- Approximately 75% of women diagnosed with
breast cancer survived their disease at least
5 years.
- Mastectomy was the only accepted surgical
option for breast cancer treatment.
- Only one randomized trial of mammography
for breast cancer screening had been conducted.
- Clinical investigation of combination
chemotherapy, using multiple drugs with
different mechanisms of action, and of hormonal
therapy as post-surgical (adjuvant) treatment for
breast cancer was in its earliest stages.
-
Hormonal treatment of inoperable or advanced
breast cancer with tamoxifen, a selective estrogen
receptor modulator (SERM), was being
investigated but had not yet been approved by
the U.S. Food and Drug Administration (FDA).
- Genes associated with an increased risk of
breast cancer had not yet been identified.
- Nearly 90% of women diagnosed with breast
cancer will survive their disease at least 5 years.
-
Breast-conserving surgery (lumpectomy)
followed by local radiation therapy has replaced
mastectomy as the preferred surgical approach
for treating women with early stage breast cancer.
- Routine mammographic screening is an accepted
standard for the early detection of breast
cancer. The results of eight randomized trials
and of the NCI-ACS Breast Cancer Detection
Demonstration Projects established that
mammographic screening can reduce mortality
from breast cancer.
-
Combination chemotherapy has become
standard in the adjuvant treatment of women
with early stage breast cancer. The goal of
this systemic therapy is to eradicate cancer
cells that may have spread beyond the breast.
Neoadjuvant chemotherapy, or chemotherapy
given before surgery to reduce the size of
the tumor and to increase the chance of
breast-conserving surgery, is being studied
in clinical trials.
- Hormonal therapy with SERMs, such as
tamoxifen, and aromatase inhibitors is now
standard in the treatment of women with
estrogen receptor-positive breast cancer, both
as adjuvant therapy and in the treatment of
advanced disease. Estrogen receptor-positive
breast cancer cells can be stimulated to grow
by the hormone estrogen. SERMS interfere
with this growth stimulation by preventing
estrogen from binding to its receptor. In
contrast, aromatase inhibitors block estrogen
production by the body. FDA-approved
aromatase inhibitors include anastrozole,
exemestane, and letrozole.
- Tamoxifen and another SERM, raloxifene,
have been shown in clinical trials to prevent
the development of invasive breast cancer in
women at high risk of this disease. Tamoxifen
has already been approved by the FDA as a
breast cancer prevention drug.
-
The monoclonal antibody trastuzumab is
being used to treat breast cancers that
overproduce a protein called human epidermal
growth factor receptor 2 or HER2. This protein
is overproduced in about 20% of breast cancers.
These HER2-overproducing cancers tend to
be more aggressive and are more likely to
recur. Trastuzumab targets the HER2 protein,
and this antibody, in conjunction with adjuvant
chemotherapy, can lower the risk of HER2-
overproducing breast cancer recurrence by
50% compared to chemotherapy alone.
- The study of large groups of related individuals
(kindreds) has led to the identification of several
breast cancer susceptibility genes, including
BRCA1, BRCA2, TP53, and PTEN/MMAC1.
Mutations in BRCA1 and BRCA2 account for
approximately 80-90% of all hereditary breast
cancers, and women who carry mutations in
these genes have a lifetime risk of breast cancer
that is roughly 10 times greater than that of the
general population.
We will exploit our rapidly increasing knowledge of
genetics, molecular biology, and immunology
to develop even more effective and less toxic
treatments for breast cancer. We will expand our
ability to target and disrupt the effects of molecular
changes that cause breast cells to become cancerous.
In addition, we will use this knowledge to
personalize breast cancer therapy. For example:
-
Gene expression analysis has led to the
identification of five subtypes of breast cancer
that have distinct biological features, clinical
outcomes, and responses to chemotherapy.
This knowledge should allow the development
of treatment strategies based on an individual's
tumor characteristics.
- A patient's response to chemotherapy is
influenced not only by the tumor's genetic
characteristics but also by inherited variation in
genes that affect a person's ability to absorb,
metabolize, and eliminate drugs. This knowledge
should allow prediction of tumor response to
and the likelihood of severe adverse effects from
individual chemotherapy drugs or classes of
drugs. It should also aid in the design of more
effective and less toxic chemotherapeutic agents.
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