Pharmacogenetics as a Predictor of Toxicity in Pre-Menopausal Women Receiving Doxorubicin and Cyclophosphamide in Early Breast Cancer

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.