previously been on hormone replacement therapy reporting a higher incidence of side effects. Among women who had been on hormone therapy prior to starting Tamoxifen, 36% reported vaginal dryness, while among women who had never been on hormone therapy prior to Tamoxifen only 15% reported vaginal dryness, a difference that was statistically significant. Similar differences were also seen with report of more frequent sleep problems among women who had previously been on hormone replacement and also more frequent reporting of hot flashes. The difference in the rate of hot flashes and in the rate of sleep problems was not statistically significant, but the trend was suggestive. One potential interpretation is that the women who had used hormone replacement therapy became accustomed to relatively high hormone levels prior to starting Tamoxifen. These results have been presented at the American Society of Preventive Oncology and are currently being prepared for publication. More analyses will be performed in the near future to evaluate additional factors such as variations in genes known to interact with Tamoxifen. For example, the genes for the receptors for estrogen, which are known to be partially blocked by Tamoxifen, will be evaluated. The investigators will use several proteins in serum which are known to be decreased by Tamoxifen as markers of the effect of Tamoxifen. The investigators hope that these analyses will lead to better predictors of which women are most likely to benefit from Tamoxifen. Dr. Ziv and his colleagues would like to thank all of the women who have participated. If you are interested in becoming a volunteer advocate with Breast SPORE Advocacy Core, please contact Julia Bruckner jbruckner@cc.ucsf.edu More information about SPORE and related studies is available at breast_spore/index.php

6 Tissues are Very Important To Research Karen Chew Each year, hundreds of women undergoing breast surgery at UCSF and CPMC donate their leftover surgical tissue for breast cancer research. Breast tissue donated for research is being used in a number of projects. Dr. Michelle Melisko is comparing breast tumors that eventually metastasize to the brain with other breast tumors that either did not metastasize, or metastasized to other organs. Dr. Koei Chin is looking at the genetics of breast cancers from African-American women compared to Caucasian women. Drs. Karla Kerlikowske and Thea Tlsty are looking at markers of recurrence in ductal carcinoma in situ tumors. Dr. Chris Benz is studying the role of estrogen receptor and age in breast cancer. UCSF Comprehensive Cancer Center 2340 Sutter Street San Francisco, CA PHONE: FAX: Outcomes Office Kelly.Bolcavage@ucsfmedctr.org Editor: Linda V. Vincent, MPH, lvvincent@earthlink.net Bay Area Breast SPORE Newsletter The Bay Area Breast Cancer SPORE Newsletter is produced annually by the SPORE Advocacy and Tissue & Outcomes Cores at UC San Francisco. It is mailed to all current study participants as well as breast care surgeons and oncologists at UCSF, CPMC and SFGH. Drs. Thea Tlsty and Karla Kerlikowske are looking at the relationship of mammographic breast density and the development of breast cancer. There are many other important studies underway which depend on the use of breast tissue. A big thank you goes to the patients who have donated their tissue. If you have any questions about tissue donation, contact Karen Chew at: chew@cc.ucsf.edu