Abstract PS5-25: Association of OPG rs2073618 and aromatase inhibitor induced musculoskeletal symptoms
Authors: Hertz Daniel L , Smith Karen Lisa , Zong Yuhua , Gersch Christina L , Pesch Andrea , Patel Arti , Lehman Jennifer , Henry N. Lynn , Kidwell Kelley M , Rae James M , Stearns Vered 
Published: February 2021

Background: Adjuvant aromatase inhibitors (AI) reduce recurrence and mortality after early stage hormone receptor-positive (HR+) breast cancer (BC). Treatment-related toxicities, including AI-induced musculoskeletal symptoms (AIMSS), are common during adjuvant AI therapy. Prior work suggests the risk of AIMSS is associated with inherited germline genetic polymorphisms in several genes, such as TCL1A, CYP19A1, OPG, and VDR. These pharmacogenetic associations require replication in independent cohorts prior to clinical translation to identify patients at risk for AIMSS. The objective of this retrospective pharmacogenetic analysis was to replicate previously reported associations for candidate germline genetic polymorphisms with AIMSS. Methods: Women with stage 0-III HR+ BC initiating adjuvant endocrine therapy (ET) with tamoxifen or an AI were enrolled in a prospective clinic-based observational cohort. The type of ET was selected by the provider. A baseline (BL) blood sample was collected for isolation of germline DNA for pharmacogenetic analysis. AIMSS were assessed by patient-reported outcomes (PRO). Participants completed PROMIS pain interference (PI), PROMIS physical function (PF) and Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) measures at BL and after 3, 6, 9, 12, 24, 48 and 60 months (mo). The FACT-ES includes one question about joint pain, rated on a 5-point scale (“not at all” to “very much”). This secondary retrospective pharmacogenetic analysis was conducted in participants receiving AI therapy for whom blood samples and PRO scores at BL and 3 and/or 6 mo were available. For the primary analysis, we defined AIMSS as a ≥4 point increase in PI T score from BL to 3 and/or 6 mo. For secondary analyses, we evaluated alternate definitions of AIMSS including a ≥4 point decrease in PF T score and a ≥1 category increase on the FACT-ES joint pain question from BL to 3 and/or 6 mo. The primary hypothesis was that TCL1A rs11849538 is associated with AIMSS. Twelve other germline variants in CYP19A1, VDR, PIRC66, OPG, ESR1, CYP27B1, CYP17A1, and RANKL previously reported to be associated with AIMSS were also analyzed. We assumed a dominant genetic effect and pre-specified the direction of effect on AIMSS for each variant. We conducted univariate logistic regression to evaluate associations between each definition of AIMSS and candidate polymorphism using an unadjusted α=0.05. Significant univariate associations in the expected direction were adjusted for age, race, body mass index (BMI), prior taxane and type of AI using multivariable logistic regression. Results: Of 182 participants on AI, 143 with PRO and genetic data available were included in this analysis. Median age was 67, 85% were white, median BMI was 27.8 and 27% had prior taxane. 78% received anastrozole, 20% letrozole and 2% exemestane. On primary analysis, participants carrying TCL1A rs11849538 were not more likely to develop AIMSS as defined by increase in PI T score by ≥4 (OR=1.29, 95% CI: 0.55-3.07, p=0.56). None of the other polymorphisms was associated with increase in PI T score by ≥4. On secondary analysis, OPG rs2073618 was associated with AIMSS, as defined by an increase on the FACT-ES joint pain question ≥1 (OR=3.33, 95% CI: 1.48-7.49, p=0.004) and this association maintained significance after covariate adjustment (OR=3.98, 95% CI: 1.61-9.84, p=0.003). Age, race, BMI, prior taxane and type of AI were not associated with AIMSS on multivariate analysis. No other polymorphisms were associated with AIMSS on secondary analyses.

Conclusions: Carriers of OPG rs2073618 may be at increased risk of AIMSS. If confirmed in other cohorts, OPG genotyping may be able to identify individuals with HR+ early BC at increased risk for AIMSS during AI therapy. Alternate ET or interventions to reduce musculoskeletal symptoms may be needed for this population.

Citation Format: Daniel L Hertz, Karen Lisa Smith, Yuhua Zong, Christina L Gersch, Andrea Pesch, Arti Patel, Jennifer Lehman, N. Lynn Henry, Kelley M Kidwell, James M Rae, Vered Stearns. Association of OPG rs2073618 and aromatase inhibitor induced musculoskeletal symptoms [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-25.