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Sunday 12th December, 2004
The results suggest that almost half of those diagnosed with
estrogen-dependent, lymph-node negative breast cancer may not need chemotherapy.
A new test can predict both the risk of breast cancer recurrence and
may identify women who will benefit most from chemotherapy, according to
research supported by the National Cancer Institute (NCI), part of the
National Institutes of Health, and performed in collaboration with the
National Surgical Adjuvant Breast and Bowel Project (NSABP) and Genomic
These results suggest that almost half of over 50,000 U.S. women
diagnosed with estrogen-dependent, lymph-node negative breast cancer*
every year are at low risk for recurrence and may not need to go through
the discomfort and side effects of chemotherapy.
The test is based on levels of expression (increased or decreased) of
a panel of cancer-related genes. This panel is used to predict whether
estrogen-dependent breast cancer will come back, according to a study
that will be published online in the New England Journal of Medicine on
Friday, December 10, 2004. Scientists on this study also will present
new results on that day at San Antonio Breast Cancer Symposium
indicating that the same test can predict which women benefit most from
chemotherapy. Women with low risk of breast cancer recurrence--about
half of the women in the recent study--do not appear to derive much
benefit from chemotherapy.
The researchers used tissue samples and medical records from women
enrolled in clinical trials of the cancer drug tamoxifen, which blocks
the effect of estrogen on breast cancer cells. These women had a kind of
breast cancer defined as estrogen receptor-positive, lymph
node-negative. The technique used is known as
reverse-transcriptase-polymerase-chain-reaction (RT-PCR). Each year, over 50,000 women are diagnosed with this kind
of breast cancer, which needs estrogen to grow but has not spread to the
lymph nodes. Currently, many women with this type of breast cancer in
the United States do receive chemotherapy in addition to hormonal
"The test has the potential to
change medical practice by sparing thousands of women each year from
the harmful short- and long-term side effects associated with
Using samples from 447 patients and a collection of 250 genes in
three independent preliminary studies, 16 cancer-related genes were
found that worked best. The scientists created a formula that generates
a "recurrence score" based on the expression patterns of these genes in
a tumor sample. Ranging from 1 to 100, the recurrence score is a measure
of the risk that a given cancer will recur.
Prior to this research, analysis of the expression of genes was
performed on tumor specimens that were frozen rather than on tissue
prepared for routine pathologic evaluation (fixed and embedded). The
expression analysis depended on measurement of RNA (the molecule
necessary for the translation of a gene into a protein), and RNA is
altered when tissues are fixed and embedded. Frozen tissues are
generally not readily available in routine practice. Researchers at
Genomic Health Inc. developed a method for performing these analyses on
tissues embedded in paraffin wax. Their method allows them to use the
altered RNA that is found in fixed tissue.
The results published in the New England Journal of Medicine validate
the ability of the recurrence score to predict risk of recurrence. Using
biopsy tissue and medical records from another NSABP tamoxifen trial,
researchers divided 668 women into low, intermediate, and high risk of
recurrence groups. Fifty-one percent were in the low risk group (with a
score of less than 18); 22 percent were at intermediate risk (recurrence
score 18 or higher but less than 31); 27 percent were at high risk (a
score of 31 or higher).
These risk group divisions correlated well with the actual rates of
recurrence of breast cancer after 10 years. There was a significant
difference in recurrence rates between women in the low and high risk
groups. In the low risk group, there was a 6.8 percent rate of
recurrence at 10 years; in the intermediate and high risk categories
these rates were 14.3 percent and 30.5 percent, respectively. Up to a
recurrence score of 50, rates of recurrence increased continuously as
the recurrence score increased. These trends held across age groups and
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"These results were generated perhaps a decade earlier than would
have been possible if the researchers had not had access to biopsy
tissue from the NSABP trials," notes Sheila E. Taube, Ph.D., associate
director of NCI's Cancer Diagnosis Program.
The same 21-gene test has also been used to predict how beneficial
chemotherapy will be for women with estrogen receptor-positive, lymph
node-negative breast cancer for women on tamoxifen in NSABP trials.
These results will be presented at the San Antonio Breast Cancer
Symposium on December 10, 2004.
"NCI staff worked with the company, NSABP and experts from other NCI
Cooperative Groups to develop an overall strategy; this plan was
fruitful and may lead to providing an important tool for physicians and
women to use in considering breast cancer treatment decisions," said
In the treatment study, women with high recurrence scores, who are
representative of about 25 percent of patients with this kind of breast
cancer, had a large benefit from chemotherapy in terms of 10 year
recurrence-free rates. Women with low recurrence scores, who represent
about 50 percent of these patients, derived minimal benefits from
chemotherapy. The group under study was not large enough to determine
whether chemotherapy is detrimental to the low risk group.
"The test has the potential to change medical practice by sparing
thousands of women each year from the harmful short- and long-term side
effects associated with chemotherapy," said JoAnne Zujewski, M.D.,
senior investigator in NCI's Cancer Therapy Evaluation Program.
Paik S, Shak S, Wolmark N, et al. A multigene assay to predict
recurrence of tamoxifen-treated, node-negative breast cancer. New
England Journal of Medicine, 351(27). December 30, 2004.