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首页> 外文期刊>Nature >Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups
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Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups

机译：乳腺癌复发的动力学揭示了晚期复发的ER阳性基因组

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摘要

The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Longterm follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis(1-6). It is therefore essential to identify patients who have a high risk of late relapse(7-9). Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns(10,11); and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression(12,13)). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47-62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials.
机译：由于缺乏具有长期详细随访数据的分子特征的患者队列，人们对乳腺癌致死性全身扩散的速率和途径了解甚少。对于那些雌激素受体（ER）阳性乳腺癌的患者而言，长期随访尤为重要，这些乳腺癌在初诊后可复发长达二十年（1-6）。因此，至关重要的是要确定晚期复发风险高的患者（7-9）。在这里，我们提供了一个统计框架，该模型可以对不同的疾病阶段（局部复发，远处复发，乳腺癌相关的死亡以及其他原因导致的死亡）进行建模，同时还可以对乳腺癌造成的死亡风险进行竞争，同时得出各个复发风险的预测。我们将此模型应用于3240例乳腺癌患者，包括1,980例可获得分子数据的患者，并描绘了不同类别分子信息（即免疫组织化学亚型; PAM50亚型，基于基因表达模式）的复发时空分布（10 ，11）;以及基于基因组拷贝数变化和基因表达模式的整合或IntClust亚型（12,13））。我们确定了四种晚期复发性亚型，包括约四分之一（26％）的ER阳性和人类表皮生长因子受体2阴性的肿瘤，每一种在基因组拷贝数方面具有特征性的肿瘤驱动改变，且具有高风险诊断后长达20年的复发率（平均47-62％）。我们还定义了一个三阴性乳腺癌亚组，其中癌症在五年后很少复发，另一个亚组则患者仍然处于危险之中。整合亚型的使用改善了晚期远距离复发的预测，超出了临床协变量（淋巴结状况，肿瘤大小，肿瘤等级和免疫组化亚型）的预测范围。这些发现凸显了改善患者分层和生物标志物驱动的临床试验的机会。

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  • 来源
    《Nature》 |2019年第7748期|399-404|共6页
  • 作者

    Rueda Oscar M.; Sammut Stephen-John; Seoane Jose A.; Chin Suet-Feung; Caswell-Jin Jennifer L.; Callari Maurizio; Batra Rajbir; Pereira Bernard; Bruna Alejandra; Ali H. Raza; Provenzano Elena; Liu Bin; Parisien Michelle; Gillett Cheryl; McKinney Steven; Green Andrew R.; Murphy Leigh; Purushotham Arnie; Ellis Ian O.; Pharoah Paul D.; Rueda Cristina; Aparicio Samuel; Caldas Carlos; Curtis Christina;

  • 作者单位

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England;

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England;

    Stanford Univ, Dept Med, Div Oncol, Sch Med, Stanford, CA 94305 USA|Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA|Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA;

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England;

    Stanford Univ, Dept Med, Div Oncol, Sch Med, Stanford, CA 94305 USA;

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England;

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England;

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England;

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England;

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England;

    Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Cambridge Breast Unit, Cambridge, England|Cambridge Univ Hosp NHS Fdn Trust, NIHR Cambridge Biomed Res Ctr, Cambridge, England|Cambridge Univ Hosp NHS Fdn Trust, Cambridge Expt Canc Med Ctr, Cambridge, England;

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England;

    Res Inst Oncol & Hematol, Winnipeg, MB, Canada;

    Kings Coll London, Canc Div, Guys & St Thomas NHS Fdn Trust & Res Oncol, NIHR Comprehens Biomed Res Ctr, London, England;

    British Columbia Canc Res Ctr, Dept Mol Oncol, Vancouver, BC, Canada;

    Univ Nottingham, Sch Med, Div Canc & Stem Cells, Nottingham, England|Nottingham Univ Hosp NHS Trust, Nottingham, England;

    Res Inst Oncol & Hematol, Winnipeg, MB, Canada;

    Kings Coll London, Canc Div, Guys & St Thomas NHS Fdn Trust & Res Oncol, NIHR Comprehens Biomed Res Ctr, London, England;

    Univ Nottingham, Sch Med, Div Canc & Stem Cells, Nottingham, England|Nottingham Univ Hosp NHS Trust, Nottingham, England;

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England|Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Cambridge Breast Unit, Cambridge, England|Cambridge Univ Hosp NHS Fdn Trust, NIHR Cambridge Biomed Res Ctr, Cambridge, England|Cambridge Univ Hosp NHS Fdn Trust, Cambridge Expt Canc Med Ctr, Cambridge, England|Univ Cambridge, Strangeways Res Lab, Cambridge, England;

    Univ Valladolid, Dept Estadist & Invest Operat, Valladolid, Spain;

    British Columbia Canc Res Ctr, Dept Mol Oncol, Vancouver, BC, Canada;

    Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Cambridge, England|Univ Cambridge, Li Ka Shing Ctr, Dept Oncol, Cambridge, England|Cambridge Univ Hosp NHS Fdn Trust, Addenbrookes Hosp, Cambridge Breast Unit, Cambridge, England|Cambridge Univ Hosp NHS Fdn Trust, NIHR Cambridge Biomed Res Ctr, Cambridge, England|Cambridge Univ Hosp NHS Fdn Trust, Cambridge Expt Canc Med Ctr, Cambridge, England;

    Stanford Univ, Dept Med, Div Oncol, Sch Med, Stanford, CA 94305 USA|Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA|Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA 94305 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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