Abubakar Mustapha, Orr Nick, Daley Frances, Coulson Penny, Ali H Raza, Blows Fiona, Benitez Javier, Milne Roger, Brenner Herman, Stegmaier Christa, Mannermaa Arto, Chang-Claude Jenny, Rudolph Anja, Sinn Peter, Couch Fergus J, Devilee Peter, Tollenaar Rob A E M, Seynaeve Caroline, Figueroa Jonine, Sherman Mark E, Lissowska Jolanta, Hewitt Stephen, Eccles Diana, Hooning Maartje J, Hollestelle Antoinette, Martens John W M, van Deurzen Carolien H M, Bolla Manjeet K, Wang Qin, Jones Michael, Schoemaker Minouk, Wesseling Jelle, van Leeuwen Flora E, Van 't Veer Laura, Easton Douglas, Swerdlow Anthony J, Dowsett Mitch, Pharoah Paul D, Schmidt Marjanka K, Garcia-Closas Montserrat
Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, SM2 5NG, UK.
Breast Cancer Now Toby Robins Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
Breast Cancer Res. 2016 Oct 18;18(1):104. doi: 10.1186/s13058-016-0765-6.
BACKGROUND: The value of KI67 in breast cancer prognostication has been questioned due to concerns on the analytical validity of visual KI67 assessment and methodological limitations of published studies. Here, we investigate the prognostic value of automated KI67 scoring in a large, multicentre study, and compare this with pathologists' visual scores available in a subset of patients. METHODS: We utilised 143 tissue microarrays containing 15,313 tumour tissue cores from 8088 breast cancer patients in 10 collaborating studies. A total of 1401 deaths occurred during a median follow-up of 7.5 years. Centralised KI67 assessment was performed using an automated scoring protocol. The relationship of KI67 levels with 10-year breast cancer specific survival (BCSS) was investigated using Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted for known prognostic factors. RESULTS: Patients in the highest quartile of KI67 (>12 % positive KI67 cells) had a worse 10-year BCSS than patients in the lower three quartiles. This association was statistically significant for ER-positive patients (hazard ratio (HR) (95 % CI) at baseline = 1.96 (1.31-2.93); P = 0.001) but not for ER-negative patients (1.23 (0.86-1.77); P = 0.248) (P-heterogeneity = 0.064). In spite of differences in characteristics of the study populations, the estimates of HR were consistent across all studies (P-heterogeneity = 0.941 for ER-positive and P-heterogeneity = 0.866 for ER-negative). Among ER-positive cancers, KI67 was associated with worse prognosis in both node-negative (2.47 (1.16-5.27)) and node-positive (1.74 (1.05-2.86)) tumours (P-heterogeneity = 0.671). Further classification according to ER, PR and HER2 showed statistically significant associations with prognosis among hormone receptor-positive patients regardless of HER2 status (P-heterogeneity = 0.270) and among triple-negative patients (1.70 (1.02-2.84)). Model fit parameters were similar for visual and automated measures of KI67 in a subset of 2440 patients with information from both sources. CONCLUSIONS: Findings from this large-scale multicentre analysis with centrally generated automated KI67 scores show strong evidence in support of a prognostic value for automated KI67 scoring in breast cancer. Given the advantages of automated scoring in terms of its potential for standardisation, reproducibility and throughput, automated methods appear to be promising alternatives to visual scoring for KI67 assessment.
背景：由于对视觉评估 KI67 的分析有效性以及已发表研究的方法局限性存在担忧，KI67 在乳腺癌预后评估中的价值受到质疑。在此，我们在一项大型多中心研究中调查自动 KI67 评分的预后价值，并将其与一部分患者中病理学家的视觉评分进行比较。 方法：我们利用了来自 10 项合作研究中 8088 例乳腺癌患者的 143 个组织微阵列，其中包含 15313 个肿瘤组织芯块。在中位随访 7.5 年期间共发生 1401 例死亡。使用自动评分方案进行集中的 KI67 评估。使用 Kaplan-Meier 生存曲线和针对已知预后因素进行调整的 Cox 比例风险回归模型，研究 KI67 水平与 10 年乳腺癌特异性生存（BCSS）的关系。 结果：KI67 最高四分位数（>12% KI67 阳性细胞）的患者 10 年 BCSS 比低三个四分位数的患者差。这种关联在雌激素受体（ER）阳性患者中具有统计学意义（基线时风险比（HR）（95%置信区间）=1.96（1.31 - 2.93）；P = 0.001），但在 ER 阴性患者中无统计学意义（1.23（0.86 - 1.77）；P = 0.248）（P 异质性 = 0.064）。尽管研究人群特征存在差异，但所有研究中 HR 的估计值是一致的（ER 阳性患者的 P 异质性 = 0.941，ER 阴性患者的 P 异质性 = 0.866）。在 ER 阳性癌症中，KI67 与淋巴结阴性（2.47（1.16 - 5.27））和淋巴结阳性（1.74（1.05 - 2.86））肿瘤的预后较差均相关（P 异质性 = 0.671）。根据 ER、孕激素受体（PR）和人表皮生长因子受体 2（HER2）进一步分类显示，无论 HER2 状态如何，在激素受体阳性患者中与预后存在统计学显著关联（P 异质性 = 0.270），在三阴性患者中也存在关联（1.70（1.02 - 2.84））。在有两种评分信息的 2440 例患者子集中，KI67 的视觉和自动测量的模型拟合参数相似。 结论：这项大规模多中心分析采用集中生成的自动 KI67 评分的结果有力支持了自动 KI67 评分在乳腺癌中的预后价值。鉴于自动评分在标准化、可重复性和通量方面的优势，自动方法似乎是 KI67 评估中视觉评分的有前景的替代方法。
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