Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
PLoS One. 2012;7(6):e38575. doi: 10.1371/journal.pone.0038575. Epub 2012 Jun 13.
Adjuvant hormonal therapy is administered to all early stage ER+ breast cancers, and has led to significantly improved survival. Unfortunately, a subset of ER+ breast cancers suffer early relapse despite hormonal therapy. To identify molecular markers associated with early relapse in ER+ breast cancer, an outlier analysis method was applied to a published gene expression dataset of 268 ER+ early-stage breast cancers treated with tamoxifen alone. Increased expression of sets of genes that clustered in chromosomal locations consistent with the presence of amplicons at 8q24.3, 8p11.2, 17q12 (HER2 locus) and 17q21.33-q25.1 were each found to be independent markers for early disease recurrence. Distant metastasis free survival (DMFS) after 10 years for cases with any amplicon (DMFS = 56.1%, 95% CI = 48.3-63.9%) was significantly lower (P = 0.0016) than cases without any of the amplicons (DMFS = 87%, 95% CI = 76.3% -97.7%). The association between presence of chromosomal amplifications in these regions and poor outcome in ER+ breast cancers was independent of histologic grade and was confirmed in independent clinical datasets. A separate validation using a FISH-based assay to detect the amplicons at 8q24.3, 8p11.2, and 17q21.33-q25.1 in a set of 36 early stage ER+/HER2- breast cancers treated with tamoxifen suggests that the presence of these amplicons are indeed predictive of early recurrence. We conclude that these amplicons may serve as prognostic markers of early relapse in ER+ breast cancer, and may identify novel therapeutic targets for poor prognosis ER+ breast cancers.
辅助激素治疗用于所有早期 ER+ 乳腺癌，显著提高了生存率。不幸的是，尽管进行了激素治疗，仍有一部分 ER+ 乳腺癌早期复发。为了确定与 ER+ 乳腺癌早期复发相关的分子标志物，采用离群分析方法对单独使用他莫昔芬治疗的 268 例早期 ER+ 乳腺癌的已发表基因表达数据集进行了分析。在 8q24.3、8p11.2、17q12（HER2 基因座）和 17q21.33-q25.1 染色体位置上聚类的一组基因的表达增加，这些基因簇的存在与这些位置的扩增一致，被发现是早期疾病复发的独立标志物。有任何扩增的病例在 10 年后的无远处转移生存率（DMFS）为 56.1%（95%CI=48.3-63.9%），显著低于无任何扩增的病例（DMFS=87%，95%CI=76.3%-97.7%）（P=0.0016）。这些区域的染色体扩增的存在与 ER+ 乳腺癌不良预后之间的关联与组织学分级无关，并在独立的临床数据集得到证实。使用基于 FISH 的检测方法在一组接受他莫昔芬治疗的 36 例早期 ER+/HER2- 乳腺癌中对 8q24.3、8p11.2 和 17q21.33-q25.1 的扩增进行验证，结果表明这些扩增确实可以预测早期复发。我们得出结论，这些扩增可能作为 ER+ 乳腺癌早期复发的预后标志物，并可能为预后不良的 ER+ 乳腺癌确定新的治疗靶点。
