Anastrozole and Letrozole After Surgery for the Treatment of Stage I-III Breast Cancer

Pharmacodynamic Study of Estrogen Suppression Threshold-Directed Therapy (ESTDT) of Anastrozole as Adjuvant Therapy for Early Stage Breast Cancer

This phase II trial studies how well anastrozole and letrozole after surgery work in treating patients with stage I-III breast cancer. Drugs, such as anastrozole and letrozole, may stop the growth of tumor cells by decreasing the amount of estrogen made by the body. Giving anastrozole and letrozole after surgery may prevent breast cancer from coming back (recurrence).

Study Overview

• Status: Completed
• Conditions: Anatomic Stage I Breast Cancer AJCC v8; Anatomic Stage IA Breast Cancer AJCC v8; Anatomic Stage IB Breast Cancer AJCC v8; Anatomic Stage II Breast Cancer AJCC v8; Anatomic Stage IIA Breast Cancer AJCC v8; Anatomic Stage IIB Breast Cancer AJCC v8; Anatomic Stage III Breast Cancer AJCC v8; Anatomic Stage IIIA Breast Cancer AJCC v8; Anatomic Stage IIIB Breast Cancer AJCC v8; Anatomic Stage IIIC Breast Cancer AJCC v8; Prognostic Stage I Breast Cancer AJCC v8; Prognostic Stage IA Breast Cancer AJCC v8; Prognostic Stage IB Breast Cancer AJCC v8; Prognostic Stage II Breast Cancer AJCC v8; Prognostic Stage IIA Breast Cancer AJCC v8; Prognostic Stage IIB Breast Cancer AJCC v8; Prognostic Stage III Breast Cancer AJCC v8; Prognostic Stage IIIA Breast Cancer AJCC v8; Prognostic Stage IIIB Breast Cancer AJCC v8; Prognostic Stage IIIC Breast Cancer AJCC v8; Invasive Breast Carcinoma; Early-Stage Breast Carcinoma
• Intervention / Treatment: Drug: Letrozole; Drug: Anastrozole

Detailed Description

PRIMARY OBJECTIVE:

I. To estimate the proportion of women who have adequate estrone (E1) and estradiol (E2) suppression after 8-10 weeks of adjuvant anastrozole 10 mg once daily (ANA10) having had inadequate E1 and E2 suppression after 8-10 weeks of standard dose anastrozole 1 mg once daily (ANA1).

SECONDARY OBJECTIVES:

I. To estimate the proportion of women with elevated E1 and E2 levels after 8-10 weeks of adjuvant ANA1.

II. To estimate the proportion of women with elevated E1 and E2 levels after 8-10 weeks of adjuvant ANA1 whose E1 and E2 levels remain elevated after 8-10 weeks of adjuvant ANA10.

III. To examine the toxicity profile of ANA1 over the 8-10 weeks of treatment, ANA10 over the 8-10 weeks of treatment, and letrozole over the 8-10 weeks of treatment.

IV. To examine concentrations of anastrozole at both the ANA1 and ANA10 dose levels.

V. To examine E1 and E2 concentrations, as well as letrozole drug levels, in patients receiving letrozole (following ANA10).

VI. To bank deoxyribonucleic acid (DNA) for examination of single-nucleotide polymorphism (SNP)-set(s) determined in the ongoing Mayo Clinic Breast Cancer Specialized Program of Research Excellence (SPORE) Project 4.

EXPLORATORY OBJECTIVE:

I. To examine association between clinical variables such as age, age at menopause, body mass index (BMI), receipt of chemotherapy, chemotherapy regimen, and dose on E1 and E2 levels after 8-10 weeks of ANA10.

OUTLINE:

Patients receive anastrozole orally (PO) once daily (QD) for 56-70 days (8-10 weeks). Patients with E1 >= 1.3 pg/ml and E2 >= 0.5 pg/ml continue to receive anastrozole PO QD for another 56-70 days (8-10 weeks). Patients then receive letrozole PO QD for 8-10 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.

• Study Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic in Arizona
  • Florida
    • Jacksonville, Florida, United States, 32224-9980
      • Mayo Clinic in Florida
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• REGISTRATION-INCLUSION CRITERIA

• Disease characteristics:

  • Histological confirmation of invasive breast carcinoma
  • Stage I-III breast cancer
  • Estrogen receptor (ER) positive disease according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines as ER >= 1% positive nuclear staining

• Completion of all planned cancer treatments prior to registration:

  • Surgical resection of breast and nodal surgery; (NOTE: Reconstructive surgery does not have to be completed)
  • Adjuvant radiation therapy, if needed
  • Neoadjuvant and/or adjuvant chemotherapy, if needed

• Post-menopausal defined as

  • Age >= 60 and amenorrhea > 12 consecutive months OR
  • Previous bilateral oophorectomy OR

  • Age < 60 and amenorrhea > 12 consecutive months and documented follicle stimulating hormone (FSH) level within post-menopausal range according to institutional standard

    • NOTE: Patients who did not meet these criteria at time of diagnosis and received pre-operative (neoadjuvant) or post-operative (adjuvant) chemotherapy will not be allowed to participate
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2
• Hemoglobin >= 8.0 g/dL (obtained =< 14 days prior to registration)
• Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 14 days prior to registration)
• Platelet count >= 70,000/mm^3 (obtained =< 14 days prior to registration)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to registration)
• Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 x ULN (obtained =< 14 days prior to registration)
• Ability to swallow oral medication
• Provide written informed consent
• Willingness to provide mandatory blood specimens for correlative research
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
• RE-REGISTRATION-INCLUSION CRITERIA
• Confirmation that baseline blood sample was drawn and submitted

• Blood estrogen levels after cycle 1 anastrozole (ANA1) must meet the following criteria:

  • E1 >= 1.3 pg/ml, AND
  • E2 >= 0.5 pg/ml

Exclusion Criteria:

• REGISTRATION-EXCLUSION CRITERIA
• Pre-menopausal women receiving ovarian function suppression (goserelin, leuprolide, etc.)
• Stage IV (metastatic) breast cancer

• HER2 positive breast cancer as defined by

  • HER2 immunohistochemistry (IHC) >= 3+
  • HER2/CEP17 >= 2.0
  • HER2/CEP17 < 2.0 and average HER2 copy number of >= 6.0 signals/cell

• Prior endocrine therapy for this breast cancer. Exceptions:

  • Pre-operative aromatase therapy (anastrozole, letrozole, or exemestane) and last treatment was >= 4 weeks prior to registration OR
  • Pre-operative tamoxifen therapy and last treatment was >= 12 weeks prior to registration

• Currently receiving any of the following cancer-directed therapies:

  • Radiation therapy
  • Systemic therapy such as chemotherapy (standard or investigational)

• Bisphosphonate therapy started < 4 weeks prior to registration

  • NOTE: If patient is currently on bisphosphonate therapy she must be on stable dose for >= 4 weeks prior to registration. Patients not currently taking bisphosphonates will be allowed to start bisphosphonate therapy after completion of anastrozole (1 mg and 10 mg daily [if given]). Information regarding bisphosphonate therapy will be collected
• Current use of systemic or topical exogenous estrogen or progesterone (menopausal hormone replacement therapy [HRT])
• Prior ovarian function suppression (leuprolide, goserelin, etc.)
• Inability to provide informed consent

• History of contralateral ductal carcinoma in situ (DCIS) or invasive breast cancer

  • NOTE: Exception allowed if

    • Patient did not receive adjuvant endocrine therapy OR
    • Patient received adjuvant endocrine therapy but has been off treatment for at least 6 months prior to registration

• Concurrent active malignancy or history of malignancy =< 3 years prior to registration

  • NOTE: Exceptions allowed for successfully treated cervical carcinoma in situ, lobular carcinoma in situ of the breast, papillary thyroid cancer, or non-melanoma skin cancer
• Prior prevention therapy with an aromatase inhibitor or a selective estrogen receptor modulator (SERM). Exception: Therapy with a SERM (tamoxifen or raloxifene) is allowed if patient has been off treatment for >= 6 months prior to registration

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: Treatment (anastrozole, letrozole); Patients receive anastrozole PO QD for 56-70 days (8-10 weeks). Patients with E1 >= 1.3 pg/ml and E2 >= 0.5 pg/ml continue to receive anastrozole PO QD for another 56-70 days (8-10 weeks). Patients then receive letrozole PO QD for 8-10 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.	Drug: Letrozole; Given PO; Other Names: CGS 20267; Femara; Drug: Anastrozole; Given PO; Other Names: Arimidex; Anastrazole; ICI D1033; ICI-D1033; ZD-1033

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Adequate Estrogen Suppression After 8 Weeks of Adjuvant Anastrozole 10 mg Daily	Percentage of women who have adequate E1 and E2 suppression (E1 < 1.3 pg/ml and/or E2 < 0.5) after 8-10 weeks of adjuvant anastrozole 10 mg daily having had inadequate E1 and E2 (E1 >= 1.3 pg/ml and E2 >= 0.5) after 8-10 weeks of adjuvant anastrozole 1 mg daily.	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing a Grade 3 or Greater Adverse Event	Patients will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Patients were to receive anastrozole 1 mg daily for 8 weeks (ANA1). After 8 weeks of ANA1, patients with E1 < 1.3 pg/ml and/or E2 < 0.5 pg/ml completed study and patients with E1 >= 1.3 pg/ml and E2 >= 0.5 pg/ml were to switch to anastrozole 10 mg daily (ANA10) for 8 weeks. After 8 weeks of ANA10, patients were to switch to letrozole 2.5 mg daily for 8 weeks. E1 and E2 levels were measured after this 8 week period. Patients were then go off study	24 weeks
Percent Change in Estrone (E1) and Estradiol (E2) Concentrations	Descriptive statistics will be used. The median percent change in E1 and E2 concentrations from pre-AI levels will be presented.	24 weeks

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Tufia C Haddad, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): April 28, 2020
• Primary Completion (Actual): December 12, 2022
• Study Completion (Actual): December 12, 2022

Study Registration Dates

• First Submitted: February 26, 2020
• First Submitted That Met QC Criteria: March 2, 2020
• First Posted (Actual): March 4, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 2, 2025
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Skin Diseases; Breast Diseases; Carcinoma; Breast Neoplasms; Antineoplastic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Enzyme Inhibitors; Steroid Synthesis Inhibitors; Hormone Antagonists; Estrogen Antagonists; Aromatase Inhibitors; Letrozole; Anastrozole
• Other Study ID Numbers: MC1931 (Other Identifier: Mayo Clinic in Rochester); P30CA015083 (U.S. NIH Grant/Contract); P50CA116201 (U.S. NIH Grant/Contract); NCI-2020-01062 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No