Hormone Replacement Therapy and the Risk of Breast Cancer Recurrence in Women With Previous Early Stage Breast Cancer

Protocol for Randomized Clinical Study Concerning Hormonal Replacement Therapy (HRT) After Previous Radical Breast Cancer Treatment

RATIONALE: Hormone replacement therapy is effective for relieving symptoms of menopause. It is not yet known if hormone replacement therapy increases the risk of breast cancer recurrence in women previously treated for early stage breast cancer.

PURPOSE: Randomized phase III trial to determine the risk of breast cancer recurrence in women with previous early stage breast cancer who are receiving hormone replacement therapy for menopause symptoms.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Menopausal Symptoms
• Intervention / Treatment: Biological: therapeutic estradiol; Drug: norethindrone acetate

Detailed Description

OBJECTIVES:

• Evaluate the safety of hormone replacement therapy, in terms of risk of recurrence, in women with previously treated, nonrecurrent stage 0-II breast cancer.
• Compare this regimen vs non-hormonal symptomatic treatment, in terms of quality of life and risk of death, in this patient population.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified by center, prior hormone replacement therapy before diagnosis, and concurrent tamoxifen therapy. Patients are randomized to one of two treatment arms.

• Arm I: Patients receive one of the following: Women with an intact uterus whose last menstrual bleeding has occurred within 2 years receive continuous oral cyclic estradiol-norethindrone combination comprising estradiol only on days 1-12, estradiol plus norethindrone on days 13-22, and then estradiol only on days 22-28. Women with an intact uterus whose last menstrual bleeding occurred more than 2 years prior to study receive continuous daily oral estradiol-norethindrone combination. Women who have had a hysterectomy receive continuous daily oral estradiol only.
• Arm II: Patients receive one or more non-hormonal therapies (e.g., clonidine, beta blockers, psychological support, physical exercise, acupuncture).

Treatment in both arms continues for 2 years in the absence of disease progression. Patients may continue their randomized treatment regimen at the discretion of the treating physician.

Quality of life is assessed 3 times during the study and then every two years thereafter. Gynecological health is assessed at 3 months, 6 months, and one year during the study and then annually for at least 5 years. Breast cancer is assessed every 6 months for 3 years and then annually thereafter or at the discretion of the treating physician.

PROJECTED ACCRUAL: A total of 1,300 patients will be accrued for this study within 5-6 years.

• Study Type: Interventional
• Enrollment (Anticipated): 1300
• Phase: Phase 3

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, FIN-00029
    • Helsinki University Central Hospital
• Norway
  • Oslo, Norway, N-0310
    • Norwegian Radium Hospital
• Poland
  • Warsaw, Poland, 02-781
    • Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
• Sweden
  • Stockholm, Sweden, S-171 76
    • Karolinska Hospital
  • Uppsala, Sweden, S-75185
    • Uppsala University Hospital
• Switzerland
  • Zurich, Switzerland, CH-8008
    • Breast Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

DISEASE CHARACTERISTICS:

• History of stage 0-II breast cancer with no more than 4 involved axillary nodes if nodal status and number of nodes investigated is known
• No current evidence of disease

• Hormone receptor status:

  • Positive, negative, or unknown

PATIENT CHARACTERISTICS:

Age:

• Not specified

Sex:

• Female

Menopausal status:

• Menopausal or perimenopausal

Performance status:

• Not specified

Life expectancy:

• Not specified

Hematopoietic:

• Not specified

Hepatic:

• No active liver disease

Renal:

• Not specified

Cardiovascular:

• No prior or concurrent deep vein thrombosis
• No hereditary traits for deep vein thrombosis
• No prior or concurrent cerebral stroke
• No prior or concurrent coronary disease

Other:

• No prior malignancy except basal cell skin cancer or carcinoma in situ of the cervix
• No porphyria
• No other serious disease that would prevent compliance or greatly limit life expectancy

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• No concurrent chemotherapy

Endocrine therapy:

• Prior hormone replacement therapy (HRT) allowed if stopped no more than 4 weeks after breast cancer diagnosis and at least 3 months prior to study
• No prior HRT initiated after breast cancer diagnosis
• No concurrent hormonal therapy for breast cancer except tamoxifen or toremifene

Radiotherapy:

• No concurrent radiotherapy

Surgery:

• Not specified

Other:

• No prior randomization into trials comparing effects of chemotherapy and bilateral oophorectomy in premenopausal women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Masking: None (Open Label)

Collaborators and Investigators

• Sponsor: Regional Oncologic Center
• Collaborators: European Organisation for Research and Treatment of Cancer - EORTC; Scandinavian Breast Group; ETOP IBCSG Partners Foundation
• Investigators: Study Chair: Lars Holmberg, MD, PhD, Uppsala University Hospital; Study Chair: Jonas Bergh, MD, PhD, Karolinska Institutet; Study Chair: C. Rageth, MD, PD, Breast Center; Study Chair: Janusz Jaskiewicz, MD, Maria Sklodowska-Curie National Research Institute of Oncology

Publications and helpful links

General Publications

• Brincat M, Muscat Baron Y, Ciantar E. Hormone replacement in women with breast cancer: the HABITS study. Endocrine. 2004 Aug;24(3):255-7. doi: 10.1385/endo:24:3:255.
• Holmberg L, Iversen OE, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, Jassem J, Dobaczewska D, Fjosne HE, Peralta O, Arriagada R, Holmqvist M, Maenpaa J; HABITS Study Group. Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst. 2008 Apr 2;100(7):475-82. doi: 10.1093/jnci/djn058. Epub 2008 Mar 25. Erratum In: J Natl Cancer Inst. 2008 May 7;100(9):685. Maenpa, Johanna [corrected to Maenpaa, Johanna].
• Holmberg L, Anderson H; HABITS steering and data monitoring committees. HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped. Lancet. 2004 Feb 7;363(9407):453-5. doi: 10.1016/S0140-6736(04)15493-7.

Study record dates

Study Major Dates

• Study Start: September 1, 1997
• Primary Completion: December 7, 2022
• Study Completion (Actual): February 1, 2004

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Estimate): September 20, 2013
• Last Update Submitted That Met QC Criteria: September 19, 2013
• Last Verified: July 1, 2001

More Information

Terms related to this study

• Keywords: stage II breast cancer; stage I breast cancer; menopausal symptoms; breast cancer in situ
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Oral, Hormonal; Estradiol; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Polyestradiol phosphate; Norethindrone; Norethindrone Acetate
• Other Study ID Numbers: CDR0000066897; ROC-HABITS; EORTC-10992; IBCSG-17-98; SBG-HABITS; EU-98077

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No