A Multi-Center Randomized Clinical Trial Correlating the Effects of 24 Months of Exemestane or Letrozole on Surrogate Markers of Response With Aromatase Polymorphism
40 Years
70 Years
Female
Breast Cancer
Trial Information
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.
Inclusion Criteria:
1. Female gender.
2. Post-menopausal status, defined as:
- age > 60; or
- less than age 60 and the last menstrual period >12 months prior to enrollment in
trial if intact uterus/ovaries; or,
- less than age 60 and the last menstrual period 6-12 months prior to enrollment
in trial if intact uterus/ovaries and meets biochemical criteria for menopause
(FSH and estradiol levels within institutional standards for menopausal status)
NOTE: These subjects will have serum estradiol levels checked at visits 0, 1,
3, 6 and 12 months to check for continued menopausal status; or,
- less than age 60 and history of bilateral oophorectomy; or,
- less than age 60 and has a history of hysterectomy and meets biochemical
criteria for menopause (FSH and estradiol levels within institutional standards
for menopausal status).
NOTE: These subjects will have serum estradiol levels checked at visits 0, 1, 3, 6
and 12 months to check for continued menopausal status; or,
- less than age 60 and taking medication designed to suppress ovarian function and
meets biochemical criteria for menopause (estradiol levels within institutional
standards for menopausal status). Women would have had to be taking the drug
for at least 30 days prior to entering the study.
NOTE: While the patient is being treated with a GnRh agonist (luprolide or
goserelin), serum estradiol levels will be checked at visits 0, 1, 3, 6 and 12 months
to check for menopausal status.
3. Patients with histologically proven ductal carcinoma in situ (DCIS/stage 0) or stage
I-III invasive carcinoma of the breast that is ER and/or PR positive by
immunohistochemical staining, who are considering aromatase inhibitor therapy.
Patients must have completed any adjuvant chemotherapy. Patients may have received
preoperative chemotherapy. Patients should have also completed local therapy;
however, enrollment/initiation of aromatase inhibitor on study may be done prior to
completion of radiation therapy. Women may receive the aromatase inhibitor on this
study as initial adjuvant hormonal treatment or following adjuvant tamoxifen.
4. ECOG performance status 0-2.
5. The patient is aware of the nature of her diagnosis, understands the study regimen,
its requirements, risks, and discomforts, and is able and willing to sign an informed
consent form.
Exclusion Criteria:
1. History of bilateral mastectomy.
2. History of radiation to the contralateral breast.
3. Prior use of an aromatase inhibitor.
4. Personal history of the following cancers: ovarian, endometrial, fallopian tube and
primary peritoneal carcinomatosis.
5. Presence of implant in contra-lateral breast.
6. Women with history of breast reduction should be entered at the discretion of the
investigator. Breast reduction during the two years of the trial is strongly
discouraged.
Type of Study:
Observational
Study Design:
Observational Model: Cohort, Time Perspective: Prospective
Principal Investigator
Anna Maria Storniolo, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
Indiana University School of Medicine
Authority:
United States: Federal Government
Study ID:
0412-14
NCT ID:
NCT00228956
Start Date:
January 2005
Completion Date:
February 2009
Related Keywords:
- Breast Cancer
- Breast Cancer
- Aromatase Inhibitor
- Letrozole
- Exemestane
- Breast Neoplasms
Name | Location |
|---|---|
| Indiana University | Indianapolis, Indiana 46202 |
| UMCCC | Ann Arbor, Michigan 48109 |
| The Sidney Kimmel Comprehensive Cancer Center at John Hopkins | Baltimore, Maryland 21231 |
