3月week3文獻(xiàn)閱讀:Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroup
乳腺癌復(fù)發(fā)動(dòng)態(tài)顯示晚期復(fù)發(fā)的ER-陽(yáng)性基因組亞群
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.
由于缺乏具有分子特征的患者群體和長(zhǎng)期詳細(xì)的隨訪數(shù)據(jù)，對(duì)乳腺癌致命全身擴(kuò)散的發(fā)生率和途徑知之甚少。
Longterm follow-up is especially important for those with oestrogenreceptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis.
對(duì)于雌激素受體(ER)陽(yáng)性的乳腺癌患者來(lái)說(shuō)不恭，長(zhǎng)期隨訪尤為重要衣陶。乳腺癌在最初診斷后20年內(nèi)可能復(fù)發(fā)。
It is therefore essential to identify patients who have a high risk of late relapse.
因此落竹，確定晚期復(fù)發(fā)風(fēng)險(xiǎn)高的患者是至關(guān)重要的泌霍。
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.
在此，我們提出了一個(gè)統(tǒng)計(jì)框架述召，該框架模擬了不同的疾病階段(局部復(fù)發(fā)朱转、遠(yuǎn)處復(fù)發(fā)蟹地、乳腺癌相關(guān)死亡和其他原因的死亡)和乳腺癌死亡率的競(jìng)爭(zhēng)風(fēng)險(xiǎn)，同時(shí)給出了個(gè)體復(fù)發(fā)風(fēng)險(xiǎn)的預(yù)測(cè)藤为。
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;and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression12,13).
我們將該模型應(yīng)用于3240例乳腺癌患者怪与，其中1980例患者的分子數(shù)據(jù)可用，并描繪時(shí)間上不同類(lèi)別的分子信息(即免疫組化亞型;PAM50亞型缅疟，基于基因表達(dá)模式;以及基于基因組拷貝數(shù)改變和基因表達(dá)模式的整合型或整合型(12,13)分别。
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.
我們識(shí)別四個(gè)late-recurring綜合子類(lèi)型,包括約四分之一(26%)的腫瘤,ER陽(yáng)性和陰性人類(lèi)表皮生長(zhǎng)因子受體2,每個(gè)特征tumour-driving改變基因組拷貝數(shù)和高復(fù)發(fā)風(fēng)險(xiǎn)的(意思是47 - 62%)后20年的診斷。
We also define a subgroup of triplenegative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk.
我們還定義了一個(gè)五年后癌癥很少?gòu)?fù)發(fā)的三叉神經(jīng)性乳腺癌的亞組存淫，以及一個(gè)患者仍然處于危險(xiǎn)中的單獨(dú)的亞組茎杂。
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).
綜合亞型的使用提高了對(duì)晚期、遠(yuǎn)處復(fù)發(fā)的預(yù)測(cè)纫雁，超出了臨床協(xié)變量(淋巴結(jié)狀態(tài)煌往、腫瘤大小、腫瘤分級(jí)和免疫組化亞型)的預(yù)測(cè)能力轧邪。
These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials.
這些發(fā)現(xiàn)強(qiáng)調(diào)了改善患者分層和生物標(biāo)志物驅(qū)動(dòng)臨床試驗(yàn)的機(jī)會(huì)刽脖。
正文：
第一段
Breast cancer is a multistate disease with clinically relevant intermediate end points, such as locoregional recurrence and distant recurrence.
乳腺癌是一種多狀態(tài)的疾病，具有臨床相關(guān)的中間終點(diǎn)忌愚，如局部復(fù)發(fā)和遠(yuǎn)處復(fù)發(fā)曲管。
A patient’s prognosis can differ considerably depending on when and where a relapse occurs, time since surgery, and time since locoregional or distant recurrence.
患者的預(yù)后可能因復(fù)發(fā)的時(shí)間和地點(diǎn)、手術(shù)后的時(shí)間以及局部或遠(yuǎn)處復(fù)發(fā)的時(shí)間而有很大差異硕糊。
These events are associated, and individual analyses of disease-free survival (DFS) or overall survival alone cannot fully capture patterns of recurrence associated with differential prognosis.
這些事件是相關(guān)的院水，單獨(dú)對(duì)無(wú)病生存(DFS)或總體生存的個(gè)體分析不能完全捕獲與不同預(yù)后相關(guān)的復(fù)發(fā)模式。
In addition, most survival analyses use disease-specific death (DSD) as the primary end point, and censor deaths from other causes.
此外简十，大多數(shù)生存分析使用疾病特異性死亡(DSD)作為主要終點(diǎn)檬某，并審查來(lái)自其他原因的死亡。
However, when competing risks of mortality occur, this approach induces bias.
然而螟蝙，當(dāng)死亡率的競(jìng)爭(zhēng)風(fēng)險(xiǎn)發(fā)生時(shí)恢恼，這種方法會(huì)導(dǎo)致偏見(jiàn)。
This is particularly problematic for breast cancer, where ER-positive patients experience higher mortality from nonmalignant causes owing to their increased age at diagnosis relative to ER-negative patients.
這對(duì)乳腺癌尤其成問(wèn)題胰默，在乳腺癌中场斑，ER-陽(yáng)性患者由于相對(duì)于ER-r陰性患者診斷年齡的增加，非惡性原因?qū)е碌乃劳雎矢摺?/p>
乳腺癌預(yù)后現(xiàn)狀以及乳腺癌生存分析存在問(wèn)題牵署。
第二段
We evaluated the extent of such bias on breast-cancer survival estimates by analysing 3,240 patients who had been diagnosed between 1977 and 2005, and for whom there was a median clinical follow-up of 14 years (referred to as the ‘full dataset’;see Extended Data Fig. 1, Supplementary Table 1 and Methods).
我們通過(guò)分析1977年至2005年間被診斷出乳腺癌的3240名患者評(píng)估了這種對(duì)乳腺癌生存評(píng)估的偏見(jiàn)程度漏隐，并對(duì)他們進(jìn)行了14年的臨床隨訪(稱(chēng)為“完整數(shù)據(jù)集”;參見(jiàn)擴(kuò)展數(shù)據(jù)圖1、補(bǔ)充表1和方法)奴迅。
We compared the naive cumulative incidence for DSD (computed as one minus the survival probability), stratified by ER status and considering only cancer-related deaths (Extended Data Fig. 2a), relative to estimates with the proper cumulative incidence functions accounting for different causes of death (Extended Data Fig. 2b).
我們比較了單純的DSD累積發(fā)病率(計(jì)算為1減去生存概率)青责，按ER狀態(tài)分層，只考慮與癌癥相關(guān)的死亡(擴(kuò)展數(shù)據(jù)圖2a)，相對(duì)于使用適當(dāng)?shù)睦鄯e發(fā)病率函數(shù)估計(jì)不同的死亡原因(擴(kuò)展數(shù)據(jù)圖2b)爽柒。
These comparisons indicate that the incidence of DSD is overestimated for ER-positive tumours relative to ER-negative tumours (0.46 versus 0.37 at 20 years) owing to the increased age of diagnosis (median 63.9 versus 53.0 years;P < 1 × 10?6;Extended Data Fig. 2c).
這些比較表明吴菠，由于診斷年齡的增加(中位數(shù)63.9歲對(duì)53.0歲)， ER-陽(yáng)性腫瘤相對(duì)于 ER-陰性腫瘤的DSD發(fā)生率被高估(20歲時(shí)為0.46對(duì)0.37);P < 1×10 - 6;擴(kuò)展數(shù)據(jù)圖2c)浩村。
Moreover, because the baseline survival functions for these subgroups are distinct, their differences cannot be adequately summarized with a single parameter in a Cox proportional hazards model.
此外做葵，由于這些亞組的基線生存函數(shù)是不同的，因此不能用Cox比例危險(xiǎn)模型中的單個(gè)參數(shù)充分總結(jié)它們之間的差異心墅。
(構(gòu)建數(shù)據(jù)分析數(shù)據(jù)集酿矢，證實(shí)生存分析使用疾病特異性死亡(DSD）的偏見(jiàn)程度，探索ER和DSD復(fù)發(fā)的關(guān)系怎燥，結(jié)論：診斷年齡的增加(中位數(shù)63.9歲對(duì)53.0歲)瘫筐， ER-陽(yáng)性腫瘤相對(duì)于 ER-陰性腫瘤的DSD發(fā)生率被高估(20歲時(shí)為0.46對(duì)0.37);P < 1×10 - 6;擴(kuò)展數(shù)據(jù)圖2c。數(shù)據(jù)+圖铐姚，總結(jié)分析結(jié)果)
第三段
To overcome these limitations, we developed a nonhomogenous (semi)-Markov-chain model that accounts for different disease states (locoregional recurrence and distant recurrence) and time scales (time since surgery or locoregional or distant recurrence), as well as competing risks of mortality and distinct baseline hazards across molecular subgroups, thereby enabling individual risk-of-relapse predictions (see Fig. 1a and Methods).
為了克服這些限制,我們開(kāi)發(fā)了一個(gè)針對(duì)非(半)馬爾可夫鏈模型,占不同疾病狀態(tài)(局部區(qū)域復(fù)發(fā)和遠(yuǎn)處復(fù)發(fā))和時(shí)間尺度(時(shí)間因?yàn)槭中g(shù)或局部區(qū)域或遙遠(yuǎn)的復(fù)發(fā)),以及競(jìng)爭(zhēng)風(fēng)險(xiǎn)的死亡率和不同的基線危險(xiǎn)分子子組,從而使個(gè)人risk-of-relapse預(yù)測(cè)和方法(見(jiàn)圖1)策肝。
The model also incorporates clinical variables known to influence breast-cancer survival，including age, tumour grade, tumour size and number of tumour-positive (‘positive’) lymph nodes (all measured at diagnosis).
該模型還納入了已知影響乳腺癌生存的臨床變量隐绵，包括年齡之众、腫瘤分級(jí)、腫瘤大小和腫瘤陽(yáng)性(“陽(yáng)性”)淋巴結(jié)數(shù)量(所有在診斷時(shí)測(cè)量的)依许。
We refer to this as the base clinical model, into which information on molecular subtype can be incorporated.
我們將其作為基本的臨床模型棺禾，將分子亞型的信息納入其中。
（作者研究開(kāi)發(fā)的模型峭跳，克服當(dāng)下模型的局限膘婶。）
第四段
We fitted this multistate model to the full dataset, and recorded the hazards of moving through distinct states and the number of transitions between each pair of states (Supplementary Table 2 and Methods).
我們將這個(gè)多狀態(tài)模型擬合到完整的數(shù)據(jù)集中，并記錄了通過(guò)不同狀態(tài)移動(dòng)的風(fēng)險(xiǎn)以及每對(duì)狀態(tài)之間的轉(zhuǎn)換次數(shù)(補(bǔ)充表2和方法)蛀醉。
As expected, most cancer-related deaths (83% in ER-positive and 87% in ER-negative tumours) occurred after distant metastasis.
不出所料悬襟，大多數(shù)與癌癥相關(guān)的死亡(83%的er陽(yáng)性腫瘤和87%的er陰性腫瘤)發(fā)生在遠(yuǎn)處轉(zhuǎn)移之后。
The remainder of the cases probably reflect undetected recurrences or death due to other malignancies.
其余病例可能反映未發(fā)現(xiàn)的復(fù)發(fā)或因其他惡性腫瘤死亡滞欠。
Age at diagnosis was associated with a transition to death by other causes (P < 1 × 10?6).
診斷年齡與其他原因引起的死亡過(guò)渡有關(guān)(P < 1×10 - 6)古胆。
Examination of the log hazard ratios and 95% confidence intervals for all other variables indicated that their effect decreased with disease progression (Extended Data Fig. 2d).
對(duì)所有其他變量的log危險(xiǎn)比和95%置信區(qū)間的檢查表明肆良，它們的影響隨著疾病進(jìn)展而降低(擴(kuò)展數(shù)據(jù)圖2d)筛璧。
That is, clinical variables related to the primary tumour were more prognostic for earlier transitions than for later transitions.
也就是說(shuō)，與原發(fā)腫瘤相關(guān)的臨床變量對(duì)早期轉(zhuǎn)移的預(yù)后比晚期轉(zhuǎn)移的預(yù)后更好惹恃。
However, several tumour characteristics informed the risk of progression from locoregional to distant recurrence, and from distant recurrence to death.
然而夭谤，一些腫瘤特征提示了從局部到遠(yuǎn)處復(fù)發(fā)以及從遠(yuǎn)處復(fù)發(fā)到死亡的風(fēng)險(xiǎn)。
In ER-positive disease, higher tumour grade, number of positive lymph nodes and tumour size all increased the risk of progression to a later state.
在er陽(yáng)性的疾病中巫糙，較高的腫瘤分級(jí)朗儒、陽(yáng)性淋巴結(jié)數(shù)目和腫瘤大小都增加了進(jìn)展到晚期的風(fēng)險(xiǎn)。
A longer time between surgery and locoregional or distant recurrence decreased the risk of transition to a later state, and was more pronounced in ER-negative disease.
手術(shù)和局部或遠(yuǎn)處復(fù)發(fā)之間的較長(zhǎng)時(shí)間降低了向晚期轉(zhuǎn)移的風(fēng)險(xiǎn)，在er陰性疾病中更明顯醉锄。
（作者們提出的模型分析數(shù)據(jù)證實(shí)乏悄，圖和文獻(xiàn)雙證實(shí)。）
第五段
A notable feature of our multistate model is that hazard rates can be transformed into transition probabilities that represent the probability of moving from one state into another after a given time.
我們的多狀態(tài)模型的一個(gè)顯著特征是恳不，危險(xiǎn)率可以轉(zhuǎn)換為表示在給定時(shí)間后從一個(gè)狀態(tài)轉(zhuǎn)移到另一個(gè)狀態(tài)的概率的轉(zhuǎn)移概率檩小。
To evaluate patterns of recurrence across established breast-cancer molecular subgroups, we turned to the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) molecular dataset.
為了評(píng)估乳腺癌分子亞群的復(fù)發(fā)模式，我們求助于乳腺癌國(guó)際聯(lián)盟(METABRIC)分子數(shù)據(jù)集的分子分類(lèi)學(xué)烟勋。
This dataset is based on 1,980 patients (Extended Data Fig. 1), and includes assignments to: immunohistochemistry (IHC) subtypes (namely ER+/ HER2+, ER+/HER2?, ER?/HER2+ and ER?/HER2?, where HER2 is human epidermal growth factor receptor 2);5 intrinsic gene-expression subtypes (otherwise known as PAM50 subtypes);and the 11 Integrative Cluster (IntClust) subtypes, which are characterized by distinct copy-number and gene-expression profiles (Supplementary Table 3). We computed the baseline transition probabilities from surgery, locoregional recurrence or distant recurrence at various time intervals (2, 5, 10, 15 and 20 years) and the corresponding standard errors of prediction (s.e.) for average individuals in each subgroup (using the full dataset for comparisons by ER status,and the molecular dataset for all others;Supplementary Table 4).
該數(shù)據(jù)集基于1980名患者(擴(kuò)展數(shù)據(jù)圖1)规求，包括分配給:免疫組化(IHC)亞型(即ER+/HER2 +、ER+/HER2?卵惦、ER?/HER2+和ER?/HER2?阻肿，其中HER2是人類(lèi)表皮生長(zhǎng)因子受體2);5個(gè)內(nèi)在基因表達(dá)亞型(又稱(chēng)PAM50亞型)和11綜合集群(IntClust)亞型,特點(diǎn)是獨(dú)特的人類(lèi)基因組和基因表達(dá)profiles(補(bǔ)充表3)。我們從手術(shù)基線轉(zhuǎn)移概率計(jì)算,局部區(qū)域復(fù)發(fā)或遠(yuǎn)處復(fù)發(fā)在不同的時(shí)間間隔(2沮尿、5丛塌、10、15畜疾、20年)和相應(yīng)的標(biāo)準(zhǔn)誤差的預(yù)測(cè)(東南部)的平均個(gè)人每個(gè)子群(使用ER狀態(tài)的完整數(shù)據(jù)集的比較,以及其他所有的分子數(shù)據(jù)集;補(bǔ)充表4)姨伤。
（分子數(shù)據(jù)集分類(lèi)，采用乳腺癌國(guó)際聯(lián)盟分子數(shù)據(jù)集的分子分類(lèi)）
第六段
After surgery, state transitions differed substantially across the various subtypes (Fig. 1b).
手術(shù)后庸疾，不同亞型的狀態(tài)轉(zhuǎn)變有很大差異(圖1b)乍楚。
For example, the transition probabilities post-surgery reveal different change points for ER-positive versus ER-negative disease.
例如，術(shù)后轉(zhuǎn)移概率顯示er陽(yáng)性和er陰性疾病的不同變化點(diǎn)届慈。
ER-negative patients had a higher risk of distant recurrence and death from cancer in the first five years, after which their risk decreased considerably.
er陰性的患者在前五年有更高的癌癥復(fù)發(fā)和死亡的風(fēng)險(xiǎn)徒溪，之后他們的風(fēng)險(xiǎn)大大降低。
By contrast, ER-positive patients had a smaller but longer risk period during the first ten years, and the risk increased at a lower rate.
相比之下金顿，er陽(yáng)性患者在前十年的風(fēng)險(xiǎn)期較小臊泌，但較長(zhǎng)，并且風(fēng)險(xiǎn)以較低的速度增加揍拆。
Among ER-negative patients, the PAM50 ‘basal-like’ subgroup was nearly indistinguishable from the ER?/HER2? subgroup, with most cancer-related deaths occurring in the first five years—similar to HER2+ patients (before the widespread use of trastuzumab).
在ER陰性患者中渠概，PAM50“堿性”亞組與ER- /HER2 -亞組幾乎沒(méi)有區(qū)別，大多數(shù)癌癥相關(guān)死亡發(fā)生在前5年嫂拴，與HER2+患者相似(在曲妥珠單抗廣泛使用之前)播揪。
By contrast, the three predominantly ER-negative IntClust subgroups (IntClust4ER?, IntClust5 and IntClust10) exhibited substantial differences in their recurrence trajectories.
相比之下，三個(gè)主要為er陰性的IntClust亞群(IntClust4ER?筒狠、IntClust5和IntClust10)的復(fù)發(fā)軌跡有顯著差異猪狈。
As expected, IntClust5 (HER2+ enriched) generally had poor prognosis at 5 years (transition probability to relapse/cancer-related death 0.48;s.e = 0.04), with the risk increasing to 0.65 (s.e. = 0.04) at 20 years.
正如所料，IntClust5 (HER2+富集)一般在5年時(shí)預(yù)后較差(復(fù)發(fā)/癌癥相關(guān)死亡的轉(zhuǎn)移概率為0.48;s.e = 0.04)辩恼， 20年后風(fēng)險(xiǎn)增加到0.65 (s.e. = 0.04)雇庙。
For IntClust10 (‘basal-like enriched’), the first 5 years after surgery largely defined patient outcomes: the probability of relapse or cancer-related death at 5 years was 0.33 (s.e. = 0.03), and this rose after 20 years only to 0.37 (s.e. = 0.04) for an average patient.
對(duì)于IntClust10(“基底樣富集”)谓形，手術(shù)后的前5年在很大程度上定義了患者的預(yù)后:5歲時(shí)復(fù)發(fā)或癌癥相關(guān)死亡的概率為0.33 (s.e. = 0.03)，而20年后這一數(shù)字僅上升到平均患者的0.37 (s.e. = 0.04)疆前。
This pattern was distinct from that seen for IntClust4ER? patients, who exhibited a persistent and increasing risk of relapse or cancer-related death with a probability of 0.30 (0.05) at 5 years and 0.49 (0.05) after 20 years.
這一模式與IntClust4ER -患者不同寒跳，后者在5年后復(fù)發(fā)或癌癥相關(guān)死亡的風(fēng)險(xiǎn)為0.30(0.05)，在20年后為0.49(0.05)竹椒，并且持續(xù)增加冯袍。
（數(shù)據(jù)集分類(lèi)分析后的亞型的狀態(tài)轉(zhuǎn)變差異例舉說(shuō)明）
第七段
The distinction between IntClust4ER? and IntClust10 is also apparent when examining the average probabilities of relapse among all patients across the IntClust subtypes after surgery or after being disease-free for five and ten years (Fig. 2a).
IntClust4ER -和IntClust10之間的區(qū)別在檢查所有IntClust亞型患者術(shù)后或無(wú)病5年和10年后復(fù)發(fā)的平均概率時(shí)也很明顯(圖2a)。
Indeed, through the course of the disease, the risk of relapse changed considerably across the integrative subtypes, and to a lesser extent across the IHC and PAM50 subtypes (Fig. 2a and Extended Data Fig. 4). Moreover, the probabilities of distant recurrence or cancer-related death among ER?/HER2? patients who were disease-free at five years after diagnosis revealed low (IntClust10) and high (IntClust4ER?) risks for late-relapse triple-negative breast-cancer (TNBC) subgroups,whereas IHC (and PAM50) subtypes homogenized this risk (Extended Data Fig. 5).
事實(shí)上,病程,復(fù)發(fā)的風(fēng)險(xiǎn)大大改變了整個(gè)綜合亞型,和一定程度上在IHC和PAM50亞型(圖2和擴(kuò)展數(shù)據(jù)圖碾牌。4)康愤。此外,遠(yuǎn)處復(fù)發(fā)的概率或癌癥相關(guān)死亡中ER / HER2??患者在診斷后5年無(wú)病顯示低(IntClust10)、高(IntClust4ER?)風(fēng)險(xiǎn)誘發(fā)late-relapse三陰乳腺癌(TNBC)子組,而IHC(和PAM50)亞型均有這種風(fēng)險(xiǎn)(擴(kuò)展數(shù)據(jù)見(jiàn)圖5)舶吗。
（進(jìn)一步解釋數(shù)據(jù)集分析結(jié)果）
第八段
Marked differences were also apparent among ER-positive patients, with patients with IntClust3, IntClust7, IntClust8 and IntClust4ER+ subtypes exhibiting a better prognosis, whereas patients with IntClust1, IntClust2, IntClust6 and IntClust9 subtypes exibited late-recurring cancer with a poor prognosis (Fig. 2a).
er陽(yáng)性患者之間也存在顯著差異征冷，其中IntClust3、IntClust7誓琼、IntClust8检激、IntClust4ER+亞型預(yù)后較好，而IntClust1腹侣、IntClust2叔收、IntClust6、IntClust9亞型患者存在晚期復(fù)發(fā)性腫瘤傲隶，預(yù)后較差(圖2a)饺律。
These latter four subgroups had an exceedingly high risk of relapse, with mean probabilities ranging from 0.47 to 0.62 up to 20 years after surgery.
后四個(gè)亞組的復(fù)發(fā)風(fēng)險(xiǎn)非常高，術(shù)后20年的平均復(fù)發(fā)概率在0.47到0.62之間跺株。
The IntClust2 subtype exhibited the worst prognosis, with a probability of relapse (0.62;s.e.m. = 0.02) second only to that of IntClust5.
IntClust2亞型預(yù)后最差复濒，有復(fù)發(fā)的可能性(0.62;s.e.m. = 0.02)僅次于IntClust5。
Collectively, these subgroups comprise 26% of ER-positive cases (Fig. 2b, c) and thus define the minority of patients who may benefit from extended monitoring and treatment given the chronic nature of their disease.
總的來(lái)說(shuō)乒省，這些亞組構(gòu)成了26%的er陽(yáng)性病例(圖2b, c)巧颈，從而確定了少數(shù)患者可能受益于延長(zhǎng)監(jiān)測(cè)和治療鑒于他們的疾病的慢性性質(zhì)。
(不同亞型的預(yù)后說(shuō)明)
第九段
Importantly, the four ‘high risk of relapse’ subgroups were enriched in characteristic genomic-copy-number alterations, which represent the likely drivers of each subgroup (Fig. 2b).
重要的是袖扛，四個(gè)“高復(fù)發(fā)風(fēng)險(xiǎn)”亞組在特征基因組拷貝數(shù)改變上得到了豐富砸泛，這代表了每個(gè)亞組的可能驅(qū)動(dòng)因素(圖2b)。
For example, IntClust2 tumours are defined by amplification and concomitant overexpression of multiple oncogenes on chromosome 11q13, including CCND1, FGF3, EMSY, PAK1 and RSF1 (refs 20–22).
例如蛆封，IntClust2腫瘤定義為11q13號(hào)染色體上多個(gè)癌基因的擴(kuò)增和伴隨過(guò)表達(dá)唇礁，包括CCND1、FGF3娶吞、EMSY垒迂、PAK1和RSF1(參考文獻(xiàn)20-22)。
IntClust2 accounts for 4.5% of ER-positive cases, 96% of which have RSF1 amplification, compared with 0–22% in other subgroups.
在er陽(yáng)性病例中妒蛇，IntClust2占4.5%机断，其中96%具有RSF1擴(kuò)增，而在其他亞組中绣夺，這一比例為0-22%吏奸。
IntClust6 (5.5% of ER-positive tumours) is characterized by focal amplification of ZNF703 (ref. 23) and FGFR1 (ref. 24) on chromosome 8p12 (100% of IntClust6 cases versus 2–21% of others).
IntClust6(5.5%的er陽(yáng)性腫瘤)的特征是ZNF703(參考文獻(xiàn)23)和FGFR1(參考文獻(xiàn)24)在8p12染色體上的局灶性擴(kuò)增(100%的IntClust6病例和2-21%的其他病例)。
IntClust1 (8% of ER-positive tumours) exhibited amplification of chromosome 17q23 in a region spanning the mTOR effector RPS6KB1 (also known as S6K1)25, which was gained or amplified in 96% and 70% of cases, respectively (versus amplification in 0–25% of other subtypes).
IntClust1(8%的er陽(yáng)性腫瘤)在橫跨mTOR效應(yīng)子RPS6KB1(也稱(chēng)為S6K1)25的區(qū)域表現(xiàn)出17q23染色體的擴(kuò)增陶耍，96%和70%的病例分別獲得或擴(kuò)增了該區(qū)域(而其他亞型的擴(kuò)增率為0-25%)奋蔚。
IntClust9 accounted for another 8% of ER-positive cases and was characterized by amplification of the MYC oncogene at chromosome 8q24, with amplification in 89% of these tumours (versus 3–42% of other groups).
在er陽(yáng)性病例中，IntClust9占8%烈钞，其特征是8q24號(hào)染色體上MYC癌基因的擴(kuò)增泊碑，其中89%的腫瘤中存在擴(kuò)增(其他組為3-42%)。
Thus the late-recurring ER-positive subgroups are defined by genomic drivers, several of which are viable therapeutic targets.
因此毯欣，晚期復(fù)發(fā)的er陽(yáng)性亞群是由基因組驅(qū)動(dòng)決定的馒过，其中一些是可行的治療靶點(diǎn)。
（圖分析結(jié)果說(shuō)明+文獻(xiàn)論證）
第十段
Similar differences in the probability of late, distant relapse were seen in the subset of patients whose tumours were ER+/HER2? (Fig. 3a, b and Extended Data Fig. 4a–f)—a group in which late relapse and strategies to target this, such as extended endocrine therapy, represent critical clinical challenges.
在腫瘤為ER+/HER2?(圖3a酗钞、b和擴(kuò)展數(shù)據(jù)圖4a-f)的患者亞群中腹忽，晚期復(fù)發(fā)和遠(yuǎn)處復(fù)發(fā)的概率存在類(lèi)似的差異，其中晚期復(fù)發(fā)和針對(duì)這一目標(biāo)的策略砚作，如延長(zhǎng)內(nèi)分泌治療窘奏，代表了關(guān)鍵的臨床挑戰(zhàn)。
In particular, the probabilities of distant recurrence or cancer-related death reveal a significant risk for IntClust subtypes 1, 2, 6 and 9 (relative to IntClust3) that varied over time.
特別是葫录，與IntClust3相比着裹，遠(yuǎn)端復(fù)發(fā)或癌癥相關(guān)死亡的概率揭示了IntClust亞型1、2米同、6和9(相對(duì)于IntClust3)隨時(shí)間變化的顯著風(fēng)險(xiǎn)求冷。
Moreover, the risk was not fully captured by a model that included IHC subtype together with clinical variables (age, tumour size, grade, number of positive lymph nodes and time since surgery) that have been shown to dictate distant-relapse outcomes even after a long disease-free interval5 (Fig. 3a).
此外，包括IHC亞型和臨床變量(年齡窍霞、腫瘤大小匠题、分級(jí)、陽(yáng)性淋巴結(jié)數(shù)目和手術(shù)后時(shí)間)在內(nèi)的模型并沒(méi)有完全捕捉到這種風(fēng)險(xiǎn)但金，這些臨床變量已經(jīng)表明韭山，即使在長(zhǎng)時(shí)間無(wú)病間隔后，也會(huì)決定遠(yuǎn)處復(fù)發(fā)的結(jié)果(圖3a)冷溃。
We therefore assessed whether the integrative subtypes provide information about a patient’s risk of late distant relapse above and beyond what could be inferred optimally from standard clinical information.
因此钱磅，我們?cè)u(píng)估了綜合亞型是否提供了關(guān)于患者晚期遠(yuǎn)處復(fù)發(fā)風(fēng)險(xiǎn)的信息，這些信息超出了可以從標(biāo)準(zhǔn)臨床信息中推斷出的最佳水平似枕。
We found that the model including clinical variables combined with IHC subtype provided substantial information about the probability of distant relapse in ER+/HER2? patients who were relapse free at five years.
我們發(fā)現(xiàn)盖淡，包括臨床變量和IHC亞型的模型提供了關(guān)于ER+/HER2?患者5年無(wú)復(fù)發(fā)的遠(yuǎn)期復(fù)發(fā)概率的大量信息。
The concordance index (C-index) predicting the risk of distant relapse was 0.63 (confidence interval 0.58–0.68) at 10 years, 0.62 (0.58–0.67) at 15 years, and 0.61 (0.57–0.66) at 20 years (Fig. 3c).
預(yù)測(cè)遠(yuǎn)處復(fù)發(fā)風(fēng)險(xiǎn)的一致性指數(shù)(c指數(shù))10年為0.63(置信區(qū)間0.58-0.68)凿歼，15年為0.62(0.58-0.67)褪迟，20年為0.61(0.57-0.66)(圖3c)冗恨。
However, including the IntClust subtypes significantly improved the predictive value: the C-index was 0.70 (confidence interval 0.64–0.75;improvement over the clinical model, P = 0.00011) at 10 years, 0.67 (0.63–0.72;P = 0.0016) at 15 years and 0.66 (0.62–0.71;P = 0.0017) at 20 years.
然而，包括IntClust亞型的預(yù)測(cè)值顯著提高:c指數(shù)為0.70(置信區(qū)間為0.64-0.75;相對(duì)于臨床模型的改進(jìn)味赃，P = 0.00011) 10年后為0.67 (0.63-0.72;15年和0.66年(0.62-0.71;20年后P = 0.0017)掀抹。
These trends were recapitulated in an external validation cohort, despite the smaller sample size and shorter follow-up times (prohibiting analyses at 20 years) (Fig. 3c and Extended Data Fig. 3e).
盡管樣本量更小，隨訪時(shí)間更短(禁止20年進(jìn)行分析)(圖3c和擴(kuò)展數(shù)據(jù)圖3e)心俗，但這些趨勢(shì)在外部驗(yàn)證隊(duì)列中得到了再現(xiàn)傲武。
Thus, information about the dynamics of late relapse that is provided by integrative subtype could not be inferred from standard clinical variables, including IHC subtype.
因此，綜合亞型提供的晚期復(fù)發(fā)動(dòng)力學(xué)信息不能從包括IHC亞型在內(nèi)的標(biāo)準(zhǔn)臨床變量中推斷出來(lái)城榛。
（晚期復(fù)發(fā)和遠(yuǎn)處復(fù)發(fā)揪利，綜合亞型提供的復(fù)發(fā)動(dòng)力學(xué)信息驗(yàn)證和局限）
第十一段
We next turned to the subset of patients who experienced a locoregional recurrence.
接下來(lái)我們轉(zhuǎn)向經(jīng)歷局部復(fù)發(fā)的患者。
Such a relapse is commonly treated with curative intent, and is thought to be a high-risk event that is associated with increased rates (45–80%) of distant relapse28.
這種復(fù)發(fā)通常是有治療目的的狠持，被認(rèn)為是一種高風(fēng)險(xiǎn)事件疟位，與遠(yuǎn)處復(fù)發(fā)的發(fā)生率增加有關(guān)(45-80%)。
The transition probabilities after locoregional recurrence varied substantially depending on the pathological features of the primary tumour at diagnosis and the molecular subtype, highlighting opportunities for intervention (Extended Data Figs. 6, 7 and Supplementary Tables 2, 3). By contrast, after the initial distant relapse, all subgroups exhibited a high probability of cancer-related death, although the median times differed (Extended Data Fig. 8 and Supplementary Tables 2, 3).
局部區(qū)域復(fù)發(fā)后的躍遷概率差異很大取決于原發(fā)性腫瘤的病理特點(diǎn)在診斷和分子亞型,強(qiáng)調(diào)干預(yù)的機(jī)會(huì)(擴(kuò)展數(shù)據(jù)無(wú)花果工坊。6献汗、7和補(bǔ)充表2、3)王污。相比之下,在最初的遙遠(yuǎn)的復(fù)發(fā),所有子組表現(xiàn)出高概率的癌癥相關(guān)的死亡,盡管中位數(shù)乘以不同(圖8和擴(kuò)展數(shù)據(jù)補(bǔ)充表2罢吃、3)。
(局部復(fù)發(fā)昭齐，綜合亞型提供的動(dòng)力學(xué)信息)
第十二段
Unique to our cohort is a subset of 618 patients (out of the 1,079 from the full dataset who relapsed) for whom a complete description of all recurrences is available (this is the recurrent-event dataset).
我們的隊(duì)列中唯一的一個(gè)子集是618名患者(從完整的復(fù)發(fā)數(shù)據(jù)集中的1079名患者中選出)尿招，他們可以獲得所有復(fù)發(fā)的完整描述(這是遞歸事件數(shù)據(jù)集)。
This enables a detailed analysis of the rates and routes of distant metastases and their lethality.
這使我們能夠詳細(xì)分析遠(yuǎn)處轉(zhuǎn)移的速度和途徑及其致命性阱驾。
These data reveal the varied time course over which metastases occurred and indicate that no sites of metastasis are exclusive to ER-positive or ER-negative disease (Extended Data Fig. 9a).
這些數(shù)據(jù)揭示了轉(zhuǎn)移發(fā)生的不同時(shí)間進(jìn)程就谜，并表明沒(méi)有轉(zhuǎn)移位點(diǎn)是er陽(yáng)性或er陰性疾病所獨(dú)有的(擴(kuò)展數(shù)據(jù)圖9a)。
Moreover, multiple distant metastases were common, even among subgroups with a favourable prognosis (Extended Data Fig. 9b).
此外里覆，即使在預(yù)后良好的亞組中丧荐，多發(fā)遠(yuǎn)處轉(zhuǎn)移也是常見(jiàn)的(擴(kuò)展數(shù)據(jù)圖9b)。
We next examined the cumulative incidence and number of metastases at different organ sites stratified by ER status (Fig. 4a).
接下來(lái)喧枷，我們檢查了按ER狀態(tài)分層的不同器官部位的累積發(fā)病率和轉(zhuǎn)移數(shù)(圖4a)虹统。
ER-negative cases harboured substantially more visceral disease than did ER-positive cases (for example, brain/meningeal, 27% versus 11%;pulmonary, 50% versus 41%).
er陰性病例比er陽(yáng)性病例有更多的內(nèi)臟疾病(例如，大腦/腦膜隧甚，27%對(duì)11%;肺部车荔，50%對(duì)41%)。
As previously reported29,30, bone metastases were more common in ER-positive than in ER-negative cases (71% versus 43%), but the cumulative incidence was similar.
正如先前報(bào)道的29,30戚扳，骨轉(zhuǎn)移在er陽(yáng)性病例中比在er陰性病例中更常見(jiàn)(71%對(duì)43%)忧便，但累積發(fā)病率相似。
Thus, the higher proportions observed in ER-positive disease appear not to reflect site- specific tropism: rather, bone metastases take a long time to develop, and ER-negative patients tend to die of other metastases first.
因此帽借，在er陽(yáng)性疾病中觀察到的較高比例似乎并不反映部位特異性取向:相反珠增，骨轉(zhuǎn)移需要很長(zhǎng)時(shí)間才能發(fā)生超歌，er陰性患者往往首先死于其他轉(zhuǎn)移。
In addition, ER-positive tumours more commonly presented with a first metastasis in the bone (76% versus 61%).
此外切平，er陽(yáng)性腫瘤更常見(jiàn)的表現(xiàn)為骨內(nèi)首次轉(zhuǎn)移(76%對(duì)61%)握础。
Similar comparisons stratified by IHC, PAM50 and IntClust subtypes reveal additional variability (Extended Data Fig. 10).
IHC辐董、PAM50和IntClust亞型的類(lèi)似比較揭示了額外的可變性(擴(kuò)展數(shù)據(jù)圖10)悴品。
Striking differences in the rates of distant metastasis are also evident: ER-negative disease was characterized by a rapid series of relapses early after diagnosis, while most ER-positive patients suffered just one early relapse (commonly bone metastases), and if a second relapse occurred, the probability of additional relapses increased (Fig. 4b and Methods).
引人注目的遠(yuǎn)處轉(zhuǎn)移率差異也很明顯:er陰性疾病特點(diǎn)是一系列快速的復(fù)發(fā)早期診斷后,雖然大多數(shù)雌激素受體陽(yáng)性患者有一個(gè)早期復(fù)發(fā)骨轉(zhuǎn)移(通常),如果發(fā)生了第二次復(fù)發(fā),額外的復(fù)發(fā)的概率增加(圖4 b和方法)。
Thus, after distant recurrence, subtype continues to dictate the rate of subsequent metastases, underscoring the importance of tumour biology.
因此简烘，在遠(yuǎn)處復(fù)發(fā)后苔严，亞型繼續(xù)決定隨后轉(zhuǎn)移的速度，強(qiáng)調(diào)腫瘤生物學(xué)的重要性孤澎。
Both the number and the site of relapses influenced the risk of death after recurrence, with brain metastasis being most predictive.
復(fù)發(fā)的數(shù)量和部位都影響復(fù)發(fā)后死亡的風(fēng)險(xiǎn)届氢，其中腦轉(zhuǎn)移是最具預(yù)測(cè)性的。
Risk estimates (Fig. 4c) were comparable between ER-positive and ER-negative tumours, suggesting that the impact of the site of metastasis on progression to death is similar.
er陽(yáng)性和er陰性腫瘤的風(fēng)險(xiǎn)估計(jì)(圖4c)相似覆旭，提示轉(zhuǎn)移部位對(duì)死亡進(jìn)展的影響相似退子。
(ER狀態(tài)分層的不同器官部位的累積發(fā)病率和轉(zhuǎn)移數(shù),數(shù)據(jù)集的進(jìn)一步分析解釋?zhuān)珽R與腫瘤風(fēng)險(xiǎn)評(píng)估)
第十三段
In summary, by leveraging a cohort of 3,240 patients—including 1,980 from METABRIC, for whom detailed molecular characterization and recurrence data are available—we have delineated the spatiotemporal dynamics of breast-cancer relapse at a high resolution.
總之，通過(guò)利用3240名患者(包括1980名來(lái)自METABRIC的患者型将，他們有詳細(xì)的分子特征和復(fù)發(fā)數(shù)據(jù))寂祥，我們以高分辨率描繪了乳腺癌復(fù)發(fā)的時(shí)空動(dòng)態(tài)。
Our analyses are based on a multistate statistical model that yields individual risk-of-relapse estimates, using tumour features, clinical, pathological and molecular covariates, and disease chronology, and is available via a web application (https://caldaslab.cruk.cam.ac.uk/brcarepred).
我們的分析基于一個(gè)多狀態(tài)統(tǒng)計(jì)模型七兜，該模型利用腫瘤特征丸凭、臨床、病理和分子共變量以及疾病年代學(xué)腕铸，得出個(gè)體復(fù)發(fā)風(fēng)險(xiǎn)的估計(jì)惜犀，并可通過(guò)web應(yīng)用程序獲得(https://caldaslab.cruk.cam.ac.uk/brcarepred)。
In contrast to existing models used to calculate the benefits of adjuvant therapy at diagnosis, such as PREDICT18, our research tool can be used to assess how a patient’s risk of recurrence changes throughout follow-up.
與用于計(jì)算診斷時(shí)輔助治療的益處的現(xiàn)有模型(如PREDICT18)相比狠裹，我們的研究工具可用于評(píng)估患者在隨訪期間復(fù)發(fā)風(fēng)險(xiǎn)的變化虽界。
Learning whether specific treatments change the outcomes of different integrative subtypes is important and will require analysis of randomized clinical trial cohorts.
了解特定治療是否會(huì)改變不同綜合亞型的結(jié)果是很重要的，這需要對(duì)隨機(jī)臨床試驗(yàn)進(jìn)行分析涛菠。
（多狀態(tài)統(tǒng)計(jì)模型總結(jié)莉御，通過(guò)web應(yīng)用程序獲得(https://caldaslab.cruk.cam.ac.uk/brcarepred)）。
第十四段
By classifying breast tumours into the 11 integrative subtypes, important differences in recurrence rates have become apparent that were obscured in the IHC and PAM50 subtypes.
通過(guò)將乳腺腫瘤分為11個(gè)綜合亞型碗暗，復(fù)發(fā)率的重要差異變得很明顯颈将，而這在IHC和PAM50亞型中是不明顯的。
Among TNBC patients, the IntClust10 cluster remains largely relapse free after five years, whereas IntClust4ER? patients continue to be at a substantial risk of recurrence.
在TNBC患者中言疗，IntClust10組患者在5年后基本沒(méi)有復(fù)發(fā)晴圾，而IntClust4ER -患者仍有很大的復(fù)發(fā)風(fēng)險(xiǎn)。
Among ER+/HER2? patients, IntClust subtypes 1, 2, 6 and 9 have a markedly increased risk of distant relapse up to 20 years after diagnosis, and together account for around one quarter of all ER-positive tumours and the vast majority of late recurrences.
在ER+/HER2?患者中噪奄，IntClust亞型1死姚、2人乓、6和9在診斷后20年遠(yuǎn)端復(fù)發(fā)的風(fēng)險(xiǎn)顯著增加，它們加在一起約占所有ER陽(yáng)性腫瘤的四分之一都毒，且絕大多數(shù)晚期復(fù)發(fā)色罚。
Moreover, the integrative subtypes markedly improved the prediction of distant recurrence after five years in ER+/HER2? patients.
此外，綜合亞型顯著提高了ER+/HER2?患者5年后遠(yuǎn)處復(fù)發(fā)的預(yù)測(cè)账劲。
Our findings thus address one of the contemporary challenges in breast oncology, namely identification of the subset of ER-positive patients who have a high risk of recurrence and tumour biomarkers that are more predictive of recurrence than are standard clinical covariates7,8.
因此戳护，我們的研究結(jié)果解決了乳腺腫瘤學(xué)當(dāng)前面臨的挑戰(zhàn)之一，即確定er陽(yáng)性患者中復(fù)發(fā)風(fēng)險(xiǎn)較高的子集瀑焦，以及比標(biāo)準(zhǔn)臨床協(xié)變量更能預(yù)測(cè)復(fù)發(fā)的腫瘤生物標(biāo)志物腌且。
Integrative subtyping may help to determine whether women who are relapse free five years after diagnosis might benefit from extended endocrine therapy or other interventions to improve late outcomes.
綜合分型可能有助于確定診斷后5年無(wú)復(fù)發(fā)的婦女是否可能受益于延長(zhǎng)內(nèi)分泌治療或其他干預(yù)措施，以改善晚期結(jié)果榛瓮。
Critically, the four late-recurring ER-positive subgroups are enriched for genomic-copy-number driver alterations that can be therapeutically targeted, paving the way for new treatment strategies for these high-risk patient populations.
至關(guān)重要的是铺董，這四個(gè)晚期復(fù)發(fā)的er陽(yáng)性亞群的基因拷貝數(shù)驅(qū)動(dòng)因子的改變，可作為治療的目標(biāo)禀晓，為這些高風(fēng)險(xiǎn)患者群體的新治療策略鋪平了道路精续。
（乳腺腫瘤分為11個(gè)綜合亞型總結(jié)和意義）
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醫(yī)學(xué)信息挖掘：
后續(xù)研究點(diǎn)：（多狀態(tài)統(tǒng)計(jì)模型研究）
提出了一個(gè)統(tǒng)計(jì)框架堪夭，該框架模擬了不同的疾病階段(局部復(fù)發(fā)、遠(yuǎn)處復(fù)發(fā)拣凹、乳腺癌相關(guān)死亡和其他原因的死亡)和乳腺癌死亡率的競(jìng)爭(zhēng)風(fēng)險(xiǎn)森爽，同時(shí)給出了個(gè)體復(fù)發(fā)風(fēng)險(xiǎn)的預(yù)測(cè)
（多狀態(tài)統(tǒng)計(jì)模型總結(jié)，通過(guò)web應(yīng)用程序獲得(https://caldaslab.cruk.cam.ac.uk/brcarepred)）嚣镜。
