雄激素受体 mRNA 水平决定三阴性乳腺癌患者的预后。
Androgen Receptor mRNA levels determine the prognosis in triple-negative breast cancer patients.
机构信息
OncoStem Diagnostics Private Limited, # 4, Raja Ram Mohan Roy Road, Aanand Tower, 2nd Floor, Bangalore, Karnataka, 560027, India.
出版信息
BMC Cancer. 2020 Aug 10;20(1):745. doi: 10.1186/s12885-020-07218-0.
BACKGROUND
Anti-Androgen Receptor (AR) therapy holds promise for a subset of AR expressing triple-negative breast cancer (TNBC) patients. However, current AR assays are suboptimal in detecting the dynamic range of AR expression, contributing to its controversial role in TNBC disease prognosis. This study is aimed at evaluating the feasibility of qRT-PCR to sensitively and robustly detect AR mRNA levels for prognostication.
METHODS
mRNA expression profiling was performed on FFPE blocks from a retrospective cohort of 101 TNBC patients using qRT-PCR and compared with AR protein expression by immunohistochemistry . Statistical analyses included Spearman's rank correlation, Chi-square and Kaplan-Meier analyses. Distant Metastasis Free Survival was used as the end point in survival analysis.
RESULTS
AR mRNA expression was observed in 34/101 patients (34%) whereas 12/80 cases (15%) were positive by IHC. qRT-PCR could thus detect more AR positive patients as compared to IHC, with 75% (9/12) concordance between the two methods. Co-expression of GATA3 and FOXA1 mRNA was observed in 85 and 88% of AR mRNA positive tumors, respectively. AR mRNA positivity was significantly correlated with age at disease onset (p = 0.02), high FOXA1/GATA3 (p < 0.05) and distant recurrence. AR mRNA positive patients had poorer DMFS (43%; p = 0.002). DMFS dropped further to 26% (p = 0.006) in AR (+)/high FOXA1/GATA3 patients. AR mRNA expression together with node positivity had the worst DMFS (23%; p < 0.0001) compared to patients who were either positive for any one of these, or negative for both AR and node status. Low Ki67 mRNA with AR mRNA positivity also had poorer DMFS (39%; p = 0.001) compared to patients expressing low Ki67 with no AR mRNA expression.
CONCLUSION
qRT-PCR was more sensitive and reliable in detecting the dynamic expression levels of AR compared to IHC and this variation could be explained by the higher sensitivity of the former method. High AR mRNA expression was strongly associated with expression of AR protein, high FOXA1/GATA3 mRNA, and with poor prognosis. qRT-PCR was more efficient in detecting the AR positive cases compared to IHC. A distinct signature involving high GATA3/FOXA1, low Ki67, and node positivity in AR mRNA positive tumors correlated with poor prognosis. Thus, AR mRNA screening can serve as an effective prognostic marker along with offering potential targeted therapy options for TNBC.
背景
抗雄激素受体（AR）治疗对表达 AR 的三阴性乳腺癌（TNBC）患者具有一定的治疗潜力。然而，目前的 AR 检测方法在检测 AR 表达的动态范围方面并不理想，这导致其在 TNBC 疾病预后中的作用存在争议。本研究旨在评估 qRT-PCR 检测 AR mRNA 水平的可行性，以实现对预后的灵敏而稳健的检测。
方法
采用 qRT-PCR 对 101 例 TNBC 患者的回顾性队列的 FFPE 块进行 mRNA 表达谱分析，并与免疫组织化学法检测的 AR 蛋白表达进行比较。统计分析包括 Spearman 秩相关、卡方和 Kaplan-Meier 分析。远处无转移生存（DMFS）是生存分析的终点。
结果
在 101 例患者中，有 34 例（34%）观察到 AR mRNA 表达，而 80 例中有 12 例（15%）为免疫组化阳性。因此，qRT-PCR 可以比免疫组化检测到更多的 AR 阳性患者，两种方法的一致性为 75%（9/12）。在 AR mRNA 阳性肿瘤中，GATA3 和 FOXA1 mRNA 的共表达分别为 85%和 88%。AR mRNA 阳性与发病年龄（p=0.02）、高 FOXA1/GATA3（p<0.05）和远处复发显著相关。AR mRNA 阳性患者的 DMFS 较差（43%；p=0.002）。在 AR（+）/高 FOXA1/GATA3 患者中，DMFS 进一步降至 26%（p=0.006）。与任何一种 AR 或淋巴结状态阳性的患者相比，AR mRNA 表达与淋巴结阳性相结合的 DMFS 最差（23%；p<0.0001）。与 AR mRNA 表达阴性且 Ki67 低的患者相比，AR mRNA 阳性且 Ki67 低的患者的 DMFS 更差（39%；p=0.001）。
结论
与免疫组化相比，qRT-PCR 更灵敏、更可靠地检测 AR 的动态表达水平，这可以用前者的高灵敏度来解释。高 AR mRNA 表达与 AR 蛋白表达、高 FOXA1/GATA3 mRNA 表达以及不良预后密切相关。qRT-PCR 比免疫组化更有效地检测到 AR 阳性病例。在 AR mRNA 阳性肿瘤中，高 GATA3/FOXA1、低 Ki67 和淋巴结阳性的特定特征与预后不良相关。因此，AR mRNA 筛查可以作为一种有效的预后标志物，并为 TNBC 提供潜在的靶向治疗选择。
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