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Low-Dose Tamoxifen for Radiation-Induced Breast Cancer Risk Reduction: A Phase IIB Randomized Placebo-Controlled Trial

Phase 2
25 Years
Open (Enrolling)
Breast Cancer

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Trial Information

Low-Dose Tamoxifen for Radiation-Induced Breast Cancer Risk Reduction: A Phase IIB Randomized Placebo-Controlled Trial


I. To determine the impact of a two-year course of low-dose tamoxifen (tamoxifen citrate)
administered at 5 mg per day on surrogate endpoint biomarkers of breast cancer (BC) risk,
including: mammographic breast density (MBD), an established radiographic biomarker of BC
risk; cytomorphology and proliferative index, tissue biomarkers closely linked to BC risk;
and sex steroid hormones and insulin growth factors, circulating biomarkers of BC risk.

II. To establish safety and tolerability of this low-dose tamoxifen regimen, assessing both
objective measures (lipid profiles, clotting factors and bone metabolism markers) and
patient-reported outcomes.

III. To examine the modifying effect of demographic, clinical, and molecular characteristics
on the risk: benefit ratio from this two-year low dose tamoxifen intervention.

IV. To explore the relationship between this low-dose tamoxifen regimen and clinical
measures of efficacy (new breast cancer and DCIS diagnoses) and toxicity (thromboembolic
events, reports of hot flashes and gynecological symptoms, liver function abnormalities, and
other cancer diagnoses).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive tamoxifen citrate orally (PO) once daily for 24 months in the
absence of disease progression or unacceptable toxicity.

ARM II: Patients receive placebo PO once daily for 24 months in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Exposure to radiation therapy (RT) delivered to the chest, axilla, and/or
supraclavicular areas at a cumulative dose of 12 Gy or more by age 40 years; in
addition, patients who received total body irradiation by age 40 may be considered

- No evidence of active disease from their primary cancer for at least 2 continuous
years prior to registration; the indication for RT is not specified but cannot be for
primary breast cancer; common examples include, but are not limited to: lymphoma,
leukemia, sarcoma, and Wilms tumor occurring in pediatric patients, and lymphoma,
leukemia, and sarcoma occurring in young adults; primary cancer therapy must have
been completed at least 6 months prior to registration

- Well-defined menopausal status falling into one of the following categories:

- Premenopausal, defined as age at registration 45 years old or younger with
regular monthly period for at least 6 consecutive months prior to registration

- Postmenopausal, defined as continuous absence of menstruation for 12 months OR
status-post bilateral oophorectomy OR follicle stimulating hormone (FSH) level
in the postmenopausal range

Exclusion Criteria:

- Subsequent malignant neoplasm (SMN) other than those listed below diagnosed within 2
years of study entry; patients with the listed indolent or pre-invasive neoplasms may
be eligible if diagnosed within 2 years and all treatment was completed at least 6
months prior to registration:

- Non-melanoma cancers of the skin

- Thyroid cancer

- Cervical cancer confined to the cervix or cervical intraepithelial neoplasia

- Ductal carcinoma in situ (DCIS) or breast intraepithelial neoplasia (IEN)
(includes atypical hyperplasia and lobular carcinoma in situ [LCIS]), or

- Superficial or non-invasive transitional cell carcinoma of the bladder

- For women with a prior history of DCIS or breast IEN, only one breast could have been
involved and all therapy must have been completed at least 6 months prior to
registration; in addition women with a prior history of invasive breast cancer may
also be eligible, as long as only one breast was involved, they were diagnosed at
least 2 years prior to study entry, and therapy was completed at least 6 months prior
to study entry

- Bilateral breast implants or status-post bilateral prophylactic mastectomy

- Evidence of malignant breast disease on any form of breast imaging; the study only
requires annual mammography; however, annual breast magnetic resonance imaging (MRI)
is considered standard of care in this patient population (per Children's Oncology
Group [COG] or National Comprehensive Cancer Network [NCCN] follow-up guidelines),
and breast ultrasound may be indicated if a palpable lesion is detected on screening
clinical breast exam; abnormal imaging may require additional radiographs and/or
breast biopsy; patients who are found to have benign breast disease with or without
atypia may continue on study as long as there is no evidence of malignancy; if there
is evidence of malignancy, and only one breast is involved, they may be reapproached
6 months after completion of therapy for consideration of the trial

- Baseline categorical mammographic density scored as BIRAD 1, or extremely fatty, in
both breasts; if the patient has a prior history of IEN (DCIS, LCIS, or atypical
hyperplasia), the contralateral breast must not have a mammographic density score of
BIRAD 1; this determination will be made at the local site

- Current or recent use (within 6 months of registration or baseline mammogram,
whichever is first) of any of the following: systemic hormone replacement therapy
(includes oral or transdermal formulations); Vagifem and Estring, two formulations of
locally applied vaginal estrogen associated with minimal systemic absorption, may be
allowed; other estrogen-containing vaginal creams, while not an exclusion, should be
avoided whenever possible; patients with a history of hormone modifying herbal
supplements are eligible, but patients will be asked to avoid their use after on

- Current or recent use (within 6 months of registration or baseline mammogram,
whichever is first) of any of the following: hormonal forms of contraception
(includes oral, transdermal, implanted, and injectable formulations): selective
estrogen receptor modifiers; aromatase inhibitors; GnRH analogs; androgens or

- Concurrent use of warfarin and strong inhibitors or CYP2D6 will not be allowed

- A personal history or a strong family of thromboembolism, including deep venous
thrombosis (DVT), pulmonary embolus (PE), or cerebrovascular accident (CVA); a
personal history of transient ischemic attack (TIA) or retinal vein thrombosis will
also not be allowed; in addition, patients with a condition known to increase
hypercoagulability, such as Factor V Leiden disease, will be excluded; patients with
atrial fibrillation will be excluded, due to risk of CVA, but patients with coronary
artery disease or congestive heart failure without atrial fibrillation will be
allowed to participate

- Current intrauterine pregnancy or plans to become pregnant within two years; in
addition, currently nursing mothers will be excluded

- Serum creatinine > 2X the institutional norm

- Total bilirubin > 2X the institutional norm

- Serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase
(SGPT) > 2X the institutional norm

- Unable to provide consent

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Outcome Measure:

Efficacy of low dose tamoxifen citrate in reducing mammographic breast density

Outcome Description:

Madena Software System

Outcome Time Frame:

At year two post treatment

Safety Issue:


Principal Investigator

Melanie R. Palomares, MD, MS

Investigator Role:

Principal Investigator

Investigator Affiliation:

City of Hope Medical Center


United States: Food and Drug Administration

Study ID:




Start Date:

September 2010

Completion Date:

May 2016

Related Keywords:

  • Breast Cancer
  • Cancer survivors
  • Low Dose Tamoxifen
  • Breast Cancer Risk Reduction
  • Breast Neoplasms
  • Neoplasms, Radiation-Induced



University of MichiganAnn Arbor, Michigan  48109-0624
Mayo ClinicRochester, Minnesota  55905
Dana-Farber Cancer InstituteBoston, Massachusetts  02115
St. Jude Children's Research HospitalMemphis, Tennessee  38105-2794
Emory University School of MedicineAtlanta, Georgia  30322
City of Hope Medical CenterDuarte, California  91010
Seattle Cancer Care AllianceSeattle, Washington  98109
University of California at Los Angeles (UCLA )Los Angeles, California  90095