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

Study Overview
=================
Brief Summary
-----------------
E1Z11 is a study to determine whether certain genetic information can predict which breast cancer patients will discontinue treatment with AIs due to the development of musculoskeletal symptoms (MSS). Women with stage 1-111 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.

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

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

Intervention / Treatment
-----------------
* Drug: anastrozole
* Other: questionnaire administration
* Other: laboratory biomarker analysis
* Other: pharmacogenomic studies


Participation Criteria
=================
Eligibility Criteria
-----------------
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 Patients must not have received 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 Plan to treat with anastrozole for at least 12 months Eastern Cooperative Oncology Group (ECOG) performance status between 0-2 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) Patients must not have a prior history of deep vein thrombosis (DVT) or pulmonary embolism in the past 5 years 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Supportive care (anastrozole)<br>Patients receive anastrozole PO QD for 12 months. | Drug: anastrozole<br>* Given PO<br>* Other names: ICI-D1033;Other: questionnaire administration<br>* Ancillary studies<br>Other: laboratory biomarker analysis<br>* Correlative studies<br>Other: pharmacogenomic studies<br>* Correlative studies<br>* Other names: Pharmacogenomic Study;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Discontinuation of treatment following development of AIMSS determined by scores on the Health Assessment Questionnaire (HAQ) instrument | Logistic regression will be used to test the association between having a minor allele and the log odds of discontinuation of treatment, adjusting for covariates. A Bonferroni adjustment will be used to account for the simultaneous testing of 10 SNPs; a one-sided p-value of 0.0025 will be considered statistically significant. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of SNPs in the estrogen receptor alpha (ESR), T-cell leukemia/lymphoma 1A (TCL1A), and CYP19A1 genes | Correlations among SNPs will be estimated, and linkage disequilibrium among pairs of SNPs will be characterized. Logistic regression models, with treatment discontinuation as the outcome variable, will be used to explore the association with SNPs, adjusting for important clinical factors. | Up to 1 year | 
| Proportions of patients with treatment discontinuation for any reason | Explored using proportional hazards models adjusting for significant genotypic and clinical predictors. Kaplan-Meier plots will be used to graphically portray the associations. | Up to 1 year | 
| Proportion of patients with symptoms determined not to be from other known etiologies as assessed by the Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) and Breast subscale | Explored using proportional hazards models adjusting for significant genotypic and clinical predictors. Kaplan-Meier plots will be used to graphically portray the associations. | Up to 1 year | 
| Proportion of patients whose symptoms improve when the AI is discontinued |  | Up to 1 year | 
| Time to discontinuation of treatment | Explored using proportional hazards models adjusting for significant genotypic and clinical predictors. Kaplan-Meier plots will be used to graphically portray the associations. | Up to 1 year | 
| Time to development of symptoms | Explored using proportional hazards models adjusting for significant genotypic and clinical predictors. Kaplan-Meier plots will be used to graphically portray the associations. | Up to 1 year |