乳腺癌雌激素受体基因的突变与变异

乳腺癌基因变异研究进展【摘要】为了解乳腺癌产生的分子过程和分子传导途径，以及产生过程中的主导因素，目前人们正在研究各个发展阶段癌细胞的基因表达情况。

从分子病理角度分析一些主要相关基因如：ERBB2、ER、BRCA1等在乳腺癌的表达，这有助于彻底的了解乳腺癌产生过程并对诊断、预后、最终发现治疗乳腺癌的新方法有着重要价值。

【关键词】乳腺肿瘤；基因；ERBB2【中图分类号】R737.9【文献标识码】A【文章编号】1673-7555［2007］03-0115-03乳腺癌多样的、且截然不同的分子表达决定其复杂多样的组织学表现、病理分级和临床表现［1-3］。

了解乳腺癌发生、发展的分子病理机制对乳腺癌的诊断、预后评价都很有价值，最终有助于治疗。

基于先进的分子生物学技术的发展，有研究者对染色体基因进行广泛筛查，发现许多基因变异表达与乳腺癌有关。

1主要相关基因的变异1.1雌激素受体基因临床医生依靠两个重要的生长因子受体的表达对乳腺癌患者进行分类治疗和预后评估,一个是雌激素受体，另一个是表皮生长因子受体-2［4］。

有着相同诊断与临床症状的乳腺癌而临床转归却截截然不同，这种不同可能归因于乳腺癌分类学的有限性，现在的分类学仅仅基于形态学将分子表现不同的疾病进行分类。

芯片技术能够同时检测10000-40000基因，使得研究者对癌症分类的方法有了改变［5］。

临床指针如：ER基因表达状态、淋巴结转移状态、肿瘤大小、肿瘤分化级别、病人绝经期的状态等都影响乳腺癌的表现，是否这些临床病理特征与不同的基因的表达有关？有研究者对ER基因及ER相关基因LIV-1、TFF3、GATA3、c-myb和BTG2［6］。

以及细胞周期相关基因MCM2、BUB1和细胞增生基因等［7-8］进行研究，发现ER的表达与上述相关基因的表达密切相关，与肿瘤分级中度相关。

研究结果［9］表明肿瘤标本可以用免疫组化法根据ER的表达状态分成两大主群：ER阴性组和ER阳性组，ER-组获得高分化肿瘤的百分比ER+组更高。

雌激素受体对乳腺癌细胞耐药及增殖凋亡作用的研究一、本文概述乳腺癌作为全球女性最常见的恶性肿瘤之一，其治疗策略一直受到广泛的关注和研究。

在乳腺癌的治疗过程中，化疗药物的应用对于控制病情、提高患者生存率具有重要意义。

然而，乳腺癌细胞对化疗药物的耐药性问题一直是困扰临床治疗的难题。

近年来，随着分子生物学的深入发展，越来越多的研究表明，雌激素受体（ER）与乳腺癌细胞耐药及增殖凋亡过程之间存在密切关联。

因此，本文旨在深入探讨雌激素受体对乳腺癌细胞耐药及增殖凋亡作用的影响机制，以期为乳腺癌的精准治疗提供新的思路和方法。

本文首先将对雌激素受体在乳腺癌细胞中的表达及其调控机制进行阐述，明确雌激素受体与乳腺癌细胞耐药性的关系。

接着，通过综述相关文献和实验数据，分析雌激素受体对乳腺癌细胞增殖和凋亡过程的影响，探讨其可能的作用机制。

结合当前乳腺癌治疗的临床实践，对雌激素受体在乳腺癌治疗中的应用前景进行展望，以期为乳腺癌的个体化治疗提供新的理论依据和实践指导。

二、雌激素受体与乳腺癌细胞耐药性的关系乳腺癌是女性最常见的恶性肿瘤之一，其发生、发展与雌激素的作用密切相关。

雌激素通过与乳腺癌细胞上的雌激素受体（ER）结合，调控细胞的生长、分化和凋亡。

因此，ER在乳腺癌的发生、发展中起着至关重要的作用。

近年来，随着乳腺癌治疗的不断进步，乳腺癌细胞的耐药性逐渐成为临床治疗的难题。

研究表明，ER与乳腺癌细胞的耐药性之间存在密切的关系。

ER阳性的乳腺癌细胞通常对内分泌治疗敏感，如抗雌激素药物他莫昔芬（Tamoxifen）和芳香化酶抑制剂等。

然而，部分ER阳性乳腺癌细胞在治疗过程中会出现耐药性，导致治疗效果不佳。

这种耐药性的产生可能与ER的表达水平、ER的变异、ER信号通路的改变等多种因素有关。

ER的表达水平可能影响乳腺癌细胞的耐药性。

高表达的ER通常意味着乳腺癌细胞对内分泌治疗的敏感性更高。

然而，随着ER表达的增加，乳腺癌细胞也可能通过上调其他生长因子受体的表达，如胰岛素样生长因子受体（IGF-1R）和表皮生长因子受体（EGFR），从而绕过ER信号通路，产生耐药性。

乳腺癌中雌激素受体表达的研究进展目前，乳腺癌已成为女性最常见的恶性肿瘤之一。

其中，雌激素受体（ER）在乳腺癌发生中起着至关重要的作用。

ER是一种核内激素受体，激活后可促进癌细胞的增殖和繁殖，从而刺激乳腺癌的发生和发展。

本文将介绍有关乳腺癌中ER表达的最新研究进展。

ER阳性乳腺癌的治疗ER阳性乳腺癌占所有乳腺癌的60-70％，这意味着肿瘤细胞对雌激素的依赖性很高。

因此，ER阳性乳腺癌的治疗通常伴随着雌激素阻断剂的使用。

常见的雌激素阻滞剂包括类似黄体酮的药物和选择性雌激素受体调节剂。

最近的研究表明，长期使用类黄酮类化合物（如灵芝提取物、图腾芸香提取物等）可有效减轻雌激素阻滞剂的副作用。

ER阴性乳腺癌的治疗ER阴性乳腺癌失去了对雌激素的依赖性，因此目前还没有专门的针对ER阴性乳腺癌的靶向治疗。

然而近年来，许多研究一致表明，该病种的预后不佳可能与其微环境有关。

因此，改善肿瘤的微环境可能是未来治疗该疾病的一个方向。

ER表达的预测意义ER的表达是否存在、水平及其阳性率是临床治疗和预后判断中常用的指标。

表达高低水平和阳性率是指在一定范围内的表达水平，这门课题带给专业人士的挑战就是需要一个清晰的定义和准确的测量方法。

学者们目前正在努力制定统一的标准和测量方法，以便更准确地确定 ER 表达的预测意义并提高诊断的准确性。

ER的意义和注重ER阳性癌细胞的出现极易让医生们忽视其它治疗重点并忽视ER阳性乳腺癌对激素的依赖性。

此外，有时为了获得更好的结果，“更多”的化疗可能成为主要治疗手段。

然而，增加化疗的剂量可能导致更严重的副作用和死亡风险。

因为 ER 表达的清单存在一些动态变化，并且可能会被化疗和其他治疗影响，所以，准确检测ER 可以防止出现过多的诊断附加值。

ER的测量目前，ER水平的测量主要使用免疫组化或原位杂交技术。

免疫组化是检测肿瘤细胞中激素受体的一种可靠方法，其测试结果通常被用来决定病例是否需要进行乳腺切除手术。

人类雌激素受体基因多态性与乳腺癌的相关性研究乳腺癌是女性最常见的恶性肿瘤之一。

根据统计数据，女性得乳腺癌的风险约为男性的100倍。

乳腺癌的发病原因至今仍然不得而知，但基因的作用在其中扮演着重要角色。

雌激素是导致乳腺癌发生的一个重要因素。

因此近年来越来越多的研究关注于雌激素受体基因多态性与乳腺癌的相关性。

雌激素受体基因（ESR1）是指人体的一种基因，主要在乳腺和生殖器官等组织中表达，可以被雌激素结合并发挥作用。

ESR1的多态性指的是该基因在人群中存在着不同的变异形式。

这些变异形式可以导致基因表达量的变化，影响雌激素对受体的结合力，并在一定程度上与乳腺癌的风险相关。

已有多项研究发现，ESR1的多态性与乳腺癌风险有关。

其中最受关注的是ESR1基因的PvuII和XbaI多态性。

研究发现，ESR1PvuII多态性中，PP基因型、Pp杂合型以及pp基因型，其乳腺癌相关风险分别为1.00、1.19、1.65。

同时，ESR1XbaI多态性中，XX基因型、Xx杂合型以及xx基因型，其乳腺癌相关风险分别为1.00、1.17、1.64。

可见，PP基因型、XX基因型对于乳腺癌的风险较低，而pp基因型、xx基因型对于乳腺癌的风险较高。

除了ESR1的PvuII和XbaI多态性外，还有其他ESR1基因多态性与乳腺癌风险相关。

如rs2234693多态性、rs9340799多态性、rs9397435多态性等。

研究发现，这些ESR1基因多态性与乳腺癌的发病风险也存在相关性，但影响大小和具体机制仍需进一步研究。

除ESR1基因的多态性外，还有一些其他基因也与乳腺癌的发病风险有关。

如雌激素合成相关基因（CYP19A1）和雌激素代谢相关基因（COMT）等。

研究表明，这些基因的多态性也会对雌激素水平和代谢产物的水平产生影响，从而影响乳腺癌的发病风险。

需要指出的是，一个基因的多态性可能与其他基因的多态性相互作用。

因此，单个基因的多态性对于乳腺癌发生风险的影响很难准确预测。

乳腺癌的细胞生物学与分子机制乳腺癌是女性最常见的恶性肿瘤之一，也可以发生在男性身上。

它的发病率一直呈上升趋势，给人们的健康带来了严重的威胁。

乳腺癌是一种复杂的疾病，其发展过程涉及到多种细胞生物学和分子机制的调控。

一、乳腺癌的细胞生物学机制乳腺癌来源于乳腺上皮细胞的恶性转化。

在乳腺组织中，乳腺上皮细胞起着重要的生理功能。

但当这些细胞发生遗传或环境等因素的突变时，它们可能会开始异常增殖和分化，并逐渐形成肿瘤。

乳腺癌的细胞增殖能力是其恶性特征之一。

正常情况下，细胞会受到多种因素的调控，包括生长因子和抑癌基因等。

然而，在乳腺癌中，这些调控机制失去了平衡，导致了细胞无限增殖的能力。

同时，乳腺癌细胞还具有癌细胞特有的侵袭性和转移能力，这使得病情更加复杂和危险。

乳腺癌的细胞分化也是其研究的重点之一。

乳腺上皮细胞正常情况下会经历不同程度的分化，分化程度越高，细胞的功能越成熟。

然而，在乳腺癌中，这种分化过程受到了干扰，细胞的分化程度降低，表现为细胞形态的混乱和功能的失调。

二、乳腺癌的分子机制乳腺癌的发生发展涉及多种分子机制的改变。

研究人员发现，乳腺癌的发生与多个基因的突变密切相关。

其中，BRCA1、BRCA2是最为典型的乳腺癌易感基因。

BRCA1和BRCA2基因的突变会导致DNA修复能力降低，增加细胞遭受损害的风险，从而增加乳腺癌的患病率。

此外，乳腺癌细胞中还存在许多其他基因的异常表达，例如HER2基因的扩增，以及雌激素受体（ER）和孕激素受体（PR）的异常表达。

乳腺癌的发生还涉及到一系列信号通路的改变。

例如，PI3K/AKT 信号通路在乳腺癌发生发展中起到了重要的作用。

该信号通路的激活可以促进细胞增殖和生存，并抑制细胞凋亡。

其异常激活与乳腺癌的发生和耐药性有着密切的关系。

此外，乳腺癌的肿瘤微环境也对其分子机制有重要影响。

肿瘤微环境包括间质细胞、免疫细胞和血管等。

这些细胞可以分泌多种生长因子、细胞因子和组织因子，直接或间接地参与乳腺癌的发展过程，并影响乳腺癌细胞的增殖、侵袭和转移。

乳腺癌的激素治疗与雌激素受体乳腺癌是一种常见的女性恶性肿瘤，对于乳腺癌的治疗，激素治疗是一个重要的方面。

激素治疗以抑制乳腺癌细胞的生长和增殖为目标，其中，与乳腺癌患者的雌激素受体(ER)状态密切相关。

本文将重点探讨乳腺癌激素治疗与雌激素受体之间的关系及其临床应用。

一、雌激素受体(ER)与乳腺癌乳腺癌细胞的表面存在着雌激素受体（Estrogen Receptor，ER），这种受体对乳腺癌的治疗有着重要意义。

ER分为雌激素受体α（ER-alpha）和雌激素受体β（ER-beta），它们分别由ESR1和ESR2基因编码。

ER与雌激素结合后，可以促进乳腺癌细胞的增殖，因此ER阳性的乳腺癌通常对雌激素敏感。

二、乳腺癌的激素治疗1. 高级别激素治疗乳腺癌的激素治疗主要包括选择性雌激素受体调节剂（SERMs）和芳香化酶抑制剂（AI）。

SERMs是通过干扰雌激素与受体结合来达到治疗效果的药物。

而AI则是通过抑制芳香化酶，降低体内雌激素水平，达到抑制乳腺癌细胞生长的目的。

2. 低级别激素治疗另一种激素治疗的方式是使用雌激素拮抗剂，这种药物能够抑制ER的活性，降低乳腺癌细胞对雌激素的敏感性。

由于乳腺癌细胞已经大量依赖于雌激素的生长，所以这种治疗方法可以有效地控制乳腺癌的发展。

三、雌激素受体在乳腺癌激素治疗中的应用根据患者的雌激素受体状态，医生可以根据乳腺癌的特点制定个体化的激素治疗方案。

对于ER阳性的患者，SERMs是首选的治疗药物。

例如，地诺孕酮（Tamoxifen）是最为常用的SERMs之一，通过干扰雌激素与ER的结合，阻止雌激素的刺激。

此外，芳香化酶抑制剂也可以用于ER阳性患者，可以通过降低体内雌激素水平来达到抑制乳腺癌细胞生长的目的。

对于ER阴性的乳腺癌患者，SERMs和芳香化酶抑制剂已经失去了治疗效果，此时需要使用低级别的激素治疗。

例如，雌激素拮抗剂如劳拉色素（Fulvestrant）可以用于抑制ER的活性，在乳腺癌细胞中诱导ER的降解。

乳腺癌易感基因突变女性治疗后结局乳腺癌易感基因BRCA1和BRCA2是重要的抑癌基因，如果发生致病突变，容易发生乳腺癌、卵巢癌等恶性肿瘤。

不过，对于BRCA2突变乳腺癌患者，各种治疗方法对生存结局的影响尚不明确。

2021年2月18日，英国癌症研究基金会《英国癌症杂志》在线发表英国、澳大利亚、意大利、波兰、加拿大、美国、挪威、奥地利的研究报告，探讨了双侧卵巢切除术和其他治疗方法对种系BRCA2突变患者乳腺癌相关生存结局的影响。

该研究对5个地区（北美、波兰、澳大利亚、英国、意大利）前瞻或回顾研究数据进行分析，确定664例早期乳腺癌种系BRCA2突变女性。

从诊断乳腺癌到乳腺癌所致死亡，对这些女性进行中位7.2年随访。

根据患者报告和医疗记录，获得肿瘤特征和癌症治疗方法。

通过多因素比例风险回归模型对其他治疗方法和预后特征进行校正后，确定生存结局预测因素。

结果，10年乳腺癌相关生存比例：•雌激素受体阳性与阴性相比：78.9%比82.3%（校正后风险比：1.23，95%置信区间：0.62～2.45，P=0.55）•双侧卵巢切除与未切除相比：89.1%比59.0%（校正后风险比：0.45，95%置信区间：0.28～0.72，P=0.001）•化疗与未化疗相比：12.9%比11.5%（校正后风险比：0.83，95%置信区间：0.65～1.53，P=0.56）因此，该多中心大样本回顾研究结果表明，对于种系BRCA2突变的乳腺癌女性，雌激素受体阳性与阴性相比、化疗与未化疗相比，生存结局相似。

双侧卵巢切除与未切除相比，乳腺癌所致死亡风险显著较低，制定治疗计划时应予考虑，故有必要进一步开展多中心大样本前瞻研究进行验证。

Br J Cancer. 2021 Feb 18. Online ahead of print.Survival from breast cancer in women with a BRCA2 mutation by treatment.D. Gareth Evans, Kelly-Anne Phillips, Roger L. Milne, Robert Fruscio, Cezary Cybulski, Jacek Gronwald, Jan Lubinski, Tomasz Huzarski, Zerin Hyder, Claire Forde, Kelly Metcalfe, Leigha Senter, Jeffrey Weitzel, Nadine Tung, Dana Zakalik, Maria Ekholm, Ping Sun, Steven A. Narod, Maria Blasińska-Morawiec, Maria Chosia, Kazimierz Drosik, Sylwia Gozdecka-Grodecka, Stanislaw Gozdz, Ewa Grzybowska, Arkadiusz Jeziorski, Aldona Karczewska, Radzislaw Kordek, Agnieszka Synowiec, Beata Kozak-Klonowska, Katarzyna Lamperska, Dariusz Lange, Andrzej Mackiewicz, Jerzy Wladyslaw Mitus, Stanislas Niepsuj, Oleg Oszurek, Karol Gugala, Zbigniew Morawiec, Tomasz Mierzwa, Michal Posmyk, Janusz Rys, Cezary Szczylik, Michal Uciński, Krzysztof Urbański, Bernard Wasko, Piotr Wandzel, Michael Friedlander, Sue Anne McLachlan, Stephanie Nesci, Sandra Picken, Sarah O'Connor, Lucy Stanhope, Andrea Eisen, Kevin Sweet, Raymond Kim, William Foulkes, Pal Moller, Susan Neuhausen, Carey Cullinane, Charis Eng, Peter Ainsworth, Fergus Couch, Christian Singer, Beth Karlan, Wendy McKinnon, Marie Wood; kConFab Investigators, Polish Hereditary Breast Cancer Consortium, Hereditary Breast Cancer Clinical Study Group.The University of Manchester, Manchester, UK; Manchester Academic Health Science Centre, The Christie, Manchester, UK; University of Melbourne, Melbourne, Australia; Peter MacCallum Cancer Centre, Melbourne, Australia; Monash University, Clayton, Australia; Cancer Council Victoria, Melbourne, Australia; Prince of Wales Hospital, Randwick, Australia; St Vincent's Hospital, Fitzroy, Australia; University of Milan-Bicocca, Milan, Italy; Pomeranian Medical University, Szczecin, Poland; Copernicus Memorial Hospital, Lodz, Poland; Regional Cancer Center, Opole, Poland; Poznan University of Medical Sciences, Poznań, Poland; HolycrossCancer Centre, Kielce, Poland; Maria Sklodowska-Curie Institute, Gliwice, Poland; Medical University of Lodz, Lodz, Poland; University School of Medical Sciences at Great Poland Cancer Center, Poznań, Poland; Military Institute of Medicine, Warsaw, Poland; Greater Poland Cancer Centre, Poznan, Poland; Maria Sklodowska-Curie Institute-Oncology Center, Gliwice, Poland; Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Krakow, Poland; Maria Sklodowska-Curie Memorial Institute of Oncology, Krakow, Poland; Regional Oncology Hospital, Olsztyn, Poland; Regional Oncology Hospital, Bydgoszcz, Poland; Regional Oncology Center, Bialystok, Poland; Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Krakow, Poland; Military Hospital, Warsaw, Poland; Institute of Oncology, Krakow, Poland; Regional Hospital, Rzeszów, Poland; Regional Hospital Bielsko-Biala, Bielsko-Biala, Poland; Women's College Hospital, Toronto, ON, Canada; Sunnybrook Health Sciences Centre, Toronto, Canada; University Health Network, Toronto, Canada; McGill University, Montreal, Canada; London Health Sciences Centre, London, Canada; Ohio State University, Columbus, Ohio, USA; Ohio State University, Columbus, OH, USA; City of Hope, Duarte, CA, USA; Beth Israel Deaconess Medical Center, Boston, MA, USA; Beaumont Health, Royal Oak, MI, USA; Cleveland Clinic, Cleveland, Ohio, USA; Mayo Clinic, Rochester, MN, USA; University of California, Los Angeles, CA, USA; University of Vermont, Burlington, VT, USA; Norwegian Radium Hospital, Oslo, Norway; Medical University of Vienna, Vienna, Austria.BACKGROUND: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateraloophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation.METHODS: We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features.RESULTS: The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR=1.23 (95% CI, 0.62-2.45, p=0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR=0.45; 95% CI, 0.28-0.72, p=0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p=0.56).CONCLUSIONS: For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.DOI: 10.1038/s41416-020-01164-1。

雌激素受体预测作用演变：乳腺癌ESR1突变状态与内分泌耐药晚期乳腺癌在既往芳香酶抑制剂治疗后会选择性出现ESR1突变。

两项Ⅲ期随机研究（SoFEA和PALOMA3）评估了ESR1突变对标准治疗敏感性的影响，这两项研究代表了目前雌激素受体阳性晚期乳腺癌标准治疗的发展方向。

2016年6月6日，美国临床肿瘤学会官方期刊《临床肿瘤学杂志》在线发表英国癌症研究所、皇家马斯登医院、美国托马斯杰弗逊大学、法国古斯塔夫·鲁西研究所、澳大利亚墨尔本大学、德国乳腺癌研究协作组、美国辉瑞的研究报告，通过分析SoFEA和PALOMA3两项研究，发现芳香酶抑制剂治疗进展后进行血浆ESR1突变检测，有助于进一步内分泌疗法的直接选择。

•SoFEA研究A.有ESR1突变（PFS：氟维司群>依西美坦，P=0.02）B.无ESR1突变（PFS：氟维司群≈依西美坦，P=0.77）•PALOMA3研究A.有ESR1突变（PFS：氟维司群＋帕泊昔布＞氟维司群，P=0.002）B.无ESR1突变（PFS：氟维司群＋帕泊昔布＞氟维司群，P<0.001）2016年7月5日，约翰·霍普金斯大学金梅尔综合癌症中心对此在线发表述评《雌激素受体作为预测生物标记物的作用演变：乳腺癌ESR1突变状态与内分泌耐药》。

J Clin Oncol. 2016 Jul 5. [Epub ahead of print]Evolving Role of the Estrogen Receptor as a Predictive Biomarker: ESR1 Mutational Status and Endocrine Resistance in Breast Cancer.Josh Lauring, Antonio C. Wolff.The Johns Hopkins Kimmel Comprehensive Cancer Center,Baltimore, MD.Approximately 70% of breast cancers express the estrogen receptor alpha (ER), and endocrine therapies targeting ER are a cornerstone of their treatment. Unfortunately, a subset of patients treated with adjuvant endocrine therapy will develop metastatic disease, and patients treated with endocrine therapies in the metastatic setting will, in time, confront tumor endocrine resistance. Many mechanisms of endocrine resistance have been identified in preclinical models and clinical studies, including growth factor receptor signaling pathways (such as human epidermal growth factor receptor 2) and alterations in transcriptional coregulators. [1] An activating mutation in ESR1, the gene encoding ER, was first described in a metastatic breast cancer in 1997. [2] However, subsequent studies performed in primary breast cancers did not identify frequent ESR1 mutations, and the potential clinical significance of ESR1 mutations was underappreciated. It was not until 2013 that a series of studies using next-generation DNA sequencing renewed interest by demonstrating a high prevalence (11% to 55%) of ESR1 mutations in metastatic ER-positive breast cancers with prior aromatase inhibitor (AI) therapy, but not in primary breast cancers (< 1%). [3-8] Most mutations occur in hotspots in the ligand-binding domain and result in constitutive, ligand-independent activity of ER, explaining how these mutations seem to be selected by the low-estrogen environment with AI therapy.Preclinical studies have shown reduced sensitivity of mutant ERs to tamoxifen, [2,5-7] suggesting that tamoxifen might only have efficacy against ESR1 mutant tumors at higher-than-standard dosages, if at all. The selective ER degrader fulvestrant seems to retain activity against mutant ERs, albeit perhaps withreduced potency, as does the cyclin-dependent kinase-4/6 inhibitor palbociclib. [3-7,9] Altogether, these data suggest that ESR1 mutations could be a major clinical mechanism of endocrine resistance. Therefore, the clinical responsiveness of ESR1 mutant breast cancers to various endocrine therapies is now a question of great interest.Numerous recent reports have demonstrated the detection of mutant DNA alleles as tumor-specific biomarkers in cell-free DNA (cfDNA) from blood. [10-13] Droplet digital polymerase chain reaction (ddPCR) is a highly sensitive and specific technique that has been used for ESR1 mutation detection in plasma. [14-18] A retrospective single-institution analysis documented that ESR1 mutations detected in plasma cfDNA by ddPCR were associated with a lack of response to subsequent AI therapy. [15] However, prospective data have been lacking, and the clinical impact of alternative endocrine therapies, including fulvestrant, has not been examined.In the report that accompanies this editorial in Journal of Clinical Oncology, Fribbens et al [19] performed a prospective-retrospective analysis of ESR1 mutations in baseline plasma samples from two randomized phase III clinical trials comparing different endocrine therapies for metastatic ER-positive breast cancer after nonsteroidal AI (NSAI). In the Study of Faslodex With or Without Concomitant Arimidex Versus Exemestane Following Progression on Non-Steroidal Aromatase Inhibitors (SoFEA) trial, women whose cancer had progressed after a period of sensitivity to NSAI, defined as recurrence after at least 12 months of adjuvant NSAI or disease progression after at least 6 months of first-line metastatic treatment with an NSAI, were randomly assigned to receive the steroidal AI exemestane, fulvestrant 250mg, or the combination of the NSAI anastrozole and fulvestrant 250 mg. [20] In the Palbociclib Ongoing Trials in the Management of Breast Cancer (PALOMA)-3 trial, women whose cancer had recurred within 12 months of completion of adjuvant endocrine therapy or had disease progression during palliative endocrine therapy were randomly assigned to receive fulvestrant 500 mg plus placebo versus fulvestrant 500 mg plus palbociclib. [21] Plasma samples were available for 521 of the PALOMA-3 patients (69.1%), but only 162 of the SoFEA patients (22.4%) because most were lost in a fire. The investigators analyzed seven ESR1 mutations using multiplex ddPCR, covering nearly all mutations described to date. Mutation status was analyzed as a binary outcome, with a positive mutation call requiring a minimum of two positive droplets in a minimum of 0.5 ml (PALOMA-3) or 1 ml (SoFEA) of plasma.Patients in SoFEA with ESR1 mutations (39.1%, of which 49.1% were polyclonal) had improved progression-free survival (PFS) receiving fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA-3, ESR1 mutations were found in the plasma of 25.3% (91/360) of patients, of which 28.6% (26/91) were polyclonal. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in patients with ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.7; P = .002) and ESR1 wild-type (HR, 0.4;, 95% CI, 0.35 to 0.70; P < .001) tumors. In multivariable analysis, ESR1 mutations were associated with AI exposure, sensitivity to prior endocrine therapy, and bone or visceral disease.Many women with metastatic ER-positive/human epidermalgrowth factor receptor 2-negative breast cancer now receive letrozole and palbociclib as first-line endocrine therapy. [22] Although Fribbens et al [19] showed encouraging activity of both fulvestrant and palbociclib against ESR1 mutant cancers, we do not know how palbociclib will affect the emergence of ESR1 mutations or whether fulvestrant plus palbociclib will have the same benefit in patients with prior palbociclib exposure. Although PFS with fulvestrant plus palbociclib was similar in patients with ESR1 mutant or wild-type tumors, this analysis lacked power to conclude that fulvestrant alone or in combination with palbociclib fully overcomes the adverse prognosis of ESR1 mutations.This work highlights the potential advantages of liquid biopsy as a noninvasive tool to monitor the emergence of ESR1 mutations and their response to treatment. The high frequency of polyclonal ESR1 mutations found in this study and others [14,15,18,23] suggests that a metastatic tissue biopsy from a single site would fail to capture the complexity of resistant disease.To date, studies to detect ESR1 mutations in cfDNA have been conducted mostly in individual research laboratories using variable sample preparation methods, primer/probe combinations, and detection cutoffs. There is currently no agreed-upon standard for quantifying mutant tumor alleles in cfDNA—as an absolute number, as a concentration relative to cfDNA genome equivalents, or as a concentration per volume of plasma. Total cfDNA quantity in a sample will vary, depending on location and burden of metastases and whether handling and processing of blood to plasma resulted in lysis of white blood cells, a source of excess wild-type DNA alleles. Use of specialblood collection tubes and handling reduces such contamination by orders of magnitude and improves rare mutation detection.[24] Thus, the reporting by Fribbens et al [19] that archived plasma samples processed using routine protocols could be analyzed successfully for ESR1 mutations is a potentially significant demonstration that could open up archived samples from many pivotal, randomized phase III trials to similar prospective-retrospective analysis of this and other cfDNA biomarkers. However, the assay analytical issues described previously will require careful attention when comparing results across studies.In addition to assay analytical validation, a clinically useful ESR1 cfDNA assay will also need to meet standards of clinical validity and clinical utility by helping the clinician select a more effective therapy or avoid an ineffective one. [25] These data raise several questions regarding such an assay. Is a binary determination of ESR1 mutation status as used by Fribbens et al [19] the most clinically useful one? Will there be a continuum of clinical outcomes on the basis of the mutant allelic fraction in the cancer or mutant allele kinetics? Is the specific mutation important? Preclinical studies have shown differences among ESR1 mutations in terms of sensitivity to endocrine therapies, [5] but clinical analyses have been underpowered and have not yet reached a consensus on this issue. [19,23,26] Consequently, the clear answer to the important question of whether ESR1 mutation testing is ready for immediate clinical use is an unequivocal “not yet.”The available data show that ESR1 mutant tumors in patients with clinical progression who are taking an NSAI do not benefit from exemestane. Clinical trials have reported varying degrees ofbenefit to exemestane after NSAI, perhaps because of differences in patient characteristics. [27,28] And, even without an ESR1 mutation test, many clinicians would be inclined to treat such a patient with fulvestrant alone or with palbociclib, [21] or with exemestane and everolimus. [28] Still, the analysis of SoFEA by Fribbens et al [19] does suggest that patients with ESR1 wild-type tumors and disease progression after initial clinical sensitivity to an NSAI might benefit from exemestane, whereas patients with ESR1 mutated tumors might be better served by fulvestrant or fulvestrant plus palbociclib. If these observations are independently confirmed, lack of ESR1 mutation could then be used to select those patients who would be treated with exemestane alone before moving on to fulvestrant, much as KRAS wild-type status is required for clinical benefit from anti–epidermal growth factor receptor antibody therapy in colon cancer. [29]These are still early days in our understanding of the biology of ESR1 mutations in breast cancer. ESR1 mutations have been detected at a much higher frequency in patients who received AI for metastatic disease than in those who only received adjuvant AI. [15] Schiavon et al [15] explained this difference by hypothesizing that preexisting ESR1 mutant subclones are selected by AI therapy, but that the tumor burden in the micrometastatic setting may be too low for many such clones to be present. ESR1 mutations have been identified only rarely in patients whose sole endocrine therapy was tamoxifen (1/49 in the PALOMA-3 analysis) [7,15,19]; however, the duration and setting (adjuvant v metastatic) of tamoxifen therapy for these patients has not been reported. Therefore, it is premature to discount the possibility that tamoxifen will select for ESR1mutations as well. Also much needed are clinical data on the sensitivity of ESR1 mutant breast cancers to tamoxifen, which may be particularly relevant for countries where access to fulvestrant, everolimus, and palbociclib is limited.The observations by Fribbens et al [19] will now support studies on earlier stages of disease. For instance, will detection of ESR1 mutations during adjuvant AI therapy affect decisions regarding therapy duration and/or a switch to an alternative adjuvant endocrine therapy? The findings now reported support the design of additional prospective-retrospective studies using plasma repositories from completed adjuvant trials of endocrine therapy. Should ESR1 mutations be detected in these studies, an immediate question of interest will be whether combination or sequential adjuvant strategies might help circumvent their emergence.In 1973, McGuire [30] asserted that detection of ER in breast cancer might serve as a predictor of response to endocrine therapy. Data by Fribbens and others in the last few years now show that mutations in ESR1 might serve as a predictor of resistance to certain endocrine therapies. However, the tortuous history of ER testing need not be repeated, [31] and assay methodologies to detect and quantify ESR1 mutations in blood and tissue must now be standardized. This will be a critical step to allow ESR1 mutational status to be used as an integral biomarker in trials on ER-positive disease and to be tested prospectively as a stratification factor, as an enrichment strategy, and as a therapeutic target in the development of new strategies to overcome endocrine resistance in breast cancer.参考文献1.Nardone A, De Angelis C, Trivedi MV, et al. The changingrole of ER in endocrine resistance. Breast. 2015;24(suppl 2):S60-S66.2.Zhang Q-X, Borg A, Wolf DM, et al. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 1997;57:1244-1249.3.Li S, Shen D, Shao J, et al. Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Reports. 2013;4:1116-1130.4.Robinson DR, Wu YM, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45:1446-1451.5.Toy W, Shen Y, Won H, et al. 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