Low-dose Tamoxifen for Radiation-Induced Breast Cancer Risk Reduction: A Phase IIB Randomized Placebo-Controlled Trial
Therese B. Bevers
The goal of this clinical research study is to learn if 2 years of low-dose tamoxifen can help to prevent breast cancer in patients who have had cancer and received radiation therapy to the chest. The safety of this drug will also be studied. In this study, tamoxifen will be compared to placebo. A placebo is not a drug. It looks like the study drug, but is not designed to treat any disease or illness. It is designed to be compared with a study drug to learn if the study drug has any real effect.
Disease Group: Cancer Prevention
Treatment Agent: Tamoxifen
Treatment Location: Both at MDACC & and Other Sites
Sponsor: The National Cancer Institue
1.1 To determine the impact of a two-year course of low-dose tamoxifen administered at 5mg 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. 1.2 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. 1.3 To examine the modifying effect of demographic, clinical, and molecular characteristics on the risk: benefit ratio from this two-year low dose tamoxifen intervention. 1.4 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).
IRB Review and Approval Date: 03/14/2014
Recruitment Status: Open
Projected Accrual: 230
1) Females, 25 years of age or older at the time of registration
2) Exposure to 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.
3) 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 of primary cancer diagnosis 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.
4) Premenopausal, defined as age at registration 45 years old or younger with regular monthly period for at least 6 consecutive months prior to registration.
5) 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.
1) 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.
2) Women with a prior history of ductal carcinoma in situ (DCIS) or breast intraepithelial neoplasia (IEN), only one breast could have been involved and all therapy must have been completed at least 6 months prior to registration.
3) 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.
4) Bilateral breast implants or status-post bilateral prophylactic mastectomy.
5) Evidence of malignant breast disease on any form of breast imaging. The study only requires annual mammography; however, annual breast MRI is considered standard of care in this patient population (per COG or 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.
6) 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.
7) Current or recent use (within 6 months of registration or baseline mammogram, which ever is first) of any of the following hormonal agents: 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.
8) Current or recent use (within 6 months of registration or baseline mammogram, which ever is first) of any of the following hormonal agents: hormonal forms of contraception (includes oral, transdermal, implanted, and injectable formulations), selective estrogen receptor modifiers (such as tamoxifen and raloxifene), aromatase inhibitors, GnRH analogs, prolactin inhibitors, or androgens or antiandrogens.
9) Concurrent use of warfarin and strong inhibitors of CYP2D6 will not be allowed: bupropion (Wellbutrin), fluoxetine (Prozac), paroxetine (Paxil), quinidine (Quinidex), duloxetine (Cymbalta), sertraline (Zoloft),terbinafine (Lamisil).
10) Current intrauterine pregnancy or plans to become pregnant within two years. In addition, currently nursing mothers will be excluded.
11) Renal or hepatic insufficiency, defined as having a serum creatinine, total bilirubin, SGOT, or SGPT greater than 2x the institutional norm.
12) Unable to provide consent.
13) A personal history or a strong family history of venous thromboembolism, (VTE), including deep venous thrombosis (DVT) or pulmonary embolus (PE). A one-time personal history of catheter-associated DVT may be allowed, as long as there were no subsequent VTE events and a strong family history is not present. Examples of a strong family history include (but are not limited to): one first degree relative with more than one VTE event in the same individual, and two family members in the same lineage with unexplained VTE or two VTE events in the same individual.
14) Patients with atrial fibrillation may not participate. However, patients with coronary artery disease or congestive heart failure without atrial fibrillation may be allowed to participate. Patients with a personal history of a cerebrovascular accident (CVA), transient ischemic attack (TIA), or retinal vein thrombosis will not be allowed to participate.
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Therese B. Bevers
Clinical Cancer Prevention
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