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A Pilot Study of Cytochrome P450 Pharmacogenetics as a Predictor of Toxicity in Pre-Menopausal Women Receiving Doxorubicin and Cyclophosphamide in Early Breast Cancer

Phase 4
18 Years
45 Years
Open (Enrolling)
Breast Cancer

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Trial Information

A Pilot Study of Cytochrome P450 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.

Type of Study:


Study Design:

Observational Model: Cohort, Time Perspective: Prospective

Principal Investigator

Bryan Schneider, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Indiana University


United States: Institutional Review Board

Study ID:




Start Date:

February 2005

Completion Date:

February 2010

Related Keywords:

  • Breast Cancer
  • Pharmacogenetics
  • Toxicity
  • Pre-Menopausal
  • Women
  • Doxorubicin
  • Cyclophosphamide
  • Breast Cancer
  • Chemotherapy
  • Breast Neoplasms



Indiana University Cancer Center Indianapolis, Indiana  46202-5265