The following datasets contain the data available for EPPT NWU2015-06-04. The description and documentation for each file is listed below. SAS7bdat and CSV versions of the actual data will be available to CDAS projects approved to use this study's data.

Analysis Datasets

Raw Datasets

These 39 datasets contain the raw form data received, excluding PII.

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Trial Summary

This Phase IIB randomized, double blind clinical trial tested oral tamoxifen against 4-hydroxytamoxifen gel in women with DCIS of the breast. The goal was to demonstrate that 2 mg once daily per breast of 4-hydroxytamoxifen (4-OHT) topical gel results in a reduction in the 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 4-10 weeks, when comparing the base-line diagnostic core biopsy to the therapeutic surgical excision sample.

Patients received either 2mg once daily per breast of 4-OHT topical gel, or 20mg daily oral TAM for 4 to 10 weeks.

Enrollment Statistics

Target Enrollment: 100

Actual Enrollment: 120

Actual Registration: 120

• 120 were evaluated for eligibility
• 13 were excluded for not meeting inclusion/exclusion criteria
• 107 were registered for 4 to 10 weeks of intervention
• 90 completed study
• 10 participant withdrawal
• 1 physician decision
• 1 protocol violation
• 5 other specify

Participant Statistics:

• Age (years):
  • Mean: 55.0
  • Median: 53.0
  • Range: 30 - 82
• Sex
  • Female: 120 (100%)
• BMI:
  • Mean: 29.6
  • Median: 27.5
  • Range: 19.0 - 46.3

Eligibility Criteria

Inclusion Criteria

• Screen-detected, 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 4mm 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.
• ECOG performance status ≤1 (Karnofsky ≥70%)
• Participants must have acceptable organ and marrow function as defined below:
• Baseline lab parameters are not standard of care for initiation of tamoxifen therapy; a minimal panel will therefore be appropriate.
• Leukocytes ≥3,000/microliter
• Platelets ≥100,000/microliter
• Total bilirubin ≤1.5 x institutional upper limit of normal (ULN)
• AST (SGOT)/ALT (SGPT) ≤1.5 x ULN
• Creatinine ≤1.5 x ULN
• 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 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 also 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.

Exclusion Criteria

• 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 (eg 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 SERMS or 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 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).

The Schema is a timeline of the study. It indicates start/end points, visits expected, major testing to be done, and any other information that is crucial to understanding how the study was completed.

Biospecimen Report

Blood samples (Screen 1 and Study Visit 1): Blood samples will be collected with an appropriate type of anti-coagulants, and processed.

1. Two 2.7mL blue top tubes (citrate) to obtain plasma for coagulation panel assays. Each tube must be a full draw. 1mL each will be aliquoted in a 1.8 mL size cryo-vial. We will make as many aliquots as available. The last aliquot may not be enough for 1 mL, but save it as well and record approximate volume available.
2. Two 10 mL lavender top tubes (K2EDTA) to obtain plasma and buffy coat. We will get approximately 3~ 4 mL plasma from one lavender top tube. 1mL each will be aliquoted in a 1.8 mL size cryo-vial. We will make as many aliquots as available. The last aliquot may not be enough for 1 mL, but save it as well and record approximate volume available. Plasma aliquots will be used for IGF-1 and SHBG assays (Screen 1 and Study Visit 1); for steroid hormone assays (estradiol, progesterone, and dehydroepiandrosterone (DHEA), androstenedione, and testosterone (Screen 1 and Study Visit 1); and for measuring tamoxifen and its metabolites [tamoxifen, N-desmethyl tamoxifen, (E) 4-OHT, (Z) 4-OHT, (E) endoxifen, and (Z) endoxifen] (Only Study Visit 1). Finally, buffy coat will be collected into one 1.8 mL cryo-vial. A total volume of buffy coat will be approximately 1 mL for future polymorphisms assays in tamoxifen metabolism genes (Screen 1 and Study Visit 1). A minimum of 15 sections will be cut from the core needle biopsy block and the surgical block, 7 for Ki67 and other IHC markers and 8 for DCIS score measurement.

Drug concentration assays (only for study visit 1):

1. Fresh benign tissue 1x1x1 cm fragments (weight of each fragment is usually 200mg~300mg) from surgical cavity, to avoid interfering with margin assessment on the main specimen. The 1x1x1 cm breast tissue sample will be split in half, and a slice of tissue about 3 mm thick will be taken from one face, and placed in formalin for at least 6 and at most 72 hours, then embedded in paraffin. The remainder of the fresh breast sample will be flash-frozen for drug assay.
2. An aliquot of plasma from the research blood sample drawn with a 10 mL Lavender top tube (K2EDTA) at the Day of Surgery (study visit 1) will be to obtain plasma for measurement of circulating drug concentrations. Measurement of drug metabolites (tamoxifen, N-desmethyltamoxifen, E and Z isomers of both 4-OHT and endoxifen These fresh frozen tissue samples along with the paraffin block, plasma, and buffy coat samples will be sent as a single shipment for each participant (frozen samples on dry ice) to NU from participating sites. FFPE blocks will be shipped in cold condition. At NUPCF, the Sample B FFPE will be sectioned and stained with H&E to determine the tissue composition of the drug concentration sample. The histology findings from this research sample will not be reported back to clinical teams.

Mastectomy sampling procedures (for subjects who opt for mastectomy)

At five sites (Cleveland Clinic, Mayo Clinic, Duke, St Elizabeth, University of Kansas), the drug concentration samples will be harvested by the grossing pathologist as described above in Section The location of these two samples will be 1) superficial, one centimeter from the superficial surface of the mastectomy specimen, and 2) deep, one centimeter from the deep aspect of the mastectomy specimen. These samples may be taken from the location that is remote to the known location of the DCIS.

At two sites (NU and MSKCC) the mastectomy specimen will be grossed according to the scheme developed for a previous topical gel study.

Paraffin blocks: As each subject is enrolled, the sites will indicate on the pre-enrollment form whether the DCNB was performed at the enrolling institution, or elsewhere. If elsewhere, the name of the hospital and contact information for the Pathology Department of that hospital will be provided. If DCNB was not done at the enrolling institution, NU-PCF NU PCF will work with the enrolling site as needed to acquire DCNB material from the site where the DCNB was performed. If DCNB was done at the enrolling institution, the study coordinator will place a request for that block to be retrieved as soon as the surgical date is known, to avoid delays caused by block retrieval.

At the end of study participation, for each subject, the paraffin blocks of the DCNB (if done at the enrolling institution) and the surgical samples will be assembled by each site as soon as the final pathology on the surgical sample has been reported. The study consent will include a statement providing permission to the hospitals involved in diagnosis and therapy (which may not be the same) to release the DCNB block and a selected surgical block to NU for study purposes. At NU PCF, the pre- and post-therapy sample blocks will be sectioned at the same time following the completion of participation of each subject. A minimum of 15 sections will be taken for: H&E, Ki67, DCIS-Score and other markers (CD68, COX2, p16), cytokeratin (CK) as epithelial classifier and at least one extra for possible repeats. All sections will be saved, vacuum-sealed and cold, until the conclusion of the study. In this way, pre- and post-therapy sections for each biomarker will be processed in the same batch.

Slide submission for Exact Sciences DCIS-Score: Eight unstained slides of DCBN pre-therapy block will be submitted immediately to GHI (so that the data can be used for radiation therapy decision if needed). Eight unstained slides of post-therapy block will be reserved in the NU PCF and shipped as a single batch after the study is complete and all participant samples have been received at NU.

Institutions that do not allow release of paraffin blocks despite participant consent. These institutions will provide unstained sections of the paraffin block as detailed above.

Institutions that do provide paraffin blocks: these will be returned to the institution where the sample was taken once the protocol-defined sections have been taken, typically within 3 months of submission to NU.

Timing of sample

Specimen is obtained without regard to time of day or fasting, it will be determined by time of study visits. Circulating biomarkers are not significantly affected by time of day.

Temperature storage requirements

• FFPE samples will be stored and shipped cold
• Fresh tissue will be stored at -80°C and shipped on dry ice
• Blood will be processed and aliquoted to yield serum, plasma, Buffy coat, stored at -80°C and shipped on dry ice.

Storage duration

Samples will be stored until analysis are completed and published, at which point it will be transferred to the DCP repository.

Of 90 participants completing treatment (mean age 55 years, 62% white), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary endpoint (oral-TAM N=40, 4OHT-gel N=35). Post-treatment Ki67-LI was 3.3% higher (80% CI 2.1%-4.6%) in the 4OHT-gel compared to oral-TAM arm, exceeding the noninferiority margin (M=2.6); DCIS Score decreased more with oral-TAM treatment (-16, 95% CI -22, -9.4) than with 4OHT-gel (-1.8, 95% CI -5.8, 2.3). Median 4-OHTconcentrations (ng/g) deep in the breast were non-significantly higher in the oral-TAM arm (5.7, IQR 4.0,7.9 vs. 3.8 IQR 1.3,7.9), whereas endoxifen was abundant in the oral-TAM and minimal in the 4OHT-gel arm (13 vs. 0.3, p<0.001). Oral-TAM caused expected adverse changes in plasma proteins and vasomotor symptoms, with minimal changes in the transdermal arm.¹