A Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS)

A Cohort Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS)

E1Z11 is a study to determine whether certain genetic information can predict which breast cancer patients will discontinue treatment with aromatase inhibitors (AIs) due to the development of musculoskeletal symptoms (MSS). Women with stage I-III breast cancer who are prescribed the aromatase inhibitor anastrozole as treatment may join.

Study Overview

• Status: Active, not recruiting
• Conditions: Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IA Breast Cancer; Stage IB Breast Cancer; Stage IIIC Breast Cancer; Recurrent Breast Cancer; Estrogen Receptor-positive Breast Cancer; Progesterone Receptor-positive Breast Cancer; Musculoskeletal Complications
• Intervention / Treatment: Drug: anastrozole

Detailed Description

PRIMARY OBJECTIVES:

I. To validate previously identified associations between 10 specific single nucleotide polymorphisms (single nucleotide polymorphisms [SNPs]) and discontinuation of treatment with aromatase inhibitors (AIs) due to the development of musculoskeletal symptoms (MSS) among women with breast cancer.

SECONDARY OBJECTIVES:

I. To determine whether other SNPs in cytochrome P450 enzymes (CYP), glucuronosyltransferases (UGT), Vitamin D, serotonin and other receptors are associated with discontinuation of treatment due to the development of severe aromatase inhibitor-associated musculoskeletal symptoms (AIMSS).

II. To determine whether other SNPs in CYP, UGT, Vitamin D, serotonin and other receptors are associated with the development of other potential complications of AI therapy.

III. To develop a gene signature that can identify patients at risk for developing severe anastrozole-related AIMSS and other potential complications of AI therapy.

IV. To determine the epidemiology and predictors of severe AIMSS and of AI discontinuation.

V. To describe patient reported outcomes for minority patients with breast cancer treated with AIs.

VI. To assess the utility of the Patient Reported Outcomes Management Information System (PROMIS) system to collect patient reported outcomes in a cooperative group study, and validate the PROMIS Physical Function 20a form in patients with AIMSS.

VII. To develop a model that incorporates patient ratings of treatment burden, fear of recurrence and adherence behaviors to describe patient decisions to continue or discontinue anastrozole.

VIII. To collect serum samples for future testing for biomarkers of AIMSS.

OUTLINE:

Patients receive anastrozole orally (PO) once daily (QD) for 12 months.

After the completion of study treatment, patients are followed up for 12 months.

• Study Type: Interventional
• Enrollment (Actual): 1046
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Eastern Cooperative Oncology Group
  • New Jersey
    • East Orange, New Jersey, United States, 07018-1095
      • Veterans Adminstration New Jersey Health Care System

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients must be post-menopausal; post-menopausal will be defined as women meeting any of the following criteria:

  • >= 60 years of age; or
  • < 60 years of age and amenorrheic for >= 12 months prior to day 1 if uterus/ovaries are intact; or
  • < 60 years of age, and the last menstrual period 6-12 months prior to day 1, if intact uterus/ovaries and meets biochemical criteria for menopause (follicle-stimulating hormone [FSH] and estradiol within institutional standard for postmenopausal status); or
  • < 60 years of age, without a uterus, and meets biochemical criteria for menopause (FSH and estradiol within institutional standards for postmenopausal status); or
  • < 60 years of age and history of bilateral oophorectomy; surgery must have been completed at least 4 weeks prior to day 1; or
  • Prior radiation castration with amenorrhea for at least 6 months
• Patients must have estrogen and/or progesterone receptor positive histologically confirmed stage I-III adenocarcinoma of the breast
• Patients must have completed recommended local therapy and adjuvant chemotherapy for breast cancer
• Plan to treat with anastrozole for at least 12 months
• Eastern Cooperative Oncology Group (ECOG) performance status between 0-2
• Patients must be disease-free of other prior invasive malignancies for ≥ 5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix. Prior early stage breast cancers are also allowed as long as prior treatment did not include aromatase inhibitors.
• Patients must have worst pain rated as less than 4 out of 10 on the following question: "In the past week, how much pain have you had on a scale of 0 to 10, where 0 equals no pain and 10 means the worst pain you can imagine; " NOTE: This question regarding patient's pain should be completed within one week prior to registration; this pain item may be completed orally prior to consent up to 7 days prior to registration; it is not necessary to complete this pain item via the PROMIS website
• Patients must have adequate hepatic, hematologic and renal functioning to be able to be administered anastrozole at the discretion of the treating physician

Exclusion Criteria:

• Prior AI therapy with exemestane, letrozole, or anastrozole as adjuvant therapy or for prevention of breast cancer; prior tamoxifen as adjuvant therapy or for prevention is allowed
• Patients must not be currently taking (or have taken in the past 6 months) ongoing, daily analgesic medication for active, chronic conditions (i.e., rheumatoid arthritis, carpal tunnel syndrome, tenosynovitis, systemic lupus erythematosus, gout, fibromyalgia, or severe osteoarthritis involving the hands, wrists, hips, knees, feet or ankles); (note: patients taking daily low dose aspirin are allowed to participate in this trial)
• Prior history of deep vein thrombosis (DVT) or pulmonary embolism in the past 5 years

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• 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: Supportive care (anastrozole); Patients receive anastrozole PO QD for 12 months.	Drug: anastrozole; Given PO; Other Names: Arimidex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	Patients were classified into two groups based on whether or not they discontinued treatment due to MSS within 12 months. The 10 SNPs evaluated include ESR1 (rs2234693, rs2347868, rs9340835), CYP19A1 (rs1062033, rs4646), TCL1A (rs11849538, rs2369049, rs7158782, rs7159713), and HTR2A (rs2296972). The associations between SNPs and discontinuation of treatment due to AIMSS are presented by odds ratios (ORs). An OR of 1 suggests no association, while an OR > 1 indicates a greater chance of treatment discontinuation in the one group compared to the reference group, and an OR < 1 suggests a lower chance.	Assessed at baseline and 3, 6, 9, 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Associations Between Other SNPs in CYP, UGT, Vitamin D, Serotonin and Other Receptors and Discontinuation of Treatment Due to the Development of Severe AIMSS	The associations between discontinuation of treatment due to AIMSS and various factors, including other SNPs in CYP, UGT, vitamin D, serotonin and other receptors are evaluated.	Assessed at baseline and 3, 6, 9, 12 months
Associations Between Development of Other Potential Complications of AI Therapy and Other SNPs in CYP, UGT, Vitamin D, Serotonin and Other Receptors	The associations between development of other potential complications of AI therapy and other SNPs in CYP, UGT, vitamin D, serotonin and other receptors are evaluated.	Assessed at baseline, and 3, 6, 9, 12 months
The Distribution of the Development of AIMSS by Genotype of the rs2296972 SNP	The association between the rs2296972 SNP in the HTR2A-AS1;HTR2A gene and the development of AIMSS was evaluated. Patients were categorized into CC, AC and AA genotypes for the rs2296972 SNP. AIMSS was defined using two criteria, physician assessment and the Stanford Health Assessment Questionnaire (HAQ) score. Patients who developed joint pain or stiffness were encouraged not to discontinue treatment and were to be seen by their treating clinician within 2 weeks of the symptom(s). At the time of the visit, the treating clinician could make an AIMSS diagnosis based on a clinical assessment. AIMSS based on HAQ was defined as ≥0.20 mean increase in scaled HAQ score at 3, 6, 9 or 12 months from baseline.	Assessed at baseline, and 3, 6, 9, 12 months
The Distribution of Development of AIMSS by Race	The association between race and the development of AIMSS was evaluated. AIMSS was defined using two criteria, physician assessment and the Stanford Health Assessment Questionnaire (HAQ) score. Patients who developed joint pain or stiffness were encouraged not to discontinue treatment and were to be seen by their treating clinician within 2 weeks of the symptom(s). At the time of the visit, the treating clinician could make an AIMSS diagnosis based on a clinical assessment. AIMSS based on HAQ was defined as ≥0.20 mean increase in scaled HAQ score at 3, 6, 9 or 12 months from baseline.	Assessed at baseline, and 3, 6, 9, 12 months
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at Baseline for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	HAQ was administered to evaluate pain among the patients. The pain scores range between 0 and 3 with 0 indicating no pain and 3 indicating very severe pain.	Assessed at baseline
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 3 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	HAQ was administered to evaluate pain among the patients. The pain scores range between 0 and 3 with 0 indicating no pain and 3 indicating very severe pain.	Assessed at 3 months
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 6 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	HAQ was administered to evaluate pain among the patients. The pain scores range between 0 and 3 with 0 indicating no pain and 3 indicating very severe pain.	Assessed at 6 months
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 9 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	HAQ was administered to evaluate pain among the patients. The pain scores range between 0 and 3 with 0 indicating no pain and 3 indicating very severe pain.	Assessed at 9 months
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 12 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	HAQ was administered to evaluate pain among the patients. The pain scores range between 0 and 3 with 0 indicating no pain and 3 indicating very severe pain.	Assessed at 12 months
To Develop a Model That Incorporates Patient Ratings of Treatment Burden, Fear of Recurrence and Adherence Behaviors to Describe Patient Decisions to Continue or Discontinue Anastrozole	To develop a model that incorporates patient ratings of treatment burden, fear of recurrence and adherence behaviors to describe patient decisions to continue or discontinue anastrozole	Assessed at baseline, diagnosis of AIMSS, discontinuation of treatment due to AIMSS, one month after treatment discontinuation due to AIMSS, and 3, 6, 9, 12 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Assess the Utility of the Reported Outcomes Management Information System (PROMIS) to Collect Patient Reported Outcomes in a Cooperative Group Study, and Validate the PROMIS Physical Function 20a Form in Patients With AIMSS	The NIH has developed a Web-based system for recording patient reported outcomes during clinical trials, the Patient Reported Outcomes Management Information System (PROMIS) that will enable the efficient collection of patient reported outcomes and decrease the logistical burdens on office practices for patients on clinical trials. The PROMIS Assessment Center is the web-based platform for dissemination of NIH PROMIS measures. The assessment center can be used to administer patient rated outcome instruments, monitor accrual, manage data, send reminders to patients, be used to deliver custom researcher developed content, and has numerous features that support both simple and complicated accrual designs.	Assessed at baseline, diagnosis of AIMSS, discontinuation of treatment due to AIMSS, one month after treatment discontinuation due to AIMSS, and 3, 6, 9, 12 months
To Collect Serum Samples for Future Testing for Biomarkers of AIMSS	Serum samples will be collected for future testing for biomarkers of AIMSS	Assessed at baseline, diagnosis of AIMSS, discontinuation of treatment due to AIMSS, one month after treatment discontinuation due to AIMSS, and 3, 6, 9, 12 months

Collaborators and Investigators

• Sponsor: ECOG-ACRIN Cancer Research Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Vered Stearns, Eastern Cooperative Oncology Group

Publications and helpful links

General Publications

• Stearns V, Jegede OA, Chang VT, Skaar TC, Berenberg JL, Nand R, Shafqat A, Jacobs NL, Luginbuhl W, Gilman P, Benson AB 3rd, Goodman JR, Buchschacher GL Jr, Henry NL, Loprinzi CL, Flynn PJ, Mitchell EP, Fisch MJ, Sparano JA, Wagner LI. A Cohort Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms: Results from ECOG-ACRIN E1Z11. Clin Cancer Res. 2024 Jul 1;30(13):2709-2718. doi: 10.1158/1078-0432.CCR-23-2137.

Study record dates

Study Major Dates

• Study Start (Actual): June 11, 2013
• Primary Completion (Actual): June 9, 2022
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: April 2, 2013
• First Submitted That Met QC Criteria: April 2, 2013
• First Posted (Estimated): April 5, 2013

Study Record Updates

• Last Update Posted (Actual): May 31, 2025
• Last Update Submitted That Met QC Criteria: May 22, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Skin Diseases; Breast Diseases; 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; Anastrozole
• Other Study ID Numbers: E1Z11; U10CA037403 (U.S. NIH Grant/Contract); NCI-2013-00426 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.

Drug and device information, study documents

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