Rastelli Francesca, Crispino Sergio
Istituto Toscano Tumori, Dipartimento Oncologico USL7, Siena, Italy.
Tumori. 2008 May-Jun;94(3):370-83. doi: 10.1177/030089160809400314.
Approximately half of metastatic breast cancers expressing estrogen and/or progesterone receptors responds to endocrine therapy, and postoperative adjuvant endocrine therapy provides about a 50% reduction in the development of recurrent disease. A number of publications have focused on the correlation of biomarkers, in particular estrogen and progesterone receptors and HER-2/neu status as well as different gene profiles, multigene assays and genetic polymorphisms with response to hormone therapy. The purpose of this article is to review the literature to identify biological markers predictive of response to tamoxifen and aromatase inhibitors.
A computerized literature search through Medline and ASCO abstract databases was performed, applying the words "endocrine therapy" and "predictive markers" and each of the following: early and metastatic breast cancer, estrogen receptors, progesterone receptors, HER2/neu, multigene assays, polymorphisms. The last search was updated in June 2007. In the examined literature, biological markers were retrospectively assayed to establish whether such variables were predictive for endocrine therapy efficacy.
The role of estrogen receptor content as a predictor of response to endocrine treatment was confirmed: benefit from endocrine treatment was directly proportional to estrogen receptor levels. Progesterone receptor status was only a strong time-dependent prognostic value, and it has not yet been validated as a predictive factor of tamoxifen efficacy. Retrospective clinical data from upfront and sequential studies of aromatase inhibitors were discordant regarding the degree of benefit of these drugs over tamoxifen according to progesterone receptor status. HER-2 positivity was associated with a significantly greater risk of endocrine therapy failure in metastatic and neoadjuvant settings. The current generation of genomic assays for tamoxifen sensitivity all contain a combination of prognostic information that it is difficult to integrate into clinical practice.
Available clinical data are inconclusive to support preferential use of aromatase inhibitors over tamoxifen in progesterone-receptor-negative and HER-2-positive tumors, but it was also clear that lower estrogen receptors, lower progesterone receptors, and positive HER-2 are associated with lower responsiveness to any type of endocrine therapy. Tumors overexpressing HER-2 are endocrine resistant and they require the blockage of the HER-2 pathway in addition to estrogen deprivation. Recent molecular studies have shown that endocrine responsiveness is to a large extent influenced by estrogen-receptor-related pathways. In the future, the key to the correct tailoring of hormone therapy will probably be the ability to subtype estrogen-receptor-positive breast cancer.
大约一半表达雌激素和/或孕激素受体的转移性乳腺癌对内分泌治疗有反应，术后辅助内分泌治疗可使复发疾病的发生率降低约50%。许多出版物聚焦于生物标志物的相关性，特别是雌激素和孕激素受体、HER-2/neu状态以及不同的基因谱、多基因检测和基因多态性与激素治疗反应的关系。本文的目的是回顾文献，以确定预测他莫昔芬和芳香化酶抑制剂反应的生物标志物。
通过Medline和美国临床肿瘤学会（ASCO）摘要数据库进行计算机文献检索，使用“内分泌治疗”和“预测标志物”以及以下各项：早期和转移性乳腺癌、雌激素受体、孕激素受体、HER2/neu、多基因检测、多态性。最后一次检索于2007年6月更新。在检索的文献中，对生物标志物进行回顾性分析，以确定这些变量是否可预测内分泌治疗疗效。
雌激素受体含量作为内分泌治疗反应预测指标的作用得到证实：内分泌治疗的获益与雌激素受体水平直接相关。孕激素受体状态仅具有很强的时间依赖性预后价值，尚未被证实为他莫昔芬疗效的预测因素。根据孕激素受体状态，芳香化酶抑制剂前期和序贯研究的回顾性临床数据在这些药物相对于他莫昔芬的获益程度方面存在不一致。在转移性和新辅助治疗中，HER-2阳性与内分泌治疗失败的风险显著增加相关。当前一代用于他莫昔芬敏感性的基因组检测均包含难以整合到临床实践中的预后信息组合。
现有临床数据尚无定论，无法支持在孕激素受体阴性和HER-2阳性肿瘤中优先使用芳香化酶抑制剂而非他莫昔芬，但也很明显，较低的雌激素受体、较低的孕激素受体和HER-2阳性与对任何类型内分泌治疗的较低反应性相关。过表达HER-2的肿瘤对内分泌治疗耐药，除了雌激素剥夺外，还需要阻断HER-2途径。最近的分子研究表明，内分泌反应性在很大程度上受雌激素受体相关途径的影响。未来，正确定制激素治疗的关键可能在于对雌激素受体阳性乳腺癌进行亚型分类的能力。
