Genetic Pathology Evaluation Centre, Vancouver Coastal Health Research Institute, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Clin Cancer Res. 2010 Nov 1;16(21):5222-32. doi: 10.1158/1078-0432.CCR-10-1282. Epub 2010 Sep 13.
To compare clinical, immunohistochemical (IHC), and gene expression models of prognosis applicable to formalin-fixed, paraffin-embedded blocks in a large series of estrogen receptor (ER)-positive breast cancers from patients uniformly treated with adjuvant tamoxifen.
Quantitative real-time reverse transcription-PCR (qRT-PCR) assays for 50 genes identifying intrinsic breast cancer subtypes were completed on 786 specimens linked to clinical (median follow-up, 11.7 years) and IHC [ER, progesterone receptor (PR), HER2, and Ki67] data. Performance of predefined intrinsic subtype and risk-of-relapse scores was assessed using multivariable Cox models and Kaplan-Meier analysis. Harrell's C-index was used to compare fixed models trained in independent data sets, including proliferation signatures.
Despite clinical ER positivity, 10% of cases were assigned to nonluminal subtypes. qRT-PCR signatures for proliferation genes gave more prognostic information than clinical assays for hormone receptors or Ki67. In Cox models incorporating standard prognostic variables, hazard ratios for breast cancer disease-specific survival over the first 5 years of follow-up, relative to the most common luminal A subtype, are 1.99 [95% confidence interval (CI), 1.09-3.64] for luminal B, 3.65 (95% CI, 1.64-8.16) for HER2-enriched subtype, and 17.71 (95% CI, 1.71-183.33) for the basal-like subtype. For node-negative disease, PAM50 qRT-PCR-based risk assignment weighted for tumor size and proliferation identifies a group with >95% 10-year survival without chemotherapy. In node-positive disease, PAM50-based prognostic models were also superior.
The PAM50 gene expression test for intrinsic biological subtype can be applied to large series of formalin-fixed, paraffin-embedded breast cancers, and gives more prognostic information than clinical factors and IHC using standard cut points.
比较适用于经他莫昔芬辅助治疗的大量雌激素受体（ER）阳性乳腺癌患者福尔马林固定、石蜡包埋组织块的临床、免疫组织化学（IHC）和基因表达预后模型。
对 786 例标本进行了 50 个基因的定量实时逆转录-PCR（qRT-PCR）检测，这些基因可鉴定内在乳腺癌亚型，并与临床（中位随访时间为 11.7 年）和 IHC[ER、孕激素受体（PR）、HER2 和 Ki67]数据相关联。使用多变量 Cox 模型和 Kaplan-Meier 分析评估预先定义的内在亚型和复发风险评分的性能。使用 Harrell 的 C 指数比较了在独立数据集（包括增殖标志物）中训练的固定模型。
尽管临床 ER 阳性，但仍有 10%的病例被分配到非 luminal 亚型。增殖基因的 qRT-PCR 特征比激素受体或 Ki67 的临床检测提供了更多的预后信息。在纳入标准预后变量的 Cox 模型中，与最常见的 luminal A 亚型相比，前 5 年随访期间乳腺癌疾病特异性生存率的风险比为 luminal B 为 1.99（95%CI，1.09-3.64），HER2 富集亚型为 3.65（95%CI，1.64-8.16），基底样亚型为 17.71（95%CI，1.71-183.33）。对于淋巴结阴性疾病，基于 PAM50 qRT-PCR 的风险分配，根据肿瘤大小和增殖加权，可识别出一组无需化疗即可获得 >95%10 年生存率的患者。在淋巴结阳性疾病中，基于 PAM50 的预后模型也更具优势。
用于内在生物学亚型的 PAM50 基因表达检测可应用于大量福尔马林固定、石蜡包埋的乳腺癌组织，并提供比临床因素和使用标准临界点的 IHC 更有预后意义的信息。
