Chemoprevention Trial - Anastrozole in Ductal Carcinoma In Situ (DCIS) in Postmenopausal Women
| Status: | Completed |
|---|---|
| Conditions: | Breast Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 2/17/2019 |
| Start Date: | September 2004 |
| End Date: | December 12, 2018 |
Phase II Chemoprevention Trial - Anastrozole in the DCIS and Early Invasive Breast Cancer in Postmenopausal Women
Breast cancer is one of the most common cancers seriously afflicting women in the United
States. Of the one million incident cases that are reported annually there are approximately
193,000 new cases of breast cancer (Greenlee, 2001). Although significant advances have been
made both in early detection and treatment of breast cancer, the impact of these on reduction
in mortality has been modest (Peta, 2000). Furthermore, despite data implicating diet and
other environmental risk factors, no lifestyle changes have yet been shown to significantly
reduce the risk of breast cancer. Therefore, chemoprevention of breast cancer is a worthwhile
approach to reduce the incidence of breast cancer.
There is every reason to believe that a detailed understanding of the initiation, promotion
and growth of breast cancer will ultimately provide a rational strategy upon which to base
prevention strategies. While the pathways of breast cancer development are not yet fully
understood, a role for estrogens in breast cancer etiology has been well established.
While many pathways are involved in breast cancer etiology, including loss of tumor
suppressor function by p53 or BRCA1 and gain of HER2 oncogene expression, their exact role in
an individual patient's cancer development may vary.
Therefore, it may be advantageous to focus on a chemoprevention strategy that may have a more
uniform impact on breast cancer development, such as estrogen exposure. Estrogen and its
metabolites, both in the circulation and locally synthesized in the breast, are important in
the pathogenesis of breast cancer. High levels of circulating estrogen in postmenopausal
women have been associated with an increased risk of breast cancer (Clemons, 2001).
Furthermore, local estrogen synthesis, i.e. aromatase activity, in the breast may also be
important in the development of breast cancer.
States. Of the one million incident cases that are reported annually there are approximately
193,000 new cases of breast cancer (Greenlee, 2001). Although significant advances have been
made both in early detection and treatment of breast cancer, the impact of these on reduction
in mortality has been modest (Peta, 2000). Furthermore, despite data implicating diet and
other environmental risk factors, no lifestyle changes have yet been shown to significantly
reduce the risk of breast cancer. Therefore, chemoprevention of breast cancer is a worthwhile
approach to reduce the incidence of breast cancer.
There is every reason to believe that a detailed understanding of the initiation, promotion
and growth of breast cancer will ultimately provide a rational strategy upon which to base
prevention strategies. While the pathways of breast cancer development are not yet fully
understood, a role for estrogens in breast cancer etiology has been well established.
While many pathways are involved in breast cancer etiology, including loss of tumor
suppressor function by p53 or BRCA1 and gain of HER2 oncogene expression, their exact role in
an individual patient's cancer development may vary.
Therefore, it may be advantageous to focus on a chemoprevention strategy that may have a more
uniform impact on breast cancer development, such as estrogen exposure. Estrogen and its
metabolites, both in the circulation and locally synthesized in the breast, are important in
the pathogenesis of breast cancer. High levels of circulating estrogen in postmenopausal
women have been associated with an increased risk of breast cancer (Clemons, 2001).
Furthermore, local estrogen synthesis, i.e. aromatase activity, in the breast may also be
important in the development of breast cancer.
Specific Aim 1: We hypothesize that a proliferative marker Ki-67 is reduced in patients with
preinvasive Ductal Carcinoma In Situ (DCIS) and very early breast cancer treated with
anastrozole. To establish reduction in Ki-67 as a primary surrogate endpoint to breast cancer
risk reduction in patients treated with anastrozole we will measure Ki-67 before and after
treatment with anastrozole. Consistent with this, it has been demonstrated by Geisler et al
that patients with advanced breast cancer show a decrease in Ki-67 on lumpectomy/mastectomy
samples when anastrozole is administered for few weeks prior to definitive surgery. In
addition, there is a trend for a more profound suppression in those achieving an objective
response. Ki-67 will be measured by routine immunohistochemistry.
Specific Aim 2: We hypothesize that histopathological tumor response will be demonstrated in
30-40 percent of patients with preinvasive (DCIS) and early invasive (less than 2 cm) breast
cancer treated with anastrozole. The percent ability to reverse early breast cancer lesions
in patients treated with anastrozole will be qualified as a secondary surrogate endpoint to
breast cancer risk reduction. Consistent with this, it has been demonstrated that 30-40
percent of patients with advanced breast cancer show an infiltration of foamy macrophages and
fibrosis on lumpectomy/mastectomy samples when chemotherapy is administered for few months
prior to definitive surgery. Further, there is a trend for a more profound change in those
achieving a complete clinical response. Importantly, a complete pathological response in
these advanced breast cancer has been shown to correlate with improved disease free survival
and overall survival in breast cancer patients. A corollary is that if reversibility of early
carcinogenic lesions is reliably demonstrated in our present proposal, it would translate
into chemoprevention of breast cancer.
Specific Aim 3: To compare the pretreatment MRI with post treatment MRI (as a secondary
surrogate endpoint to breast cancer risk reduction). We hypothesize that tumor response can
be measured by contrast washout characteristic in patients with preinvasive and very early
breast cancer treated with aromatase inhibitor. Consistent with this, we have previously
demonstrated that patients with advanced breast cancer show a reduction in vascularity in
response to chemotherapy. Further, there is a trend for a more profound suppression in those
achieving a pathological response on lumpectomy/mastectomy specimen.
Specific Aim 4: To compare the pretreatment markers of angiogenesis with post treatment
markers of angiogenesis (as a secondary surrogate endpoint to breast cancer risk reduction).
We hypothesize that tumor response can be measured by reduction in CD31 (microvessel count),
CD105 (endoglin) and VEGF in response to hormonal therapy. There may be upregulation of
TSP-1, an angiogenesis inhibitor in response to anastrozole. Angiogenic activity has been
reported for ligands of the nuclear hormone receptor superfamily such as estrogens.
Inhibition of the proangiogenic effects of estrogens could underlie the chemopreventive
action of hormone modulators on mammary carcinogenesis. A group of investigators have indeed
coined the word angioprevention as a mechanism of chemoprevention that reverses the
angiogenic switch from preinvasive to invasive cancer. Additionally, it has been demonstrated
that patients with various cancers whose tumor vascularity is targeted with VEGF inhibitor
show higher response than patients who are treated with chemotherapy alone. Our present
proposal capitalizes on the data obtained in advanced breast cancer as to the efficacy of
antiangiogenesis mechanism as an option in treatment and prevention .
preinvasive Ductal Carcinoma In Situ (DCIS) and very early breast cancer treated with
anastrozole. To establish reduction in Ki-67 as a primary surrogate endpoint to breast cancer
risk reduction in patients treated with anastrozole we will measure Ki-67 before and after
treatment with anastrozole. Consistent with this, it has been demonstrated by Geisler et al
that patients with advanced breast cancer show a decrease in Ki-67 on lumpectomy/mastectomy
samples when anastrozole is administered for few weeks prior to definitive surgery. In
addition, there is a trend for a more profound suppression in those achieving an objective
response. Ki-67 will be measured by routine immunohistochemistry.
Specific Aim 2: We hypothesize that histopathological tumor response will be demonstrated in
30-40 percent of patients with preinvasive (DCIS) and early invasive (less than 2 cm) breast
cancer treated with anastrozole. The percent ability to reverse early breast cancer lesions
in patients treated with anastrozole will be qualified as a secondary surrogate endpoint to
breast cancer risk reduction. Consistent with this, it has been demonstrated that 30-40
percent of patients with advanced breast cancer show an infiltration of foamy macrophages and
fibrosis on lumpectomy/mastectomy samples when chemotherapy is administered for few months
prior to definitive surgery. Further, there is a trend for a more profound change in those
achieving a complete clinical response. Importantly, a complete pathological response in
these advanced breast cancer has been shown to correlate with improved disease free survival
and overall survival in breast cancer patients. A corollary is that if reversibility of early
carcinogenic lesions is reliably demonstrated in our present proposal, it would translate
into chemoprevention of breast cancer.
Specific Aim 3: To compare the pretreatment MRI with post treatment MRI (as a secondary
surrogate endpoint to breast cancer risk reduction). We hypothesize that tumor response can
be measured by contrast washout characteristic in patients with preinvasive and very early
breast cancer treated with aromatase inhibitor. Consistent with this, we have previously
demonstrated that patients with advanced breast cancer show a reduction in vascularity in
response to chemotherapy. Further, there is a trend for a more profound suppression in those
achieving a pathological response on lumpectomy/mastectomy specimen.
Specific Aim 4: To compare the pretreatment markers of angiogenesis with post treatment
markers of angiogenesis (as a secondary surrogate endpoint to breast cancer risk reduction).
We hypothesize that tumor response can be measured by reduction in CD31 (microvessel count),
CD105 (endoglin) and VEGF in response to hormonal therapy. There may be upregulation of
TSP-1, an angiogenesis inhibitor in response to anastrozole. Angiogenic activity has been
reported for ligands of the nuclear hormone receptor superfamily such as estrogens.
Inhibition of the proangiogenic effects of estrogens could underlie the chemopreventive
action of hormone modulators on mammary carcinogenesis. A group of investigators have indeed
coined the word angioprevention as a mechanism of chemoprevention that reverses the
angiogenic switch from preinvasive to invasive cancer. Additionally, it has been demonstrated
that patients with various cancers whose tumor vascularity is targeted with VEGF inhibitor
show higher response than patients who are treated with chemotherapy alone. Our present
proposal capitalizes on the data obtained in advanced breast cancer as to the efficacy of
antiangiogenesis mechanism as an option in treatment and prevention .
Inclusion Criteria:
- Patients must have suspicion of DCIS or early invasive breast cancer on mammography.
- Patients must have histologically confirmed diagnosis of DCIS or early invasive breast
cancer on core biopsy for final registration.
- Patients must be over 18 years of age
- "Patients must be postmenopausal as defined by one of the following criteria:
1. Prior bilateral oophorectomy OR
2. > 12 months since LMP with no prior hysterectomy OR
3. a & b not applicable AND age >=50
- Patients must be positive for either ER or PR or both
- Patients must be informed of the investigational nature of this study and must sign
and give written informed consent in accordance with institutional and federal
guidelines.
Exclusion Criteria:
- Patients must not have diagnosis of osteoporosis (T-score -2.5 according to the WHO)
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