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:
- Imaging, Biomarkers, and Molecular Pathology: Improving Detection and Diagnosis
- Innovative Treatment Modalities: Search for a Cure
Research Conclusions
Breast Cancer Functional Imaging with Optics and
MRI
Researchers are trying to develop new imaging
techniques that can identify breast cancers better
than mammography, which is currently the best
tool available. Nola Hylton, Ph.D., at the University
of California, San Francisco and John Butler,
M.D, and Bruce Tromberg, Ph.D., at the University
of California, Irvine, are developing a laser
breast scanner that, like mammography, could be
used for breast cancer screening and detection.
The research team previously demonstrated that
their hand-held laser breast scanner, which uses
diffuse optical spectroscopy (DOS), was able to
detect both cancerous and non-cancerous tumors.
They have now developed a new technique that
combines MRI and DOS information to assess
breast density. Drs. Butler, Hylton, and Tromberg
demonstrated that DOS can find breast tumors
in both pre-menopausal and post-menopausal
women; generated maps of tumor biochemistry;
and developed ways to identify absorption patterns
that differentiate malignant tumors from
normal tissue. They also demonstrated that DOS
can measure a tumor’s response to chemotherapy
given prior to surgery. This work could lead
to the introduction of new tools for breast cancer
screening and diagnosis. Findings from this
research were published in Journal of Biomedical
Optics 2004(9)230 and 534, 2005(10)5150;
Disease Markers 2004(19)95; Technology in
Cancer Research and Treatment 4(2005)549;
and Breast Cancer Research 2005(7)279.
Early Breast Cancer Detection Using 3D Ultrasound
Tomography
Early detection is one of the main tools we currently
have to improve breast cancer survival.
Mammography is the current “gold standard” for
diagnosing breast disease. But it doesn’t work
well in women with dense breast tissue, and is
not adequate for those who are high-risk. For
these women, ultrasound is an important adjunct
to mammography. However, ultrasound is operator
dependent and the lack of consistency between
centers limits widespread acceptance. To
address this problem, Thomas Nelson, Ph.D., at
the University of California, San Diego, and colleagues
constructed and tested a prototype volume
breast ultrasound scanner that can standardize
the acquisition of ultrasound data from the
breast. This work has the potential to improve
early detection of breast disease, especially in
women with dense breast tissue. Findings from
this research were published in IEEE Transactions
on Biomedical Engineering 2007(54)1885 and
Medical Physics 2008(35)1078.
New Technology to Enhance PET Imaging of
Breast Cancer
Currently, Positron Emission Tomography (PET)
is impractical for routine breast imaging. This
is because the PET system is large, expensive,
and requires a long scan time. Furthermore, it is
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VII Research Funding and Results
unable to detect very small lesions. Craig Levin,
Ph.D., at Stanford University, Palo Alto, is working
in collaboration with Dr. James Matteson, at
the University of California San Diego Center for
Astrophysics and Space Studies, to develop a
high-performance, compact, cost effective PET
system dedicated to breast imaging. They are
trying to develop a system that can see smaller
lesions, that will have a shorter scan time, and
that will cost significantly less than the currently
available machine. If successful, this work
could increase the role of PET in breast cancer
management as well as bring PET to smaller
clinics nationwide. Findings from this research
were published in PET Clinics 2007(2)125 and IEEE Transactions in Nuclear Science 2007(M19-
35)3700.
Combined Imaging Modalities for Breast Cancer
Dynamic contrast enhanced (DCE) MRI has
become the most popular imaging technique
for screening young women for breast cancer.
DCE-MRI is also considered the best method
available for screening women who have breast
implants or scar tissue. However, DCE-MRI also
detects many benign lesions, which can lead
to unnecessary anxiety, biopsies, or over-treatment.
Gultekin Gulsen, Ph.D., at the University
of California, Irvine, is developing a novel type
of MRI that will improve upon the current DCEMRI
screening technology. The final version of
this new imaging device is expected to be ready
soon, and Dr. Gulsen and his colleagues have
received funding from another source to continue
their clinical research studies. This work
has the potential to bring a new imaging device
that surpasses what is currently available into
the clinic setting. Results from this study were
published in Physics in Medicine and Biology 2008(53)3189-200.
In Vivo MRS for Cancer Diagnosis and Treatment
Monitoring
Magnetic resonance spectroscopy (MRS) is a
non-invasive technique that can provide information
about a tumor’s metabolism. This information
may be able to improve a doctor’s ability to
diagnose and treat breast cancer. Hyeon-Man
Baek, Ph.D., at the University of California, Irvine,
investigated whether MRS improves the ability
of dynamic contrast enhanced MRI (DCE-MRI)
both to diagnosis breast cancer and to evaluate a
tumor’s response to chemotherapy given prior to
surgery. Dr. Baek’s team found that MRS did not
improve the sensitivity (the false negative rate)
of DCE-MRI in detecting breast cancer tumors. It
did, however, improve the specificity (the false
positive rate), which is consistent with previously
published research. Dr. Baek also found
that MRS appears to be better at detecting a
tumor’s response to chemotherapy than the current
method, which involves physically measuring
the tumor’s size. Dr. Baek intends to conduct
additional research on MRS in conjunction with
DCE-MRI. This work could lead to improvements
in how MRI is used to guide breast cancer treatment.
Three papers were published with this
grant support, including Annals of Oncology
2008(19)1022-4.
Removing Respiratory Artifacts in Nuclide Breast
Imaging
Positron emission tomography (PET) breast
exams typically require several minutes to acquire
data, and the resulting image represents an
averaging of tumor motion over several breathing
cycles. This can make the picture of the breast
cancer tumor blurry; it can also make it easy to
miss a tumor. Brian Thorndyke, Ph.D., at Stanford
University, Palo Alto, explored ways to separate
and the recombine the data acquired during
a PET scan to reduce the impact breathing has
on breast cancer PET imaging. His initial studies
suggested that the technique he developed could
have the potential to reveal small tumors that
would otherwise have been missed. This work
could lead to the development of data collection
methods that improve the ability of PET scans to
find breast cancer tumors.
rADDs: Novel Disintegrins Targeting Breast Cancer
Breast cancer cells have proteins on their surface
that can be used as targets for anti-cancer treatments.
These proteins can also be detected with
special imaging agents. Stephen Swenson, Ph.D.,
at the University of Southern California, Los Angeles,
is exploring whether a fragment of a type
of protein called natural human ADAM (A Disintegrin
And Metalloproteinase) can bind to breast
cancer cells and stop both tumor and blood vessel
growth. Dr. Swenson and his team produced a recombinant ADAM-Derived Disintegrin (rADD)
protein, and studied the effect it had on breast
cancer cell lines and the extracellular matrix (the
scaffolding that surrounds and supports cells).
They then used a mouse model to evaluate
whether the rADD protein could limit cancer cell
growth and stop tumors from making the blood
vessels they need to grow and spread. In addition,
they put an imaging agent on rADD proteins
so that they could be identified on primary and
metastatic tumors during a Positron Emission
Tomography (PET) scan. This work could lead to
the development of new ways of diagnosing and
treating breast cancer.
Inhibition of the BRCA2-RAD51 Interaction in
Breast Cancer
Women who inherit a mutation in the gene called
BRCA2 (BReast CAncer 2) are at increased risk
of developing breast cancer. BRCA2 works with
a protein, called Rad51, to repair DNA breaks. If
this BRCA2-Rad51 interaction is disrupted in a
breast cancer cell, the cell will be more likely to
respond to anti-cancer drugs. Jiewen Zhu, Ph.D.,
at the University of California, Irvine, and colleagues
had previously identified two small compounds,
IBR1 and IBR2, which disrupt the BRCA2-
Ra51 interaction, inhibit breast cancer cell
growth, and make breast cancer cells more likely
to respond to radiation or the chemotherapy drug
cisplatin. In this project, Dr. Zhu tried to modify
these two compounds to improve their effectiveness.
So far, the new compounds Dr. Zhu and his
team have developed have not proven to be more
effective than IBR1 and IBR2. However, they
have found compounds that are more soluble and
stable, which is important for new drug development.
Dr. Zhu and colleagues are continuing to
search for a new, more effective IBR compound.
This work could lead to the development of new
treatments specifically for women with breast
cancer who carry a BRCA2 mutation.
Breast Tumor Inhibition by Vitamin D in a Mouse
Model
Clinical trials have demonstrated that the active
form of vitamin D, called calcitriol, can delay cancer
progression and prolong survival in prostate
cancer patients without causing serious side effects.
David Feldman, M.D., at Stanford University,
Palo Alto, used a mouse model to examine
whether calcitriol is an effective breast cancer
treatment when combined with non-steroidal antiinflammatory
drugs (NSAIDs) or an aromatase
inhibitor. (Aromatase inhibitors are used to treat
hormone-responsive tumors.) Dr. Feldman and
his team found that when given alone, calcitriol
decreased levels of COX-2, an enzyme that
helps prostaglandins stimulate aromatase. It also
decreased levels of aromatase and estrogen receptor
alpha. A follow-up study found that when
calcitriol and an aromatase inhibitor were given
together, it was more effective in inhibiting tumor
growth than either calcitriol or an aromatase inhibitor
alone. These findings could pave the way
for clinical trials that would evaluate whether a
combination of calcitriol and an aromatase inhibitor
were more effective than an aromatase inhibitor
alone in treating women with breast cancer.
Inhibition of Breast Cancer Aggressiveness by
Cannabidiol
Investigators are continually trying to identify
effective cancer treatments that do not cause
serious side effects. Sean McAllister, Ph.D., at
the California Pacific Medical Center Research Institute,
San Francisco, and colleagues previously
discovered that cannabidiol, a non-psychotropic
component of the Cannabis sativa (marijuana)
plant, can inhibit aggressive breast cancer cells
from growing and spreading. This research
project allowed Dr. McAllister and his team to
conduct additional studies on cannabidiol’s effectiveness
in treating breast cancer. The research
team discovered that cannabidiol was able to
slow breast cancer growth in both a cell model
and a mouse model. They also demonstrated, for
the first time, that cannabidiol is able to decrease
production of a protein, called Id-1, which is
believed to make breast cancer more aggressive.
Building on these findings, Dr. McAllister and his
team made small structural changes to cannabidiol
that could make it even better at inhibiting Id-1
and aggressive breast cancers. These findings
could lead to the development of cannabinoid
compound-based treatments for aggressive types
of breast cancer. Findings from this research
were published in Molecular Cancer Therapeutics 2007(6)2921.
Artemisinin Disrupts Estrogen Receptor-Alpha
and Cell Growth
Breast cancer treatments that have fewer side
effects than those currently available are widely
needed. Natural plant compounds provide a potential
source for these treatments. One promising
natural compound is Artemisinin, which
has been used by Chinese traditional medicine
practitioners for at least two thousand years
to treat fever. It has also been used since the
1970s as an anti-malaria drug. Gary Firestone,
Ph.D., at the University of California, Berkeley,
and colleagues discovered that artemisinin is able
to disrupt estrogen responsiveness in human
hormone-responsive breast cancer cell lines. They
also observed that artemisinin inhibits estrogen
receptor-alpha (ER-alpha) without having any effect
on estrogen receptor-beta (ER-beta). Following
up on this finding, Dr. Firestone and his team
uncovered an artemisinin-regulated region of
ER-alpha that makes the ER-alpha gene sensitive
to artemisinin. In addition, they demonstrated
that not only does artemisinin disrupt estrogen
responsiveness and the growth of human breast
cancer cells, but that artemisinin and anti-estrogens
work together to slow the growth of estrogen
responsive breast cancer cells. This work
could lead to the development of new artemisinin-
based cancer treatments.
A Targeted Therapy for Wound-like Breast Cancers
When an injury occurs, cells that are normally
dormant begin to divide rapidly in an effort to
close up the wound. The cells’ work includes
remodeling the extracellular matrix that surrounds
them, migrating across tissue planes,
and sending out chemical signals to recruit new
blood vessels. Howard Chang, Ph.D., at Stanford
University, Palo Alto, and colleagues previously
discovered that some breast cancers exhibit
wound-like features that can be distinguished by
a specific pattern of 512 genes, which they call
a “wound signature.” They also showed that this
wound signature is found primarily in tumors that
are likely to metastasize. This project allowed
Dr. Chang and his colleagues to identify cancer
treatments that are able to target the breast cancer
cells that exhibit this wound signature. One
of the drugs they studied was bortezomib. It is
an FDA-approved drug that is the first in a new
class of medicines called proteasome inhibitors.
Dr. Chang and his team found that bortezomib
has the potential to be effective in treating breast
tumors that have this wound signature. Dr. Chang
and his team also were able to identify how bortezomib
is able to block human breast cancer cell
growth. This work could lead to new treatments
for the subset of breast cancers that have the
genetic pattern known as the wound signature.
Neural Stem Cell Therapy for Breast Cancer Brain
Metastases
Breast cancer is the main source of metastatic
brain disease in women, and nearly 30% of all
women with advanced breast cancer will be diagnosed
with brain metastasis. Brunhilde Felding-
Habermann, Ph.D., at the Scripps Research Institute,
La Jolla, is exploring whether breast cancer
brain cells can be targeted with neural stem cells,
which are the body’s own mechanism for healing
and regeneration in the brain. Dr. Felding-Habermann
and her colleagues previously showed that
neural stem cells seek out cancerous areas in the
brain and follow spreading breast cancer lesions
within the brain tissue. In this research project,
Dr. Felding-Habermann and her team used human
and mouse tumor cell systems to follow the progression
of metastasis development and observe
how neural stem cells track the tumor cells in real
time. This work showed that implanted neural
stem cells seek out even widespread metastatic
breast cancer lesions within the brain tissue. Dr.
Felding-Habermann was funded by the CBCRP
to continue to explore the safety and effectiveness
of neural stem cell based treatments. This
work could lead to new treatments for metastatic
breast cancer that has spread to the brain.
Vascular Targeting Therapy for Breast Cancer
Women whose tumors express a large amount
of a protein called Her-2/neu are at increased
risk of having their cancer recur or of developing
metastatic disease. The immune response does
not respond to Her-2/neu because the protein is
naturally present on the body’s epithelial cells.
Albert Deisseroth, M.D., Ph.D., at the Sidney
Kimmel Cancer Center, San Diego, and colleagues
have developed a vaccine that can trick the immune
system into responding to both Her-2/neu
and the blood vessels that breast tumors develop
as if they were a viral infection. In this project, which used an animal model, Dr. Deisseroth and
his team found that combining their vaccine with
conventional chemotherapy resulted in a greater
levels of immune response and cancer suppression
than either the their vaccine or chemotherapy
alone. Dr. Deisseroth and his team intend to
conduct additional research on this new vaccine.
This work could lead to new breast cancer
treatments that are more effective than traditional
chemotherapy regimens. Results from this
research were published in Molecular Therapy
2008(16)1753-60.
Symposium on the Intraductal Approach to Breast
Cancer
The Dr. Susan Love Research Foundation is committed
to advancing research and developing
resources that explore the intraductal approach
to the breast. As part of this effort, Susan Love,
M.D., M.B.A., at the Dr. Susan Love Research
Foundation, Santa Monica, and colleagues hosted
The 5th International Symposium on the Intraductal
Approach to Breast Cancer in Santa Monica,
California, March 1-4, 2008. In attendance were
more than 120 oncologists, epidemiologists, biostatisticians,
surgeons, biochemists, pathologists,
radiologists, endocrinologists, and breast cancer
advocates who are currently conducting, or are
interested in, research utilizing the intraductal
approach.
The Symposium addressed topics ranging from “Anatomy of the Breast,” and “Ductoscopy and Imaging,” to “Intraductal Therapy,” and “Nipple Aspirate Fluid: The Optimal Approach to Screening?” It also provided participants with the opportunity to observe demonstrations of ductoscopy and ductal lavage with ultrasound. A Public Panel provided the community with information about ongoing intraductal research. At the close of the Symposium, the Foundation awarded $100,000 in pilot grants to 12 research studies.
Grants in Progress: 2008 Breast Cancer Treatment Monitoring Combining
MRI and Optics Chemical Inhibitors of Hsp70 for Breast Cancer Determinants of Response to Microtubule Stabilizing
Drugs Differential Optical Mammography Engineering EGFR Antagonists for Breast Tumor
Targeting Exploring the Role of PARP Inhibitors in Breast
Cancer Factors Influencing Breast Cancer Screening
Among Older Thai ID4: A Prognostic Factor of Breast Cancer Metastasis Inhibition of Brain Metastases in Breast Cancer Intraductal Therapy of DCIS: a Presurgery Study Intraoperative Assessment of Surgical Lumpectomy
Margins Mechanisms of HSP90 Inhibitor Action in Breast
Cancer Modulation of Breast Cancer Stem Cell Response
to Radiation Molecular Imaging of Breast Cancer Using Breast
PET/CT Molecular Imaging of Metastatic Lymph Nodes in
Breast Cancer Multinuclear MRI of Breast Tumors Neural Stem Cell Therapy for Breast Cancer Brain
Metastases |
Novel Cytokine Immunotherapy for Breast Cancer Nur77-derived Peptides as a Novel Breast Cancer
Therapy Polyamide HIF Inhibitors to Block Breast Cancer
Metastasis Real-Time 3D Ultrasound Image-Guidance for
Breast Surgery Sulforaphane: Its Potential for Treatment of
Breast Cancer Topoisomerase-IIa as a Predictor of Anthracycline
Response Research Initiated in 2008 Functional Breast MRI with BOLD Contrast Genetics of Tamoxifen Response Imaging of Novel Stem Cell Therapy Targeting
Breast Cancer Inhibition of TF Signaling as Novel Breast Cancer
Therapy Nanotherapy for Breast Cancer Targeting Tumor
Macrophages Novel Anti-HER2 Fragments for Better Detection
and Therapy Novel Small Proteins for PET Imaging of Breast
Cancer Stratifying DCIS Biopsies for Risk of Future Tumor
Formation Topoisomerase-IIa as a Predictor of Anthracycline
Response Treating BC Brain Metastasis with Cytotoxic
Lymphocytes |
