Tamoxifen or Letrozole in Treating Women With Ductal Carcinoma in Situ

Primary Hormonal Therapy for Ductal Carcinoma in Situ: Exploration of a Novel Approach to the Clinical Management of Noninvasive Breast Cancer

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using tamoxifen or letrozole may fight breast cancer by blocking the use of estrogen by the tumor cells or by lowering the amount of estrogen the body makes.

PURPOSE: This clinical trial is studying how well tamoxifen or letrozole work in treating women with ductal carcinoma in situ.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Procedure: neoadjuvant therapy; Procedure: conventional surgery; Drug: tamoxifen citrate; Drug: letrozole

Detailed Description

OBJECTIVES:

• Determine the clinical response in women with estrogen receptor-positive ductal carcinoma in situ (DCIS) treated with neoadjuvant hormonal therapy comprising tamoxifen or letrozole, by evaluating the maximal change in tumor diameter on mammography and MRI following treatment.
• Identify those cellular antigens which are altered by hormonal therapy.
• Determine which cellular antigens are predictive of clinical response to hormonal therapy.
• Evaluate whether genomic changes or gene expression in DCIS are altered by hormonal therapy and find candidate genes which are correlated with response to treatment.

OUTLINE: This is a pilot study.

Patients who are premenopausal receive oral tamoxifen once daily for 3 months in the absence of unacceptable toxicity. Patients who are post menopausal receive oral letrozole once daily for 3 months in the absence of unacceptable toxicity.

After 3 months of hormonal therapy, patients undergo lumpectomy or mastectomy.

After completion of study treatment, patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 40 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 79
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

DISEASE CHARACTERISTICS:

• Diagnosis of ductal carcinoma in situ (DCIS) on core biopsy
• No evidence of contralateral breast disease or palpable masses on breast examination
• No presence or suspicion of invasive cancer, including contralateral invasive cancer, on core biopsy and MRI
• No documented ipsilateral axillary adenopathy
• Planning to undergo lumpectomy or mastectomy
• Estrogen receptor (ER)-positive tumor by immunohistochemistry

PATIENT CHARACTERISTICS:

• Female patient

• Premenopausal or postmenopausal

  • Postmenopausal is defined by any of the following:

    • No spontaneous menses for >= 1 year
    • Bilateral oophorectomy
    • Radiation castration and amenorrheic for >= 3 months
    • Follicle-stimulating hormone (FSH) > 20 IU/L AND off all hormonal therapy (e.g., hormone replacement therapy or birth control pills) for >= 1 month
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

• No co-morbidities contraindicating the use of tamoxifen, including any of the following:

  • Prior history of thrombotic events
  • History of hypercoagulable state
  • History of endometrial hyperplasia
  • Abnormal vaginal bleeding
• No history of contrast dye-related allergies/reactions
• No history of metal-containing prostheses or implants

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: tamoxifen or letrozole; tamoxifen or letrozole work in treating women with ductal carcinoma in situ	Procedure: neoadjuvant therapy; Procedure: conventional surgery; Drug: tamoxifen citrate; Drug: letrozole

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median Change in 6-month Tumor Volume Compared to Baseline Using Mammography	Change in size of Ductal Carcinoma in situ (DCIS) for participants on hormonal therapy, as determined by mammography are determined by (1) largest diameter of tumor, as visualized on mammography (2) extent of disease on mammography (3) quantification of mammographically-detected change from baseline to 6-month and used to generate the change in tumor volume of mammographic extent of disease from baseline. Since values were not normally distributed, the median change was calculated, and Wilcoxon sign rank tests were used to evaluate the significance of these changes	Baseline and 6 months
Median Change in 6-month Tumor Volume Compared to Baseline Using Magnetic Resonance Imaging (MRI)	Change in size of Ductal Carcinoma in situ (DCIS) on hormonal therapy, as determined by MRI are determined by (1) largest diameter of tumor, as visualized on MRI (2) extent of disease on MRI (3) quantification of MR-detected change from baseline to 6-month and used to generate the change in tumor volume of MRI extent of disease from baseline. Since values were not normally distributed, the median change was calculated, and Wilcoxon sign rank tests were used to evaluate the significance of these changes.	Baseline and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Responders to Neoadjuvant Therapy at Month 3	MRI volume response at each time point was classified as follows: 90% image-complete response (ICR90) is defined as a >90% reduction in tumor volume, 80% image-complete response (ICR80) is defined as an 81-90% reduction in tumor volume , partial response (PR) is defined as a 20-80% reduction in tumor volume, and sustained disease or progressive disease (SD/PD) defined as a <20% reduction or increase in volume.	3 months
Number of Responders to Neoadjuvant Therapy at Month 6	MRI volume response at each time point was classified as follows: 90% image-complete response (ICR90) is defined as a >90% reduction in tumor volume, 80% image-complete response (ICR80) is defined as an 81-90% reduction in tumor volume , partial response (PR) is defined as a 20-80% reduction in tumor volume, and sustained disease or progressive disease (SD/PD) defined as a <20% reduction or increase in volume.	6 months
Median Reduction in Tumor Volume by Estrogen Receptor Hormone (ER H-) Quartile Group	Tumor volume changes between baseline and surgery were calculated at month 6 and compared across baseline ER Hormone (H-) Score quartile. The ER H- scores are a percentage that tells you how many cells out of 100 stain positive for hormone receptors. Each participant is assigned an ER H- score at baseline with the full score range between 0 (none have receptors) and 100 (all have receptors). The participants were grouped into quartiles (four equal groups) based on their baseline ER H- score. ER H- score and the reduction in tumor volume from baseline to month 6 was measured for each quartile group.	Baseline and 6 months
Median Reduction in Tumor Volume by PgR H-score by Quartile Group	Tumor volume changes between baseline and surgery were calculated at month 6 and compared across baseline PgR Hormone (H-) Score quartile. The PgR H-scores are a percentage that tells you how many cells out of 100 stain positive for hormone receptors. Each participant is assigned a PgR H- score at baseline with the full PgR H score ranges between 0 (none have receptors) and 100 (all have receptors). The participants were grouped into quartiles (four equal groups) based on their baseline PgR H- score and the reduction in tumor volume from baseline to month 6 was measured for each quartile group. A wilcoxon sign rank tests were used to evaluate the significance of these changes	Baseline and 6 months
Median Reduction in Tumor Volume by Ki-67 Average Score	Tumor volume changes between baseline and surgery were calculated at month 6 by Baseline Ki-67 Average Score which is divided into 2 groups: (1) <=10% or (2) >10% to 100%. In est results, the Ki-67 findings expressed as a percentage with less than 10% considered low Ki-67 expression and > than 10% or higher considered high. A "high" score means that the breast tumor is more likely to be aggressive and spread quickly. A wilcoxon sign rank tests were used to evaluate the significance of these changes	Baseline and 6 months
Correlation Between Pathologic Tumor Size at Radiographic (MRI) Tumor Size	Correlations between pathologic tumor size and maximum diameters of baseline and 6-month MRI extent of disease were evaluated using Spearman correlation coefficient measure of association. The Spearman's rank-order correlation (rs) measures the strength and direction of association between two variables. The Spearman correlation coefficient, rs, can take values from +1 to -1 where a value of +1 indicates a perfect association, an rs of 0 indicates no association and an rs of -1 indicates a perfect negative association. The closer rs is to 0, the weaker the association.	6 months
Correlation Between Pathologic Tumor Size and Mammographic Tumor Size	Correlations between pathologic tumor size and maximum diameters of baseline and pre-surgical mammographic extent of disease were evaluated using Spearman correlation coefficient measure of association. The Spearman's rank-order correlation (rs) measures the strength and direction of association between two variables. The Spearman correlation coefficient, rs, can take values from +1 to -1 where a value of +1 indicates a perfect association, an rs of 0 indicates no association and an rs of -1 indicates a perfect negative association. The closer rs is to 0, the weaker the association.	6 months

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Novartis
• Investigators: Principal Investigator: E. Shelley Hwang, MD, MPH, University of California, San Francisco; Principal Investigator: Frederic M. Waldman, MD, PhD, University of California, San Francisco; Principal Investigator: Rita Mukhtar, MD, University of California, San Francisco

Publications and helpful links

General Publications

• Chen YY, DeVries S, Anderson J, Lessing J, Swain R, Chin K, Shim V, Esserman LJ, Waldman FM, Hwang ES. Pathologic and biologic response to preoperative endocrine therapy in patients with ER-positive ductal carcinoma in situ. BMC Cancer. 2009 Aug 18;9:285. doi: 10.1186/1471-2407-9-285.
• Swain RS, Chen YY, Wa C, et al.: Pathologic and biologic response to neoadjuvant anti-estrogen (AE) therapy in patients with ductal carcinoma in situ (DCIS). [Abstract] United States and Canadian Academy of Pathology 95th Annual Meeting, February 11-17, 2006, Atlanta, GA. A-186, 2006.

Study record dates

Study Major Dates

• Study Start (Actual): February 19, 2002
• Primary Completion (Actual): July 31, 2009
• Study Completion (Actual): June 30, 2011

Study Registration Dates

• First Submitted: February 9, 2006
• First Submitted That Met QC Criteria: February 9, 2006
• First Posted (Estimate): February 13, 2006

Study Record Updates

• Last Update Posted (Actual): December 4, 2020
• Last Update Submitted That Met QC Criteria: November 10, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Keywords: breast cancer in situ; ductal breast carcinoma in situ
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Breast Diseases; Neoplasms, Ductal, Lobular, and Medullary; Breast Carcinoma In Situ; Carcinoma in Situ; Breast Neoplasms; Carcinoma; Carcinoma, Ductal; Carcinoma, Intraductal, Noninfiltrating; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Bone Density Conservation Agents; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Selective Estrogen Receptor Modulators; Estrogen Receptor Modulators; Letrozole; Tamoxifen
• Other Study ID Numbers: 017513; UCSF-H10367-19435-05 (Other Identifier: University of California, San Francisco); NCI-2011-01273 (Registry Identifier: NCI Clinical Trials Reporting Program (CTRP)); CDR0000465205 (Other Identifier: University of California, San Francisco)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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