Brodsky Alexander S, Xiong Jinjun, Yang Dongfang, Schorl Christoph, Fenton Mary Anne, Graves Theresa A, Sikov William M, Resnick Murray B, Wang Yihong
Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Lifespan Medical Center, Warren Alpert Medical School of Brown University, Providence, USA.
Department of Pathology, Rhode Island Hospital and Lifespan Medical Center, Providence, RI, 02903, USA.
BMC Cancer. 2016 Apr 18;16:274. doi: 10.1186/s12885-016-2302-5.
The influence of the tumor microenvironment and tumor-stromal interactions on the heterogeneity of response within breast cancer subtypes have just begun to be explored. This study focuses on patients with estrogen receptor-positive/human epidermal growth factor receptor 2-positive (ER+/HER2+) breast cancer receiving neoadjuvant chemotherapy and HER2-targeted therapy (NAC+H), and was designed to identify novel predictive biomarkers by combining gene expression analysis and immunohistochemistry with pathologic response.
We performed gene expression profiling on pre-NAC+H tumor samples from responding (no or minimal residual disease at surgery) and non-responding patients. Gene set enrichment analysis identified potentially relevant pathways, and immunohistochemical staining of pre-treatment biopsies was used to measure protein levels of those pathways, which were correlated with pathologic response in both univariate and multivariate analysis.
Increased expression of genes encoding for stromal collagens, including Col10A1, and reduced expression of immune-associated genes, reflecting lower levels of total tumor-infiltrating lymphocytes (TILs), were strongly associated with poor pathologic response. Lower TILs in tumor biopsies correlated with reduced likelihood of achieving an optimal pathologic response, but increased expression of the Col10A1 gene product, colXα1, had greater predictive value than stromal abundance for poor response (OR = 18.9, p = 0.003), and the combination of increased colXα1 expression and low TILs was significantly associated with poor response in multivariate analysis. ROC analysis suggests strong specificity and sensitivity for this combination in predicting treatment response.
Increased expression of stromal colXα1 and low TILs correlate with poor pathologic response in ER+/HER2+ breast tumors. Further studies are needed to confirm their predictive value and impact on long-term outcomes, and to determine whether this collagen exerts a protective effect on the cancer cells or simply reflects other factors within the tumor microenvironment.
肿瘤微环境和肿瘤-基质相互作用对乳腺癌亚型内反应异质性的影响刚刚开始被探索。本研究聚焦于接受新辅助化疗和HER2靶向治疗（NAC+H）的雌激素受体阳性/人表皮生长因子受体2阳性（ER+/HER2+）乳腺癌患者，旨在通过将基因表达分析、免疫组织化学与病理反应相结合来鉴定新的预测生物标志物。
我们对反应良好（手术时无或仅有少量残留疾病）和反应不佳患者的NAC+H治疗前肿瘤样本进行了基因表达谱分析。基因集富集分析确定了潜在相关通路，预处理活检组织的免疫组织化学染色用于测量这些通路的蛋白水平，在单变量和多变量分析中这些蛋白水平与病理反应相关。
编码包括Col10A1在内的基质胶原蛋白的基因表达增加，以及免疫相关基因表达降低，反映出肿瘤浸润淋巴细胞（TILs）总数较低，这与病理反应不佳密切相关。肿瘤活检中较低的TILs与获得最佳病理反应的可能性降低相关，但Col10A1基因产物colXα1的表达增加对反应不佳的预测价值高于基质丰度（OR = 18.9，p = 0.003），在多变量分析中，colXα1表达增加和TILs低的组合与反应不佳显著相关。ROC分析表明该组合在预测治疗反应方面具有很强的特异性和敏感性。
基质colXα1表达增加和TILs低与ER+/HER2+乳腺肿瘤的病理反应不佳相关。需要进一步研究以证实它们的预测价值及其对长期结局的影响，并确定这种胶原蛋白是否对癌细胞发挥保护作用或仅仅反映肿瘤微环境中的其他因素。
