Tamoxifen for Breast Cancer Risk Reduction

Recruiting at 10 trial locations

Age: 18 - 65

Sex: Female

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inducers, CYP2D6 inhibitors, Warfarin

Disqualifiers: Invasive breast cancer, Bilateral breast surgery, Thromboembolism, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 6 months

200 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, specifically strong CYP3A4 inducers or strong CYP2D6 inhibitors, unless you can switch to an alternative medication with your doctor's guidance. If you are currently taking Warfarin, you will not be eligible to participate.

What data supports the effectiveness of the drug Tamoxifen for reducing breast cancer risk?

Research shows that Tamoxifen can reduce the risk of developing breast cancer by at least 49% in women who are at increased risk. It is particularly beneficial for women with certain genetic mutations or pre-existing conditions, and it also helps in extending survival and reducing the chance of cancer in the other breast. ^{1 2 3 4 5}

Is tamoxifen generally safe for humans?

Tamoxifen has been used for many years to treat breast cancer and reduce its risk, but it can have side effects. Some women may experience bone loss, uterine issues like polyps or cancer, and mild side effects. Regular check-ups are recommended to monitor these risks. ^{1 2 4 5 6}

How is the drug Tamoxifen unique for breast cancer risk reduction?

Tamoxifen is unique because it works by blocking estrogen receptors in breast tissue, which can help reduce the risk of developing breast cancer. This mechanism is different from other treatments that may target cancer cells directly or use different pathways to prevent cancer growth. ^{7 8 9 10 11}

What is the purpose of this trial?

This phase II trial evaluates response-guided low-dose tamoxifen for reducing breast density in women who are at higher than average risk for breast cancer. Increasing breast density is a well established risk factor for breast cancer. Tamoxifen is a selective estrogen receptor modulator. It works by blocking the effects of the hormone estrogen in the breast. Tamoxifen has been shown to reduce breast density, even at reduced dosages, and is approved for the prevention of breast cancer.

Research Team

Seema A. Khan, M.D.

Principal Investigator

Northwestern University

Eligibility Criteria

This trial is for premenopausal women at higher than average risk for breast cancer, particularly those with dense breasts. The study aims to find the best dose of Tamoxifen that can reduce breast density and thus lower the risk of developing breast cancer.

Inclusion Criteria

I am a woman taking medication to control my HSV infection.

Women of child-bearing potential agreeing to use adequate contraception

Ability to understand and sign a written informed consent document

Exclusion Criteria

Receiving any other investigational agents

Uncontrolled intercurrent illness or psychiatric illness/social situations limiting compliance

I have used SERMs for more than a year in the last 5 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive tamoxifen 5mg PO QD for 6 months. Dose escalation based on response.

6 months

Monthly visits (in-person)

Dose Escalation

Participants with less than 10% reduction in dense area escalate to 10mg or 20mg tamoxifen.

6-12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Tamoxifen

Trial Overview The RENAISSANCE Trial is testing low-dose Tamoxifen's effectiveness in reducing breast density among high-risk women. It includes assessments like questionnaires, biopsies, biospecimen collection, and mammography to monitor changes and responses.

Participant Groups

Group I: Prevention (tamoxifen) Experimental Treatment 5 Interventions

Participants receive tamoxifen 5mg PO QD for 6 months. Participants with aDAR \>= 10% on mammogram at 6 months continue receiving tamoxifen 5mg PO QD for 12 months. Participants with aDAR \< 10% at 6 months are escalated to receive tamoxifen 10mg PO QD for 6 months. Participants with aDAR \>= 10% after 6 months of tamoxifen 10mg continue receiving tamoxifen 10 mg PO QD for 6 months. Participants with aDAR \< 10% after 6 months of tamoxifen 10mg are given the option of continuing tamoxifen 10mg or escalating to receive tamoxifen 20mg PO QD for 6 months. Participants undergo mammography and collection of blood samples at screening and on study. Participants may optionally undergo biopsy at screening and on study.

Tamoxifen is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Nolvadex for:

• Breast cancer
• Infertility
• Gynecomastia

Approved in United States as Tamoxifen citrate for:

• Breast cancer
• Reduction in breast cancer incidence in high-risk women
• McCune-Albright Syndrome

Approved in Canada as Tamoxifen for:

• Breast cancer
• Reduction in breast cancer incidence in high-risk women

Approved in Japan as Tamoxifen for:

• Breast cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

Tamoxifen citrate has been a crucial treatment for breast cancer over the past 25 years, significantly improving survival rates and reducing the risk of developing cancer in the other breast.

Patients appreciate the additional benefits of tamoxifen on cholesterol levels and bone health, but they also express concerns about potential side effects affecting their daily lives.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tamoxifen's impact on the management of breast cancer: patient perspectives. Reichman, BS.[2013]

In a study of 50 postmenopausal women with metastatic breast cancer who had not responded to previous treatments, tamoxifen citrate led to a complete remission in 8% and a partial remission in 28% of patients, with a median response duration of eight months.

Tamoxifen was found to significantly prolong survival in responders compared to nonresponders, and the side effects of the treatment were mild, making it a favorable option for patients after other therapies have failed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tamoxifen. Use in treatment of metastatic breast cancer refractory to combination chemotherapy. Legha, SS., Buzdar, AU., Hortobagyi, GN., et al.[2019]

Tamoxifen can reduce the risk of developing invasive breast cancer by at least 49% in women at increased risk, particularly benefiting those with a 5-year risk of 1.67% or greater, lobular carcinoma-in-situ, or atypical hyperplasia.

While postmenopausal women also benefit from tamoxifen in reducing breast cancer risk and bone fractures, they must consider the potential risks of invasive endometrial cancer and thromboembolic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reducing the risk of breast cancer with tamoxifen in women at increased risk. Vogel, VG.[2013]

Only 27.4% of surveyed primary care physicians prescribed tamoxifen for breast cancer prevention in the past year, indicating that its use is not widespread among these doctors.

Factors influencing the decision to prescribe tamoxifen included personal connections to breast cancer, patient inquiries about the drug, and the belief that its benefits outweigh the risks, while concerns about endometrial cancer risk had less impact on prescribing decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prescription of tamoxifen for breast cancer prevention by primary care physicians. Armstrong, K., Quistberg, DA., Micco, E., et al.[2015]

Tamoxifen is being evaluated in ongoing clinical trials involving over 24,000 healthy women to determine its effectiveness in preventing breast cancer, with results expected by the year 2000.

While tamoxifen may provide significant benefits in breast cancer prevention, it is associated with adverse effects such as transient bone loss in premenopausal women and potential uterine complications in postmenopausal women, leading to investigations of alternative drugs like raloxifene and toremifene.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Status of antiestrogen breast cancer prevention trials. Powles, TJ.[2016]

Tamoxifen has been proven effective in improving recurrence-free and overall survival rates in breast cancer patients, making it the preferred long-term treatment for selected individuals.

While tamoxifen carries a small risk of developing endometrial cancer (approximately 2 per 1,000 women annually), most cases are detected early and are highly treatable, suggesting that the benefits of tamoxifen generally outweigh the risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of tamoxifen on the endometrium. Barakat, RR.[2013]

In a study of 114 women with rheumatoid arthritis treated with leflunomide for 12 months, there was no significant association found between the CAG repeat polymorphism in the androgen receptor gene and the effectiveness of the treatment.

The results indicate that genetic variations in the androgen receptor do not influence the response to leflunomide in improving disease activity in women with rheumatoid arthritis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of association between CAG repeat polymorphism in the androgen receptor gene and the outcome of rheumatoid arthritis treatment with leflunomide. Dziedziejko, V., Kurzawski, M., Safranow, K., et al.[2021]

In a study of 105 rheumatoid arthritis patients, those with the CYP1A2*1F CC genotype had a significantly higher risk (9.7 times) of experiencing toxicity from leflunomide compared to those with the A allele, indicating a genetic factor influencing drug safety.

No significant associations were found between the CYP2C19 and CYP2C9 genotypes and leflunomide toxicity, suggesting that CYP1A2 is the primary genetic determinant affecting the drug's adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. Bohanec Grabar, P., Rozman, B., Tomsic, M., et al.[2021]

In a study of 3,325 veterans, leflunomide (LEF) was found to be relatively safe, with the most common reasons for discontinuation being inefficacy and gastrointestinal symptoms.

The data indicated that younger patients, older patients, and those with lower income were more likely to discontinue LEF, suggesting that these factors may influence treatment adherence and outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide use during the first 33 months after food and drug administration approval: experience with a national cohort of 3,325 patients. Siva, C., Eisen, SA., Shepherd, R., et al.[2018]

In a study of 105 patients with rheumatoid arthritis, 34 discontinued leflunomide due to toxicity, highlighting a significant issue with treatment adherence.

Carriers of the C allele of the CYP1A2 gene were found to have a 2.29 times higher risk of stopping leflunomide due to side effects, suggesting a genetic factor that may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis. Hopkins, AM., Wiese, MD., Proudman, SM., et al.[2021]

Leflunomide (LEF), a drug typically used for rheumatoid arthritis, showed promising antitumor effects in oral squamous cell carcinoma (OSCC) by inhibiting cell proliferation and blocking the cell cycle at the S phase.

LEF not only reduced tumor growth in a xenograft model but also affected key cellular processes by upregulating cyclin A and downregulating dihydroorotate dehydrogenase, suggesting its potential as a new treatment option for OSCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Leflunomide inhibits proliferation and tumorigenesis of oral squamous cell carcinoma. Ren, A., Fu, G., Qiu, Y., et al.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Tamoxifen's impact on the management of breast cancer: patient perspectives. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Tamoxifen. Use in treatment of metastatic breast cancer refractory to combination chemotherapy. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Reducing the risk of breast cancer with tamoxifen in women at increased risk. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Prescription of tamoxifen for breast cancer prevention by primary care physicians. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

Status of antiestrogen breast cancer prevention trials. [2016]

6. United States pubmed.ncbi.nlm.nih.gov

The effect of tamoxifen on the endometrium. [2013]

7. Germany pubmed.ncbi.nlm.nih.gov

Lack of association between CAG repeat polymorphism in the androgen receptor gene and the outcome of rheumatoid arthritis treatment with leflunomide. [2021]

8. Germany pubmed.ncbi.nlm.nih.gov

Genetic polymorphism of CYP1A2 and the toxicity of leflunomide treatment in rheumatoid arthritis patients. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Leflunomide use during the first 33 months after food and drug administration approval: experience with a national cohort of 3,325 patients. [2018]

10. England pubmed.ncbi.nlm.nih.gov

Genetic polymorphism of CYP1A2 but not total or free teriflunomide concentrations is associated with leflunomide cessation in rheumatoid arthritis. [2021]

11. Greece pubmed.ncbi.nlm.nih.gov

Leflunomide inhibits proliferation and tumorigenesis of oral squamous cell carcinoma. [2018]