Pretreatment vitamin D level and response to neoadjuvant chemotherapy in women with breast cancer on the I‐SPY trial (CALGB 150007/150015/ACRIN6657)

Abstract

Laboratory studies suggest that vitamin D (vitD) enhances chemotherapy-induced cell death. The objective of this study was to determine whether pretreatment vitD levels were associated with response to neoadjuvant chemotherapy (NACT) in women with breast cancer. Study patients (n = 82) were enrolled on the I-SPY TRIAL, had HER2-negative tumors, and available pretreatment serum. VitD levels were measured via DiaSorin radioimmunoassay. The primary outcome was pathologic residual cancer burden (RCB; dichotomized 0/1 vs. 2/3). Secondary outcomes included biomarkers of proliferation, differentiation, and apoptosis (Ki67, grade, Bcl2, respectively) and 3-year relapse-free survival (RFS). Mean and median vitD values were 22.7 ng/mL (SD 11.9) and 23.1 ng/mL, respectively; 72% of patients had levels deemed “insufficient” (<30 ng/mL) by the Institute of Medicine (IOM). VitD level was not associated with attaining RCB 0/1 after NACT (univariate odds ratio [OR], 1.01; 95% CI, 0.96–1.05) even after adjustment for hormone receptor status (HR), grade, Ki67, or body mass index (BMI). Lower vitD levels were associated with higher tumor Ki67 adjusting for race (OR, 0.95; 95% CI, 0.90–0.99). VitD level was not associated with 3-year RFS, either alone (hazard ratio [HzR], 0.98; 95% CI, 0.95–1.02) or after adjustment for HR, grade, Ki-67, BMI, or response. VitD insufficiency was common at the time of breast cancer diagnosis among women who were candidates for NACT and was associated with a more proliferative phenotype. However, vitD levels had no impact on tumor response to NACT or short-term prognosis.

Prognostic associations of 25 hydroxy vitamin D in NCIC CTG MA.21, a phase III adjuvant randomized clinical trial of three chemotherapy regimens in high-risk breast cancer

“…The results of this study are in agreement with those of other correlative studies nested in RCTs involving women with early-stage breast cancer (MA.14 and I-SPY) that did not show an association between vitamin D with outcome [8,9]. MA.21 is the largest of these studies and it provides additional information regarding this controversial biomarker.…”

“…In contrast to these results, two post hoc correlative studies conducted in randomized treatment trials, one in the adjuvant (MA.14) and one in the neoadjuvant (I-SPY) setting, did not identify a link between 25 OH vitamin D and breast cancer prognosis [8,9]. In an attempt to understand this inconsistency, we undertook an analysis of the association of 25 OH vitamin D with breast cancer outcome in MA.21, a large, multicenter, Phase III adjuvant trial [10].We hypothesized that patients with lower levels of vitamin D would have an increased risk of recurrence or death.…”

Reducing the Risk of Breast Cancer Recurrence: an Evaluation of the Effects and Mechanisms of Diet and Exercise

“…Though evidence from in vitro, animal, and observational studies support the role of vitamin D in improving breast cancer outcomes, data from prospective [38] and observational studies nested randomized trials [39, 40•, 41] in women with breast cancer have not suggested prognostic associations [39, 40•, 41]. The physiological mechanism underpinning the inhibitory action of vitamin D on breast cancer centers on calcitriol, the hormonally active form of vitamin D. Calcitriol inhibits proliferation of human breast cancer cell lines and arrests tumor growth in xenograft models through several processes that ultimately suppress estrogen pathways in breast cancer cells (reviewed in Krishnan et al [42]).…”

“…The mechanistic evidence is in agreement with observational data supporting an adverse association between breast cancer recurrence and levels of serum 25-hydroxyvitamin D [25(OH)D], the precursor to calcitriol [43, 44]. In contrast, findings from observational studies contradict these results, as no associations between serum 25(OH)D levels and breast cancer outcomes have been observed in a secondary analysis of the WHEL data [38], or in adjuvant (MA.21 [40•], MA.14 [41]) or neo-adjuvant (I-SPY [39]) settings. Although the nesting of observational studies in randomized trials such as that in Clark et al [39], Lohmann et al [40•], and Pritchard et al [41] has its limitations, the RCTs provide greater standardization of tumor, treatment, and outcome characterizations than the non-therapeutic observational studies.…”

“…In contrast, findings from observational studies contradict these results, as no associations between serum 25(OH)D levels and breast cancer outcomes have been observed in a secondary analysis of the WHEL data [38], or in adjuvant (MA.21 [40•], MA.14 [41]) or neo-adjuvant (I-SPY [39]) settings. Although the nesting of observational studies in randomized trials such as that in Clark et al [39], Lohmann et al [40•], and Pritchard et al [41] has its limitations, the RCTs provide greater standardization of tumor, treatment, and outcome characterizations than the non-therapeutic observational studies. Clearly, therapeutic interventions involving vitamin D supplementation would be desirable in evaluating the effects of vitamin D on breast cancer outcomes, as neither observational nor post hoc correlative studies provide substantive evidence on which to base recommendations.…”