Effects of exemestane and letrozole therapy on plasma concentrations of estrogens in a randomized trial of postmenopausal women with breast cancer.

PURPOSE: Inter-individual differences in estrogen concentrations during treatment with aromatase inhibitors (AIs) may contribute to therapeutic response and toxicity. The aim of this study was to determine plasma concentrations of estradiol (E2), estrone (E1), and estrone sulfate (E1S) in a large cohort of AI-treated breast cancer patients. METHODS: In a randomized, multicenter trial of postmenopausal women with early-stage breast cancer starting treatment with letrozole (n = 241) or exemestane (n = 228), plasma estrogen concentrations at baseline and after 3 months were quantitated using a sensitive mass spectrometry-based assay. Concentrations and suppression below the lower limit of quantification (LLOQ) were compared between estrogens and between drugs. RESULTS: The ranges of baseline estrogen concentrations were

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

BACKGROUND: Early discontinuation of aromatase inhibitors (AIs) is common and leads to poor outcomes but is challenging to predict. In the Exemestane and Letrozole Pharmacogenetics trial, a high rate of early discontinuation due to intolerance was observed. We hypothesized that early changes in patient-reported outcomes (PROs) predict AI discontinuation and that biochemical factors are associated with changes in PROs. PATIENTS AND METHODS: Postmenopausal women with early-stage breast cancer enrolled in a prospective randomized trial of exemestane versus letrozole completed questionnaires at baseline and serially over 24 months to assess overall quality of life (EuroQOL Visual Analog Scale [VAS]); mood; and multiple symptoms, including a musculoskeletal symptom cluster. A joint mixed-effects/survival model was used to estimate the effect of the change in PROs on AI discontinuation. Associations between biochemical factors and change in PROs were examined. RESULTS: A total of 490 patients were analyzed. Worsening of EuroQOL VAS and the musculoskeletal cluster were associated with the highest risk for early discontinuation (hazard ratio [HR], 2.77 [95% confidence interval (CI), 2.72-2.81; p = .015]; HR, 4.39 [95% CI, 2.40-8.02; p < .0001], respectively). Pharmacokinetics and estrogen metabolism were not consistently associated with change in PRO measures. No clinically significant differences in any PRO between AIs were observed. CONCLUSION: Changes in PROs early during AI therapy were associated with treatment discontinuation. Identification of these changes could be used to target interventions in patients at high risk for early discontinuation. IMPLICATIONS FOR PRACTICE: Early changes in patient-reported outcomes (PROs) can predict nonpersistence to aromatase inhibitor therapy. If used in clinical practice, PROs might identify women at highest risk for early discontinuation and allow for interventions to improve tolerance before significant toxicities develop. Further research is needed to improve capturing PROs in routine clinical practice.

Association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort.

Women with reduced CYP2D6 activity have low endoxifen concentrations and likely worse long term benefits from tamoxifen. We investigated the association between CYP2D6 genotype and tamoxifen-induced hot flashes in a prospective cohort. We collected hot flash frequency and severity data over 12 months from 297 women initiating tamoxifen. We performed CYP2D6 genotyping using the AmpliChip CYP450 test and correlated inherited genetic polymorphisms in CYP2D6 and tamoxifen-induced hot flashes. Intermediate metabolizers had greater mean hot flash scores after 4 months of tamoxifen therapy (44.3) compared to poor metabolizers (20.6, P = 0.038) or extensive metabolizers (26.9, P = 0.011). At 4 months, we observed a trend toward fewer severe hot flashes in poor metabolizers compared to intermediate plus extensive metabolizers (P = 0.062). CYP2D6 activity may be a modest predictive factor for tamoxifen-induced hot flashes. The presence or absence of hot flashes should not be used to determine tamoxifen's efficacy.

Predictors of aromatase inhibitor discontinuation as a result of treatment-emergent symptoms in early-stage breast cancer.

PURPOSE: Aromatase inhibitors (AIs) are effective for treatment of hormone receptor-positive breast cancer, but adherence and persistence with therapy are poor. Predictors of treatment discontinuation are not clearly defined. It is unknown whether patients with intolerable toxicity from one AI are able to tolerate another. PATIENTS AND METHODS: Women with early-stage breast cancer initiating AI therapy were enrolled onto a multicenter, prospective, open-label randomized trial of exemestane versus letrozole. Patients completed symptom questionnaires at baseline and serially during therapy. Patients who developed AI-associated intolerable symptoms and discontinued treatment were given the option to switch to the other study AI after a 2- to 8-week washout period. RESULTS: Of the 503 enrolled women, 32.4% discontinued initial AI therapy within 2 years because of adverse effects; 24.3% discontinued specifically because of musculoskeletal symptoms. Median time to treatment discontinuation as a result of any symptom was 6.1 months (range, 0.1 to 21.2 months) and was significantly shorter in patients randomly assigned to exemestane (hazard ratio [HR], 1.5; 95% CI, 1.1 to 2.1; P = .02). Younger age and taxane-based chemotherapy were associated with higher likelihood of treatment discontinuation (HR, 1.4; 95% CI, 1.02 to 1.9; P = .04; and HR, 1.9; 95% CI, 1.00 to 3.6; P = .048, respectively). Of the 83 patients who chose to switch to the second AI, 38.6% continued the alternate AI for a median of 13.7 months. CONCLUSION: Premature discontinuation of initial AI therapy as a result of symptoms is common, although more than one third of patients may be able to tolerate a different AI medication. Additional research is needed to identify predictive tools and interventions for AI-associated treatment-emergent symptoms.