Detection, Prognosis, and Treatment: Delivering Clinical Solutions

Overview: We know that breast cancer mortality rates have recently begun to decline. The underlying reasons are believed to be a combination of improved screening rates, better prognostic information available to clinicians, and more varied treatment options. However, the most significant factor for improved survival appears to be the diagnosis of smaller tumors at an earlier stage. Examining 25 years of breast cancer records, lead researcher Elena Elkin, Ph.D., at Memorial Sloan-Kettering Cancer Center in New York, recently concluded that smaller tumor size accounted for over 60 percent of the improvement in survival when cancer had not spread beyond the breast, and almost 30 percent when it had spread minimally. Thus, improved detection and imaging technologies are essential to continue this beneficial trend. Although yearly X-ray mammography screening is the gold standard, many questions have emerged over its real value. We know that mammography is less effective in pre-menopausal women or post-menopausal women on hormone replacement therapy. It often fails to detect tumors in high-density breast tissue, irrespective of age and hormone use. Almost one-third of diagnosed tumors are missed in mammography screening, and false-positives lead to unnecessary biopsies, cost, and stress.

In terms of improved breast cancer prognosis, gene-based profiling of cancer patients is now commercially available. In addition to existing tests for BRCA1 and BRCA2 mutations, companies like Genomic Health in Redwood City have recently introduced Oncotype DXTM. This test profiles the activity of 21 genes and determines risk of recurrence in early stage breast cancer as well as the potential benefit of chemotherapy in certain patients. These genetic tests are expected to emerge as an improvement over single-marker analysis, such as estrogen receptor and Her-2 oncogene. Certainly, genetic testing is beginning to open the door to individualized medicine.

In the past few years the treatment situation for breast cancer has also seen significant advances. Aromatase inhibitors are now used as a first line drug in place of tamoxifen in postmenopausal women. They seem to work well in preventing cancer recurrence and are associated with reduced side effects compared to selective estrogen-receptor modulators (SERMs). Angiogenesis inhibitors, such a Genentech’s AvastinTM, are showing promising results in late clinical trials for metastatic breast cancer and should be widely available in the near future.

Four research areas show promise in developing new and more effective breast cancer treatment strategies. First, we need to apply our improved understanding of the cellular, genetic basis of the disease, and translate this information to the clinic. Genetic profiling has identified major cancer subtypes, so that research efforts can be directed towards more aggressive, less differentiated, and highly metastatic subtypes that are poorly addressed in current clinical practice. This would be a big step towards individualized therapy. Emerging models of breast cancer that point towards a stem cell origin and the existence of a treatment-resistant population of breast cancer stem cells represent another significant milestone. Second, combination therapies to target multiple tumor cell growth and signaling pathways are needed to allow better management of the disease and reduce recurrence. Third, incorporation of scientific paradigms from such disciplines as cell and human aging (senescence), inflammation, and the tissue microenvironment (e.g. stromal-epithelial interactions) promise a better conceptual framework to either envision new treatments or test existing treatments (e.g. COX-2 inhibitors) in the appropriate preventive or clinical setting. Finally, in terms of the pre-clinical aspects of drug development, more appropriate cell and animal models are needed to better duplicate the heterogeneity seen in the human disease. A promising step in this direction is the NCI’s Mouse Models of Human Cancers Consortium (MMHCC). This collaborative program is designed to derive and characterize mouse models, to generate resources, and to use innovative approaches in pre-clinical trials and drug development.

Two of the CBCRP’s research topics are represented in this section:

• Imaging, Biomarkers, and Molecular Pathology: Improving Detection and Diagnosis
• Innovative Treatment Modalities: Search for a Cure

Funding Data:
 

Proportion of Total

Detection, Prognosis, and Treatment grants awarded in 2005:

9

17%

Funded amount:

$1,412,329

18%

Detection, Prognosis, and Treatment Portfolio Summary:

Three new grants in 2005 address the topic of breast cancer imaging. Two of them have evolved from research funding provided by the CBCRP to John Boone, Ph.D., at the University of California, Davis. Dr. Boone built the first dedicated breast computerized tomography (CT) scanner during the past five years. To enable this technology he overcame two barriers. First, he was able to show that the radiation dose for breast imaging could be reduced to make annual screening by CT a reality. Second, he was able to develop a special table for breast imaging that had the advantages of not exposing other parts of the body to radiation and not requiring breast compression, a major discomfort in mammography. These solutions combined to make the dedicated breast CT scanner a practical alternative to mammography. Currently, the new breast CT scanner is undergoing a Phase II clinical trial using NIH funding. In a new IDEA grant, Dr. Boone will be adding a positron emission tomography (PET) capability to his CT scanner. This will enable molecular imaging capabilities. In PET imaging a patient is injected with a radioactively labeled or tagged compound to show the chemical functioning of tissues. If the combined CT-PET scanner develops further, then this hybrid technology will allow both anatomical and physiological images of the breast.

Thomas Nelson, Ph.D., at the University of California, San Diego, is developing a novel three-dimensional ultrasound scanner that will use the same patient mechanical platform as Dr. Boone’s CT scanner. In fact, the 3-D ultrasound technology will be compared to CT images to validate performance in a clinical setting. Traditional ultrasound imaging is currently limited by weak resolution and operator variability, so this new approach from Dr. Nelson may well provide a critical breakthrough to stimulate more acceptance of ultrasound as a detection-diagnostic tool for breast cancer.

Brian Thorndyde, Ph.D., from Stanford University is funded through a postdoctoral fellowship to improve PET imaging by reducing respiratory artifacts. PET scans take several minutes and the breast image quality is degraded by body movements associated with breathing. Dr. Thorndyke is developing and testing a way to sort imaging data and use algorithms to improve resolution.

The remaining six new grants funded by the CBCRP in 2005 in this section are in the treatment topic. Two projects focus on metastasis.

Brunhilde Felding-Habermann, Ph.D., at The Scripps Research Institute, La Jolla, will attempt to treat brain metastasis in animal models of breast cancer by delivering single-chain fragments (scFv) of human antibodies via inhalation through the nose. The technical approach is to place the antibodies as parts of special viruses, called phage, that can be taken-up nasally, cross the blood-brain barrier, and localize to tumor cells resident in the brain. This is truly high risk-high reward research that attempts to treat the most lethal of breast cancer metastatic sites.

David Hoon, Ph.D., from the John Wayne Cancer Institute, Santa Monica, will be testing a potential new biomarker to predict metastasis. The ID4 gene is a member of the “inhibitor of DNA-binding” protein family, which blocks a group of DNA-binding transcription factors, called helix-loop-helix. The point of Dr. Hoon’s project is to determine whether ID4 analysis on primary tumor samples can be used to separate groups of patients that require sentinel lymph node biopsy from patients who will not benefit. This might significantly improve patient prognosis and spare some patients the need for this expensive, and possibly dangerous, procedure.

The remaining treatment grants deal with the structural aspects of key tumor genes and proteins that, when understood better at the molecular level, might prove to be drug targets or improve the application of current drugs in breast cancer treatment.

Mark Moasser, M.D., is a clinician-scientist at the University of California, San Francisco, whose interest focuses on the ErbB family of tyrosine kinases. Although the launch of Herceptin® by Genentech in 1999 was the first molecular therapeutic for Her-2, many patients receiving it do not respond. Dr. Moasser is interested in the portion of the ErbB receptors that resides inside of the cell and represents the signaling, kinase portion. Her-3 in breast cancer cells can serve to restore function to Her-2, and is a potential culprit in allowing cancer cells to evade drug treatment such as Herceptin®. This project employs novel siRNA techniques to find the link between Her-3 and the key PI3K/Akt signaling pathway in breast cancer cells to develop a new therapeutic angle.

Sanjay Saldahna, Ph.D., also at The Scripps Research Institute, is funded for a postdoctoral fellowship to study a major cellular signaling protein kinase, called protein kinase A (PKA). Although PKA is found in many cells and would seem to be an unlikely target for selective cancer therapy, Dr. Saldahna is targeting a single regulatory PKA alpha subunit. This subunit, when repressed, appears to have a significant effect on breast cancer cells. The aim of Dr. Saldahna’s project is to find small drug candidates that block the binding of cyclic-AMP, a ubiquitous intracellular messenger, to the PKA alpha-subunit that would repress breast cancer.

Jiewen Zhu, Ph.D., at University of California, Irvine, is also interested in finding candidate drugs, but works on the mechanism of DNA repair that depends on BRCA2 and an associated protein called Rad51. If the association of BRCA2 and Rad51 can be disrupted, then it is thought that cancer cells will become hypersensitive to radiation therapy. This strategy, if successful, would permit much smaller doses of DNA-damaging chemotherapy and radiotherapy. The aim is to lessen the side-effects associated with these treatments.

Although SERMS (e.g., tamoxifen) remain frontline therapies for women with estrogen receptor positive disease, they fail to help some patients. A key underlying reason is that the ER-associated gene regulatory machinery is very complex and not completely understood. Oksana Tyurina, Ph.D., at University of California, San Diego, is studying the role of inflammatory cytokines, often present at tumor sites due to the presence of macrophages, as potential modulators of how well SERMs function. Apparently under certain conditions, proteins normally found in the nucleus can migrate to the cytoplasm to mediate a reversal of SERM actions on the estrogen receptor. If Dr. Tyurina can dissect these novel pathways, it could open the door to new approaches to make SERMs work in more patients for a longer duration.

Detection, Prognosis, and Treatment Grants Funded in 2005:

Imaging, Biomarkers, and Molecular Pathology

Molecular Imaging of Breast Cancer Using Breast PET/CT
John M. Boone, Ph.D.
University of California, Davis
Award type: IDEA
$100,000

Early Breast Cancer Detection Using 3-D Ultrasound Tomography
Thomas R. Nelson, Ph.D.
University of California, San Diego
Award type: IDEA
$149,879

Removing Respiratory Artifacts in Nuclide Breast Imaging
Brian Thorndyke, Ph.D.
Stanford University
Award type: Postdoctoral fellowship
$90,000

Innovative Treatment Modalities

Inhibition of Brain Metastases in Breast Cancer
Brunhilde Felding-Habermann, Ph.D.
The Scripps Research Institute
Award type: IDEA
$278,850

ID4: A Prognostic Factor of Breast Cancer Metastasis
David S. Hoon, Ph.D.
John Wayne Cancer Institute
Award type: IDEA
$283,200

HER3 Infidelity and Resistance to Tyrosine Kinase Inhibitors
Mark M. Moasser, M.D.
University of California, San Francisco
Award type: IDEA
$150,000

cAMP Antagonists of Protein Kinase as Breast Cancer Drugs
Sanjay Adrian Saldanha, Ph.D.
The Scripps Research Institute
Award type: Postdoctoral fellowship
$90,000

An Approach to Antiestrogen Resistance in Breast Cancer
Oksana V. Tyurina, Ph.D.
University of California, San Diego
Award type: Postdoctoral fellowship
$135,000

Inhibition of the BRCA2-RAD51 Interaction in Breast Cancer
Jiewen Zhu, Ph.D.
University of California, Irvine
Award type: Postdoctoral fellowship
$135,400