A Multi-Center Randomized Clinical Trial Correlating the Effects of 24 Months of Exemestane or Letrozole on Surrogate Markers of Response With Aromatase Polymorphism

Primary Objective To determine baseline breast density and the change in this parameter that occurs in post-menopausal women with hormone-receptor positive primary breast cancer taking letrozole or exemestane for 24 months, and to correlate the changes with wild type or variant aromatase (CYP19).

Secondary Objectives

1. To determine serum estrone sulfate concentrations at baseline and following one, three and 24 months of letrozole or exemestane therapy. We will use these concentrations to test the hypothesis that candidate genes involved in estrogen metabolism in post-menopausal women, or in the metabolism and disposition of exemestane or letrozole, influence the ability of aromatase inhibitors to reduce estrogen metabolite concentrations.
2. To determine bone density and bone turnover metabolites in post-menopausal women. The bone densitometry will be done at baseline and following 24 months of letrozole or exemestane therapy. The bone turnover metabolites will be done at baseline, three, six and 24 months following letrozole or exemestane therapy. These data will allow us to test the hypothesis that variants in candidate genes involved in estrogen metabolism or signaling alter the ability of exemestane or letrozole to bring about changes in bone.
3. To objectively measure hot flashes at baseline and monitor changes in hot flashes after one, three, six and 12 months of letrozole or exemestane therapy, and correlate these changes with serum FSH and LH concentrations. We will test the hypothesis that aromatase or estrogen receptor variants influence the phenotype of hot flashes at baseline or during treatment as part of a broader approach in which we will test for associations with other candidate genes involved in estrogen metabolism and signaling, or with aromatase inhibitor metabolism and disposition.
4. To measure changes in symptoms that may be related to hot flashes and estrogen deprivation such as menopausal symptoms, mood (depression, anxiety), sleep quality and sleep disturbance and overall quality of life at baseline and after one, three, six, twelve and 24 months of treatment.
5. To measure changes in fasting lipid profiles at baseline and after 3 months of letrozole or exemestane therapy.
6. To determine letrozole and exemestane serum concentrations at baseline and after one, three, six, twelve and 24 months of treatment to test the hypothesis that genetic variants in drug metabolizing enzymes predict drug concentrations and effects.
7. To measure serum thyroid binding globulin and sex hormone binding globulin concentrations before and after one and three months of treatment, to test whether changes in these parameters brought about by aromatase inhibitor treatment are altered by genetic variants in candidate genes involved in estrogen metabolism or signaling.
8. To categorize the rheumatic adverse effects experienced by patients on aromatase inhibitors by specifically characterizing anatomic structures involved and documenting the presence or absence of inflammation in these tissues; to identify any correlations between changes in musculoskeletal symptoms and the duration of therapy with aromatase inhibitors; and to identify any correlations between changes in musculoskeletal symptoms and levels of circulating estrogen and its metabolites. This will be done at baseline and after one, three, six, twelve and 24 months of treatment.
9. To determine a number of specific platelet functions before and after 3 months of letrozole and exemestane treatment. This is a sub-study that will be performed only at the Indiana University site. Platelet function will be measured by ex vivo platelet aggregation tests. Production of regulators of platelet function, including thromboxane A2 (TXA2), proscyclin (PGI2) and serotonin will also be assessed. These data will allow us to test the hypothesis that genetic polymorphisms in candidate genes in estrogen-regulated pathways alter the effect of letrozole and exemestane treatment on platelet activity, which may be relevant to their effects on cardiac risks.