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    • br Predictors of benefit from bisphosphonates Randomized con

    2019-06-12


    Predictors of benefit from bisphosphonates Randomized control studies of adjuvant BP therapy in early breast cancer show benefit related to “low estrogen states” [1,2,5,6]. Unfortunately, thus far, only one study has assessed systemic estrogen levels to substantiate these results. This is clearly going to remain an issue as accurate assays for estradiol measurement in postmenopausal women [69–71] and women on aromatase inhibitors in particular are not widely available [72]. We therefore have to explore the literature for evidence to support this hypothesis. It is known that postmenopausal women go through two phases of bone loss: an initial accelerated phase in early menopause, followed by a more gradual, continuous phase [26]. The greatest loss of bone mineral density (BMD) has been shown to occur within the first five years of menopause during the early phase, when estrogen levels dramatically decline compared to premenopausal levels [73,74]. Bone turnover markers are highest in perimenopausal women and significantly decrease with increasing age [75]. This suggests that early postmenopausal women would be at the highest risk of breast cancer recurrence to the bone during this period given the rate of bone turnover and increased release of growth factors, creating a fertile environment for tumor growth. Contrary to expectations, subgroup analysis from the AZURE trial only showed a significant improvement in IDFS and OS at 5-years in women treated with adjuvant zolendronic brompheniramine maleate who where postmenopausal for five years or more compared to the control arm. This suggests that the benefit of adjuvant BPs in early breast cancer patients may depend on more than simply a “low estrogen environment”.
    Biomarker studies Studies on predictive markers for developing bone metastases have been done to identify those early breast cancer patients at highest risk for disease recurrence [76–78]. The bone microenvironment is constantly in flux through continuous resorption and formation (bone turnover). This process releases bone turnover markers (BTM) into the serum, such as C-terminal telopeptide (CTx), which can be measured giving an estimate of the rate of bone turnover [79]. Growth factors are also mobilized through this process, which is hypothesized to provide a favorable environment for tumor cells to proliferate [34,35]. In theory, elevated levels of BTMs may predict the risk of early breast cancer patients developing bone metastases and would be clinically useful. The MA.14 phase III clinical trial, set out to explore this question. Pre-treatment serum CTx concentrations were collected from 621 primary breast cancer patients who were treated with adjuvant tamoxifen with or without octreotide with the aim of testing the ability of this marker at predicting disease recurrence [78]. After a median 7.9 years of follow-up, 123 of 621 (19.8%) patients developed breast cancer recurrence and of those, 19 had isolated bone metastases. Analysis of patients with bone-only disease showed a significantly shorter recurrence-free survival (RFS) in those with elevated pretreatment serum CTx concentrations. This suggests that increased bone turnover provides a favorable environment for breast cancer and that CTx may be a good predictive marker for developing bone metastases in patients with early breast cancer. Recent research has explored the utility of the BTMs procollagen type I N-terminal propeptide (P1NP), osteocalcin, IL-6 and CTx, as markers to predict bone metastases in stage I-III breast cancer patients [76]. This study showed that elevated serum P1NP levels (≥75ng/ml) predicted a 2.7 fold increase in the risk of bone metastases (P=0.031) and a significant decrease in OS (P=0.031) in this patient population. CTx surprisingly did not demonstrate any correlation with bone metastases despite the MA.14 results [78] and other studies showing elevated CTx levels in patients with bone metastases [77,80]. In contrast, data from a follow-up biomarker analysis from the AZURE trial presented at the 2012 San Antonio Breast Cancer Symposium showed that vitamin D levels and not BTMs predict risk of breast cancer relapse in women with early breast cancer [65]. In the study, patient with high baseline levels of 25-OH vitamin D (30ng/ml) had a significantly lower risk of developing bone metastases (HR 0.11; P=0.0257). Both P1NP and CTx levels however, failed to demonstrate any association with bone relapse. These findings demonstrate that predicting risk of breast cancer recurrence is clearly complex and a single predictor marker may not be an effective strategy.