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).
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
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.
Observational Model: Cohort, Time Perspective: Prospective
Anna Maria Storniolo, MD
Indiana University School of Medicine
United States: Federal Government
|Indiana University||Indianapolis, Indiana 46202|
|UMCCC||Ann Arbor, Michigan 48109|
|The Sidney Kimmel Comprehensive Cancer Center at John Hopkins||Baltimore, Maryland 21231|