Chemoprevention Trial - Anastrozole in Ductal Carcinoma In Situ (DCIS) in Postmenopausal Women

• Sponsor: Rita Sanghvi, Mehta (Other)
• Overall Status: Completed
• CT.gov ID: NCT00256217
• Collaborator: AstraZeneca (Industry)
• Enrollment: 42
• Location: 1
• Arm: 1
• Actual Duration (Months): 170.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
DCIS	Drug: Anastrozole	Phase 2

Detailed Description

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 .

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Chemoprevention Trial - Anastrozole in the DCIS and Early Invasive Breast Cancer in Postmenopausal Women
• Actual Study Start Date: Sep 21, 2004
• Actual Primary Completion Date: Dec 12, 2018
• Actual Study Completion Date: Dec 12, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Anastrozole	Drug: Anastrozole; 1 mg. oral every day for 2 - 4 weeks; Other Names: ARIMIDEX

Outcome Measures

Primary Outcome Measures

1. Number of Participants With a Change in Ki-67 Level [Baseline and up to 4 weeks]

Secondary Outcome Measures

1. Histopathological Response [Baseline and up to 4 weeks]

   Assessed by changes in Nottingham grade

2. To Compare Pretreatment Vascular Density With Post Treatment Vascular Density Using MRI [Baseline and 4 weeks after anastrozole]

3. To Compare Pretreatment Markers of Angiogenesis With Post Treatment Marker of Angiogenesis [Baseline and up to 4 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Chao Family Comprehensive Cancer Center	Orange	California	United States	92868

Sponsors and Collaborators

• Rita Sanghvi, Mehta
• AstraZeneca

Investigators

• Principal Investigator: Rita Mehta, MD, Chao Family Comprehensive Cancer Center

Study Documents (Full-Text)

• Study Protocol, Statistical Analysis Plan, and Informed Consent Form - Apr 25, 2011

More Information

Additional Information:

• Phase II chemoprevention trial: Anastrozole in DCIS and early invasive hormone-receptor (HR) positive breast cancer in postmenopausal women.

Publications

None provided.

• Responsible Party: Rita Sanghvi, Mehta, Dr. Rita Mehta, University of California, Irvine
• ClinicalTrials.gov Identifier: NCT00256217
• Other Study ID Numbers: UCI 03-16 [HS# 2004-3681]; 2004-3681; NCI-2010-00361
• First Posted: Nov 21, 2005
• Last Update Posted: May 11, 2021
• Last Verified: Apr 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Anastrozole

Study Results

Participant Flow

Arm/Group Title	Anastrozole
Arm/Group Description	Anastrozole: 1 mg. oral every day for 2 - 4 weeks
Period Title: Overall Study
STARTED	42
COMPLETED	34
NOT COMPLETED	8

Baseline Characteristics

Arm/Group Title	Anastrozole
Arm/Group Description	Anastrozole: 1 mg. oral every day for 2 - 4 weeks
Overall Participants	34
Age, Customized (years) [Mean (Full Range) ]
Mean (Full Range) [years]	63.2
Sex: Female, Male (Count of Participants)
Female	34 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	4 11.8%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 8.8%
White	27 79.4%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With a Change in Ki-67 Level
Time Frame	Baseline and up to 4 weeks

Outcome Measure Data

Analysis Population Description

23 patients had both baseline data and off-treatment data available

Arm/Group Title	Anastrozole
Arm/Group Description	Anastrozole: 1 mg. oral every day for 2 - 4 weeks
Measure Participants	23
Decreased Ki-67 level	15 44.1%
No Change in Ki-67	5 14.7%
Increased Ki-67 level	3 8.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anastrozole
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.9
	Confidence Interval	(2-Sided) 95%; 1.8 to 8.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Histopathological Response
Description	Assessed by changes in Nottingham grade
Time Frame	Baseline and up to 4 weeks

Outcome Measure Data

Analysis Population Description

24 patients had baseline data and post-treatment available.

Arm/Group Title	Anastrozole
Arm/Group Description	Anastrozole: 1 mg. oral every day for 2 - 4 weeks
Measure Participants	24
Decreased	7 20.6%
No Change	17 50%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Anastrozole
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; 0.10 to 0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	To Compare Pretreatment Vascular Density With Post Treatment Vascular Density Using MRI
Time Frame	Baseline and 4 weeks after anastrozole

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Anastrozole
Arm/Group Description	Anastrozole: 1 mg. oral every day for 2 - 4 weeks
Measure Participants	17
Decreased	7 20.6%
No Change	9 26.5%
Increased	1 2.9%

4. Secondary Outcome

Title	To Compare Pretreatment Markers of Angiogenesis With Post Treatment Marker of Angiogenesis
Time Frame	Baseline and up to 4 weeks

Outcome Measure Data

Analysis Population Description

Data was not collected and analysis of this outcome measure was not done.

Arm/Group Title	Anastrozole
Arm/Group Description	Anastrozole: 1 mg. oral every day for 2 - 4 weeks
Measure Participants	0

Adverse Events

Time Frame	First receipt of first of study drug until 30 days have elapsed following cessation of study drug, a total of up to 8 weeks.
Adverse Event Reporting Description	There were no reported serious adverse events for this trial.
Arm/Group Title	Anastrozole
Arm/Group Description	Anastrozole: 1 mg. oral every day for 2 - 4 weeks
All Cause Mortality
	Anastrozole
	Affected / at Risk (%)	# Events
Total	2/42 (4.8%)
Serious Adverse Events
	Anastrozole
	Affected / at Risk (%)	# Events
Total	0/42 (0%)
Other (Not Including Serious) Adverse Events
	Anastrozole
	Affected / at Risk (%)	# Events
Total	1/42 (2.4%)
General disorders
Sores in mouth and between fingers	1/42 (2.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.