Abemaciclib

引言当你面对一场激烈的对抗，强大的对手在你的重重打击下似乎败退，正当你以为胜利在望时，它却突然变得更加强大，轻松化解你的攻势。这并非科幻电影，而是转移性乳腺癌治疗中常常遇到的棘手挑战：最初有效的内分泌治疗或靶向治疗后，肿瘤会变得耐药。为什么肿瘤会“反扑”？研究人员知道，这背后是肿瘤细胞获得了新的基因变异。但这些变异是如何产生的？是谁在幕后悄悄地推动着肿瘤的基因组发生变化，使其能够逃脱药物的魔爪？找到这个“幕后黑手”，或许是攻克耐药性的关键。5月16日发表在《Nature Genetics》上的重磅研究“APOBEC3 mutagenesis drives therapy resistance in breast cancer”，对数千份乳腺癌患者肿瘤样本进行了深入的基因组“侦查”。他们不放过基因组中的任何蛛丝马迹，通过分析肿瘤DNA上留下的特定“突变指纹”（mutational signatures），试图揭示耐药性产生的根本原因。研究人员惊人地发现，一个被称为APOBEC3酶家族介导的突变（APOBEC3 mutagenesis）过程，竟然是驱动乳腺癌耐药性的一个重要且普遍的“引擎”！这种酶促活动在治疗后的转移性乳腺癌中异常活跃，并与患者更差的治疗结果紧密相关。更关键的是，有证据表明，这个“麻烦制造者”的活动可能早在患者开始治疗前就已经存在。这项研究不仅揭示了肿瘤耐药性背后的一个重要“基因组犯罪现场”，更可能为我们预测肿瘤耐药风险、甚至开发全新的抗癌策略打开大门。APOBEC3，这个潜藏在肿瘤细胞中的“黑手”，它的真面目究竟是什么？它又是如何帮助肿瘤逃脱治疗的？基因组里的“侦探故事”：在海量肿瘤样本中寻找线索要找到隐藏在肿瘤耐药性背后的驱动力，首先需要足够多的证据。这项研究的起点是一个庞大的临床队列——来自纪念斯隆-凯特琳癌症中心（Memorial Sloan Kettering Cancer Center）的3880份乳腺癌患者肿瘤样本，这些样本都进行了肿瘤-正常组织配对测序（tumor-normal sequencing）。通过对比肿瘤和正常组织的基因组差异，研究人员能够精确识别肿瘤中发生的体细胞突变（somatic mutations）。想象一下这是一个巨大的数据库，里面记录了各种类型乳腺癌在不同治疗阶段的基因组信息。研究人员并没有漫无目的地搜索，他们运用了生物信息学工具SigMA，专门用来识别肿瘤基因组中的突变特征。这些突变特征就像是特定突变过程留下的DNA损伤模式，比如紫外线暴露会留下一种模式，吸烟会留下另一种。而研究人员特别关注的是与APOBEC3酶相关的突变特征，通常表现为特定的碱基替换模式，比如C>T或C>G突变，尤其是在TCN（T后面跟着C，C后面跟着任意一个碱基N）这样的DNA序列中。对这3880份样本进行SigMA分析后，研究人员发现，与APOBEC3相关的突变特征是乳腺癌中最普遍的主导突变过程（dominant mutational process）。更重要的是，这种APOBEC3主导特征在转移性乳腺癌样本中比在原发性肿瘤样本中更常见。例如，在激素受体阳性（HR+）/HER2阴性（HR+/HER2-）乳腺癌中，APOBEC3主导特征在原发性样本中占15.7%，而在转移性样本中则高达28.7%。这意味着，肿瘤在转移和进展过程中，APOBEC3的活动可能更加活跃。研究人员进一步分析了基因组不稳定性（genomic instability）的指标，比如肿瘤突变负荷（tumor mutational burden, TMB）和基因组改变分数（fraction of genome altered, FGA）。他们发现在APOBEC3主导的HR+转移性乳腺癌中，FGA显著高于同类型的原发性肿瘤。而在APOBEC3主导的HR+和三阴性乳腺癌（TNBC）中，TMB中位数显著更高。尤其是在TMB高（每兆碱基突变数≥10）的HR+/HER2-和HR-/HER2+（即HER2阳性）肿瘤中，APOBEC3主导特征在大多数样本中都是最突出的突变过程。这强烈暗示APOBEC3突变活动与肿瘤更高的基因组不稳定性和突变负荷有关。有趣的是，研究还发现APOBEC3突变特征在浸润性小叶乳腺癌（invasive lobular breast cancers, ILC）中比浸润性导管癌（invasive ductal carcinoma, IDC）更常见，无论样本是原发性还是转移性。例如，在所有样本中，约33.1%的ILC表现出APOBEC3主导突变特征，而IDC中这一比例约为20.6%。这表明APOBEC3的活动可能在不同乳腺癌组织亚型中存在差异。这些初步的基因组“指纹”证据让APOBEC3成为了驱动乳腺癌进展和耐药性的一个主要“嫌疑犯”。分子层面的“疑犯画像”：APOBEC3酶如何执行“破坏”任务既然突变特征指向了APOBEC3，那么是APOBEC3家族中的哪个成员在起作用？APOBEC3家族有11个成员，但先前的研究表明，APOBEC3A（A3A）和APOBEC3B（A3B）是导致大多数APOBEC3相关突变的主要驱动者。为了证实这一点，研究人员检测了APOBEC3酶在乳腺癌组织中的表达。他们对130份肿瘤样本进行了免疫组织化学（immunohistochemistry, IHC）染色，使用了针对A3A的特异性抗体和可检测A3A/A3B/A3G的抗体。结果显示，在20份具有APOBEC3主导突变特征的样本中，有17份样本使用A3A/B/G抗体检测到弱到强的蛋白表达，8份样本使用A3A特异性抗体检测到蛋白表达。虽然检测到的蛋白表达水平与突变特征暴露程度相关性并不算特别强（可能是因为酶的表达具有周期性或短暂性，而突变特征是累积效应），但这确实提供了APOBEC3酶在这些肿瘤中存在的直接证据。为了更直接地验证A3A或A3B是否能在乳腺癌细胞中诱导APOBEC3突变并导致耐药性，研究人员设计了精巧的细胞实验。他们在缺乏内源性APOBEC3活性的ER阳性乳腺癌细胞（T47D细胞）中，过表达了野生型（wild-type, WT）A3A、A3B或它们催化活性失活的突变体。催化活性是APOBEC3酶执行DNA脱氨基（deamination）功能、制造突变的关键。细胞实验首先确认，过表达野生型A3A和A3B的细胞确实获得了DNA脱氨基活性，而过表达突变体的细胞则没有。这就像给细胞安装了具有潜在破坏力的“工具”。实验室里的“通缉演习”：亲眼目睹耐药性的发生接下来，研究人员进行了关键的耐药性实验。他们将过表达野生型A3A、A3B或其突变体的T47D细胞暴露于常用的内分泌治疗药物氟维司群（fulvestrant），这是一种选择性雌激素受体降解剂（selective estrogen receptor degrader, SERD）。他们惊人地发现，过表达野生型A3A的细胞比过表达突变体的细胞显著更快地获得了对氟维司群的耐药性。在另一个实验中，使用突变能力稍弱的A3B，研究人员观察到三组过表达野生型A3B的细胞中有两组获得了耐药性，而过表达突变体的三组细胞在84天的连续药物暴露后都没有发展出耐药性。这就像是让“黑手”直接进入细胞，发现它们能加速肿瘤对抗生素药物的抵抗。不仅是内分泌治疗，APOBEC3的“破坏”活动还影响了靶向治疗。研究人员测试了A3A过表达细胞对CDK4/6抑制剂（CDK4/6i）阿贝西利（abemaciclib）的反应。他们发现，过表达野生型A3A的细胞在阿贝西利治疗下获得了选择性生长优势。这意味着，在药物压力下，具有APOBEC3活性的细胞能更好地生存和增殖。为了进一步确认是内源性（endogenous）APOBEC3酶在起作用，研究人员使用了另一种HER2阳性乳腺癌细胞系BT-474，这种细胞本身就具有活跃的内源性APOBEC3活性，主要由A3A驱动。他们将野生型BT-474细胞与敲除了A3A基因（A3A KO）的BT-474细胞进行对比，发现野生型细胞比A3A敲除细胞显著更快地获得了对HER2酪氨酸激酶抑制剂（tyrosine kinase inhibitor）拉帕替尼（lapatinib）的耐药性。野生型细胞还对其他抗HER2疗法表现出获得性耐药，包括另一种酪氨酸激酶抑制剂奈拉替尼（neratinib）、下游AKT激酶抑制剂MK2206以及抗体偶联药物T-DXd。这些有力的细胞实验证据表明，APOBEC3酶，特别是A3A和A3B，不仅能在实验室条件下制造突变，更能在药物治疗的压力下，显著加速乳腺癌细胞获得对多种重要抗癌药物的耐药性。它们就是驱动肿瘤进化的“分子引擎”。耐药性的“基因路径图”：APOBEC3偏爱攻击哪些要害基因？APOBEC3酶是通过制造突变来驱动耐药性的，那么它们是随机攻击基因组，还是有偏爱的“攻击目标”？研究人员回到临床队列数据，深入分析了APOBEC3主导的肿瘤样本中哪些基因发生了改变，特别是那些APOBEC3偏爱的突变类型（即APOBEC3-context mutations）。他们发现，在APOBEC3主导的转移性或治疗后HR+/HER2-肿瘤中，一些已知与耐药性相关的基因（如PIK3CA, CDH1, KMT2C等）的致病性突变显著富集。例如，PIK3CA基因中一些热点突变（hotspot mutations），如E545K和E542K，它们都是APOBEC3-context mutations，在APOBEC3主导的HR+/HER2-治疗后样本中普遍存在（E545K突变的P值低至2 x 10⁻¹⁰）。PIK3CA基因的改变会导致PI3K/AKT信号通路（PI3K/AKT pathway）异常激活，这是乳腺癌中非常常见的耐药机制。另一个重要的发现是关于RB1基因。RB1是一个肿瘤抑制基因（tumor suppressor gene），其失活是CDK4/6抑制剂耐药性的主要机制之一。研究人员发现在APOBEC3主导的肿瘤中，RB1基因的APOBEC3-context mutations（如Q217截短突变）显著富集。在一个APOBEC3主导的临床样本中，就观察到了RB1 Q217突变，这个突变在APOBEC3主导病例中尤其普遍。在细胞实验中，野生型A3A过表达导致T47D细胞获得了对阿贝西利的耐药性，而在这些耐药细胞中，研究人员发现RB1发生了功能丧失性突变（loss-of-function mutations），导致RB1蛋白完全缺失。这直接证实了APOBEC3活动可以诱导RB1突变，进而导致对CDK4/6抑制剂的耐药。在他们的APOBEC3阳性细胞系女儿克隆中，他们观察到在APOBEC3阳性的6个细胞系中，有3个细胞系在第13号染色体（RB1基因所在的位置）上出现了杂合性缺失（loss of heterozygosity, LOH），而10个阴性细胞系中均未出现（P=0.035）。这表明APOBEC3活动可能通过诱导LOH等方式促进RB1失活。对于内分泌治疗，研究人员发现ESR1基因中的E380Q突变（也是一个APOBEC3-context substitution）在APOBEC3主导的HR+/HER2-治疗后样本中显著富集（q值低至7.8 x 10⁻¹²）。然而，ESR1基因中其他常见的激活性突变（如L536X, Y537X, D538X）并不是APOBEC3-context mutations，并且在APOBEC3主导的样本中非常罕见（仅占8%）。这提示APOBEC3主导的肿瘤可能不主要通过经典的ESR1热点突变来获得内分泌耐药，而是通过E380Q等APOBEC3偏好的位点。总而言之，APOBEC3并非随机破坏，它像一个有策略的攻击者，偏爱在特定的DNA序列中制造突变，而这些偏爱的位置恰好位于PIK3CA、RB1、ESR1等与治疗耐药性紧密相关的要害基因中。基因组“大爆炸”：突变不仅仅是单个碱基的变化APOBEC3酶的主要功能是引起单个碱基的替换，但研究发现，APOBEC3的活动造成的基因组损伤远不止于此。在APOBEC3主导的肿瘤样本和细胞模型中，研究人员观察到了更复杂的基因组改变。一个突出的现象是“kataegis”，它表现为基因组中一连串密集分布的、与APOBEC3特征高度一致的碱基替换。这项研究在APOBEC3阳性的细胞系和患者样本中都发现了这种现象。Kataegis区域通常伴随着其他类型的基因组改变，例如插入缺失（indels）、拷贝数变异（copy number alterations, CNAs）甚至染色体断裂重排形成的复杂结构变异，即染色体碎裂（chromothripsis）。染色体碎裂是一种灾难性的单次事件，导致染色体在短时间内发生大量断裂和错误的重排。这项研究发现，染色体碎裂也是APOBEC3活动的一个特征。例如，在其中一个APOBEC3阳性细胞系中，过表达A3A后，细胞在获得阿贝西利耐药性的同时，发生了染色体11上的YAP1基因座染色体碎裂事件。这个事件导致了YAP1蛋白表达升高，进而增加了下游靶基因CDK6的表达。CDK6是CDK4/6抑制剂的靶点，CDK6表达增加是已知的CDK4/6抑制剂耐药机制，而且是可以被靶向治疗的。这就像是APOBEC3“炸毁”了基因组的一个区域，意外地引发了下游基因的连锁反应，最终导致了耐药性。这些复杂的基因组改变，包括密集突变簇、拷贝数变异和结构变异，与单纯的单碱基替换共同构成了APOBEC3活动的“破坏力全景图”。它们协同作用，加速了肿瘤的进化，帮助肿瘤细胞找到各种绕过治疗的“生路”。耐药性的“早期预警”：APOBEC3特征能否预测风险？这项研究最令人兴奋的发现之一，在于APOBEC3的“破坏”活动可能并非只在治疗后才出现。如果能在治疗开始前就识别出APOBEC3的活跃迹象，那将为临床决策提供宝贵的“早期预警”。研究人员分析了配对的原发性-转移性乳腺癌样本，这些样本来自同一位患者在不同时间点（早期和晚期）采集的肿瘤。他们发现，在晚期样本中表现出APOBEC3主导突变特征的病例中，有超过60%的早期样本就已经显示出了APOBEC3突变特征的存在。这些早期样本的APOBEC3突变暴露程度中位数达到64%（四分位距39%-85%）。这表明，APOBEC3诱导的突变过程在许多乳腺癌中是持续存在的，可能在肿瘤发展的早期阶段就已经开始活跃，而不是仅仅在药物治疗压力下才“启动”。这就像是发现一个潜在的纵火犯早已埋下了“火种”。这个发现意义重大：它提示我们，通过检测APOBEC3突变特征，即使是在治疗开始前的肿瘤样本中，我们也可能识别出那些具有APOBEC3高活性、更容易在未来对现有疗法产生耐药性的肿瘤。这为开发APOBEC3特征作为预测性生物标志物（predictive biomarker）奠定了基础。如果能提前知道哪些患者面临更高的耐药风险，医生就可以更早地考虑采取更积极或不同的治疗策略，比如联合治疗，或者参与APOBEC3相关的新药临床试验。未来治疗的“新方向”：是靶向APOBEC3还是利用它的“弱点”？这项研究不仅揭示了APOBEC3在驱动乳腺癌耐药性中的关键作用，也为未来的治疗策略指明了方向。首先，正如“早期预警”部分所讨论的，APOBEC3突变特征本身具有成为预测性生物标志物的巨大潜力。在治疗前检测APOBEC3的活跃程度，可以帮助我们区分出高风险患者，避免不必要的治疗，并将他们导向可能更有效的治疗方案。其次，这项研究发现APOBEC3偏好攻击特定的基因。这些被APOBEC3“改造”的基因，可能反而成为了肿瘤的“弱点”。例如，研究发现APOBEC3主导的肿瘤中PIK3CA热点突变普遍存在，甚至有更高比例出现双重PIK3CA突变（double PIK3CA mutations）。先前的研究表明，双重PIK3CA突变可能使肿瘤对PI3Kα选择性抑制剂（PI3Kα-selective inhibitors）更敏感。这项研究中的数据也显示，在接受PI3K抑制剂治疗的HR+/HER2-转移性乳腺癌患者中（尽管样本量有限），APOBEC3主导的病例中有一定比例获得了较好的疾病控制，有患者甚至响应超过30个月。这提示，对于具有APOBEC3特征并伴有PIK3CA突变的肿瘤，靶向PI3K通路可能是一个有效的治疗策略。此外，TMB高是免疫检查点抑制剂（immune checkpoint blockade）疗效的潜在生物标志物。这项研究发现APOBEC3主导的肿瘤通常伴随高TMB。尽管在这项研究中，抗PD-1免疫疗法在APOBEC3主导和非APOBEC3主导肿瘤中的中位PFS没有显著差异，但在接受早期线治疗（一线或二线）的APOBEC3主导TMB高患者中，确实观察到了一些较长的PFS。这提示APOBEC3特征也许能帮助我们更好地筛选出可能受益于免疫治疗的患者亚群。最后，最直接的思路是能否直接靶向APOBEC3酶的活性？目前还没有特异性且安全的APOBEC3抑制剂问世。由于APOBEC3在免疫系统中扮演重要角色，直接抑制它可能会带来副作用。未来的研究需要探索如何在抑制肿瘤中APOBEC3突变活性的同时，保留其正常的免疫功能，或者找到间接抑制APOBEC3介导突变的方法。这项发表在《自然·遗传学》上的研究，通过分析海量临床样本和精密的细胞实验，首次系统性地证实了APOBEC3突变活动是驱动乳腺癌，特别是HR+乳腺癌治疗耐药性的重要且普遍的机制。它揭示了APOBEC3偏爱在RB1、PIK3CA等关键耐药基因中制造突变，甚至引发更复杂的基因组重排。更重要的是，研究发现APOBEC3的活跃迹象可能早在肿瘤治疗前就已存在，这为其作为耐药风险的早期预测生物标志物打开了大门。理解肿瘤如何进化产生耐药性，是战胜癌症的关键。APOBEC3这项“黑手”的暴露，不仅仅是一个令人警醒的发现，更带来了希望。它为我们提供了新的靶点和生物标志物，有望在未来帮助医生更精准地预测患者的耐药风险，选择更有效的治疗方案，甚至开发出能够直接抑制APOBEC3驱动的肿瘤进化的新药物。这就像是，我们不仅找到了敌人的秘密武器，还找到了他们的“兵工厂”及其制造武器的“习惯”，从而能够提前设防，甚至反过来利用他们的破绽发起攻击。乳腺癌的治疗战役依然艰巨，但每揭示一个肿瘤演化的秘密，我们就向最终的胜利更近一步。参考文献Gupta A, Gazzo A, Selenica P, Safonov A, Pareja F, da Silva EM, Brown DN, Shao H, Zhu Y, Patel J, Blanco-Heredia J, Stefanovska B, Carpenter MA, Chen Y, Vegas I, Pei X, Frosina D, Jungbluth AA, Ladanyi M, Curigliano G, Weigelt B, Riaz N, Powell SN, Razavi P, Harris RS, Reis-Filho JS, Marra A, Chandarlapaty S. APOBEC3 mutagenesis drives therapy resistance in breast cancer. Nat Genet. 2025 May 16. doi: 10.1038/s41588-025-02187-1. Epub ahead of print. PMID: 40379787.声明：本文仅用于分享，不代表平台立场，如涉及版权等问题，请尽快联系我们，我们第一时间更正，谢谢！往期热文：Nature Biotechnology | 小身材，大作为：研究人员如何“炼”出超强迷你基因编辑器NovaIscB？Science | 大脑神经元配对秘籍：如何将“3D海选”变“1D精准奔现”Science | 颠覆认知！有丝分裂新模式：细胞“不变形”也能造就多样性Cell | 核糖体“撞车”引发的基因命运：m⁶A调控mRNA降解的意外发现！Cell | 乳酸，不只是运动“负担”，更是激活免疫记忆的新钥匙！N Engl J Med | 网红药司美格鲁肽，不止减肥，竟能“逆转”脂肪肝硬化风险！

Preliminary efficacy analysis from the elacestrant plus everolimus and ribociclib cohorts of the ELEVATE study, along with updated safety data from additional cohorts of elacestrant plus targeted therapy combination arms, will be presented. These data highlight elacestrant’s potential role as an endocrine therapy backbone in combination with various targeted agents for patients with ER+/HER2- mBC. The robust elacestrant clinical development program across wide-ranging studies further solidifies its potential in monotherapy and combination settings, in mBC and in early breast cancer. FLORENCE, Italy and NEW YORK, May 22, 2025 (GLOBE NEWSWIRE) -- The Menarini Group (“Menarini”), a leading international pharmaceutical and diagnostics company, and Stemline Therapeutics, Inc. (“Stemline”), a wholly-owned subsidiary of the Menarini Group, focused on bringing transformational oncology treatments to cancer patients, will present updated preliminary efficacy and safety results from the Phase 1b/2 ELEVATE study in patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) locally advanced or metastatic breast cancer (mBC). The ELEVATE study was designed to evaluate the safety and efficacy of oral-oral combination treatment options to overcome different resistance mechanisms observed in ER+/HER2- mBC and improve patient outcomes. Additionally, various other trial-in-progress updates will be presented, investigating elacestrant’s potential to become an endocrine therapy (ET) backbone across the spectrum of breast cancer. These data will be presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. The ELEVATE study is comprised of six treatment regimens evaluating elacestrant in combination with CDK4/6 inhibitors (palbociclib, abemaciclib and ribociclib) and with inhibitors of the PI3K/AKT/mTOR pathway (everolimus, alpelisib and capivasertib). ELEVATE results reported at ASCO 2025 (abstract 1070/49) include updated efficacy data which demonstrate favorable preliminary progression-free survival (PFS) from the elacestrant plus ribociclib and the elacestrant plus everolimus cohorts. A recommended phase 2 dose (RP2D) was determined to be elacestrant 345 mg plus ribociclib 400 mg. The RP2D of elacestrant 345 mg plus everolimus 7.5 mg was previously reported. “It is encouraging to see the positive preliminary efficacy and safety results when everolimus and ribocilib, respectively, are combined with elacestrant. These findings are consistent with the promising elacestrant plus abemaciclib cohort data from the same study that was presented last December, which also demonstrated favorable preliminary efficacy and safety in this setting,” said Hope S. Rugo, MD, Director, Women's Cancers Program and Division Chief, Breast Medical Oncology, City of Hope Comprehensive Cancer Center. “As the progression-free survival data and safety data continue to mature across the various cohorts of the ELEVATE study, we are encouraged by elacestrant’s potential to become an endocrine therapy backbone in combination regimens for the treatment of metastatic breast cancer.” Additional data reported separately (abstract 1079/58) provided updated Phase 1b/2 safety results from four cohorts of the ELEVATE study, including elacestrant plus ribociclib, everolimus, alpelisib, and capivasertib. These updated preliminary results show that the combinations are consistent with the known safety profiles of each targeted therapy plus standard of care endocrine therapy. “These data continue to underscore the potential value of elacestrant as a combination partner in the ER+/HER2- metastatic breast cancer treatment landscape,” said Elcin Barker Ergun, CEO of the Menarini Group. “We are also exploring the potential of elacestrant in other patient populations, including our currently enrolling ELEGANT study, which is designed to assess its potential benefit in early breast cancer patients with high risk of recurrence.” In addition, the company will be presenting other data at the ASCO Annual Meeting. See below for a complete list of Menarini Stemline abstracts. Menarini Stemline Abstracts: Presentation Title: Elacestrant (Ela) combinations with ribociclib (Ribo) and everolimus (Eve) in patients (pts) with ER+/HER2- locally advanced or metastatic breast cancer (mBC): Update from ELEVATE, a phase (Ph) 1b/2, open-label, umbrella study. Abstract Number: 1070 Presentation Date & Time: Monday, June 2, 9:00 AM – 12:00 PM CT Location: Poster Bd 49 Presenting Author: Hope S. Rugo Presentation Title: Elacestrant combinations in patients (pts) with ER+/HER2- locally advanced or metastatic breast cancer (mBC): Safety update from ELEVATE, a phase (Ph) 1b/2, open-label, umbrella study. Abstract Number: 1079 Presentation Date & Time: Monday, June 2, 9:00 AM – 12:00 PM CT Location: Poster Bd 58 Presenting Author: Nancy Chan Presentation Title: ADELA: a double-blind, placebo-controlled, randomized phase 3 trial of Elacestrant (ELA) + everolimus (EVE) versus ELA + placebo (PBO) in ER+/HER2- advanced breast cancer (aBC) patients with ESR1-mutated tumors progressing on endocrine therapy (ET) + CDK4/6i. Abstract Number: TPS1129 Presentation Date & Time: Monday, June 2, 9:00 AM – 12:00 PM CT Location: Poster Bd 103b Presenting Author: Antonio Llombart-Cussac Presentation Title: ELCIN: Elacestrant in women and men with CDK4/6 Inhibitor (CDK4/6i)-naïve estrogen receptor-positive (ER+), HER2-negative (HER2-) metastatic breast cancer (mBC): an open-label multicenter phase 2 study. Abstract Number: TPS1127 Presentation Date & Time: Monday, June 2, 9:00 AM – 12:00 PM CT Location: Poster Bd 102b Presenting Author: Virginia G. Kaklamani Presentation Title: ELEGANT: Elacestrant versus standard endocrine therapy (ET) in women and men with node-positive, estrogen Receptor-positive (ER+), HER2-negative (HER2-), early breast cancer (eBC) with high risk of recurrence in a global, multicenter, randomized, open-label phase 3 study. Abstract Number: TPS619 Presentation Date & Time: Monday, June 2, 9:00 AM – 12:00 PM CT Location: Poster Bd 210a Presenting Author: Aditya Bardia Presentation Title: EORTC-2129-BCG: Elacestrant for treating ER+/HER2- breast cancer patients with ctDNA relapse (TREAT ctDNA) Abstract Number: TPS620 Presentation Date & Time: Monday, June 2, 9:00 AM – 12:00 PM CT Location: Poster Bd 210b Presenting Author: Michail Ignatiadis About The Elacestrant Clinical Development Program Elacestrant is also being investigated in several company-sponsored clinical trials in metastatic breast cancer disease, alone or in combination with other therapies. ELEVATE ( NCT05563220 ) is a phase 1b/2 clinical trial evaluating the safety and efficacy of elacestrant combined with alpelisib, everolimus, capivasertib, palbociclib, ribociclib or abemaciclib. ELECTRA ( NCT05386108 ) is an open-label phase 1b/2, multicenter study evaluating elacestrant in combination with abemaciclib in patients with ER+, HER2- breast cancer. The phase 2 portion evaluates this treatment regimen in patients with brain metastases. ELCIN ( NCT05596409 ) is a phase 2 trial evaluating the efficacy of elacestrant in patients with ER+, HER2- advanced/metastatic breast cancer who received one or two prior hormonal therapies and no prior CDK4/6 inhibitors in the metastatic setting. ADELA ( NCT06382948 ) is a phase 3 randomized, double-blinded trial evaluating elacestrant in combination with everolimus in patients with ER+, HER2- mBC with ESR1-mut tumors. Elacestrant is also being evaluated in additional investigator-led trials, in trials conducted in collaboration with other companies, in metastatic breast cancer as well as in early disease. About ORSERDU (elacestrant) U.S. Indication: ORSERDU (elacestrant), 345 mg tablets, is indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1 -mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Full prescribing information for the U.S. can be found at www.orserdu.com . Important Safety Information Warning and Precautions Dyslipidemia : Hypercholesterolemia and hypertriglyceridemia occurred in patients taking ORSERDU at an incidence of 30% and 27%, respectively. The incidence of Grade 3 and 4 hypercholesterolemia and hypertriglyceridemia were 0.9% and 2.2%, respectively. Monitor lipid profile prior to starting and periodically while taking ORSERDU. Embryo-Fetal Toxicity : Based on findings in animals and its mechanism of action, ORSERDU can cause fetal harm when administered to a pregnant woman. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ORSERDU and for 1 week after the final dose. Adverse Reactions Serious adverse reactions occurred in 12% of patients who received ORSERDU. Serious adverse reactions in >1% of patients who received ORSERDU were musculoskeletal pain (1.7%) and nausea (1.3%). Fatal adverse reactions occurred in 1.7% of patients who received ORSERDU, including cardiac arrest, septic shock, diverticulitis, and unknown cause (one patient each). The most common adverse reactions ( > 10%) , including laboratory abnormalities, of ORSERDU were musculoskeletal pain (41%), nausea (35%), increased cholesterol (30%), increased AST (29%), increased triglycerides (27%), fatigue (26%), decreased hemoglobin (26%), vomiting (19%), increased ALT (17%), decreased sodium (16%), increased creatinine (16%), decreased appetite(15%), diarrhea (13%), headache (12%), constipation (12%), abdominal pain (11%), hot flush (11%), and dyspepsia (10%). Drug interactions Concomitant use with CYP3A4 Inducers and/or inhibitors : Avoid concomitant use of strong or moderate CYP3A4 inhibitors with ORSERDU. Avoid concomitant use of strong or moderate CYP3A4 inducers with ORSERDU. Use in specific populations Lactation : Advise lactating women to not breastfeed during treatment with ORSERDU and for 1 week after the last dose. Hepatic Impairment : Avoid use of ORSERDU in patients with severe hepatic impairment (Child-Pugh C). Reduce the dose of ORSERDU in patients with moderate hepatic impairment (Child-Pugh B). The safety and effectiveness of ORSERDU in pediatric patients have not been established. To report SUSPECTED ADVERSE REACTIONS, contact Stemline Therapeutics, Inc. at 1-877-332-7961 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . About The Menarini Group The Menarini Group is a leading international pharmaceutical and diagnostics company, with a turnover of $4.7 billion and over 17,000 employees. Menarini is focused on therapeutic areas with high unmet needs with products for cardiology, oncology, pneumology, gastroenterology, infectious diseases, diabetology, inflammation, and analgesia. With 18 production sites and 9 Research and Development centers, Menarini’s products are available in 140 countries worldwide. For further information, please visit www.menarini.com . About Stemline Therapeutics Inc. Stemline Therapeutics, Inc. (“Stemline”), a wholly-owned subsidiary of the Menarini Group, is a commercial-stage biopharmaceutical company focused on bringing transformational oncology treatments to patients. Stemline commercializes elacestrant, an oral endocrine therapy indicated for the treatment of postmenopausal women or adult men with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, ESR1 -mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy, in the U.S., Europe, and other global regions. Stemline also commercializes tagraxofusp-erzs, a novel targeted therapy directed to CD123, for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic cancer, in the United States, Europe, and other global regions. In addition, Stemline commercializes selinexor, an XPO1 inhibitor for multiple myeloma, in Europe. The company is also conducting multiple label-expansion studies with elacestrant and tagraxofusp in breast and hematologic cancer indications, respectively, and has an extensive clinical pipeline of additional drug candidates in various stages of development for a host of solid and hematologic cancers. Media Contacts The Menarini Group Valeria Speroni Cardi Email: pressoffice@menarini.com Stemline Therapeutics, Inc. Cheya Pope Email: media@menarinistemline.com Legal Disclaimer: EIN Presswire provides this news content "as is" without warranty of any kind. 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