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Gene expression ratio identifies risk
of recurrence in breast cancer patients receiving tamoxifen
Research from MGH, Arcturus could
indicate which patients need alternative treatment
BOSTON - June 3, 2004 -A simple measurement of the expression
levels of two genes in breast cancer tissue appears to identify
tumors that are more likely to recur in women treated with tamoxifen
for early-stage disease. Determining patients for whom tamoxifen
treatment is likely to fail would allow earlier use of other therapies
that could be more effective for those women.
Researchers from the Massachusetts General Hospital (MGH) Cancer
Center and Arcturus
Bioscience, Inc., describe their findings in a report to be
published in the June issue of Cancer
Cell. The paper is being released online today because related
material is being presented at the June 5-8 American Society for
Clinical Oncology meeting. The study was supported by grants from
the Avon
Foundation, the U.S. Department of Defense, and the National
Cancer Institute.
Tamoxifen, which blocks the interaction between the hormone estrogen
and its receptor protein, is used to treat breast cancers that express
the estrogen receptor. However, only two thirds of these patients
have a prolonged response to the drug. "Until now, there has
been no way to predict which estrogen-receptor-positive patients
will not respond to tamoxifen treatment," says Dennis Sgroi,
MD, director of Breast Pathology at MGH who led the hospital's research
team. "Identifying those for whom tamoxifen is likely to fail
could allow physicians to choose other drugs, for instance the aromatase
inhibitors that more completely block estrogen's action." Sgroi
is an associate professor of Pathology at Harvard Medical School.
The hormone estrogen can stimulate both the normal growth of breast
tissue and the uncontrolled growth of breast cancer. Cells from
most breast tumors contain estrogen receptor molecules, indicating
that the tumor's growth is likely to be sensitive to the hormone's
action. Estrogen-blocking drugs have been used in recent years to
prevent hormone-sensitive breast tumors from recurring after surgery
and to treat metastasis. More than 500,000 U.S. women currently
take tamoxifen, making it the most frequently used drug of this
class.
The MGH and Arcturus research teams have collaborated for several
years on studies of the molecular characteristics of breast tumors.
Last year they published a study
showing that advanced analysis technologies that identify which
genes are expressed, or "turned on," in tumors can characterize
the tumor's aggressiveness. As a follow-up to that work, the research
teams led by Sgroi and Mark Erlander, PhD, Arcturus chief scientific
officer, began to investigate whether such molecular signatures
could help identify which drugs would be the best options for particular
patients.
The researchers gathered tumor samples from patients who had received
tamoxifen treatment for early-stage, estrogen-receptor-positive
breast cancer. They identified 60 frozen samples suitable for gene
expression analysis for which clinical follow-up information was
available. Of those 60 patients, 32 had remained disease-free for
an average of eight years, while 28 had recurrence of their tumor
or metastasis.
Expression profile analysis demonstrated that the ratio between
the expression levels of two genes - HOXB13 and IL17BR - was the
strongest predictor of whether a tumor would recur. The higher the
expression level of HOXB13 and the lower the expression of IL17BR,
the greater the chance of tumor recurrence. Data from an additional
20 samples of tamoxifen-treated tumors supported the predictive
power of the two-gene expression ratio.
"Many clinical laboratories currently have the capability to
utilize Arcturus technology to measure the relative expression of
these two genes," says Erlander. "Several centralized
laboratories are developing a test that will be available this summer."
Because HOXB13 is known to be overexpressed in some breast tumors,
the researchers investigated whether the gene might also play a
role in tumor development. Using cells from normal breast tissues,
they induced the expression of the HOXB13 gene. Cells in which the
gene was activated showed obvious structural changes and appeared
to have an increased ability to move and invade other tissues, characteristics
of tumor cells. While that result must be confirmed by future studies,
it suggests that the pathway controlled by HOXB13 could be a new
therapeutic target.
The report's co-authors are first author Xiao-Jun Ma, PhD, Ranelle
Salunga, J. Todd Tuggle, Yen Tran, Diem Tran, Ana Sollberger, Paul
Amon, Wilson Wang, Wei Wang, Kimberly Stecker, Eden Estepa-Sabal
and Thomas Baer, PhD, of Arcturus; Zuncai Wang, PhD, Paula Ryan,
MD, PhD, Anne Barmettler, Andrew Fuller, Beth Muir, Gayatry Mohapatra,
PhD, Barbara Smith, MD, PhD, Jerry Younger, MD, Ulysses Balis, MD,
Atul Bhan, MD, Karleen Habin, RN, and Daniel Haber, MD, PhD, of
the MGH; and Steven Isakoff, MD, PhD, and Joan Brugge, PhD, of Harvard
Medical School.
Massachusetts General Hospital, established in 1811, is the original
and largest teaching hospital of Harvard Medical School. The MGH
conducts the largest hospital-based research program in the United
States, with an annual research budget of more than $400 million
and major research centers in AIDS, cardiovascular research, cancer,
cutaneous biology, medical imaging, neurodegenerative disorders,
transplantation biology and photomedicine. In 1994, MGH and Brigham
and Women's Hospital joined to form Partners HealthCare System,
an integrated health care delivery system comprising the two academic
medical centers, specialty and community hospitals, a network of
physician groups, and nonacute and home health services.
Arcturus Bioscience, Inc., the leading company in laser microdissection
instruments and reagents for the analysis of microscopic tissue
samples. These tools enable researchers to perform rapid cell-based
analysis of disease progression utilizing the smallest and purest
samples possible to date. The company has developed this unique
technology platform for genetic analysis of biopsy samples and has
applied its platform to discover cell-specific gene signatures associated
with human diseases such as cancer. Arcturus is a private company
headquartered in Mountain View, California.
Media Contact: Sue
McGreevey, MGH Public Affairs
Kevin Knight, Arcturus Bioscience,
214-739-0353
MGH Physician Referral Service: 1-800-388-4644
Information about MGH Clinical Trials
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