Pharmacogenetics as a Predictor of Toxicity in Pre-Menopausal Women Receiving Doxorubicin and Cyclophosphamide in Early Breast Cancer
Pharmacogenetics as a Predictor of Toxicity in Pre-Menopausal Women Receiving Doxorubicin and Cyclophosphamide in Early Breast Cancer
The goal of this pilot study is to delineate the role of genetic variations in premature
 menopause, hot flashes, and other toxicities in a cohort of premenopausal women with early
 breast cancer.

 Primary Objective- To ascertain the effect of common variant alleles of CYP450 2B6, 2C19,
 2C9, and 3A5 in pre-menopausal women with breast cancer receiving anthracycline and
 cyclophosphamide based chemotherapy as it relates to occurrence of premature menopause
 (defined as more than 12 months of amenorrhea and serum estradiol and FSH levels consistent
 with post-menopausal status)

 Secondary Objective #1- To obtain pilot data on the effect of common variant alleles of
 CYP450 2B6, 2C19, 2C9, and 3A5 in pre-menopausal women with breast cancer receiving
 anthracycline and cyclophosphamide based chemotherapy as it relates to occurrence of hot
 flash frequency, and other common toxicities of therapy requiring dose delay or reduction.

 Secondary Objective #2- To obtain pilot data on the correlation of hot flashes with serum
 levels of serotonin, tryptophan, and their metabolites and with polymorphisms of the
 serotonin transporter and receptor genes.
There is a clear survival benefit with the use of adjuvant cytotoxic therapy for most women
 with invasive breast cancer, even in those who have hormone receptor positive disease and
 receive adjuvant hormonal therapy with tamoxifen.1 In addition, several trials have shown a
 benefit for anthracycline based regimens over the more classic combination of
 cyclophosphamide, methotrexate, and 5-fluorouracil.1-4 The improved efficacy with taxanes in
 the adjuvant setting has more recently been demonstrated for patients with lymph-node
 positive disease.5-8 Despite clear survival benefits with cytotoxic therapy, the 10
 year-disease specific mortality remains suboptimal at 69-78% and 49-53% for patients with and
 without lymph node involvement, respectively.9

 Of the 180,000 women diagnosed with breast cancer in the United States, about one-fourth are
 pre-menopausal.10-13 Breast cancer clearly represents one of the most commonly diagnosed
 malignancies in this patient population. With the common use of adjuvant chemotherapy,
 long-term sequelae of treatment are becoming increasingly important. In addition to the acute
 toxicities of anthracycline and cyclophosphamide-based regimens,5 one side effect with both
 psycho-social and physical implications is pre-mature menopause.13-17 The frequency of
 menopause induced by poly-agent chemotherapy ranges from 34-89%.16,18,19 Multiple factors
 (both patient and drug-related) play a role in explaining this large variability. The age of
 the patient (at time of therapy),13,19,20 type of chemotherapy drugs,18,21 and duration and
 intensity22 of therapy all influence the overall likelihood of a patient prematurely entering
 menopause after therapy. In a previously reported study, age and systemic therapy were
 important variables in determining menopause in women with loco-regional breast cancer in
 multivariate analysis.19 Women with advancing age had a higher rate of menopause as expected.
 Hormonal therapy, and to a much greater degree, systemic therapy predicted early menopause.
 The combination of systemic and hormonal therapy appeared to have an additive effect on
 induction of menopause. Of importance, however, the added impact of hormonal therapy (when
 added to cytotoxic therapy) appears to play a minimal role in the induction of menopause when
 compared to cytotoxic therapy alone. It is also likely that intrinsic host genetic
 variability may also play a role as well. The variable ability to metabolize and clear a drug
 may, in part, affect efficacy and toxicity of these drugs and may ultimately impact the
 effect of the drug on ovarian function. One important example of this relates to
 polymorphisms in enzymes important in the clearance of the described drugs. To date, little
 work has been done to understand the importance of inter-individual, host specific
 variability on the risk of a breast cancer patient experiencing drug-induced, pre-mature
 menopause.
Inclusion Criteria:

 1. Histologically or cytologically confirmed adenocarcinoma of the breast and appropriate
 for treatment with Doxorubicin and Cyclophosphamide.

 2. Age > 18 years and <45 years.

 3. ECOG performance status of 0 to 2.

 4. Signed informed consent.

 5. Premenopausal: defined as regularly occurring menstrual cycles or serologic estradiol
 and FSH levels consistent with premenopausal status.

 Exclusion Criteria:

 1. Patients with distant metastatic disease will be excluded.

 2. Pregnancy or breast feeding (women of childbearing potential must have a negative
 pregnancy test). Women of childbearing potential must be willing to consent to using
 effective contraception (oral contraceptive pill or implant or barrier method) while
 on treatment and for a 30 days after taking the last dose of chemotherapy.

 3. Male sex will be excluded.

 4. Use of agent designed to suppress ovarian function (i.e. LHRH agonist).

 5. Use of exogenous estrogen (hormone replacement therapy) will be prohibited with the
 exception of topical vaginal preparations (as deemed necessary by the treating
 physician) and oral contraceptives.