Li Jiali, Rugo Hope S
University of California San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
Breast Dis. 2011;33(2):83-92. doi: 10.3233/BD-2010-0326.
Bone is the most common site of relapse in breast cancer. Unlike many other malignancies, breast cancer is often associated with late-onset metastases, most commonly seen in bone and soft tissue. Pre-clinical and clinical evidence suggest that micrometastases occur at a very early stage of cancer development but do not become overt metastases until a later time when the microenvironment is more suitable. Bisphosphonates (BPs), especially zoledronic acid (ZOL), decrease bone resorption by suppressing the activity of osteoclasts and are used to prevent further bone loss in patients with osteoporosis. In addition, pre-clinical and clinical evidence suggest that potent BPs have direct and/or indirect anti-tumor effects, through induction of apoptosis, inhibition of invasion and metastases as well as angiogenesis, and through alteration of the immune system. ZOL is approved for the treatment of metastatic cancer to bone, and has been shown to prevent skeletal related events and reduce associated pain, without a clear impact on survival. Several large clinical trials (ABSCG 12, ZO-FAST and AZURE) have studied the direct anti-tumor effect of BPs in early stage breast cancer. The results are controversial, suggesting that ZOL may have benefits in specific settings. Targeting patients at particularly high risk for relapse, and identifying surrogate markers of BP effect is clearly a critical component necessary to understand the anti-tumor effect of these agents. Disseminated tumor cells (DTCs) are surrogate markers that have been correlated with an increased risk of recurrence in patients with early stage breast cancer. Several studies have either used the presence of DTCs to assess risk and determine eligibility for BP treatment, or have used DTCs as a surrogate marker of BP anti-tumor effect. This review summarizes the pre-clinical data supporting anti-tumor effects of BPs as well as their impact on DTCs in clinical studies. New candidates for bone-targeted therapy are briefly discussed.
骨是乳腺癌最常见的复发部位。与许多其他恶性肿瘤不同，乳腺癌常伴有晚期转移，最常见于骨和软组织。临床前和临床证据表明，微转移在癌症发展的非常早期阶段就已发生，但直到后期微环境更适宜时才会发展为明显转移。双膦酸盐（BPs），尤其是唑来膦酸（ZOL），通过抑制破骨细胞活性来减少骨吸收，用于预防骨质疏松症患者的进一步骨质流失。此外，临床前和临床证据表明，强效双膦酸盐具有直接和/或间接的抗肿瘤作用，可通过诱导凋亡、抑制侵袭和转移以及血管生成，以及改变免疫系统来实现。ZOL已被批准用于治疗骨转移癌，并已证明可预防骨相关事件并减轻相关疼痛，但对生存率没有明显影响。几项大型临床试验（ABSCG 12、ZO-FAST和AZURE）研究了双膦酸盐在早期乳腺癌中的直接抗肿瘤作用。结果存在争议，表明ZOL在特定情况下可能有益。针对复发风险特别高的患者，并确定双膦酸盐作用的替代标志物，显然是理解这些药物抗肿瘤作用所需的关键组成部分。播散肿瘤细胞（DTCs）是与早期乳腺癌患者复发风险增加相关的替代标志物。几项研究要么使用DTCs的存在来评估风险并确定双膦酸盐治疗的 eligibility，要么使用DTCs作为双膦酸盐抗肿瘤作用的替代标志物。本综述总结了支持双膦酸盐抗肿瘤作用的临床前数据及其在临床研究中对DTCs的影响。简要讨论了骨靶向治疗的新候选药物。
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