Detection, Prognosis, and Treatment

Until we learn how to prevent all breast cancers, detection, prognosis and treatment are research areas that need to be pursued. The detection, prognosis, and treatment topics funded by the CBCRP continue to change as novel technologies and approaches come under investigation. Breast cancer detection technology is moving past traditional mammography; diagnosis is depending on understanding the genetic profile of tumors rather than the anatomy; and treatment is moving toward more tailored and personalized approaches. Alternative therapies and drugs, especially those derived from plants, engender intriguing areas of investigation. Taken together these advances are leading to patient care that treats women appropriately and spares them unnecessary side effects.

Two research topics are represented in this section:

Research Concluded in 2010

6th Symposium on the Intraductal Approach to Breast Cancer
The Dr. Susan Love Research Foundation works to eradicate breast cancer by advancing research and developing resources that explore the intraductal approach to the breast. As part of this effort, and with principal support from the CBCRP, Dixie Mills, M.D., and her colleagues at the Dr. Susan Love Research Foundation in Santa Monica, hosted the 6th International Symposium on the Intraductal Approach to Breast Cancer in February 2009. The Symposium included the mini-Symposium “A Novel Etiology for Breast Cancer: Inflammation;” live demonstrations of ductoscopy, ductosonography, and methods of collecting nipple aspirate fluid; and a Public Panel that provided the local community with an opportunity to learn more about the intraductal approach to breast cancer. At the close of the Symposium, the Foundation awarded $84,000 in pilot grants to eight new investigators for their unique studies in the intraductal field.

Chemical Inhibitors of Hsp70 for Breast Cancer
Heat shock protein 70 (Hsp70) is a molecule that protects cells. In normal cells it is found in only small amounts. However, in cancer cells the level of Hsp70 is hundreds of times higher, which helps to protect it from the toxic effects of chemotherapy. Chung-Wai Shiau, Ph.D., at Sanford-Burnham Medical Research Institute in La Jolla, attempted to create chemicals that could inhibit Hsp70 and that might eventually be used as new breast cancer treatments. Dr. Shiau and his colleagues screened 60,000 compounds, and a number of potential compounds were identified before Dr. Shiau was required to return to his home country, Taiwan.

Real-Time 3D Ultrasound Image-Guidance for Breast Surgery
The surgeon’s goal during breast cancer surgery is to remove the entire tumor as well as a small margin of healthy tissue surrounding the tumor. If a sufficient margin is not removed during the initial surgery, cancer cells may be left behind, substantially increasing the risk of a cancer recurrence. Michael Bax, M.S., at Stanford University in Palo Alto, is developing an advanced ultrasound-based, three-dimensional (3D) visualization and navigation tool that doctors can use prior to, during, and after surgery to ensure successful removal of the cancer. The system is now ready to be evaluated in a clinical environment, where it will be further refined and improved for use in the surgical setting.

Inhibition of Brain Metastases in Breast Cancer
New and better approaches are desperately needed to treat brain metastases. Brunhilde Felding-Habermann, Ph.D., and colleagues at the Scripps Research Institute in La Jolla, developed unique new human breast cancer cell models and analytical systems that allowed them to follow the development of breast cancer brain metastases step-by-step and to evaluate how these lesions respond to treatment. Using these models they showed that integrin avß3 (a receptor important in tumor growth and spread) very strongly promotes breast cancer cell survival in the brain and central nervous system. Next, they isolated antibodies that can keep avß3 from functioning. Lastly, they showed that treatment with these antibodies could interfere with early metastatic disease and reach breast cancer metastasis in the brain. This work overcomes a major hurdle that has been a stumbling block for research on brain metastases, and it will allow Dr. Felding-Habermann to investigate new treatments for brain metastases. If successful, this approach could lead to the development of a new therapy for brain metastases in breast cancer patients. Findings from this research appeared in Cancer Research 67(2007)1472 and Clinical Cancer Research 13(2007)1656.

Mechanism of HSP90 Inhibitor Action in Breast Cancer
Aromatase is an enzyme that converts androgen into estrogen. Breast cancer tumors that are hormone sensitive are often treated with anti-estrogen therapies called aromatase inhibitors. However, over time, tumors can become resistant to these drugs. Cynthie Wong, B.S., B.A., and colleagues at the Beckman Research Institute of the City of Hope, in Duarte, are investigating whether HSP90 inhibitors, such as 17-DMAG, might be an effective therapy for breast cancer tumors that have stopped responding to aromatase inhibitors. Their studies demonstrated that at low doses 17-DMAG kills cancer cells, but not normal cells, which is crucial for a targeted therapy. The team is continuing to investigate how aromatase inhibitor- and tamoxifen-resistant breast tumors respond to HSP90 inhibitors. This work could lead to new treatments for hormone-sensitive breast cancer tumors that have stopped responding to aromatase inhibitors.

Polyamide Inhibitors to Block Estrogen Receptor Function
A low level of oxygen, or hypoxia, causes a cell to increase its levels of a DNA-binding protein called hypoxia inducible factor (HIF). In addition to activating genes involved in blood vessel formation, HIF also activates genes directly implicated in invasion and metastasis that allow the cell to detach from its neighbors and move through the extracellular matrix. This suggests that HIF plays a role in breast cancer progression. John Phillips, M.S., and colleagues at the California Institute of Technology, in Pasadena, attempted to design a small molecule called a DNA-binding polyamide that could inhibit the estrogen receptor, a key gene that controls the progression of many breast cancers. Although the compound performed well in cell-free systems, it was not successful in inhibiting ER function in breast cancer cells. Dr. Phillips and his colleagues are now studying other small molecules that may have the potential to become effective breast cancer treatments.

Engineering EGFR Antagonists for Breast Tumor Targeting
Epidermal growth factor receptor (EGFR) protein is found on up to 90% of breast cancer cells, and its presence correlates with tumor aggressiveness and poor clinical prognosis. EGFR must be activated before it can transmit extracellular signals. This activation occurs when specific binding partners attach to the protein. Jennifer Lahti, M.S., and colleagues at Stanford University in Palo Alto are using an experimental technique known as directed evolution to engineer EGFR inhibitors that will prevent receptor activation and, in turn, inhibit breast cancer growth. Ms. Lahti and her colleagues were unable to identify molecules sufficient for further development. However, they did explore and publish alternative protein engineering approaches to develop EGFR inhibitors, which will be useful in the development of new breast cancer therapies. Findings from this research were published in the Journal of Molecular Biology 385(2009)1064 and PLoS Computational Biology 5(2009) e1000499.

Molecular Imaging of Metastatic Lymph Nodes in Breast Cancer
Breast cancer surgery typically includes a sentinel node biopsy or axillary node dissection. These procedures are used to assess whether the cancer has spread to the lymph nodes, which helps determine both the cancer’s stage and treatment options. Ella Jones, Ph.D., and colleagues at the University of California, San Francisco are trying to develop a non-invasive imaging probe that could be used as an alternative to lymph node surgery. The probe would characterize lymph nodes and breast cancer metastases at a molecular level by looking for the presence of a protease called Cathepsin B, which is produced in large quantities on the surface of malignant cancer cells. If successful, the molecular imaging probe could provide quantifiable information about tumor invasion. Its use could also reduce or eliminate side effects, like lymphedema, that are associated with lymph node removal.

Breast Cancer Treatment Monitoring Combining MRI and Optics
Chemotherapy given before surgery (neoadjuvant treatment) is used to reduce the size of a large tumor prior to surgery. However, not all tumors will respond to chemotherapy. Having an early way to identify these tumors could help patients avoid a toxic and ineffective treatment as well as expedite the use of an alternative therapy. Catherine Klifa, Ph.D., and colleagues at the University of California, San Francisco are developing a way to use magnetic resonance imaging (MRI) along with diffuse optical spectroscopy to quantify changes in the breast tissue of patients undergoing neoadjuvant chemotherapy. Their goal is to identify new markers of treatment response that could be evaluated after treatment begins. If successful, this work could lead to a safe, fast, and inexpensive test that could be used to monitor the tumor’s response during cancer treatment.

Neural Stem Cell Therapy for Breast Cancer Brain Metastases
Few therapies exist for treating breast cancer brain metastases, and those that are available prolong survival for only a few weeks or months. Brunhilde Felding-Habermann, Ph.D., and colleagues at the Scripps Research Institute in La Jolla are exploring whether brain metastases can be treated with neural stem cells (NSCs), which have a natural ability to seek out diseased areas in the brain and regenerate damaged brain tissue. Dr. Felding-Habermann and her team have developed new models of breast cancer brain metastasis that faithfully reflect the spectrum of cell types seen in the clinic. This has allowed them to identify the earliest cellular events that occur when breast cancer brain metastasis develop, document how the brain responds to incoming cancer cells, and identify a mechanism by which breast cancer cells thrive within the brain tissue. If successful, this work could lead to the development of new therapies for treating breast cancer brain metastases. Findings from this research appeared in Clinical & Experimental Metastasis 27(2010)217; American Journal of Pathology 176(2010)2958; Methods in Molecular Biology 568(2009)249; and the Proceedings of the National Academy of Sciences of the United States of America 106(2009)10666.

Nanotherapy for Breast Cancer Targeting Tumor Macrophages
Tumor associated macrophages (TAMs) comprise up to 80% of the cells in a breast tumor. Studies have shown that TAMs can promote tumor cell proliferation, angiogenesis, and metastasis, suggesting that a drug that can target TAMs could be an effective breast cancer treatment. Gaurav Sharma, Ph.D., at Sanford-Burnham Medical Research Institute in La Jolla, developed a nanoparticle therapy that targets and delivers drugs to TAMs. Dr. Sharma’s nanoparticles are fabricated from polylactic-co-glycolic acid (PLGA) polymer, which is approved by the FDA for a variety of drug delivery applications; encapsulate clodronate (a bisphosphonate originally used to treat osteoporosis) as an anti-macrophage drug; and are “decorated” with a peptide called Lyp-1 that can selectively target TAMs. To further boost drug-delivery, Dr. Sharma changed the shape of the nanoparticle to stimulate internalization by macrophages. These studies provide the proof-of-concept for targeting TAMs and could lead the development of a new breast cancer treatment.

Functional Breast MRI with BOLD Contrast
Magnetic resonance imaging (MRI) is increasingly being used for early breast cancer detection. However, MRI is associated with many false-positive findings, leading to unnecessary biopsies. It also requires intravenous injection of a contrast agent, such as gadolinium. Rebecca Rakow-Penner, M.S., and colleagues at Stanford University in Palo Alto are investigating whether it is feasible to use blood oxygen level dependent (BOLD) contrast to help characterize tumors, predict susceptibility to treatment, and monitor chemotherapeutic response. This technique has traditionally been used to study the brain, but it has the potential to evaluate tumor metabolism and angiogenesis. Ms. Rakow-Penner and her team developed a robust methodology for detecting BOLD contrast on healthy volunteers and evaluated the method on three breast cancer patients. They now intend to test the protocol on a larger population. Findings from this research appeared in the Journal of Magnetic Resonance Imaging 32(2010)120.

Novel Anti-HER2 Fragments for Better Detection and Therapy
A breast tumor’s treatment is determined by its HER2 status. Currently, immunohistochemistry of a tumor biopsy is used to assess HER2 status; however, this method is both invasive and time-consuming. Shannon Sirk, Ph.D., and colleagues at the University of California, Los Angeles, investigated whether whole body breast imaging would aid in earlier and more accurate detection and diagnosis of HER2-positive tumors. Dr. Sirk and her team created a novel HER2-targeting biomolecule that can carry cargo to HER2-positive tumors in vivo, and developed a streamlined method for radiolabeling biomolecules for same-day, high-contrast imaging applications. This work has the potential to improve non-invasive detection, diagnosis, and treatment of HER2-positive breast cancer. Findings from this research appeared in Bioconjugate Chemistry 20(2009)1474 and 19(2008)2527.

Inhibition of TF Signaling as a Novel Breast Cancer Therapy
Blood clotting is often seen in cancer patients. Tissue factor (TF), the initiator of blood clotting, is expressed on the surface of many cell types, including cancer cells. In addition to initiating blood clotting, TF also initiates internal cell signaling by turning on the protease-activated receptor 2 (PAR2). This suggests that TF-PAR2 signaling plays a role in tumor growth, tumor angiogenesis, and metastasis. Wolfram Ruf, M.D., and colleagues at the Scripps Research Institute in La Jolla evaluated the effects of an antibody they identified that can block direct TF signaling without altering TF-induced clotting. Using mouse models and human breast cancer cell lines, they showed that blocking TF signaling with this antibody in an aggressive breast cancer model reduced tumor growth. They also showed that the antibody worked well when used along with other cancer drugs that block angiogenesis. This work has the potential to lead to the development of a new breast cancer drug that works by blocking TF signaling.

Imaging Novel Stem Cell Therapy Targeting Breast Cancer
Chemotherapy kills cancer cells but it also kills normal cells, resulting in significant side effects. Targeted therapies that only kill cancer cells have the potential to be more effective, and less toxic. Joseph Wu, M.D., Ph.D, and colleagues at Stanford University in Palo Alto have significant expertise in the cultivation, differentiation, and transplantation of human embryonic stem cells (ESCs). Their goal is to develop a stem cell-based cancer therapy that will target both angiogenesis (the growth of new blood vessels) and the breast tumor itself. This work could lead to the development of a novel stem cell therapy for breast cancer. Findings from this research appeared in Cancer Research 69(2009)2709, Experimental Biology Annual Meeting 4(2009)e7040, and PLOS One 4(2009)e8443.

Treating BC Brain Metastases with Cytotoxic Lymphocytes    
As women with metastatic breast cancer live longer, brain metastases is becoming more common. However, the currently available treatments for brain metastases are ineffective. Barbara Mueller, Ph.D., and colleagues at the Sidney Kimmel Cancer Center in San Diego are investigating whether allo-reactive cytotoxic lymphocytes (alloCTL) are an effective therapy for brain metastases. Dr. Mueller has established a protocol to generate alloCTL from unrelated blood donors directed against human breast cancer cells, and she has demonstrated that this therapy can specifically kill breast cancer cells. Her team has now shown that this therapy suppresses brain metastases in a mouse model. This work could lead to the development of an effective, non-toxic therapy for breast cancer that has metastasized to the brain.

Novel Small Proteins for PET Imaging of Breast Cancer
HER2 is an important breast cancer biomarker that helps determine treatment options. A technology that can accurately test HER2 status would advance clinical management of breast cancer patients. Zhen Cheng, Ph.D., and colleagues at Stanford University in Palo Alto are developing a positron emission tomography (PET) probe that uses a new class of scaffold proteins, called Affibody molecules, to non-invasively image HER2 status in breast cancer. If successful, this new PET imaging agent could be used in the clinic to provide a real-time, non-invasive assay of HER2 expression in patients. Findings from this research were published in ChemBioChem 10(2009)1293 and Journal of Nuclear Medicine 50(2009)1492.

Diffusion-Weighted MRI in Monitoring Breast Cancer Treatment
Chemotherapy given prior to surgery (neoadjuvant treatment) is used to shrink the breast tumor, allowing for less extensive surgery. Giving chemotherapy before surgery also provides information about whether the tumor will later respond to chemotherapy. Lisa Singer, B.S., and colleagues at the University of California, San Francisco are investigating whether the apparent diffusion coefficient (ADC) obtained from diffusion-weighted magnetic resonance imaging (DW-MRI)—a non-invasive, non-contrast, and non-ionizing way to detect microscopic changes in cell density and cell content—can improve the ability to predict tumor response to neoadjuvant chemotherapy. Their results suggest that ADC measurement can be improved and made more time-effective, but these technical advances must be compared to standard methods. Large, prospective studies are now needed to determine whether ADC is valuable in predicting treatment response and should have a place in the clinical setting.

Research Initiated in 2010

A Novel Mediator of AI Resistance in Breast Cancer         
Karineh Petrossian
Beckman Research Institute of the City of Hope

Breast Cancer Neoadjuvant Chemotherapy Response with miRNA
Shizhen Emily Wang
Beckman Research Institute of the City of Hope

Electronics for High Resolution Breast-Dedicated PET       
Frances Lau
Stanford University

Enhancing Trastuzumab Therapy with an NK Activating Antibody
Ronald Levy
Stanford University

HER2 Co-Amplified Genes and Treatment Response             
Michael Press
University of Southern California

Inhibiting Breast Cancer Brain Metastasis with Cilengitide 
Brunhilde Felding-Habermann
Scripps Research Institute

Measuring Real-World Breast Cancer Outcomes
Allison Kurian
Stanford University

MRI Guided Focused Ultrasound in Breast Cancer Treatment   
Rachel Bitton
Stanford University
         
MRI Registration for Therapy Evaluation and Annual Screening
Muqing Lin
University of California, Irvine
      
Multimarker miR Blood Assay for Breast Cancer Detection    
Dave Hoon
John Wayne Cancer Institute
     
New Estrogen Receptor Downregulators for Breast Cancer     
Richard Pietras
University of California, Los Angeles

Receptor Re-expression in ER and PR Negative Breast Cancer 
Dennis Holmes
University of Southern California

The Role of ANCCA in Tamoxifen Resistant Breast Cancer     
Nicolas Andrews
University of California, Davis
 
Salivary Biomarkers for Early Detection of Breast Cancer   
Lei Zhang
University of California, Los Angeles

Targeting Brain Metastasis with a Cell-based Approach      
Mihaela Lorger
Scripps Research Institute
                
Targeting breast tumor stem cells with cell cycle inhibitors
Noelle Huskey
University of California, San Francisco

Targeting Drug Resistant Breast Cancer by microRNAs
Hailiang Hu
University of California, Los Angeles

Towards Highly Effective Inactivation of HER2-HER3 Signaling
Mark Moasser
University of California, San Francisco

Research in Progress

Antibody-based Targeting of Breast Cancer Stem Cells
Claudia Gottstein
University of California, Santa Barbara

Chemerin as an Immunotherapeutic Agent in Breast Cancer
Russell Pachynski
Palo Alto Institute for Research & Education

Combating Breast Cancer with the Wellderly Immune Repertoire
Brunhilde Felding-Habermann
Scripps Research Institute

Compounds Blocking Assembly of LRH-1 in Breast Cancer
Cindy Benod
University of California, San Francisco

Development of a Breast MRI Computer-Aided Diagnosis System
Ke Nie
University of California, Irvine

Genetics of Tamoxifen Response
Elad Ziv
University of California, San Francisco

ID4: A Prognostic Factor of Breast Cancer Metastasis
Dave Hoon
John Wayne Cancer Institute

Inhibitors of Condensin I as Chemotherapy for Breast Cancer
Kyoko Yokomori
University of California, Irvine

Intraductal Therapy of DCIS: a Presurgery Study
Susan Love
Dr. Susan Love Research Foundation

Membrane-associated Estrogen Receptors in Breast Cancer
Richard Pietras
University of California, Los Angeles

Metabolite Imaging to Identify Drug Resistant Breast Cancer
Trent Northen
Lawrence Berkeley National Laboratory

Modulation of Breast Cancer Stem Cell Response to Radiation
Frank Pajonk
University of California, Los Angeles

A Predictive Factor for Eribulin Treatment of Breast Cancer
Jennifer Smith
University of California, San Francisco

Sound Speed Tomography for Early Breast Cancer Detection
Jakob Nebeker
University of California, San Diego

Stratifying DCIS Biopsies for Risk of Future Tumor Formation
Thea Tlsty
University of California, San Francisco

Survival in de novo and recurrent metastatic breast cancer
Sumanta Pal
Beckman Research Institute of the City of Hope

Targeting DNA Repair Function of Breast Cancer Stem Cells
Xiaohua Wu
Scripps Research Institute

Topoisomerase-IIa as a Predictor of Anthracycline Response
Michael Press
University of Southern California

Reducing Surgical Morbidity of Breast Cancer Staging
Steven Chen
University of California, Davis