Xu Junnan, Bao Hua, Wu Xue, Wang Xiaonan, Shao Yang W, Sun Tao
Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Key Laboratory of Liaoning Breast Cancer Research, Shenyang, Liaoning 110042, P.R. China.
Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, ON M5G 1L7, Canada.
Oncol Lett. 2019 Jul;18(1):449-455. doi: 10.3892/ol.2019.10287. Epub 2019 Apr 30.
Immunotherapy has been found to be efficient in a variety of cancers and, therefore, may be a promising strategy for breast cancer (BC), particularly due to the limited therapeutic options currently available for triple-negative BC (TNBC). However, heterogeneity of tumor mutation burden (TMB), immune gene expression and mismatch repair (MMR) gene activity across BC subtypes has not been well characterized. In the present study, a comprehensive analysis of TMB, expression levels of immune cell type marker genes, and expression levels of MMR-associated genes was performed. A total of 5 MMR-associated genes, including and , were analyzed. Patients that harbored at least two MMR genes with expression levels in the lower 10% percentile across the cohort were considered as potentially aberrant (lost expression). Hormone receptor (HR)-negative BC is associated with a higher TMB and immune gene expression compared with HR-positive BC [TMB, estrogen receptor (ER)-negative vs. ER-negative, 55 vs. 32, respectively; P=4.1×10; progesterone receptor (PR)-negative vs. PR-positive, 53 vs. 31, respectively; P<2.2×10]. By contrast, human epidermal growth factor receptor 2 (HER2)-negative BC tended to have a lower TMB and decreased immune gene expression compared with HER2-positive BC (TMB, HER2-negative vs. HER2-positive, 36 vs. 48, respectively; P=0.02). Furthermore, aberrant expression of MMR genes was found to be more common in HR-negative compared with HR-positive BC (P<0.001). Significantly higher expression levels of each immune marker gene of four major immune cell types were found in patients who were HR-negative compared with patients who were HR-positive (P<0.001). The findings of the present study suggest that HR-negative or HER2-positive BC exhibits elevated TMB and immunogenic activity, and immunotherapeutic options are recommended.
免疫疗法已被发现在多种癌症中有效，因此，对于乳腺癌（BC）可能是一种有前景的策略，特别是由于目前三阴性乳腺癌（TNBC）的治疗选择有限。然而，乳腺癌各亚型之间肿瘤突变负担（TMB）、免疫基因表达和错配修复（MMR）基因活性的异质性尚未得到很好的描述。在本研究中，对TMB、免疫细胞类型标记基因的表达水平以及MMR相关基因的表达水平进行了全面分析。总共分析了5个MMR相关基因，包括……和……。在整个队列中，至少有两个MMR基因表达水平处于最低10%的患者被认为可能存在异常（表达缺失）。与激素受体（HR）阳性乳腺癌相比，HR阴性乳腺癌的TMB和免疫基因表达更高[TMB，雌激素受体（ER）阴性与ER阳性分别为55和32；P = 4.1×10；孕激素受体（PR）阴性与PR阳性分别为53和31；P < 2.2×10]。相比之下，与人类表皮生长因子受体2（HER2）阳性乳腺癌相比，HER2阴性乳腺癌的TMB往往较低，免疫基因表达降低（TMB，HER2阴性与HER2阳性分别为36和48；P = 0.02）。此外，发现MMR基因的异常表达在HR阴性乳腺癌中比在HR阳性乳腺癌中更常见（P < 0.001）。与HR阳性患者相比，HR阴性患者中四种主要免疫细胞类型的每种免疫标记基因的表达水平显著更高（P < 0.001）。本研究结果表明，HR阴性或HER2阳性乳腺癌表现出升高的TMB和免疫原性活性，建议采用免疫治疗方案。
