Download Aromatase Inhibitors

Aromatase Inhibitors
Before describing how AI’s works, it's important to understand the effects of estrogen on cancer.
Hormone dependent breast cancers contain protein molecules called estrogen receptors. When
no estrogen is present, the estrogen receptors remain inactive. When the estrogen receptors are
exposed to estrogen, however, they trigger a chain of events that may result in tumor cell growth
and multiplication, as illustrated here.
Tumors that contain these estrogen receptors are known as estrogen receptor-positive (ER+)
tumors. A test is done to determine whether breast cancer is estrogen receptor-negative (ER-) or
ER+. A tumor must have been diagnosed as estrogen receptor-positive or estrogen receptorunknown for aromatase inhibitors to be prescribed.
Aromatase is the enzyme that produces estrogen in postmenopausal women. By interfering with
the production of estrogen triggered by aromatase, aromatase inhibitors actually reduce the total
amount of estrogen in the body. As a result, less estrogen can reach breast cancer cells. So, in
essence, aromatase inhibitors helps to starve breast cancer cells by depriving them of estrogen.
Surgery, radiation and chemotherapy all strive to remove breast cancer cells from the body.
However, even if a woman has undergone one or all three forms of treatment, a small number of
breast cancer cells may remain.The next illustration shows the effect aromatase inhibitors have
on the multiplication of those breast cancer cells.
Before therapy:
Androgen (a hormone
found in both men and
women) is produced by
fat, muscle, and adrenal
glands. Aromatase
enzyme is needed to
convert androgen into
estrogen, which results
in tumor growth.
With therapy: Aromatase
inhibitors binds to the
aromatase enzyme and
blocks it from converting
androgen to estrogen,
thereby reducing growth of
the tumor.
Indication
Femara (letrozole tablets) or Arimidex (anastrozole) are aromatase inhibitors and approved for
the adjuvant (following surgery) treatment of postmenopausal women with hormone receptorpositive early stage breast cancer..
AIs are approved for the extended adjuvant treatment of early stage breast cancer in
postmenopausal women who are within three months of completion of five years of tamoxifen
therapy.
In addition, aromatase inhibitors are approved for the treatment of postmenopausal women with
hormone receptor-positive or hormone receptor-unknown breast cancer that has spread to
another part of the body (metastatic cancer).
Possible Side Effects of Aromatase Inhibitors
Based on information from a study in patients with early breast cancer, women with a history of
blockages in heart arteries (ischemic heart disease) who take Aromatase Inhibitors may have a
slight increase in this type of heart disease compared to similar patients who take tamoxifen.
Aromatase inhibitors can cause bone softening/weakening (osteoporosis) increasing the chance
of fractures. In a clinical study in early breast cancer, there were more fractures (including
fractures of the spine, hip, and wrist) with aromatase inhibitors (10%) than with tamoxifen (7%).
In a clinical study in early breast cancer, some patients taking aromatase inhibitors had an
increase in cholesterol. Skin reactions, allergic reactions, and changes in blood tests of liver
function have also been reported.
In the early breast cancer clinical trial, the most common side effects seen with aromatase
inhibitors include hot flashes, joint symptoms (including arthritis and arthralgia), weakness, mood
changes, pain, back pain, sore throat, nausea and vomiting, rash, depression, high blood
pressure, osteoporosis, fractures, swelling of arms/legs, insomnia, and headache.
Patients taking aromatase inhibitors were less likely than those taking tamoxifen to stop
treatment because of side effects.
SELECTIVE ESTROGEN RECEPTOR MODULATORS
In working on the development of antiestrogens, scientists have made a somewhat surprising
discovery. Some drugs that block the action of estrogen in certain tissues actually can mimic the
action of estrogen in other tissues.
Such selectivity is made possible by the fact that the estrogen receptors of different target
tissues vary in chemical structure. These differences allow estrogen-like drugs to interact in
different ways with the estrogen receptors of different tissues. Such drugs are called selective
estrogen receptor modulators, or SERMs, because they selectively stimulate or inhibit the
estrogen receptors of different target tissues. For example, a SERM might inhibit the estrogen
receptor found in breast cells but activate the estrogen receptor present in uterine endometrial
cells. A SERM of this type would inhibit cell proliferation in breast cells, but stimulate the
proliferation of uterine endometrial cells.
Tamoxifen, the generic name of Nolvadex, is the oldest and most-prescribed SERM. Tamoxifen is
approved by the U.S. Food and Drug Administration (FDA) to treat:


women diagnosed with hormone-receptor-positive, early-stage breast cancer after
surgery (or possibly chemotherapy and radiation) to reduce the risk of hormonereceptor-positive breast cancer coming back (recurring)
women and men diagnosed with advanced (metastatic) hormone-receptor-positive
disease to produce regression and remission of the disease
Tamoxifen also is used to:

reduce breast cancer risk in women who haven't been diagnosed but are at higher-thanaverage risk for disease
Tamoxifen won't work on hormone-receptor-negative breast cancer.
Tamoxifen is a pill taken once a day. Most doctors recommend taking tamoxifen at the same time
each day.
Since its approval in 1998, tamoxifen has been used to treat millions of women and men
diagnosed with hormone-receptor-positive breast cancer. While an aromatase inhibitor is the first
hormonal therapy medicine choice for post-menopausal women, tamoxifen is the first choice for
pre-menopausal women and is still a good choice for post-menopausal women who can't take an
aromatase inhibitor.
Tamoxifen can:





reduce the risk of breast cancer coming back by 40% to 50% in post-menopausal
women and by 30% to 50% in pre-menopausal women
reduce the risk of a new cancer developing in the other breast by about 50%
shrink large, hormone-receptor-positive breast cancers before surgery
slow or stop the growth or advanced (metastatic) hormone-receptor-positive breast
cancer in both pre- and post-menopausal women
lower breast cancer risk in women who have a higher-than-average risk of disease but
have not been diagnosed
Tamoxifen offers other health benefits that aren't related to treating cancer. Because it's a SERM,
it selectively either blocks or activates estrogen's action on specific cells. While tamoxifen blocks
estrogen's action on breast cells, it activates estrogen's action in bone and liver cells. So
tamoxifen can:


help stop bone loss after menopause
lower cholesterol levels
Raloxifene is an oral (SERM) that has estrogenic actions on bone and anti-estrogenic actions on
the uterus and breast. It is used in the prevention of osteoporosis in postmenopausal women. It
was announced in April 2006 that raloxifene is as effective as tamoxifen in reducing the incidence
of breast cancer in certain high risk groups of females, though with a reduced risk of
thromboembolic events and cataracts in patients taking raloxifene versus those taking
tamoxifen.[1] On September 14, 2007, the FDA announced approval of raloxifene for reducing
the risk of invasive breast cancer in postmenopausal women with osteoporosis and in
postmenopausal women at high risk for invasive breast cancer.[2]
There has been criticism in the mainstream oncology press of the way that information about the
drug was released.[3] There has been some confusion in the lay media about the meaning of the
trial results. There is no specific clinical evidence for the use of raloxifene in the adjuvent
treatment of breast cancer over established drugs such as tamoxifen or anastrozole..
THE STAR TRIAL
The Study of Tamoxifen and Raloxifene, or STAR, is a clinical trial designed see how the drug
raloxifene compares with the drug tamoxifen in reducing the incidence of breast cancer in
postmenopausal women who are at increased risk of the disease. One of the largest breast
cancer prevention studies ever, STAR took place at more than 500 centers across the United
States, Canada, and Puerto Rico (NMCSD Breast Health Center
was one of the centers that was part of the trial)
Initial results of STAR show that the drug raloxifene is as
effective as tamoxifen in reducing the breast cancer risk of the
women on the trial. In STAR, both drugs reduced the risk of
developing invasive breast cancer by about 50 percent. In
addition, within the study, women who were assigned to take
raloxifene daily and who were followed for an average of about
four years, had 36 percent fewer uterine cancers and 29
percent fewer blood clots than the women who were assigned
to take tamoxifen. Uterine cancers, especially endometrial
cancers, are a rare but serious side effect of tamoxifen. Both
tamoxifen and raloxifene are known to increase a woman's risk
of blood clots.
Taxanes
Taxanes are a group of drugs that includes paclitaxel (Taxol) and docetaxel (Taxotere), which are
used in the treatment of cancer. Taxanes have a unique way of preventing the growth of cancer
cells: they affect cell structures called microtubules, which play an important role in cell
functions. In normal cell growth, microtubules are formed when a cell starts dividing. Once the
cell stops dividing, the microtubules are broken down or destroyed. Taxanes stop the
microtubules from breaking down; cancer cells become so clogged with microtubules that they
cannot grow and divide.
Paclitaxel is a compound that was originally isolated from the bark of the Pacific yew tree (Taxus
brevifolia). Early research using paclitaxel was limited due to difficulties in obtaining the drug.
The amount of paclitaxel in yew bark is small, and extracting it is a complicated and expensive
process. In addition, bark collection is restricted because the Pacific yew is a limited resource
located in forests that are home to the endangered spotted owl.
As demand for paclitaxel grew, NCI, in collaboration with other Government agencies and the
pharmaceutical company Bristol-Myers Squibb, worked to increase the availability and find other
sources of paclitaxel besides the bark of the Pacific yew tree. This work led to the production of a
semi-synthetic form of paclitaxel derived from the needles and twigs of the Himalayan yew tree
(Taxus bacatta), which is a renewable resource. The FDA approved the semi-synthetic form of
paclitaxel in the spring of 1995. This form of paclitaxel has now replaced the drug derived from
the bark of the Pacific yew tree
Dose Dense Chemotherapy
Dose-dense chemotherapy (DDC) is a concept of chemotherapy administration that is being used
more and more nowadays. Understanding DDC requires an understanding of tumor cell
replication and growth, sometimes referred to as the Gompertzian growth curve. This theory
represents the fact that tumor growth follows a mathematically predictable growth curve, with
rapid growth initially, then leveling off to slower growth. For example, while a tumor is small and
often undetectable by available tests, its cells grow very rapidly. Eventually, the tumor reaches a
size where it outgrows the available nutrients and blood supply, and tumor growth slows down.
Cells are most sensitive to chemotherapy when they are rapidly dividing, therefore the early
stage, smaller tumors are often more sensitive to chemotherapy. This is also why surgery may be
used to remove as much of the tumor as possible, leaving a small number of cells to then be
treated by chemotherapy. Standard chemotherapy regimens call for a standard dose of
chemotherapy given every 3 weeks (or 4, depending on the regimen), allowing for healthy cells
to recover between doses (such as blood counts, oral mucosa, and GI lining). However, we now
understand that this 3-week break may also allow the now smaller, more rapidly dividing tumor
cells to start growing rapidly again.
Dose-Dense Chemotherapy (DDC) aims to achieve maximum tumor kill by increasing the rate of
chemotherapy delivery, not by increasing dosage (which is the theory behind many stem cell
transplant protocols). By administering the same doses of chemotherapy previously given every 3
weeks on an every 2 week schedule instead, the chemotherapy interrupts the rapid growth phase
of the tumor cells. Thus, the therapeutic drugs interfere with the Gompertzian curve, hitting the
tumor cells at the time when they are just beginning to grow rapidly again. In other words, hit
them while they are down. This model was called the Norton-Simon model, after the researchers
who first described it.
You may ask why we haven't tried this before? The concern has always been that giving
chemotherapy more frequently would lead to neutropenia and infection, a potentially deadly
combination in a patient receiving chemotherapy. Through the use of growth factors ( Neupogen,
Neulasta, Leukine), we are able to have faster recovery of white blood cells, decreasing the
chance of infection. Several DDC studies have shown a higher incidence of anemia and bone pain
(likely related to the use of a growth factor) with these regimens, but the DDC regimens also
mean a decrease in the length of therapy by 4-6 weeks, which may be appealing to some.
While the theory seems logical, in practice the results have not been so clear. The first study was
done in women with node-positive breast cancer who were receiving chemotherapy with cytoxan,
adriamycin, and taxol. The women who received DDC had an overall survival of 92% three years
after treatment, versus 90% for the every 3 week regimen. As for recurrence of their cancer,
82% of women receiving DDC remained cancer-free, compared to 75% of the women on the
every three week regimen. Longer follow-up will give additional information in the coming years.
Two additional studies in women with node-positive breast cancer and using different
chemotherapy medications did not find a statistically significant difference (the method
researchers use to determine if the rate is greater than what might happen by chance) in survival
or recurrence rates. However, both studies showed a trend toward improved survival and fewer
recurrences. This may mean that certain subgroups of women would benefit from DDC. A trial for
women with metastatic breast cancer looked at giving paclitaxel weekly, compared with the
standard every three weeks, and saw a benefit in response and survival for the DDC group.
Several studies utilizing DDC prior to breast surgery (neoadjuvant chemotherapy) have shown
improved response rates in operable breast cancer. Studies are ongoing looking at various drug
regimens in dose-dense format and in combination with newer biologic therapies, such as
Herceptin. It appears that certain high-risk women (such as those with positive lymph nodes
and/or negative estrogen/progesterone receptors) or those for whom neoadjuvant chemotherapy
is an option would benefit most from DDC.
It is clear that there is a benefit to DDC for certain patients. Determining who will benefit is the
focus of current studies. In addition, longer follow-up of previously reported studies will give
more information on the use of DDC and long term benefits or complications.
HER2+ Breast Cancer
HER2 stands for Human Epidermal growth factor Receptor 2. Each normal breast cell contains
copies of the HER2 gene, which helps normal cells grow. The HER2 gene is found in the DNA of
a cell, and this gene contains the information for making the HER2 protein. 4
The HER2 protein, also called the HER2 receptor, is found on the surface of some normal cells in
the body. In normal cells, HER2 proteins help send growth signals from outside the cell to the
inside of the cell. These signals tell the cell to grow and divide. 4
In HER2+ breast cancer, the cancer cells have an abnormally high number of HER2 genes per
cell. When this happens, too much HER2 protein appears on the surface of these cancer cells.
This is called HER2 protein overexpression. Too much HER2 protein is thought to cause cancer
cells to grow and divide more quickly. This is why HER2+ breast cancer is considered aggressive.
Approximately 25% of breast cancer patients have tumors that are HER2+. -3
Herceptin
Herceptin (Trastuzumab) is the first humanized antibody approved for the treatment of HER2positive metastatic breast cancer. Herceptin is designed to target and block the function of HER2
protein overexpression.
Research has shown that HER2-positive breast cancer is a more aggressive disease with a
greater likelihood of recurrence, a poorer prognosis, and a decreased chance of survival
compared with HER2-negative breast cancer.
Adjuvant indications Herceptin is indicated for adjuvant treatment of HER2-overexpressing nodepositive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer:



As part of a treatment regimen containing doxorubicin, cyclophosphamide, and either
paclitaxel or docetaxel
With docetaxel and carboplatin
As a single agent following multi-modality anthracycline-based therapy
Metastatic indications Herceptin is indicated:


In combination with paclitaxel for the first line treatment of HER2-overexpressing
metastatic breast cancer
As a single agent for treatment of HER2-overexpressing breast cancer in patients who
have received one or more chemotherapy regimens for metastatic disease
Status The U.S. Food and Drug Administration (FDA) approved Herceptin in September 1998. In
November 2006, the FDA approved Herceptin as part of a treatment regimen containing
doxorubicin, cyclophosphamide and paclitaxel, for the adjuvant treatment of patients with HER2positive, node-positive breast cancer.
In January 2008, the FDA approved Herceptin as a single agent for the adjuvant treatment of
HER2-overexpressing node-negative (ER/PR-negative or with one high-risk feature) or nodepositive breast cancer, following multi-modality anthracycline-based therapy
Oncotype DX
The Oncotype DX assay is a 21-gene assay that provides an individualized prediction of
chemotherapy benefit and 10-year distant recurrence to inform adjuvant treatment decisions in
certain women with early-stage breast cancer.
The Oncotype DX assay provides clinical experience information:

For women with node-negative, estrogen-receptor-positive invasive breast cancer
AND

For post-menopausal women with node-positive, hormone-receptor-positive invasive
breast cancer
Recurrence Score® Result
Because breast cancer is a heterogeneous disease, it is important to have an assay that provides
a continuous view of the biology.
The likelihood of distant recurrence at 10 years increases continuously with an increase in the
Oncotype DX assay Recurrence Score result
NSABP B-20—Prospective Analysis of Archival Tissue: Magnitude of Benefit from Chemotherapy
The Oncotype DX assay predicts the magnitude of benefit from chemotherapy: Proportion
without distance recurrence at 10 years with vs. without treatment
651 patient samples that were node-negative, estrogen-receptor-positive from the NSABP B-20
Study were studied
-227 patients were treated with tamoxifen alone
-424 patients were treated with chemotherapy (CMF) and tamoxifen
Patients with tumors that have Recurrence Score results of:
-Greater than or equal to 31 have a substantial absolute benefit from chemotherapy
-18 to 30 did not appear to receive a substantial benefit from chemotherapy, but a clinically
important benefit cannot be excluded
-Less than 18 derive minimal, if any, benefit from chemotherapy
Multiple studies in both the academic and community settings were pooled to examine the
treatment selection based on Recurrence Score results. A low Recurrence Score result provided
actionable information for physicians that led to a recommendation for no chemotherapy (91%)
and resulted in no chemotherapy given (95%) in virtually all low Recurrence Score result
patients.