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

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
(CIN)

- 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
study

- 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
antiandrogens

- 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