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Association between body mass index and response to duloxetine for aromatase inhibitor-associated musculoskeletal symptoms in SWOG S1202.

ABSTRACT: BACKGROUND:Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) negatively impact adherence to and persistence with therapy. In SWOG S1202, patients with AIMSS who were treated with duloxetine, a serotonin norepinephrine reuptake inhibitor, reported improvement in pain by 12 weeks compared with placebo. Based on the authors' prior observation that responses to pain interventions differ between obese and nonobese patients, the current study examined whether response to duloxetine therapy differed by obesity status. METHODS:In SWOG S1202, a total of 299 AI-treated postmenopausal women with stage I to III (AJCC 7th Edition) breast cancer who developed new or worsening average pain were enrolled, randomized to duloxetine or placebo, and treated for 12 weeks. Patient-reported outcomes were obtained at baseline and through 12 weeks. Patients were categorized into nonobese (body mass index [BMI] <30 kg/m2 ) or obese (BMI ?30 kg/m2 ). The authors tested the interaction between intervention and obesity with respect to average pain at 12 weeks in the 289 eligible patients, using a P value of .05 to indicate statistical significance. RESULTS:In approximately 54% of evaluable patients with a BMI ?30 kg/m2 , the reduction in the mean average pain score between baseline and 12 weeks was statistically significantly greater for patients treated with duloxetine compared with those receiving placebo (-2.73 vs -1.64 points; P = .003). Conversely, in the nonobese patients, the reduction in the mean average pain score was similar in the 2 cohorts (-2.46 vs -2.34 points; P = .75). The P value for interaction was .02, thereby meeting the threshold criteria of the current study. Similar findings were evident for other pain-related patient-reported outcomes. CONCLUSIONS:In this trial, obese patients with AIMSS obtained more analgesic benefit from duloxetine compared with nonobese patients. Additional studies are warranted to determine the biologic basis for these findings.

SUBMITTER: Henry NL

PROVIDER: S-EPMC6675412 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Association between body mass index and response to duloxetine for aromatase inhibitor-associated musculoskeletal symptoms in SWOG S1202.

Henry N Lynn NL Unger Joseph M JM Till Cathee C Schott Anne F AF Crew Katherine D KD Lew Danika L DL Fisch Michael J MJ Moinpour Carol M CM Wade James L JL Hershman Dawn L DL

Cancer 20190312 12

<h4>Background</h4>Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) negatively impact adherence to and persistence with therapy. In SWOG S1202, patients with AIMSS who were treated with duloxetine, a serotonin norepinephrine reuptake inhibitor, reported improvement in pain by 12 weeks compared with placebo. Based on the authors' prior observation that responses to pain interventions differ between obese and nonobese patients, the current study examined whether response to dul ...[more]

PMID: 30861098

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Project description:ObjectiveAromatase inhibitors (AIs) are commonly used to treat hormone receptor positive (HR +) breast cancer. AI-induced musculoskeletal syndrome (AIMSS) is a common toxicity that causes AI treatment discontinuation. The objective of this genome-wide association study (GWAS) was to identify genetic variants associated with discontinuation of AI therapy due to AIMSS and attempt to replicate previously reported associations.MethodsIn the Exemestane and Letrozole Pharmacogenetics (ELPh) study, postmenopausal patients with HR + non-metastatic breast cancer were randomized to letrozole or exemestane. Genome-wide genotyping of germline DNA was conducted followed by imputation. Each imputed variant was tested for association with time-to-treatment discontinuation due to AIMSS using a Cox proportional hazards model assuming additive genetic effects and adjusting for age, baseline pain score, prior taxane treatment, and AI arm. Secondary analyses were conducted within each AI arm and analyses of candidate variants previously reported to be associated with AIMSS risk.ResultsFour hundred ELPh participants were included in the combined analysis. Two variants surpassed the genome-wide significance level in the primary analysis (p value < 5 × 10-8), an intronic variant (rs79048288) within CCDC148 (HR = 4.42, 95% CI: 2.67-7.33) and an intergenic variant (rs912571) upstream of PPP1R14C (HR = 0.30, 95% CI: 0.20-0.47). In the secondary analysis, rs74418677, which is known to be associated with expression of SUPT20H, was significantly associated with discontinuation of letrozole therapy due to AIMSS (HR = 5.91, 95% CI: 3.16-11.06). We were able to replicate associations for candidate variants previously reported to be associated with AIMSS in this cohort, but were not able to replicate associations for any other variants previously reported in other patient cohorts.ConclusionsOur GWAS findings identify several candidate variants that may be associated with AIMSS risk from AI generally or letrozole specifically. Validation of these associations in independent cohorts is needed before translating these findings into clinical practice to improve treatment outcomes in patients with HR + breast cancer.

Project description:Treatment with aromatase inhibitors (AIs) is fundamental in women with hormone receptor-positive breast cancer in the adjuvant as well as the metastatic setting. Even though it is considered to be a well-tolerated therapy, aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) is the most common adverse event encountered by breast cancer patients. CDK4/6 inhibitors have emerged as a new treatment strategy in metastatic hormone receptor-positive breast cancer. However, the impact of CDK4/6 inhibitors on musculoskeletal symptoms caused by AIs is not well-defined. This systematic review aims to identify the frequency of joint symptoms induced by treatment with AIs and CDK4/6 inhibitors in the metastatic setting. Eligible articles were identified by a search of existing literature for the period 2005/01/01-2021/01/01; The algorithm consisted of a predefined combination of the following keywords "breast", "cancer", "aromatase inhibitors", "CDK4/6", "phase III". This study was performed in accordance with PRISMA guidelines. All randomized controlled Phase III trials (RCTs) evaluating the administration of third-generation aromatase inhibitors (AIs) and CDK4/6 inhibitors in postmenopausal women in the metastatic setting were considered eligible for this review. Overall, 16 randomized control trials (RCTs) were retrieved, of which nine studies explored the administration of AIs in the metastatic setting and seven studies investigated the combination of CDK4/6 inhibitors and AIs. Arthralgia was reported in 1-47% of patients treated with AIs and 5.8-33.3% of patients treated with CDK4/6 inhibitors. Myalgias occurred in 2-23.7% of patients receiving AIs compared with 4.8-11.9% of patients treated with CDK4/6 inhibitors. The incidence of back pain was 7-32.9% vs. 2.9-8.5% in postmenopausal women with metastatic disease treated with AIs and CDK4/6 inhibitors, respectively. Bone pain was reported in 7-32.9% of postmenopausal women treated with AIs and 2.9-8.5% of women treated with CDK4/6 inhibitors. AI treatment-induced musculoskeletal syndrome is an adverse event affecting over one-third (20-47%) of postmenopausal patients treated with AIs that often leads to treatment discontinuation. Data from RCTs provide evidence that the incidence of musculoskeletal symptoms is relatively decreased upon CDK4/6 inhibitor administration. CDK4/6 inhibitors may provide a protective role against AIMSS development.

Project description:Almost one-half of aromatase inhibitor (AI)-treated breast cancer patients experience AI-associated musculoskeletal symptoms (AIMSS); 20%-30% discontinue treatment because of severe symptoms. We hypothesized that we could identify predictors of pain reduction in AIMSS intervention trials by combining data from previously conducted trials. We pooled patient-level data from 3 randomized trials testing interventions (omega-3 fatty acids, acupuncture, and duloxetine) for AIMSS that had similar eligibility criteria and the same patient-reported outcome measures. Only patients with a baseline Brief Pain Inventory average pain score of at least 4 of 10 were included. The primary outcome examined was 2-point reduction in average pain from baseline to week 12. Variable cut-point selection and logistic regression were used. Risk models were built by summing the number of factors statistically significantly associated with pain reduction. Analyses were stratified by study and adjusted for treatment arm. For the 583 analyzed patients, the 4 factors statistically significantly associated with pain reduction were Functional Assessment of Cancer Therapy Functional Well-Being greater than 24 and Physical Well-Being greater than 14 (higher scores reflect better function), and Western Ontario and McMaster Universities Osteoarthritis Index less than 50 and Modified Score for the Assessment and Quantification of Chronic Rheumatoid Affections of the Hands less than 33 (lower scores reflect less pain). Patients with all 4 factors were greater than 6 times more likely to experience at least a 2-point pain reduction (odds ratio = 6.37, 95% confidence interval = 2.31 to 17.53, 2-sided P < .001); similar results were found for secondary 30% and 50% pain reduction endpoints. Patients with AIMSS who have lower symptom and functional distress at study entry on AIMSS intervention trials are more likely to experience meaningful pain reduction. Baseline symptom and functional status should be considered as stratification factors in future interventional trials.

Dataset Information

Association between body mass index and response to duloxetine for aromatase inhibitor-associated musculoskeletal symptoms in SWOG S1202.

Publications

Association between body mass index and response to duloxetine for aromatase inhibitor-associated musculoskeletal symptoms in SWOG S1202.

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