Refining Tamoxifen Dose for Premenopausal Breast Cancer Risk Reduction (RENAISSANCE): A Phase II Single Arm 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.

Inclusion Criteria:

- Premenopausal women at the time of enrollment defined by any of the following:

- Age under 50 years and regular menstruation (most recent period within the past
3 months)

- Age under 50 years and continuous hormonal contraception use and at least one
intact ovary

- Women who are not postmenopausal based on serum hormone levels (estradiol =< 30
pg/mL, follicle-stimulating hormone [FSH] >= 30 IU/mL)

- Women with any of the following:

- A history of unilateral estrogen receptor (ER) positive ductal carcinoma in
situ (DCIS) with local therapy completed (as determined by treating physician
recommendation and patient acceptance) at least 3 months prior to study entry.
(The untreated breast will be the study breast, for both imaging and optional
biopsy)

- Recent or prior lobular carcinoma in situ (LCIS), or any form of epithelial
atypia

- Are risk eligible for preventive medication based on a five-year risk of 1.7%
or greater, estimated with a validated model: the National Cancer Institute
(NCI) Breast Cancer Risk Assessment Tool, Tyrer-Cusick, Breast Cancer
Surveillance Consortium

- Are tamoxifen-eligible by American Society of Clinical Oncology (ASCO)
guidelines (>= 2-fold increased risk compared to peer if age >= 45 years, and
>= 4-fold increased risk if age < 45 years)

- A history of mantle radiotherapy

- A moderate penetrance germline pathogenic variant

- Participants ≥ 18 and ≤ 55 years old will be enrolled. Our trial objectives are not
relevant to females under 18 years of age since breast cancer is extraordinarily
rare in this age group, and there are no guidelines regarding use of tamoxifen in
children, even if know to be at very high risk for breast cancer when older. Because
no dosing or adverse event (AE) data are currently available on the use of tamoxifen
in participants < 18 years of age

- Eastern Cooperative Oncology Group (ECOG) performance status must be =< 2 (Karnofsky
>= 60%)

- Human immunodeficiency virus (HIV)-infected patients are eligible to participate if
they are on effective anti-retroviral therapy with undetectable viral load within
the prior 6 months

- Women with evidence of chronic hepatitis B virus (HBV) infection, are also eligible
if the HBV viral load is undetectable; they may be on suppressive therapy, if
indicated

- Women with a history of hepatitis C virus (HCV) infection are eligible if treated
and cured. For those who are currently on treatment, they are eligible if they have
an undetectable HCV viral load

- Women with herpes simplex virus (HSV) infection are eligible if on chronic or as
needed (due to a flare) suppressive antiviral therapy

- Hormonal contraceptive users are eligible and should maintain the same oral
contraceptive preparation throughout the duration of the trial. For women who have a
levonorgestrel-coated intra-uterine device, removal for medical reasons will be
allowed

- The effects of tamoxifen on the developing human fetus at the recommended
therapeutic dose are unknown. For this reason and because tamoxifen is known to be
teratogenic, women of child-bearing potential must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation. Should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her study physician immediately

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

Exclusion Criteria:

- Breast Imaging Reporting and Data System (BIRADS) breast density category A on most
recent mammogram

- History of selective estrogen receptor modulator (SERM) use within the past 5 years
and duration of use > 1 year

- History of invasive breast cancer

- Prior bilateral breast surgery (mastectomy or breast augmentation surgery including
breast implants)

- Women with "mosaic mammographic screening views", i.e., whose larger breast size
precludes being imaged within a single mammographic screening view

- Current use of a strong CYP3A4 inducer or a strong CYP2D6 inhibitor unless willing
and able to discontinue use and switch to an alternative medication for the duration
of participation, under the advice of their physician. If the physician believes the
current medication is medically necessary, the participant will not be eligible

- Planning to become pregnant within the next two years. Potential study participants
will be questioned about this and excluded if they are planning pregnancy over the
next 20 months

- History of thromboembolism. A history of superficial thrombophlebitis is allowed

- History of uterine cancer or atypical uterine hyperplasia with uterus intact

- Participants may not be receiving any other investigational agents

- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to tamoxifen

- Uncontrolled intercurrent illness or psychiatric illness/social situations that
would limit compliance with study requirements

- Pregnant women are excluded from this study because tamoxifen a category D agent
with the potential for teratogenic or abortifacient effects. Because there is an
unknown but potential risk for AEs in nursing infants secondary to treatment of the
mother with tamoxifen. Breastfeeding should be discontinued if the mother is treated
with tamoxifen