Trial Outcomes & Findings for A Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS) (NCT NCT01824836)

NCT ID: NCT01824836

Last Updated: 2025-05-31

Results Overview

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.

• Recruitment status: ACTIVE_NOT_RECRUITING
• Study phase: NA
• Target enrollment: 1046 participants
• Primary outcome timeframe: Assessed at baseline and 3, 6, 9, 12 months
• Results posted on: 2025-05-31

Participant Flow

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

Participant milestones

Measure	Anastrozole Patients receive anastrozole PO QD for 12 months.
Overall Study STARTED	1046
Overall Study Treated and Adverse Events Assessed	1014
Overall Study Evaluable Patients	970
Overall Study Evaluable Patients With rs2296972 SNP Data Available	959
Overall Study Evaluable Patients With Baseline HAQ Data Available	954
Overall Study Evaluable Patients With 3-month HAQ Data Available	878
Overall Study Evaluable Patients With 6-month HAQ Data Available	809
Overall Study Evaluable Patients With 9-month HAQ Data Available	781
Overall Study Evaluable Patients With 12-month HAQ Data Available	772
Overall Study COMPLETED	766
Overall Study NOT COMPLETED	280

Reasons for withdrawal

Measure	Anastrozole Patients receive anastrozole PO QD for 12 months.
Overall Study Adverse Event	48
Overall Study Withdrawal by Subject	63
Overall Study Other complicating disease	116
Overall Study Disease progression	5
Overall Study Alternative therapy	2
Overall Study Depression	1
Overall Study Non-compliance	3
Overall Study Patient regained ovarian function	3
Overall Study Lost to Follow-up	8
Overall Study Physician Decision	2
Overall Study Research office was closed	3
Overall Study Relocation	3
Overall Study Insurance-related issue	1
Overall Study Transportation issue	1
Overall Study Patient transferred care	1
Overall Study Unknown reasons	4
Overall Study Never started treatment	16

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Anastrozole n=1046 Participants Patients receive anastrozole PO QD for 12 months.
Age, Continuous	63 years n=5 Participants
Sex: Female, Male Female	1046 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	17 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	1009 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	20 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants
Race (NIH/OMB) Asian	185 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	9 Participants n=5 Participants
Race (NIH/OMB) Black or African American	199 Participants n=5 Participants
Race (NIH/OMB) White	631 Participants n=5 Participants
Race (NIH/OMB) More than one race	13 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	8 Participants n=5 Participants

PRIMARY outcome

Timeframe: Assessed at baseline and 3, 6, 9, 12 months

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

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.

Outcome measures

Measure	Anastrozole n=970 Participants Patients receive anastrozole PO QD for 12 months.	AC Genotype Patients with AC genotype for the rs2296972 SNP	AA Genotype Patients with AA genotype for the rs2296972 SNP
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 Interval 0.59 to 1.34	—	—
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 Interval 0.49 to 1.41	—	—
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 Interval 0.71 to 1.6	—	—
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 Interval 0.6 to 1.4	—	—
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 Interval 0.58 to 1.37	—	—
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 Interval 0.71 to 1.61	—	—
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 Interval 0.64 to 1.57	—	—
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 Interval 0.59 to 1.4	—	—
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 Interval 0.66 to 1.61	—	—
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 Interval 0.77 to 1.8	—	—

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Assessed at baseline, and 3, 6, 9, 12 months

Population: Eligible and treated patients with the rs2296972 SNP data available

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.

Outcome measures

Measure	Anastrozole n=460 Participants Patients receive anastrozole PO QD for 12 months.	AC Genotype n=381 Participants Patients with AC genotype for the rs2296972 SNP	AA Genotype n=118 Participants Patients with AA genotype for the rs2296972 SNP
The Distribution of the Development of AIMSS by Genotype of the rs2296972 SNP Developed AIMSS	179 Participants	170 Participants	60 Participants
The Distribution of the Development of AIMSS by Genotype of the rs2296972 SNP Did not develop AIMSS	281 Participants	211 Participants	58 Participants

SECONDARY outcome

Timeframe: Assessed at baseline, and 3, 6, 9, 12 months

Population: Eligible and treated patients with SNP data available

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.

Outcome measures

Measure	Anastrozole n=600 Participants Patients receive anastrozole PO QD for 12 months.	AC Genotype n=181 Participants Patients with AC genotype for the rs2296972 SNP	AA Genotype n=189 Participants Patients with AA genotype for the rs2296972 SNP
The Distribution of Development of AIMSS by Race Did not develop AIMSS	369 Participants	92 Participants	95 Participants
The Distribution of Development of AIMSS by Race Developed AIMSS	231 Participants	89 Participants	94 Participants

SECONDARY outcome

Timeframe: Assessed at baseline

Population: Evaluable patients with baseline HAQ data available

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.

Outcome measures

Measure	Anastrozole n=954 Participants Patients receive anastrozole PO QD for 12 months.	AC Genotype Patients with AC genotype for the rs2296972 SNP	AA Genotype Patients with AA genotype for the rs2296972 SNP
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at Baseline for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	0.11 score on a scale Standard Deviation 0.14	—	—

SECONDARY outcome

Timeframe: Assessed at 3 months

Population: Evaluable patients with 3-month HAQ data available

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.

Outcome measures

Measure	Anastrozole n=878 Participants Patients receive anastrozole PO QD for 12 months.	AC Genotype Patients with AC genotype for the rs2296972 SNP	AA Genotype Patients with AA genotype for the rs2296972 SNP
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 3 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	0.14 score on a scale Standard Deviation 0.29	—	—

SECONDARY outcome

Timeframe: Assessed at 6 months

Population: Evaluable patients with 6-month HAQ data available

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.

Outcome measures

Measure	Anastrozole n=809 Participants Patients receive anastrozole PO QD for 12 months.	AC Genotype Patients with AC genotype for the rs2296972 SNP	AA Genotype Patients with AA genotype for the rs2296972 SNP
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 6 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	0.15 score on a scale Standard Deviation 0.29	—	—

SECONDARY outcome

Timeframe: Assessed at 9 months

Population: Evaluable patients with 9-month HAQ data available

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.

Outcome measures

Measure	Anastrozole n=781 Participants Patients receive anastrozole PO QD for 12 months.	AC Genotype Patients with AC genotype for the rs2296972 SNP	AA Genotype Patients with AA genotype for the rs2296972 SNP
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 9 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	0.17 score on a scale Standard Deviation 0.30	—	—

SECONDARY outcome

Timeframe: Assessed at 12 months

Population: Evaluable patients with 12-month HAQ data available

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.

Outcome measures

Measure	Anastrozole n=772 Participants Patients receive anastrozole PO QD for 12 months.	AC Genotype Patients with AC genotype for the rs2296972 SNP	AA Genotype Patients with AA genotype for the rs2296972 SNP
Patient Reported Outcomes (Health Assessment Questionnaire [HAQ] Pain Scores) at 12 Months for Patients With Breast Cancer Treated With Aromatase Inhibitors (AIs).	0.17 score on a scale Standard Deviation 0.31	—	—

SECONDARY outcome

Timeframe: 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

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Serum samples will be collected for future testing for biomarkers of AIMSS

Outcome measures

Outcome data not reported

Adverse Events

Anastrozole

Serious events: 59 serious events

Other events: 546 other events

Deaths: 43 deaths

Serious adverse events

Measure	Anastrozole n=1014 participants at risk Patients receive anastrozole PO QD for 12 months.
Cardiac disorders Heart failure	0.10% 1/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
General disorders Fatigue	0.20% 2/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
General disorders Pain	0.10% 1/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Gastrointestinal disorders Dry mouth	0.10% 1/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Gastrointestinal disorders Dyspepsia	0.10% 1/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Investigations Weight gain	0.10% 1/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Arthralgia	3.4% 34/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Arthritis	1.1% 11/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Back pain	0.10% 1/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Bone pain	0.39% 4/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Joint range of motion decreased	0.20% 2/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Myalgia	0.99% 10/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Neck pain	0.20% 2/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Pain in extremity	1.6% 16/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Musculoskeletal and connective tissue disorder - Other, specify	0.10% 1/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Psychiatric disorders Depression	0.10% 1/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Respiratory, thoracic and mediastinal disorders Dyspnea	0.10% 1/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Reproductive system and breast disorders Vaginal dryness	0.10% 1/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Vascular disorders Hot flashes	0.20% 2/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Vascular disorders Hypertension	0.30% 3/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Vascular disorders Thromboembolic event	0.20% 2/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.

Other adverse events

Measure	Anastrozole n=1014 participants at risk Patients receive anastrozole PO QD for 12 months.
Musculoskeletal and connective tissue disorders Arthralgia	45.3% 459/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Arthritis	18.5% 188/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Bone pain	12.8% 130/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Joint range of motion decreased	9.2% 93/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Myalgia	18.5% 188/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Neck pain	6.7% 68/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Pain in extremity	19.5% 198/1014 • Assessed while on treatment and after the end of treatment up to 5 years Patients who received treatment were included in the analysis of adverse events. All patients enrolled on this study were included in the analysis of all-cause mortality.

Additional Information

Study Statistician

ECOG-ACRIN Statistical Office

Phone: 617-632-3012

Email: eatrials@jimmy.harvard.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60