Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies

BackgroundImmunohistochemical markers are often used to classify breast cancer into subtypes that are biologically distinct and behave differently. The aim of this study was to estimate mortality for patients with the major subtypes of breast cancer as classified using five immunohistochemical markers, to investigate patterns of mortality over time, and to test for heterogeneity by subtype.Methods and FindingsWe pooled data from more than 10,000 cases of invasive breast cancer from 12 studies that had collected information on hormone receptor status, human epidermal growth factor receptor-2 (HER2) status, and at least one basal marker (cytokeratin [CK]5/6 or epidermal growth factor receptor [EGFR]) together with survival time data. Tumours were classified as luminal and nonluminal tumours according to hormone receptor expression. These two groups were further subdivided according to expression of HER2, and finally, the luminal and nonluminal HER2-negative tumours were categorised according to expression of basal markers. Changes in mortality rates over time differed by subtype. In women with luminal HER2-negative subtypes, mortality rates were constant over time, whereas mortality rates associated with the luminal HER2-positive and nonluminal subtypes tended to peak within 5 y of diagnosis and then decline over time. In the first 5 y after diagnosis the nonluminal tumours were associated with a poorer prognosis, but over longer follow-up times the prognosis was poorer in the luminal subtypes, with the worst prognosis at 15 y being in the luminal HER2-positive tumours. Basal marker expression distinguished the HER2-negative luminal and nonluminal tumours into different subtypes. These patterns were independent of any systemic adjuvant therapy.ConclusionsThe six subtypes of breast cancer defined by expression of five markers show distinct behaviours with important differences in short term and long term prognosis. Application of these markers in the clinical setting could have the potential to improve the targeting of adjuvant chemotherapy to those most likely to benefit. The different patterns of mortality over time also suggest important biological differences between the subtypes that may result in differences in response to specific therapies, and that stratification of breast cancers by clinically relevant subtypes in clinical trials is urgently required. Please see later in the article for the Editors' Summary研究背景：免疫组化标记物（immunohistochemical markers）常被用于将乳腺癌划分为具有独特生物学特性与临床行为的亚型。本研究旨在评估基于5种免疫组化标记物分型的主要乳腺癌亚型患者的死亡率，探究死亡率随时间的变化模式，并检验不同亚型间的异质性。 方法与研究结果：我们整合了来自12项研究的1万余例浸润性乳腺癌病例数据，这些研究均收集了激素受体状态、人表皮生长因子受体2（HER2）状态、至少1种基底标记物（细胞角蛋白[CK]5/6或表皮生长因子受体[EGFR]）的相关信息，同时包含生存时间数据。研究人员根据激素受体的表达情况将肿瘤分为管腔型（luminal）与非管腔型两大类；随后依据HER2表达情况对这两大类肿瘤进行进一步细分；最终，管腔型与非管腔型的HER2阴性肿瘤再根据基底标记物的表达情况进行分类。不同亚型的死亡率随时间的变化模式存在差异：在管腔型HER2阴性亚型的女性患者中，死亡率随时间保持稳定；而管腔型HER2阳性与非管腔型亚型的死亡率往往在诊断后5年内达到峰值，随后逐渐下降。在诊断后的前5年，非管腔型肿瘤患者的预后更差；但随着随访时间延长，管腔型亚型患者的预后更差，其中诊断后15年预后最差的为管腔型HER2阳性肿瘤患者。基底标记物的表达可将HER2阴性的管腔型与非管腔型肿瘤划分为不同亚型，且上述死亡率变化模式不受系统性辅助治疗的影响。 研究结论：基于5种标记物表达定义的6种乳腺癌亚型具有截然不同的生物学行为，其短期与长期预后均存在显著差异。将这些标记物应用于临床场景，有望实现辅助化疗的精准靶向，使最有可能获益的患者接受治疗。不同亚型随时间变化的死亡率模式也提示，各亚型间存在重要的生物学差异，这可能导致其对特定治疗的应答存在区别；因此，在临床试验中依据临床相关亚型对乳腺癌进行分层研究迫在眉睫。详见本文后续的编辑总结（Editors' Summary）