The goal of this research study is to evaluate the efficacy and safety of low-dose exemestane versus low-dose tamoxifen in post-menopausal women at high risk for breast cancer.

The names of the study drugs involved in this study are:

• Exemestane (a type of steroidal aromatase inhibitor)
• Tamoxifen (a type of selective estrogen receptor modulator)

This randomized, double-blind, phase II trial is to evaluate the efficacy and safety of low-dose "baby" exemestane versus low-dose "baby" tamoxifen in post-menopausal women at high risk for breast cancer. Both medications are used at full doses for breast cancer treatment and to reduce breast cancer risk. Low dose tamoxifen has been shown to be effective at reducing risk with better tolerance.

Participants will be randomized into one of two study groups: Group A: Exemestane versus Group B: Tamoxifen. Randomization means a participant is placed into a study group by chance. Neither a participant or the research doctor will choose or know what group a participant is placed in. This is called a "double-blind".

The U.S. Food and Drug Administration (FDA) has not approved tamoxifen or exemestane for ER+ DCIS, High Risk Lesions, or being at high-risk for breast cancer but it has been approved for other uses.

The research study procedures include screening for eligibility, in-clinic visits, questionnaires, blood tests, Mammography scans, and bone density (DEXA) scans.

Participation in this research study is expected to last about 12 months. It is expected that about 140 people will take part in this research study. The Breast Cancer Research Foundation is supporting this research study by providing funding. MRIGlobal is providing support by supplying the study drugs.

Inclusion Criteria:

• Postmenopausal state is defined⁸ as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy.

• Any of the following criteria must be met:

  • Recent (within 12 months from date of consent form signature) histologic diagnosis of ER+ve (>5%) DCIS (patients with DCIS should have undergone breast-conserving therapy i.e. lumpectomy to remove the tumor with negative surgical margins followed by radiotherapy (see footnote 1 below)) diagnosis within 3 years of HRL (ADH, LCIS, ALH), or;
  • At least 3% breast cancer risk at 5 years (or 5% risk at 10yrs) per one of the following risk models: the Breast Cancer Surveillance Consortium risk calculator V3 or Tyrer-Cuzick model V8 or;
  • Known carriers of a germline pathogenic/likely pathogenetic variant in the following moderate penetrance genes (CHEK2 or ATM), or women with chest wall irradiation before age of 30 years

• Eastern Cooperative Oncology Group - Performance Status (ECOG-PS) 0-1

• Able to swallow oral medications

• Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Specifically, all cancers diagnosed since 3 years or longer except for breast and endometrial are eligible.

• Ability to understand and the willingness to sign a written informed consent document

• Mammography performed up to 6 months before the trial consent form signature

• DEXA performed up to 12 months before the trial consent form signature

• Life expectancy ≥ 10 years

• Normal liver function tests and blood cell count

• Negative gynecological examination performed up to 6 months before the trial consent form signature.

ᶥ While DCIS and ADH are routinely excised, and treatment of DCIS often includes radiotherapy, lobular neoplasia (ALH and classic LCIS) are not routinely excised in most US centers unless radiologic-pathologic findings are discordant given the very low risk of an associated cancer.11,12 Participants with DCIS should have undergone breast-conserving therapy i.e. lumpectomy to remove the tumor with negative surgical margins followed by radiotherapy. All DCIS will require excision to clear margins per the SSO/ASCO/ASTRO margin guidelines for DCIS.88 In selected cases, the decision to omit RT might be taken according to low risk clinical-pathological factors (e.g., age>70, low grade, size < 1 cm, and genomic assays if available) as well as patient preference after full discussion of the risks and benefits.

Exclusion Criteria:

• Pre/perimenopausal women: exemestane is only effective in post-menopausal women
• History of DVT or PE: tamoxifen can increase tendency to blood clot
• Endometrial cancer: full-dose tamoxifen is associated with increased risk of endometrial cancers
• Macular disorders: tamoxifen is associated with retinal damage
• Inability to comply with study procedures: standard
• Prior use of antiestrogens within 12 months from the date of the trial consent form signature: there can be long duration effects from antiestrogens that could influence trial drug effects
• Use of hormone replacement therapy (HRT) within 3 months from the date of the trial consent form signature: similarly, wish to avoid any long lasting effect before alternate effect from study drugs
• Severe osteoporosis (T score ≤ 2.5 at either spine or hip), or recent vertebral fracture (within 6 months) not treated with zoledronic acid or denosumab: Exemestane is an aromatase inhibitor which can worsen bone loss (osteoporosis)
• Current use of terbinafine, quinidine, cinacalcet, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John's wort, warfarin, erythromycin, cyclosporin, nifedipine and any concomitant coumarin-type anti-coagulant therapy: these drugs compete for the Cytochrome P450 metabolic pathways of tamoxifen and exemestane
• Moderate or severe renal impairment: Exemestane is eliminated equally by liver and renal metabolism
• Known hypersensitivity to study drugs: standard

Screening Eligibility Criteria

To register a participant to the screening phase, the following documents should be provided by the participating site:

Signed participant consent form

• Postmenopausal status, and any of the following:

  • Histological report of ER-positive DCIS within 12 months, or HRL of the breast within 3 years from date of consent form signature, or;
  • Report of risk assessment ≥3% in 5 years or 5% in 10 years of breast cancer according to the selected risk model(s) different criteria within 6 months from screening, or;
  • Documentation of women carriers of a germline pathogenic/likely pathogenetic variant in a moderate penetrance gene (CHEK2 or ATM), or;
  • Documented history of chest wall radiotherapy before age 30.

• Inclusion of Women and Minorities

Only women will be recruited in the study given that breast cancer is much more frequent in women than men and because exemestane is contraindicated in men because of risk of uncontrolled gonadal stimulation. Women of all races and ethnic groups are eligible for this trial. At participating sites, efforts will be made to enroll women from diverse ethnic and socio-economic backgrounds, including recruitment of non-white women in a selected New York city area.

NIH policy requires that women and members of minority groups and their subpopulations be included in all NIH-supported biomedical and behavioral research projects involving NIH-defined clinical research unless a clear and compelling rationale and justification establishes to the satisfaction of the funding Institute & Center (IC) Director that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. Exclusion under other circumstances designated by the Director, NIH, upon the recommendation of an IC Director based on a compelling rationale and justification. Cost is not an acceptable reason for exclusion except when the study would duplicate data from other sources. Women of childbearing potential should not be routinely excluded from participation in clinical research.

The Dana-Farber / Harvard Cancer Center encourages and supports the responsible and ethical sharing of data from clinical trials. De-identified participant data from the final research dataset used in the published manuscript may only be shared under the terms of a Data Use Agreement. Requests may be directed to: [contact information for Sponsor Investigator or designee]. The protocol and statistical analysis plan will be made available on Clinicaltrials.gov only as required by federal regulation or as a condition of awards and agreements supporting the research.

Data can be shared no earlier than 1 year following the date of publication

DFCI- Contact the Belfer office for Dana -Farber Innovations (BODFI) at innovations@dfci.harvard.edu