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

Study Description

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Brief Summary:

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.

Condition or disease
Breast Cancer

Detailed Description:

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.

Study Design

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Study Type :	Observational
Actual Enrollment :	23 participants
Observational Model:	Cohort
Time Perspective:	Prospective
Official Title:	A Pilot Study of Cytochrome P450 Pharmacogenetics as a Predictor of Toxicity in Pre-Menopausal Women Receiving Doxorubicin and Cyclophosphamide in Early Breast Cancer
Study Start Date :	February 2005
Actual Primary Completion Date :	January 13, 2009
Actual Study Completion Date :	January 13, 2009

Groups and Cohorts

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Outcome Measures

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Biospecimen Retention:   Samples With DNA

Whole blood Plasma

Eligibility Criteria

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	18 Years to 45 Years (Adult)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No
Sampling Method:	Non-Probability Sample

Study Population

Oncology clinics.

Criteria

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.

Contacts and Locations

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Indiana
Indiana University Cancer Center
Indianapolis, Indiana, United States, 46202

Sponsors and Collaborators

Indiana University School of Medicine

Investigators

Principal Investigator:	Bryan Schneider, MD	Indiana University

More Information

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Study Description Study Design Groups and Cohorts Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Bryan Schneider, Associate Professor of Medicine, Indiana University
ClinicalTrials.gov Identifier:	NCT00352872 History of Changes
Other Study ID Numbers:	0501-37
First Posted:	July 17, 2006
Last Update Posted:	March 2, 2018
Last Verified:	February 2018

Keywords provided by Bryan Schneider, Indiana University:

Pharmacogenetics; Toxicity; Pre-Menopausal; Women	Doxorubicin; Cyclophosphamide; Breast Cancer; Chemotherapy

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Cyclophosphamide; Liposomal doxorubicin; Doxorubicin; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs	Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Antibiotics, Antineoplastic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors