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

28 de febrero de 2018 actualizado por: Bryan Schneider, Indiana University School of Medicine

A Pilot Study of Cytochrome P450 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.

Descripción general del estudio

Estado

Terminado

Condiciones

Descripción detallada

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.

Tipo de estudio

De observación

Inscripción (Actual)

23

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Ubicaciones de estudio

    • Indiana
      • Indianapolis, Indiana, Estados Unidos, 46202
        • Indiana University Cancer Center

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

18 años a 45 años (Adulto)

Acepta Voluntarios Saludables

No

Géneros elegibles para el estudio

Femenino

Método de muestreo

Muestra no probabilística

Población de estudio

Oncology clinics.

Descripción

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.

Plan de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Investigadores

  • Investigador principal: Bryan Schneider, MD, Indiana University

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio

1 de febrero de 2005

Finalización primaria (Actual)

13 de enero de 2009

Finalización del estudio (Actual)

13 de enero de 2009

Fechas de registro del estudio

Enviado por primera vez

13 de julio de 2006

Primero enviado que cumplió con los criterios de control de calidad

13 de julio de 2006

Publicado por primera vez (Estimar)

17 de julio de 2006

Actualizaciones de registros de estudio

Última actualización publicada (Actual)

2 de marzo de 2018

Última actualización enviada que cumplió con los criterios de control de calidad

28 de febrero de 2018

Última verificación

1 de febrero de 2018

Más información

Términos relacionados con este estudio

Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .

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