Patient-Reported Outcomes and Early Discontinuation in Aromatase Inhibitor-Treated Postmenopausal Women With Early Stage Breast Cancer

Kadakia, Kunal C.; Snyder, Claire; Kidwell, Kelley M.; Seewald, Nicholas J.; Flockhart, David A.; Skaar, Todd C.; Desta, Zereunesay; Rae, James M.; Otte, Julie L.; Carpenter, Janet S.; Storniolo, Anna Maria; Hayes, Daniel F.; Stearns, Vered; Henry, Norah Lynn

doi:10.1634/theoncologist.2015-0349

Cited by 61 publications

(54 citation statements)

References 35 publications

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“…30 and that up to 70% of women who begin one hormonal therapy drug will be forced to discontinue and/or switch to another hormonal therapy drug due to intolerable and undesirable toxic side effects (toxic responders). 13,[38][39][40] The molecular basis of non-response and toxic responses could be linked to genetic variations within the organic anion-transporting polypeptides (OATPs). Our data support the strong role of OATP1B1 in the disposition of exemestane.…”

Section: The Impact Of Common Oatp1b1 and Oatp1b3 Snps On Exemestanmentioning

confidence: 99%

Impact of the OATP1B1 c.521T>C single nucleotide polymorphism on the pharmacokinetics of exemestane in healthy post-menopausal female volunteers

et al. 2017

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What is known and objective OATP1B1 mediates the transport of a diverse range of amphiphilic organic compounds that includes bile acids, steroid conjugates, and hormones. This retrospective pharmacogenetic study was conducted to assess the impact of the OATP1B1 c.521T>C single nucleotide polymorphism (SNP) on the pharmacokinetics of the steroidal aromatase inhibitor drug exemestane in healthy volunteers. Methods Exemestane (25 mg) was administered orally to 14 healthy postmenopausal women. All of the 14 subjects were sampled for pharmacokinetic (PK) analyses and retrospectively genotyped for OATP1B1 c.521T>C (rs 4149056). Results and discussion Of the 14 subjects enrolled in the study, 5 were carriers of the minor C allele (OATP1B1 c.521TC+CC), and the remaining 9 were carriers of the OATP1B1 c.521TT genotype. PK was assessed over 8 hours post-dosing. Our results showed statistically significant differences (P = 0.04) in the plasma exemestane AUC0–8 between the OATP1B1 genotype groups. Our data also showed statistically significant differences (P = 0.04) in the plasma AUC0–8 of 17-hydroexemestane (the major biologically active metabolite) between the OATP1B1 genotype groups. What is new and conclusion Our data suggest that the OAPTP1B1 c.521T>C SNP may influence exemestane pharmacokinetics in humans.

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Section: The Impact Of Common Oatp1b1 and Oatp1b3 Snps On Exemestanmentioning

confidence: 99%

Impact of the OATP1B1 c.521T>C single nucleotide polymorphism on the pharmacokinetics of exemestane in healthy post-menopausal female volunteers

et al. 2017

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“…3, 4 AI-associated toxicity, which is primarily musculoskeletal in nature, negatively impacts the quality of life of breast cancer survivors, 5 and can result in worse breast cancer outcomes. 4, 6 Despite considerable research, the mechanism that underlies this AI-associated musculoskeletal syndrome (AIMSS) remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Associations Between Patient and Anthropometric Characteristics and Aromatase Inhibitor Discontinuation

Henry

Speth

Lintermans³

et al. 2017

Clinical Breast Cancer

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Background Toxicity can lead to nonpersistence with adjuvant endocrine therapy (ET). We hypothesized that ET-induced change in grip strength would predict for early discontinuation of therapy because of musculoskeletal toxicity, and would be associated with BMI. Patients and Methods Postmenopausal women with breast cancer starting a new adjuvant ET were enrolled. Patients were monitored for 12 months to assess symptoms and ET adherence as well as change in grip strength and body mass index (BMI). The association between the change in grip strength and time to discontinuation was assessed using a joint longitudinal and survival model. Results 40.9% of 93 AI-treated and 9% of 22 tamoxifen-treated patients discontinued ET within 12 months because of toxicity (p=0.019). There was a trend towards a greater decrease in grip strength in AI-treated patients over time (p=0.055), which was not significantly associated with time to discontinuation (p=0.96). Receipt of an AI (HR 5.49, p= 0.019) and baseline pain (HR 1.19, p=0.004) significantly decreased the time to discontinuation. Conclusion In contrast with prior reports, change in grip strength was not associated with time to discontinuation of AI therapy. Future research should focus on proactive management of patients at increased risk of AI intolerance, such as those with high levels of pre-existing pain.

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“…These variables could be useful for personalizing AI dosing, if drug concentrations are predictive of a meaningful clinical outcome. However, currently, there is little evidence to support doing so[24]. In this analysis, we attempted to demonstrate that systemic drug concentrations were predictive of the magnitude of estrogen suppression, which in turn may be a surrogate of treatment outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…However, despite their more robust estrogen suppression, EXE and LET have not demonstrated superior efficacy when compared with anastrozole in clinical trials[26–28]. Similarly, there is limited direct evidence verifying the hypothesis[6,7] that AI toxicities are associated with estrogen suppression[24,29–31]. Additional research is needed to verify the putative associations between the AI drug concentrations or estrogen suppression with meaningful treatment outcomes, to warrant further discovery of the causal factors associated with these endophenotypes.…”

Section: Discussionmentioning

confidence: 99%

Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients

Hertz

Speth

Kidwell

et al. 2017

Breast Cancer Res Treat

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Summary Purpose The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Methods Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3 months of AI treatment and drug concentrations were measured after 1 or 3 months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3 months using several complementary statistical procedures. Results Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n=200, LET n=200). Thirty (7.6%) patients (EXE n=13, LET n=17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42–63.8 pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p>0.05). Conclusions Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

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Patient-Reported Outcomes and Early Discontinuation in Aromatase Inhibitor-Treated Postmenopausal Women With Early Stage Breast Cancer

Cited by 61 publications

References 35 publications

Impact of the OATP1B1 c.521T>C single nucleotide polymorphism on the pharmacokinetics of exemestane in healthy post-menopausal female volunteers

Impact of the OATP1B1 c.521T>C single nucleotide polymorphism on the pharmacokinetics of exemestane in healthy post-menopausal female volunteers

Associations Between Patient and Anthropometric Characteristics and Aromatase Inhibitor Discontinuation

Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients

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