Letrozole in Treating Postmenopausal Women With Ductal Carcinoma in Situ

Phase II Study of Neoadjuvant Letrozole for Postmenopausal Women With Estrogen Receptor Positive Ductal Carcinoma In SITU (DCIS)

RATIONALE: Estrogen can cause the growth of breast cancer cells. Hormone therapy using 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 phase II trial is studying how well letrozole works in treating women with ductal carcinoma in situ.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Procedure: MRI; Procedure: conventional surgery; Drug: letrozole

Detailed Description

Treatment with letrozole begins within 21 days of registration, and only after notification has been received from the UCSF Breast MRI Research Laboratory that the baseline MRI is acceptable. Protocol therapy will consist of 6 months of letrozole, administered orally at a dose of 2.5 mg/day. Patients will have a MRI for disease evaluation at months 3 and 6. All patients will continue to take study drug until the day prior to surgery, whether at month 3 or at month 6 or may stop if they experience unacceptable toxicity. It is expected that decisions regarding any adjuvant treatment (eg, radiation and hormonal therapy) will be made individually based on the best practice guidelines, using informed and shared decision making between patient and provider. The primary and secondary objectives are provided below.

Primary objective:

1. To estimate the mean change in MRI tumor volume from pretreatment to completion of preoperative endocrine therapy in estrogen receptor-positive (ER+) ductal carcinoma in situ (DCIS), as well as to determine whether 3-month change in volume correlates with 6-month change.

Secondary objectives:

1. To assess radiographic-pathologic correlation between MRI findings and histopathology, including the prevalence of occult invasive cancer in patients undergoing neoadjuvant endocrine therapy for DCIS.
2. To compare changes in MRI maximum lesion diameter and mammographic extent at baseline and following treatment. These are two additional radiographic parameters which may also biological response to therapy.
3. To determine practice patterns of adjuvant hormonal and radiation therapy in patients who complete neoadjuvant letrozole therapy for DCIS.
4. To determine whether Ki67 is reduced with neoadjuvant letrozole treatment for DCIS, and to compare the reduction in proliferation between radiographic responders and non-responders.
5. To identify baseline IHC and expression biomarkers predictive of response to treatment, with response determined by extent of Ki67 reduction. Subsets showing the greatest reduction in Ki67 would be the most likely candidates for non-operative treatment in future studies.
6. To examine whether germline polymorphisms are associated with clinical endpoints, including treatment-related toxicity or efficacy outcomes, or with expression of biomarkers in serum or tumor.
7. To assess quality-of-life and musculoskeletal symptoms associated with neoadjuvant letrozole for ER positive DCIS.

Patients will be followed up to 6 months post-surgery.

• Study Type: Interventional
• Enrollment (Actual): 108
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • Oakland, California, United States, 94609
      • Bay Area Tumor Institute
    • San Francisco, California, United States, 94115
      • UCSF Medical Center-Mount Zion
  • Colorado
    • Denver, Colorado, United States, 80218
      • Exempla Saint Joseph Hospital
  • Delaware
    • Newark, Delaware, United States, 19713
      • Helen F Graham Cancer Center
    • Newark, Delaware, United States, 19713
      • Delaware Clinical and Laboratory Physicians PA
    • Newark, Delaware, United States, 19713
      • Medical Oncology Hematology Consultants PA
    • Newark, Delaware, United States, 19718
      • Christiana Care Health System-Christiana Hospital
    • Newark, Delaware, United States, 19713
      • Regional Hematology and Oncology PA
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa/Holden Comprehensive Cancer Center
  • Kentucky
    • Edgewood, Kentucky, United States, 41017
      • Saint Elizabeth Medical Center South
    • Fort Thomas, Kentucky, United States, 41075
      • Saint Elizabeth Fort Thomas
    • Lexington, Kentucky, United States, 40503
      • Baptist Health Lexington
  • Maryland
    • Randallstown, Maryland, United States, 21133
      • Northwest Hospital Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana Farber Cancer Institute
  • Michigan
    • Lansing, Michigan, United States, 48912
      • Sparrow Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital of Kansas City
    • Saint Louis, Missouri, United States, 63131
      • Missouri Baptist Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
    • Hendersonville, North Carolina, United States, 28791
      • Margaret R Pardee Memorial Hospital
  • Ohio
    • Columbus, Ohio, United States, 43214
      • Riverside Methodist Hospital
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center
    • Columbus, Ohio, United States, 43215
      • Grant Medical Center
    • Portsmouth, Ohio, United States, 45662
      • Southern Ohio Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Houston, Texas, United States, 77030
      • M. D. Anderson Cancer Center
  • Virginia
    • Hampton, Virginia, United States, 23666
      • Sentara Cancer Institute at Sentara CarePlex Hospital
    • Norfolk, Virginia, United States, 23502
      • Sentara Leigh Hospital
    • Norfolk, Virginia, United States, 23507
      • Sentara Hospitals

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Eligibility Criteria:

1. Histologic documentation: Pathologic confirmation of ductal carcinoma in situ (DCIS) of the female breast without invasive cancer, with diagnosis rendered on core biopsy only, completed within 60 days before registration. Patients diagnosed with DCIS on the basis of surgical biopsy are not eligible for this study.

   1. Patients with microinvasion on diagnostic core biopsy, defined as tumor ≤ 1 mm in greatest dimension, will be allowed to participate.
   2. All patients must have a clip placed, either at the time of the diagnostic biopsy or at the time of the baseline MRI prior to the start of treatment.
2. Tissue samples: Patient has diagnostic tissue available for correlative studies.
3. Clinical stage: Tis or T1mi N0, M0
4. Hormone receptor status: DCIS must express estrogen and/or progesterone receptor, as determined by immunohistochemical methods on the diagnostic pathology sample, according to the local institution's standard protocol. Greater than or equal to 1% cells will be considered to be positive.

5. Menopausal status: Patients must be postmenopausal defined as:

   1. Age ≥ 55 years and one year or more of amenorrhea
   2. Age < 55 years and one year or more amenorrhea, with an estradiol assay < 20pg/ml
   3. Surgical menopause with bilateral oophorectomy (at least 28 days must elapse from surgery to time of study registration)

   The use of GnRH analogs to achieve post menopausal status is not allowed.

6. Prior treatment:

   1. No prior surgical excision in the index breast for current DCIS diagnosis of DCIS
   2. Any exogenous hormone therapy must be completed 4 weeks prior to registration
   3. Any patients with a history of tamoxifen or raloxifene use within two years of current DCIS diagnosis are not eligible
   4. No prior neoadjuvant/adjuvant therapy for current DCIS diagnosis
7. Contraindication to MRI: No contraindications to breast MRI

8. Measurable disease: Mammographic extent of calcifications must be accurately measurable in at least one dimension with each lesion ≥ 1 cm and ≤ 7 cm

   1. DCIS must be visible on MRI based on central review.
   2. Patients with palpable DCIS or adenopathy are not eligible to participate.
   3. Patients with multifocal or bilateral disease are eligible.
9. History of osteoporosis: Women diagnosed with osteoporosis may participate in this trial provided they are receiving appropriate therapy or if they have declined therapy.
10. Age: Patients ≥ 18 years of age
11. Performance Status: ECOG performance status 0 or 1
12. Pregnancy/nursing status: Not pregnant or nursing

13. Required Initial Laboratory Values:

    1. ANC ≥ 1,000/μL
    2. Platelet count ≥ 100,000/μL
    3. Serum creatinine ≤ 1.7 mg/dL
    4. Bilirubin ≤ 2.0 mg/dL
    5. AST/ALT ≤ 2.5 times upper limit of normal
    6. Serum estradiol level assay < 20 pg/mL *Required for patients < 55 years of age and one year or more of amenorrhea

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: letrozole + MRI + surgery; Patients receive letrozole (2.5 mg) one tablet each day after confirmation that the MRI is acceptable. There is a 3 and 6 month disease evaluation by MRI of both breasts. If the DCIS has grown, the patient will have surgery to remove it and will continue to take letrozole until the day before surgery. It is expected that decisions regarding any adjuvant treatment will be made individually based on best practice guidelines, using informed and shared decision making between the patient and provider.

Procedure: MRI; Procedure: conventional surgery; Drug: letrozole

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Total MRI Functional Tumor Volume (FTV) Change From Baseline to Month 3 (V3)	Mean total MRI FTV change from baseline to month 3 (V3): For patients with more than one measureable lesion on the MRI, the sum over all measureable lesions on the MRI was calculated at each time point. V3 was calculated by subtracting the total MRI FTV measured (i.e. the sum over all lesions present with MRI FTV measurements) at 3 months from the total MRI FTV measured at baseline. For V3 the raw change in the volume will be calculated for each patient and a mean and 95% confidence interval will be constructed using two-sided t-tests.	up to 3 months from start of treatment
Mean Total MRI Functional Tumor Volume (FTV) Change From Baseline to Month 6 (V6)	Mean total MRI FTV change from baseline to month 6 (V6): For patients with more than one measureable lesion on the MRI, the sum over all measureable lesions on the MRI was calculated at each time point. V6 was calculated by subtracting the total MRI FTV measured at 6 months from the total MRI FTV measured at baseline. For V6 the raw change in the volume will be calculated for each patient and a mean and 95% confidence interval will be constructed using two-sided t-tests.	up to 6 months from start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Total MRI Tumor Diameter Change From Baseline to Month 3	To ascertain the change in maximum tumor diameter from baseline to 3 months (D3) the same methods as in Primary outcome #1 will be used but on diameter instead of volume. For patients with more than one lesion longest diameter measurement, the sum of all lesion longest diameter measurements was calculated.	3-months
Change in Maximum Diameter at 6-months Based on Mammographic Measurement (MD6)	Change in maximum diameter at 6-months based on mammographic measurement (MD6) will be estimated using the methods in Primary Outcome #1, but using the mammographic measurements instead.	6-months
Type of Primary Surgery (Mastectomy or Lumpectomy)	Rate of Mastectomy will be estimated as the number of mastectomies divided by the number of surgeries. A 95% confidence interval will be constructed using exact binomial methods. Rate of Lumpectomy will be estimated as the number of lumpectomies divided by the number of surgeries. A 95% confidence interval will be constructed using exact binomial methods.	up to 6 months
Number of Re-excisions Required to Obtain Clear Margins		3-months and 6-months
Extent of Residual DCIS Post Surgery		Up to 6 months post-surgery
Presence of Invasive Cancer at Surgery		3-months and 6-months
Size of Margins (Smallest) at Surgery		3-months and 6-months
Incidence of Toxicity as Assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0	The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. The percentage of patients with a maximum grade 3 or higher adverse event at least possibly related to the study treatment are reported below.	Up to 6 months post surgery
Mean Total MRI Tumor Diameter Change From Baseline to Month 6	Mean total MRI tumor diameter change from baseline to month 6: To ascertain the change in maximum tumor diameter from baseline to 6 months (D6) the same methods as in Primary Outcome #2 will be used but on diameter instead of volume.	6 months
Mean Total MRI Tumor Diameter Change From Baseline to Month 6	To ascertain the change in maximum tumor diameter from baseline to 6 months (D6) the same methods as in Primary outcome #2 will be used but on diameter instead of volume. For patients with more than one lesion longest diameter measurement, the sum of all lesion longest diameter measurements was calculated.	6 months

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Shelley Hwang, MD, MPH, Duke University

Publications and helpful links

General Publications

• Hwang ES, Hyslop T, Hendrix LH, Duong S, Bedrosian I, Price E, Caudle A, Hieken T, Guenther J, Hudis CA, Winer E, Lyss AP, Dickson-Witmer D, Hoefer R, Ollila DW, Hardman T, Marks J, Chen YY, Krings G, Esserman L, Hylton N. Phase II Single-Arm Study of Preoperative Letrozole for Estrogen Receptor-Positive Postmenopausal Ductal Carcinoma In Situ: CALGB 40903 (Alliance). J Clin Oncol. 2020 Apr 20;38(12):1284-1292. doi: 10.1200/JCO.19.00510. Epub 2020 Mar 3.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2012
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: September 21, 2011
• First Submitted That Met QC Criteria: September 21, 2011
• First Posted (Estimate): September 23, 2011

Study Record Updates

• Last Update Posted (Actual): March 27, 2018
• Last Update Submitted That Met QC Criteria: February 26, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: estrogen receptor-positive breast cancer; ductal breast carcinoma in situ
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Neoplasms, Ductal, Lobular, and Medullary; Breast Carcinoma In Situ; Carcinoma in Situ; 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; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: CALGB-40903; U10CA037447 (U.S. NIH Grant/Contract); CDR0000701992 (Registry Identifier: Physician Data Query); NCI-2011-03452 (Registry Identifier: NCI Clinical Trials Reporting Office)