The greatest success in breast cancer prevention has been with two agents, tamoxifen and raloxifene, both of which are approved by the US Food and Drug Administration (FDA) for the risk reduction of invasive breast cancer in high-risk women. However, these agents are only effective in preventing a certain percentage of estrogen receptor–positive disease. New agents are needed to prevent invasive breast cancer in a broader population of women. Phase I/II clinical trials are conducted with the intent of investigating agent efficacy via surrogate endpoint biomarkers. They also allow us to refine the population that may benefit from a given intervention. In this article, we review the important components of early phase trials including study design, cohort, surrogate endpoint biomarkers, and the challenges of recruiting to prevention trials. We discuss some early-phase trials for which results have recently been reported at meetings or through publications, as well as those trials that have recently been opened.

Update on Phase I/II Breast Cancer Prevention Trials

In addition to its role in calcium homeostasis and bone health, vitamin D has also been reported to have anticancer activities against many cancer types, including breast cancer. The discovery that breast epithelial cells possess the same enzymatic system as the kidney, allowing local manufacture of active vitamin D from circulating precursors, makes the effect of vitamin D in breast cancer biologically plausible. Preclinical and ecologic studies have suggested a role for vitamin D in breast cancer prevention. Inverse associations have also been shown between serum 25-hydroxyvitamin D level (25(OH)D) and breast cancer development, risk for breast cancer recurrence, and mortality in women with early-stage breast cancer. Clinical trials of vitamin D supplementation, however, have yielded inconsistent results. Regardless of whether or not vitamin D helps prevent breast cancer or its recurrence, vitamin D deficiency in the U.S. population is very common, and the adverse impact on bone health, a particular concern for breast cancer survivors, makes it important to understand vitamin D physiology and to recognize and treat vitamin D deficiency. In this review, we discuss vitamin D metabolism and its mechanism of action. We summarize the current evidence of the relationship between vitamin D and breast cancer, highlight ongoing research in this area, and discuss optimal dosing of vitamin D for breast cancer prevention.

Vitamin D and Breast Cancer

Background: Vitamin D has diverse biological effects on proliferation, differentiation, and apoptosis in multiple tissues, including the breast. Observational studies have demonstrated that serum 25-hydroxyvitamin D (25-OHD), an objective measure of vitamin D status, is inversely related to breast cancer risk, such that levels >40 ng/ml are associated with a 40% reduction in breast cancer risk compared to women who are vitamin D deficient (25-OHD Methods: Twenty high-risk premenopausal women (5-year Gail risk score ≥1.67%, history of LCIS or DCIS, BRCA1 or BRCA2 mutation carrier) were assigned to a 1-year intervention of cholecalciferol (vitamin D3) 30,000 IU weekly (cohort 1, N=10) or 20,000 IU weekly (cohort 2, N=8/10). Eligibility criteria included baseline serum 25-OHD ≥32 ng/ml and no history of kidney stones. Participants were monitored for toxicity, particularly hypercalcemia and hypercalciuria, every 3 months during the 1-year intervention. They underwent a digital mammogram and random core breast biopsy at baseline and 12 months, as well as serial blood collections at 0, 6, and 12 months. Serum 25-OHD was measured by Diasorin radioimmunoassay. Results: From November 2007 to March 2010, 18 of 20 participants were enrolled and 12 have completed the 1-year intervention (10 in cohort 1; 2 in cohort 2). Median age: 47 (37-52); White/Hispanic/Black: 8/9/1; Median body mass index: 27.7 kg/m2 (21.5-35.4); Elevated Gail risk/LCIS/DCIS: 11/6/1; Mean baseline serum 25-OHD: 19 ng/ml (11-27). Women assigned to a dose of 30,000 IU weekly (cohort 1) rose to a mean serum 25-OHD of 55 ng/ml (26-75) at 6 months and 59 ng/ml (49-71) at 12 months. The dose of 20,000IU weekly (cohort 2) resulted in a mean serum 25-OHD of 48 ng/ml (35-59) at 3 months and 50 ng/ml (42-63) at 6 months. No significant hypercalcemia (serum calcium >10.5 mg/dl) or hypercalciuria (spot urine calcium/creatinine >0.37) occurred at either dose level. One woman dropped out due to worsening gastroesophageal reflux symptoms. Biomarker analyses for samples collected from cohort 1 are ongoing. Discussion: We have demonstrated that a 1-year intervention of high-dose vitamin D3 20,000 IU or 30,000 IU weekly is well-tolerated and able to increase serum 25-OHD above 40 ng/ml in all participants, without any episodes of hypervitaminosis D. The effects of high-dose vitamin D on mammographic density, tissue and serum-based biomarkers of breast cancer risk are currently being evaluated. Large-scale randomized controlled trials are necessary to determine the safety, efficacy, optimal dose and duration of vitamin D supplementation for breast cancer chemoprevention. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-07-01.

Abstract P1-07-01: Safety of High-Dose Vitamin D Supplementation in Premenopausal Women at High Risk for Breast Cancer

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Abstract P1-07-01: Safety of High-Dose Vitamin D Supplementation in Premenopausal Women at High Risk for Breast Cancer