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)

Status

Active, not recruiting

Phases

Unknown

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01824836

Enrollment

1046

Registered

2013-04-05

Start date

2013-06-11

Completion date

2026-12-01

Last updated

2026-08-27

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Estrogen Receptor-positive Breast Cancer, Musculoskeletal Complications, Progesterone Receptor-positive Breast Cancer, Recurrent Breast Cancer, Stage IA Breast Cancer, Stage IB Breast Cancer, Stage II Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer

Brief summary

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.

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.

Interventions

DRUGanastrozole

Given PO

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

SUPPORTIVE_CARE

Masking

NONE

Eligibility

Sex/Gender

FEMALE

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	Assessed at baseline and 3, 6, 9, 12 months	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.

Secondary

Measure	Time frame	Description
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 6 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	Assessed at 6 months	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.
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 9 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	Assessed at 9 months	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.
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 12 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	Assessed at 12 months	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.
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	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
Associations Between Other SNPs in CYP, UGT, Vitamin D, Serotonin and Other Receptors and Discontinuation of Treatment Due to the Development of Severe AIMSS	Assessed at baseline and 3, 6, 9, 12 months	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.
Associations Between Development of Other Potential Complications of AI Therapy and Other SNPs in CYP, UGT, Vitamin D, Serotonin and Other Receptors	Assessed at baseline, and 3, 6, 9, 12 months	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.
The Distribution of the Development of AIMSS by Genotype of the rs2296972 SNP	Assessed at baseline, and 3, 6, 9, 12 months	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.
The Distribution of Development of AIMSS by Race	Assessed at baseline, and 3, 6, 9, 12 months	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.
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 3 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	Assessed at 3 months	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.
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at Baseline for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	Assessed at baseline	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.

Countries

United States

Contacts

PRINCIPAL_INVESTIGATORVered Stearns

Eastern Cooperative Oncology Group

Participant flow

Recruitment details

A total of 1046 patients were enrolled between June 11, 2013 and October 22, 2018.

Participants by arm

Arm	Count
Anastrozole Patients receive anastrozole PO QD for 12 months.	1,046
Total	1,046

Baseline characteristics

Characteristic	Anastrozole
Age, Continuous	63 years
Ethnicity (NIH/OMB) Hispanic or Latino	17 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1009 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	20 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants
Race (NIH/OMB) Asian	185 Participants
Race (NIH/OMB) Black or African American	199 Participants
Race (NIH/OMB) More than one race	13 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	9 Participants
Race (NIH/OMB) Unknown or Not Reported	8 Participants
Race (NIH/OMB) White	631 Participants
Sex: Female, Male Female	1046 Participants
Sex: Female, Male Male	0 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	43 / 1,046
other Total, other adverse events	546 / 1,014
serious Total, serious adverse events	59 / 1,014

Outcome results

Primary

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.

Time frame: Assessed at baseline and 3, 6, 9, 12 months

Population: Eligible and treated patients that have SNP data available were included in this analysis.

Arm	Measure	Group	Value (NUMBER)
Anastrozole	Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	SNP - rs1062033 : CYP19A1	0.89 odds ratio
Anastrozole	Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	SNP - rs11849538 : TCL1A	0.83 odds ratio
Anastrozole	Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	SNP - rs2234693 : ESR1	1.07 odds ratio
Anastrozole	Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	SNP - rs2296972 : HTR2A-AS1; HTR2A	1.07 odds ratio
Anastrozole	Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	SNP - rs2347868 : ESR1	1 odds ratio
Anastrozole	Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	SNP - rs2369049 : TCL1A	0.91 odds ratio
Anastrozole	Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	SNP - rs4646 : CYP19A1	1.03 odds ratio
Anastrozole	Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	SNP - rs7158782 : TCL1A	0.91 odds ratio
Anastrozole	Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	SNP - rs7159713 : TCL1A	0.89 odds ratio
Anastrozole	Associations Between Pre-specified Single Nucleotide Polymorphisms (SNPs) and Discontinuation of Treatment With Aromatase Inhibitor (AI) Due to the Development of Musculoskeletal Symptoms (MSS)	SNP - rs9340835 : ESR1	1.18 odds ratio

Secondary

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.

Time frame: Assessed at baseline, and 3, 6, 9, 12 months

Secondary

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.

Time frame: Assessed at baseline and 3, 6, 9, 12 months

Secondary