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Women At Risk

Recent WAR-funded Research Projects

A vital part of WAR's mission is to enhance the lives of women through funding innovative breast cancer research projects. Over the past several years, WAR has awarded grants to thirty-nine breast cancer pilot studies that cover a broad range of topics including surgery, oncology, radiology, laboratory, epidemiology, genetics, and complementary/ alternative medicine. WAR's research grants are dedicated to better understanding the complex causes of breast cancer and developing new methods for prevention, early intervention, and effective treatment.

2009

Chemopreventive and Anticancer Potential of Vitamin D And Rosemary on Breast Cancer
Linda S. Einbond, PhD, Associate Research Scientist, Department of Rehabilitation Medicine, Columbia University College of Physicians & Surgeons

Although chemopreventive agents aid in the reduction of risk for developing breast cancer, they are limited by their effectiveness among certain subsets of women and their unwanted toxicities. Women who lack estrogen and progesterone receptors as well as HER2 amplification, those with “triple negative” tumors, do not benefit from using these existing hormonal therapies. Literature suggests that vitamin D may have a protective effect against the development of breast cancer. However, high doses of vitamin D have also been associated with unwanted side effects such as increased levels of calcium in the blood. Rosemary contains carnosic acid, which is believed to have the ability to not only enhance the anti-cancer effects of vitamin D, but also to inhibit the growth of estrogen-receptor-negative breast cancer. The aim of this study is to compare the effects of calcitrol (a form of vitamin D) and rosemary/carnosic alone and in combination on the proliferation of normal mammary epithelial cells as well as in triple negative breast cancer cell lines. A second aim is to examine the specific signaling pathways and cellular targets involved in the actions of calcitrol and carnosic acid. Findings from this study could elucidate how to utilize vitamin D as a chemopreventive agent while avoiding the unwanted side effects caused by high doses of vitamin D.

Exploiting the Mutant P53 and Mutant Brca Status In Transgenic Breast Cancer Models
Robert L. Fine, MD, Associate Professor of Medicine, Division of Hematology/Oncology, Columbia University College of Physicians & Surgeons

BRCA1 tumors have distinct gene expression profiles and are classified as "triple negatives." This means that they are negative for estrogen and progesterone receptors as well as HER2 amplification. Treatment options for patients with basal-like breast cancer, “triple negative” tumors, are limited, and prognosis is poor. Mutant p53 is also expressed at higher levels in human breast cancer cases. It is approximated that 80-85% of BRCA1 and BRCA2 tumors express mutant p53. Recently, mice models were created which bear a resemblance to basal-like breast carcinoma by altering the BRCA1 and BARD1 genes. This study proposes to utilize the new genetically modified mice models to examine new therapeutic biologics and chemicals that are designed to target pathways, which are commonly mutated in human breast cancer cases. More specifically it is hypothesized that by utilizing p53 tetrapetide and cross-linking alkylators, p53 function could be restored. Findings from this study could potentially impact not only breast cancer treatment but also breast cancer prevention strategies as well.

Chromosome 17 Telomere Length and Breast Cancer Risk
Jing Shen, PhD, Assistant Professor of Clinical, Department of Environmental Health Sciences, Columbia University Mailman School of Public Health

All humans have 23 pairs of chromosomes, which compose our genetic make-up. Telomeres are composed of a large number of tandem repeats, which are located at the ends of our chromosomes. Each cell cycle, telomere length decreases by roughly 20-200 base pairs. Several important breast cancer genes (e.g. BRCA1, HER2) are located on one particular chromosome, chromosome 17. Both chromosomes 17p (short arm) and 17q (long arm) also have shorter telomeres compared to other chromosomes. The study will examine if shortened telomere lengths in chromosomes 17p and 17q individually are associated with increased breast cancer risk. Whether the telomere lengths of these chromosomes are modified by smoking, body mass index, menopausal status and global telomere length to affect the risk of developing breast cancer will also be examined. Potential findings from this study could impact breast cancer prevention strategies.

Genetic Synthetic Lethality: Genetics Approaches for Personalized Breast Cancer Therapy
Jose M. Silva, PhD, Assistant Professor of Pathology, Department of Pathology & Cell Biology, Institute for Cancer Genetics/Irving Cancer Research Center, Columbia University College of Physicians & Surgeons

Newer cancer therapies have been designed with the goal of reducing the toxicity of their classical counterparts, while also creating more individualized treatment plans. It is believed that genetic synthetic lethal interactions can be utilized to identify new targets for the development of these more personalized therapies. Genetic synthetic lethal interactions happen when two individually innocuous appearing genetic alterations work in tandem to inhibit cell growth. The theory is that these interactions can be utilized to find which genes limit viability of tumor cells that carry specific genetic lesions. This study aims to identify genes that show synthetic lethality with major breast cancer alterations in vitro (utilizing a 3D model of breast acici morphogenesis) and subsequently confirm these results in vivo (using a mosaic mouse model of breast tumorigenesis). This study could potentially significantly impact the creation of new, more individualized breast cancer therapies.

2008

Mammography Screening and Satisfaction with Health Care Among Latina Women
Ana Abraido-Lanza, PhD, Associate Professor of Sociomedical Sciences, Department of Sociomedical Sciences, Columbia University Mailman School of Public Health

Despite growing interest in cancer-related disparities and access to health care, relatively little is known about different aspects of care among Latinas, their satisfaction with the care they receive, the predictors of satisfaction, and whether these variables influence women's screening practices. This study will examine whether various access to health care factors predict satisfaction with health care and utilization of mammography screening among Latina women from the Dominican Republic living in New York City. The potential outcomes and benefits of the study are to identify the most important predictors of screening, which can be used to inform health interventions and health care policies that address disparities in breast cancer between Latinas and non-Latinas.

Phytoestrogens And Breast Cancer Prevention: Mechanisms Of Action
Hari K. Bhat, PhD, Assistant Professor of Environmental Health Sciences, Columbia University Mailman School of Public Health

Phytoestrogens are a class of plant-derived compounds that are structurally similar to estrogens. Studies have shown that dietary factors, particularly phytoestrogens, may inhibit cancer growth. We hypothesize that phytoestrogens exert their chemoprotective effects against breast cancer by shifting estrogen metabolic pathways, reducing oxidative stress and altering breast development. We will use animal models of breast cancer to analyze the role of phytoestrogens in estrogen metabolism and determine whether phytoestrogens can prevent estrogen-induced breast tumors. The long-term goal of our study is to suggest the use of specific phytoestrogens for the chemoprevention of breast cancer. The successful completion of the proposed study would provide innovative new ideas for breast cancer prevention strategies.

Quantitative Ultrasound Study Of Radiation-Induced Normal Tissue Toxicity In Breast
Tian Liu, PhD, Assistant Professor of Medical Physics, Department of Radiation Oncology, Columbia University College of Physicians & Surgeons

Breast-conservation surgery in combination with radiation therapy is an effective treatment for women with early stage breast cancer. Radiation therapy reduces recurrence and prevents development of additional breast tumors. However, efficacy of radiation treatment is limited by radiation injury to normal tissue. Currently there is no objective means of measuring breast tissue injury/toxicity in the clinical setting. Ultrasound is safe and cost-effective imaging modality. This proposed study is the first clinical application of a novel, non-invasive and quantitative ultrasound-based technique to examine acute and late radiation toxicity in the breast.

HMGA2 Expression And Breast Cancer
Jeanine D'Armiento, MD, PhD, Associate Professor of Medicine, Division of Molecular Medicine, Columbia University College of Physicians & Surgeons

Recent studies have identified a molecular marker for breast cancer, HMGA2, which appears to have a role in tumor progression and metastasis. Interestingly, HMGA2 has not been identified in healthy patients. Further studies have shown that HMGA2 mRNA expression in the blood of breast cancer patients correlates with poorer survival and can be a better predictor of survival than even lymph node metastasis. We hypothesize that in patients with locally advanced and metastatic breast cancer, HMGA2 expression can be an important predictor of clinical response to treatment. Our aim is to compare HMGA2 expression at the protein level in tissue samples using a novel technique (ELISA) in the peripheral blood of cancer patients to determine the feasibility of its use in prognosis and clinical management.

2007

Psychosocial Approaches To Participation In Breast Cancer Genetic Assessment Programs Among African American Women
Sherri Sheinfeld Gorin, PhD, Research Associate Professor of Health Education, Department of Health & Behavior Studies, Columbia University

There are currently no established psychosocial protocols to address the needs of the African American women in familial risk programs. This study is a two-arm randomized clinical trial, assigning African American women who are first degree relatives of those diagnosed with breast cancer at random to either a 1) Culturally-Tailored Cognitive-Affective-Social Network Intervention (CT-CASN); or 2) a General Health Education Group as a control. The proposed intervention (CT-CASN) is culturally tailored to African American women to systematically counsel individuals about the cognitive, affective, and social network barriers they are likely to experience with regard to breast cancer genetic susceptibility programs.

Long-Term Neurotoxicity In Breast Cancer Patients Treated With Taxane-Based Chemotherapy
Dawn Hershman, MS, MD, Florence Irving Assistant Professor of Medicine and Epidemiology, Co-Director, Breast Program, Herbert Irving Cancer Center, Columbia University Medical Center

The purpose of this study is to evaluate the long-term prevalence, severity, and natural history of neuropathy induced by taxanes in breast cancer patients. A greater understanding of factors which may predispose to the development of taxane-induced peripheral neuropathy may lead to interventions to treat and prevent this therapy-related side effect.

Pilot Biomarker Modulation Study Of Vitamin D In Premenopausal Women At High Risk For Breast Cancer
Katherine D. Crew, MD, MS, Assistant Professor of Medicine and Epidemiology, Columbia University College of Physicians & Surgeons, Division of Oncology, Columbia University Medical Center

Several studies suggest that vitamin D may influence breast cancer development, which has resulted in increased interest in the use of vitamin D for the treatment and prevention of breast cancer. The purpose of this trial is to determine the biological effects of a one-year intervention of vitamin D on biomarkers of breast cancer risk. The results of this pilot study will be used to implement a larger multicenter trial of vitamin D for breast cancer chemoprevention.

Hybrid Breast Implants From Stem Cells And Biomaterials
Eduardo K. Moioli, PhD, Postdoctoral Research Scientist, College of Dental Medicine, Columbia University Medical Center

Current methods for breast implants rely either on artificial materials such as silicone gel filled and saline filled implants or tissue flaps obtained from other parts of the body such as muscle, fat and skin. All these procedures are associated with certain risks and complications. This study proposes to explore current technologies that have been developed to regenerate fat tissue from stem cells, which may be used as a natural implant material for reconstruction of the breast, avoiding the common complications associated with artificial breast implants (allergic and foreign body reactions) and tissue flaps (lack of tissue donor site, donor site scarring, and tissue flap death). Stem cells have the potential to revolutionize medical practice, providing skillful doctors and surgeons with better alternatives for effective treatments. The results obtained here will serve as valuable preliminary data for larger scale grant proposals for the further development of stem cell based breast implants and future transition from the research laboratory to bedside treatments.

Research Using Data from the Women At Risk (WAR) High-Risk Registry

Breast Cancer Risk Factors In Young Women
Ben Pocock, MD, Jennifer Chun, MPH, Kathie-Ann Joseph, MD, MPH, Laura Klein, MD, Mahmoud El-Tamer, MD, Freya Schnabel, MD, Department of Surgery, Columbia University Comprehensive Breast Center, Women At Risk, New York Presbyterian Hospital, Columbia University Medical Center

This study queried the Registry for women ≤35 years to determine the significance of established risk factors over time in a population of high-risk younger women. High-risk was defined as having one or more of the following: a strong family history of breast cancer (FHBC), a biopsy-proven history of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in situ (LCIS). Descriptive analyses were used to look at these factors over time and to compare women with and without breast cancer. Out of 1412 high-risk women, 199 were identified as ≤35 years of age with a median follow-up of 4 years. The median age was 32 years (range 15-35 years). 178 (89%) women had a strong FHBC, 21 (11%) had ADH, 5 (3%) had ALH and 12 (6%) had LCIS. Only 3 (1.5%) developed breast cancer during the study period; all of these 3 cases had a strong FHBC and none had a prior high-risk lesion. Patients who had high-risk lesions but no FHBC did not develop breast cancer during this follow-up period. In conclusion, being ≤35 years of age and having a strong family history of breast cancer appeared to be associated with the development of breast cancer, while other well-established histologic risk factors were not. Therefore, ADH, ALH, and LCIS may have different prognostic significance in young women. These findings help us to better understand risk factors in this group of younger women and may aid in the evolution of defining age-appropriate risk management and strategies.

Results of the study were presented at the 24th Annual Miami Breast Cancer Conference in Miami, FL.

The Interaction Of Increasing Age And Breast Cancer Risk Factors
Jennifer Chun, MPH, Ben Pocock, MD, Kathie-Ann Joseph, MD, MPH, Laura Klein, MD, Mahmoud El-Tamer, MD, Freya Schnabel, MD, Department of Surgery, Columbia University Comprehensive Breast Center, Women At Risk, New York Presbyterian Hospital, Columbia University Medical Center

Currently, there is no information on how risk factors predict breast cancer incidence in women who are ≥70 years of age. This study explored the impact of known risk factors on high-risk women 70 years of age or older. Out of 1412 women in the WAR Registry, 82 women were ≥70 years of age (range 70-91). Twenty had a history of ADH (24%), 5 had ALH (6%), 27 had LCIS (33%), and 52 women had FHBC (63%). With a mean follow-up of 4 years, 6 of these women developed breast cancer (7.3%). The mean Gail score for the ≥70 age group was 4.3, as compared to 4.7 in the subset with cancer. Of the 6 breast cancer cases, two patients presented with DCIS. The remaining four were stage I at diagnosis. All tumors were low-grade with positive estrogen receptors. The Fisher's exact tests demonstrated that ADH (p=0.15), ALH (p=1.0), LCIS (p=0.66), and FHBC (p=0.62) were not statistically significant predictors of breast cancer within this age group of high-risk women. Preliminary data on high-risk women who are ≥70 years indicate that having a history of ADH, ALH, LCIS and FHBC were not strong predictors of breast cancer in this population. These findings contribute to a better understanding of the interaction of established risk factors and age. This study also emphasizes the importance of defining age-appropriate recommendations for breast cancer risk management, including surveillance and chemoprevention, for women who are 70 years of age or older. Results of the study were presented at the 31st Annual Symposium of the American Society of Breast Disease in San Francisco, CA.