Tamoxifen Citrate or Afimoxifene in Treating Patients with Estrogen Receptor Positive Breast Cancer
- Screen-detected, estrogen receptor (ER) positive DCIS of the breast proven on core needle biopsy, defined as 10% ER positive cells; microinvasion will be allowed; the size of the DCIS in the core biopsy sample must be at least 4 mm for a single core or total at least 5 mm if multiple cores are summed and must be estimated on the deepest step section (if step sections are taken)
- Age >= 18 years. DCIS of the breast is almost exclusively an adult condition. Because no dosing or adverse event (AE) data are currently available on the use of tamoxifen in participants < 18 years of age, children are excluded from this study
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- Leukocytes >= 3,000/microliter (baseline lab parameters are not standard of care for initiation of tamoxifen therapy; a minimal panel will therefore be appropriate)
- Platelets >= 100,000/microliter (baseline lab parameters are not standard of care for initiation of tamoxifen therapy; a minimal panel will therefore be appropriate)
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (baseline lab parameters are not standard of care for initiation of tamoxifen therapy; a minimal panel will therefore be appropriate)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 1.5 x ULN (baseline lab parameters are not standard of care for initiation of tamoxifen therapy; a minimal panel will therefore be appropriate)
- Creatinine =< 1.5 x ULN (baseline lab parameters are not standard of care for initiation of tamoxifen therapy; a minimal panel will therefore be appropriate)
- The effects of topical 4-OHT gel on the developing human fetus at the recommended therapeutic dose are unknown; for this reason and because tamoxifen is known to be teratogenic, all heterosexually active women who may become pregnant must agree to use a reliable non-hormonal contraceptive method or a hormonal intrauterine device (IUD) during the study and for 2 months after completing study medications; reliable nonhormonal methods of contraception include barrier contraception and an intra-uterine device (IUD); hormonal IUDs are allowable methods of birth control; (Note: Women who had tubal ligation or had a partner who had undergone a vasectomy [and are monogamous] are eligible for the study and are not required to use barrier contraception.)
- Willingness to avoid exposing breast skin to natural or artificial sunlight (i.e. tanning beds) for the duration of the study
- Ability to understand and the willingness to sign a written informed consent document
- Exogenous sex steroid use within 4 weeks prior to diagnostic core needle biopsy (DCNB); use of vaginally administered estrogens and hormone coated IUD such as Mirena is permitted and use should continue until surgery
- History of any prior ipsilateral breast radiotherapy; previous unilateral radiation of the contralateral side is allowed
- History of other prior breast cancer-specific therapy within the previous 2 years (chemotherapy, anti-HER2 agents, endocrine agents, everolimus, CDK4-6 inhibitors)
- Skin lesions on the breast that disrupt the stratum corneum (e.g. eczema, ulceration)
- History of endometrial neoplasia
- History of thromboembolic disease (history of varicose veins and superficial phlebitis is allowed)
- Current smokers
- Current users of potent inhibitors of tamoxifen metabolism must be 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; the potent inhibitors of tamoxifen metabolism are: bupropion, cinacalcet, fluoxetine, paroxetine, quinidine
- Prior use of selective estrogen receptor modulator (SERMS) and aromatase inhibitors (AIs) including tamoxifen, raloxifene, anastrozole, letrozole, or exemestane for prevention or therapy within 5 years
- Participants may not be receiving any other investigational agents within 30 days of enrollment or during this study
- History of allergic reactions attributed to tamoxifen or compounds of similar chemical or biologic composition
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women are excluded from this study; because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with tamoxifen, breastfeeding should be discontinued by nursing mothers who agree to participate in the study
- Men are excluded from this study since DCIS of the breast is exceedingly rare in men, and there are no data regarding skin penetration of 4-OHT though male chest wall skin (which is thicker and hairier than female chest wall skin)
I. To demonstrate that 2 mg once daily per breast of afimoxifene (4-OHT) topical gel results in a reduction in the immunohistochemical (IHC) Ki-67 labeling index of ductal breast carcinoma in situ (DCIS) lesions that is not inferior to that seen with 20 mg daily oral tamoxifen citrate (TAM) for 4 to 10 weeks, when comparing the base-line diagnostic core biopsy (pre-therapy) sample to the therapeutic surgical excision (post-therapy) sample.
I. To compare changes from pre-therapy to post-therapy in the Oncotype DCIS-Score between arms (this is a validated reverse transcriptase-polymerase chain reaction [RT-PCR] assay for 12 genes).
II. To compare between group post-therapy breast tissue and plasma levels of TAM and its metabolites (N-desmethyl tamoxifen [NDT], [E] and [Z] isomers of 4-hydroxytamoxifen [4-OHT], N-desmethyl-4-hydroxytamoxifen [endoxifen]).
III. To compare the Ki-67 labeling index in the terminal duct lobular units (TDLUs), evaluated in the same manner as the primary endpoint.
IV. To compare changes from pre-therapy to post-therapy in plasma proteins involved in coagulation: Factors VIII and IX, von Willebrand Factor, total protein S between arms.
V. To compare changes from pre-therapy to post-therapy in plasma markers of systemic estrogenic effect (IGF-1, IGFBP-3, and SHBG).
VI. To compare changes from pre-therapy to post-therapy in symptoms as captured in the Breast Cancer Prevention Trial (BCPT) Eight Symptom Scale (BESS) questionnaire and skin reactions to 4-OHT gel.
I. To compare changes in DCIS lesions in the expression of protein IHC markers (CD-68, p16, COX-2).
II. To compare changes from pre-therapy to post-therapy in breast tissue and plasma levels of steroid hormones (estradiol and progesterone).
III. To compare the fraction of subjects with no residual DCIS in the surgical specimen.
OUTLINE: Patients are randomized into 1 of 2 arms.
ARM I: Patients apply afimoxifene gel to both breasts and receive placebo orally (PO) daily for up to 10 weeks in the absence of disease progression or unexpected toxicity. Beginning 4-10 weeks after beginning the study agent, patients undergo surgery.
ARM II: Patients apply placebo gel to both breasts and receive tamoxifen citrate orally PO daily for up to 10 weeks in the absence of disease progression or unexpected toxicity. Beginning 4-10 weeks after beginning the study agent, patients undergo surgery.
After completion of study treatment, patients are followed up within 21 days, up to 35 days and within 5 weeks.
Trial Phase Phase II
Trial Type Prevention
Seema Ahsan Khan
- Primary ID NCI2015-06-04
- Secondary IDs NCI-2016-01911, NWU2015-06-04, N01-CN-2012-00035
- Clinicaltrials.gov ID NCT02993159