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Phase IIB Randomized Controlled Biomarker Modulation Study of Vitamin D in Premenopausal Women at High Risk for Breast Cancer

Phase 2
18 Years
50 Years
Open (Enrolling)
brca1 Mutation Carrier, brca2 Mutation Carrier, Breast Cancer

Thank you

Trial Information

Phase IIB Randomized Controlled Biomarker Modulation Study of Vitamin D in Premenopausal Women at High Risk for Breast Cancer


- To assess whether mammographic density is reduced in premenopausal women at high risk
of breast cancer taking high-dose vitamin D3 (oral cholecalciferol 20,000 IU weekly) vs
placebo for 1 year.

- To assess whether proliferation as measured by Ki-67 staining of breast epithelial
cells is reduced in women receiving these treatments.

- To explore the difference in the expression of other biomarkers (including cleaved
caspase-3 [apoptosis marker], ER, vitamin D receptor [VDR], and 1α-hydroxylase) in
breast tissue obtained from these women.

- To assess whether parathyroid hormone, IGF-1, IGFBP-3, 25(OH)D, and 1,25(OH)D serum
levels are altered in these women at baseline and at 6 and 12 months.

- To explore whether a change in mammographic density correlates with polymorphisms in
the VDR gene.

- To assess other sources of vitamin D (sunlight exposure, diet) in these women using a
validated questionnaire administered at baseline and at 12 and 24 months.

- To collect and bank serum, plasma, and breast tissue from these women before and after
a 1-year intervention with vitamin D for future biomarker analysis.

- To assess the toxicity of high-dose cholecalciferol compared to placebo in this

OUTLINE: This is a multicenter study. Participants are stratified according to baseline
serum 25(OH)D level (< 20 ng/mL vs 20-32 ng/mL or < 50 nmol/L vs 50-80 nmol/L), baseline
mammographic density (11-50% vs > 50%), and designated biopsy site (yes vs no). Participants
are randomized to 1 of 2 treatment arms.

- Arm I: Participants receive oral cholecalciferol once weekly and oral vitamin D once
daily. Treatment repeats for 12 months in the absence of evidence of cancer or
unacceptable toxicity.

- Arm II: Participants receive oral placebo once weekly and oral vitamin D once daily.
Treatment repeats for 12 months in the absence of evidence of cancer or unacceptable

Blood samples are collected at baseline and periodically thereafter for biomarkers and
25(OH)D level. Participants undergo a mammogram at baseline and at 12 months. Participants
may also undergo random core-needle breast biopsy at baseline and at 12 months.

Participants complete a questionnaire at baseline and at 12 and 24 months.

After completion of study therapy, participants are followed up at 1 and 12 months.

Inclusion Criteria


- At an elevated risk of breast cancer by at least one of the following criteria:

- Diagnosis of ADH, ALH, lobular carcinoma in situ (LCIS) or resected ductal
carcinoma in situ (DCIS) or small invasive breast cancers (pTmi or pT1a N0) if
no pior RT, tamoxifen, or systemic breast cancer treatment within 28 days prior
to registration OR diagnosis of resected Stage I (T1b-c N0-N1mi) through Stage
II breast cancer for which the participant has been disease-free for at least 5
years and has completed all adjuvant treatment OR

- A known* deleterious mutation in BRCA1, BRCA2, PTEN, or TP53 NOTE: *The
participant must be a documented carrier to meet this criterion. If there is a
known mutation in a hereditary breast cancer susceptibility gene in a
participant's family member, the participant herself must have undergone genetic
testing as per NCCN clinical guidelines to be eligible per this criterion.

- Modified Gail Model/CARE model** risk at 5 years ≥ 1.67% or lifetime risk ≥ 20%
by Claus, BRCAPro, Tyrer-Cuzick or IBIS models OR

- Mammographic density ≥ 50% (heterogenously dense) NOTE: **Risk models are to be
used only if there is no known previous diagnosis of resected DCIS or LCIS and
there is no known deleterious mutation in BRCA1, BRCA2, PTEN, or TP53.

- At least one breast available for imaging and biopsy (a previously irradiated breast
[i.e., for resected DCIS] is not evaluable for breast imaging or biopsy)

- Baseline mammogram (performed within 10 days after starting their last menstrual
period on a digital mammography machine) that shows either normal or benign findings

- Baseline mammographic density > 10% based upon the classification system (2 =
11-50%, "scattered fibroglandular densities"; 3 = 51-75%, "heterogeneously
dense"; 4 = >75, "extremely dense". Women with a baseline mammographic density
of ≤ 10% (1 = ≤ 10% breasts are almost entirely fat)will not be eligible.


- Premenopausal, defined as ≥ 1 of the following criteria:

- Less than 6 months since the last menstrual period, no prior bilateral
oophorectomy, and no use of hormone-replacement therapy

- Has undergone a prior hysterectomy but no prior bilateral oophorectomy AND
follicle-stimulating hormone values measured within the past 28 days are
consistent with the normal values for the premenopausal state

- Zubrod performance status 0-1

- Serum creatinine ≤ upper limit of normal (ULN)

- Serum calcium or corrected calcium ≤ ULN

- Spot urine calcium:creatinine ratio < 0.37 mg/dL

- INR ≤ 1.5 times ULN+

- PT and PTT ≤ ULN*

- Baseline serum 25(OH)D level ≤ 32 ng/mL (or 80 nmol/L)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective contraception

- No other prior malignancy except for the following:

- Adequately treated basal cell or squamous cell skin cancer

- In situ cervical cancer

- Adequately treated stage I or II (including resected Stage I, T1b-c N0-N1mi
through Stage II breast cancer) from which the participant is currently in
complete remission

- Any other cancer (including contralateral breast) for which the participant has
been disease-free for ≥ 5 years

- No history of kidney stones

- No medical conditions requiring calcium or vitamin D supplementation (i.e.,

- No known hypersensitivity to vitamin D

- No known allergy to soy NOTE: +For patients undergoing breast biopsy.


- Prior breast reduction surgery allowed

- No bilateral breast implants

- More than 1 month since prior surgery or radiotherapy to the breast for resected DCIS

- At least 28 days since prior tamoxifen

- Prior anticoagulant therapy allowed provided it is discontinued ≥ 7 days before
breast biopsy

- No concurrent calcium or additional vitamin D supplements

- Concurrent multivitamins allowed provided that the dose of vitamin D in the
multivitamin does not exceed 400 IU daily

- No concurrent participation in any other clinical trial for the treatment or
prevention of cancer unless the participant is no longer receiving the intervention
and is in the follow-up phase only (participants must not join such a trial while
participating in this study)

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Outcome Measure:

Change in mammographic density at 12 months compared to baseline

Outcome Time Frame:

12 months

Safety Issue:


Principal Investigator

Laurence H. Baker, DO, FACOI

Investigator Role:

Principal Investigator

Investigator Affiliation:

Southwest Oncology Group - Group Chair's Office


United States: Food and Drug Administration

Study ID:




Start Date:

November 2011

Completion Date:

July 2015

Related Keywords:

  • brca1 Mutation Carrier
  • brca2 Mutation Carrier
  • Breast Cancer
  • breast cancer
  • ductal breast carcinoma in situ
  • lobular breast carcinoma in situ
  • BRCA1 mutation carrier
  • BRCA2 mutation carrier
  • Breast Neoplasms



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