Estrogens, Conjugated

引言我们常常用身份证上的年龄来定义自己，但身体的衰老却远比这个数字复杂。你是否想过，当你40岁时，你的心脏可能已经像50岁一样疲惫，而你的大脑却依然保持着30岁的活力？这种生理年龄与实际年龄之间的差异，被称为“生物学年龄”(biological age)。然而，一个更深层次的问题是：我们的身体是一个统一衰老的整体，还是一个由不同衰老速度的器官组成的“联邦”？如果后者是正确的，我们能否知道每个器官各自的“真实年龄”？这听起来像是科幻小说里的情节，但一篇于7月9日发表在《Nature Medicine》上的重磅研究“Plasma proteomics links brain and immune system aging with healthspan and longevity”，正将这一想象变为科学现实。这项基于英国生物银行(UK Biobank)近45,000人的大规模研究，不仅巧妙地构建了11个主要器官的“年龄时钟”，还揭示了一个惊人的发现：大脑和免疫系统的“年轻态”，可能是决定我们能否健康长寿的终极密码。这不仅仅是对衰老现象的重新审视，更可能预示着一个全新“个性化衰老管理”时代的到来。打造“器官时钟”：如何倾听来自器官的“密语”？要评估一个远在身体内部器官的年龄，我们总不能把它取出来看看。那么，研究人员是如何做到“隔空诊断”的呢？答案隐藏在我们的血液中——那些由各个器官释放的蛋白质“信使”。蛋白质的“产地标签”想象一下，血液是我们身体的“信息高速公路”，无数的蛋白质分子在其中穿梭，传递着各种信号。如果把每个器官比作一个工厂，那么它们生产的某些蛋白质就带有独特的“产地标签”。例如，肝脏工厂会生产一些其他工厂几乎不生产的特殊蛋白质。当这些蛋白质出现在血液这条高速公路上时，我们就能追溯到它的来源。研究人员正是利用了这一原理。他们首先求助于一个名为“基因组织表达图谱”(Genotype-Tissue Expression, GTEx)的庞大数据库。这个数据库详尽地记录了人体不同组织和器官中，哪些基因是活跃的（即正在“表达”并生产蛋白质）。通过筛选这个数据库，他们找到了那些在某个特定器官中表达水平比其他任何器官都高出至少四倍的基因。这些基因编码的蛋白质，就被认为是该器官的“特产”，即“器官富集蛋白”(organ-enriched proteins)。机器学习的巧妙“配方”找到了这些带有“产地标签”的蛋白质后，下一步就是训练一个能够解读它们信息的“智能模型”。研究人员采用了LASSO回归(LASSO regression)的机器学习算法。这个过程就像训练一位聪明的厨师，让他学会根据一堆食材（血液中各种器官富集蛋白的水平）来预测一位客人的真实年龄。研究人员将44,498名参与者的数据分成了两半：一半用于“训练”厨师（训练集，n=23,140），另一半用于“考核”厨师（测试集，n=21,358）。对于每一个器官，比如心脏，研究人员都会“告诉”LASSO模型：“这里有几百位参与者心脏富集蛋白的水平，以及他们对应的实际年龄。请你学习一下，找出哪些蛋白质水平的变化与年龄增长关系最密切，并给它们分配不同的权重，最终得出一个能最准确预测年龄的‘数学配方’。”通过这种方式，研究人员为11个主要器官——包括脂肪组织(adipose tissue)、动脉(artery)、大脑(brain)、心脏(heart)、免疫系统(immune system)、肠(intestine)、肾(kidney)、肝(liver)、肺(lung)、肌肉(muscle)和胰腺(pancreas)——分别打造了专属的“年龄预测模型”。“年龄差距”：衡量你的器官是“年轻”还是“衰老”当模型训练完成后，就可以用它来预测任何一个人的器官年龄了。将一个人的血液蛋白质数据输入模型，模型就会输出一个“预测年龄”(predicted age)。这个预测年龄本身不是最重要的，最关键的是它与你实际年龄(chronological age)的差值——研究人员称之为“年龄差距”(age gap)。举个例子，一位实际年龄50岁的人，如果他的心脏年龄模型预测出他的心脏年龄是58岁，那么他的心脏“年龄差距”就是+8岁，说明他的心脏比同龄人“老”了8岁。反之，如果预测出是44岁，那他的心脏就比同龄人“年轻”6岁。为了在不同器官之间进行公平比较（因为不同模型的预测精度不同），研究人员还巧妙地将所有年龄差距进行了标准化处理(z-score normalization)。这样，无论是心脏的+1岁还是大脑的+1岁，都代表了在同龄人中相似的“衰老”程度。这项研究的一个基础性发现是，不同器官的“年龄差距”之间相关性很弱，平均相关系数仅为0.21。这意味着，一个拥有“衰老”心脏的人，他的肝脏或大脑可能依然非常“年轻”。这有力地证明了，人体衰老并非铁板一块，不同器官确实拥有自己独立的衰老轨迹，因此，为每个器官建立专属的“时钟”是完全必要的。大脑的惊人“预言”：提前看见阿尔茨海默病的未来如果“器官年龄”仅仅是一个有趣的数字，那它的意义将大打折扣。这项研究真正的震撼之处在于，它证明了这些数字拥有强大的预测能力，能够预见未来数年甚至十几年后可能发生的疾病。研究人员动用了强大的统计学工具——Cox比例风险回归模型(Cox proportional hazard regression)，在长达17年的随访数据中，分析了基线（第一次抽血时）的器官年龄差距与未来各种疾病风险之间的关系。结果是惊人的，器官年龄与对应的疾病风险之间存在着强烈的“亲缘关系”：心脏年龄的“过早衰老”，与未来发生房颤(atrial fibrillation)和心力衰竭(heart failure)的风险急剧升高紧密相关。心脏年龄差距每增加一个标准差，房颤的风险增加75% (风险比HR=1.75)，心力衰竭的风险增加83% (HR=1.83)。胰腺和肾脏的加速衰老，是未来患上慢性肾病(chronic kidney disease)的强烈信号。肺部年龄的增加，则与慢性阻塞性肺疾病(COPD)的风险显著相关。而在所有这些关联中，最引人深思的，是大脑年龄与阿尔茨海默病(Alzheimer's disease)之间的深刻联系。大脑年龄 vs. 阿尔茨海默病最强遗传风险阿尔茨海默病是认知健康的“头号杀手”，其最强的遗传风险因素是APOE4基因。携带一个APOE4等位基因会使患病风险增加数倍。与之相对，APOE2基因则具有保护作用。长久以来，我们似乎认为基因在很大程度上决定了我们的命运。但这项研究提供了一个全新的视角。研究发现，在排除了年龄、性别等因素后，大脑年龄差距每增加一个标准差，未来患上阿尔茨海默病的风险就会增加80% (HR=1.80)。研究人员进一步聚焦于那些“极端”案例——大脑年龄“极端年轻”（比同龄人年轻超过1.5个标准差）和“极端衰老”（比同龄人衰老超过1.5个标准差）的人群。结果令人瞠目结舌：拥有“极端衰老”大脑的人，其阿尔茨海默病风险增加了3.11倍。这个风险水平，与携带一个APOE4基因拷贝所带来的风险惊人地相似。拥有“极端年轻”大脑的人，其风险则降低了74% (HR=0.26)。这种保护效果，堪比携带两个APOE2保护性基因拷贝。最关键的是，这种由“大脑年龄”带来的风险或保护，是独立于APOE基因型之外的。这意味着，即使你没有携带APOE4风险基因，一个“衰老”的大脑依然会把你推向危险的边缘；而即使你携带了风险基因，一个“年轻”的大脑也可能成为你强大的“护身符”。在长达17年的观察期里，在2,628名拥有“衰老”大脑的参与者中，有120人（4.56%）最终患上了阿尔茨海默病。而在1,998名拥有“年轻”大脑的参与者中，只有区区7人（0.35%）患病。两者之间超过13倍的巨大差异，直观地展示了大脑“真实年龄”的强大预测力。为了让这个发现更加坚实，研究人员还将血液蛋白质组学数据与参与者大约9年后进行的脑部磁共振成像(MRI)数据进行了关联分析。他们发现，基线时“更老”的大脑年龄差距，与9年后大脑中脑室的扩大和皮层区域的萎缩显著相关。这就像一个完美的证据闭环：血液中的分子信号，不仅预测了未来的临床诊断，还与大脑的物理结构变化遥相呼忿，证明这个“大脑时钟”确实捕捉到了大脑衰老的真实生物学过程。衰老的“交响乐”：当器官们步调不再一致既然器官们可以独立衰老，那么当多个器官同时响起“衰老警报”时，会发生什么？这就像一场交响乐，当越来越多的乐器开始跑调，整场演出将不可避免地走向灾难性的结局。衰老器官的累积效应：死亡风险的“指数级”攀升研究人员考察了体内“极端衰老”器官的数量与全因死亡率之间的关系。结果呈现出一种可怕的“剂量效应”：与“正常衰老者”（没有极端衰老器官）相比，体内有2到4个极端衰老器官的人，其在随访期内的死亡风险增加了2.3倍。当衰老器官数量达到5到7个时，死亡风险飙升至4.5倍。而对于那些体内有8个或更多极端衰老器官的不幸者，死亡风险更是达到了惊人的8.3倍！这是一个极其严峻的信号。超过60%的拥有8个及以上衰老器官的参与者，在抽血后的15年内去世。这表明，全身性的、多器官的衰老累积，是通往生命终点站的“快车道”。长寿的“双重密钥”：大脑与免疫系统的年轻态那么反过来，拥有多个“年轻”器官，是否就能获得“长寿护符”呢？答案出人意料。研究发现，拥有多个极端年轻器官的人，其死亡率与正常人相比并没有显著差异。更奇怪的是，拥有“年轻”动脉的人，死亡风险甚至还有轻微升高。研究人员发现这可能与一种名为THBS2的蛋白质有关，它随着年龄增长而减少，但却与较高的死亡风险正相关，揭示了衰老与健康之间复杂的非线性关系。在众多器官中，只有两个器官的“年轻态”脱颖而出，被证明是长寿的真正守护者——大脑和免疫系统。拥有“极端年轻”大脑的参与者，死亡风险降低了40% (HR=0.60)。拥有“极端年轻”免疫系统的参与者，死亡风险降低了42% (HR=0.58)。这两者就像是长寿之路上的“左膀右臂”，任何一个都能提供显著的保护。而当它们联手时，奇迹发生了。同时拥有“年轻大脑”和“年轻免疫系统”的“天选之子”，他们的死亡风险大幅降低了56% (HR=0.44)，是所有组合中保护效果最强的！在长达17年的随访中，普通衰老者群体的死亡率约为7.92%，而这个“超级幸运组”的死亡率仅为3.8%。这一发现将我们的目光牢牢锁定在了“脑-免疫轴”(brain-immune axis)上。它暗示我们，维持大脑的认知健康和免疫系统的平衡稳定，可能是对抗衰老、延长健康寿命的核心策略。这两大系统的协同作用，共同构成了抵御时间侵蚀的最坚固防线。我们能拨慢“器官时钟”吗？生活方式的深远影响这项研究最激动人心的地方，在于它没有将我们置于宿命论的绝望之中。器官年龄并非一成不变的“出厂设置”，它对我们的生活方式、环境和选择非常敏感。这意味着，我们手握拨慢“器官时钟”的钥匙。研究人员分析了18种生活方式和环境因素与13个年龄差距（11个器官年龄+1个全身年龄+1个常规模型年龄）之间的关系，发现了许多意料之中却又意义深远的联系：加速衰老的“坏习惯”： 吸烟、饮酒、食用加工肉类、失眠，以及代表社会经济地位较低的汤森剥夺指数(Townsend Deprivation Index)，这些因素都与多个器官的“年龄加速”显著相关。它们就像踩在我们器官时钟上的“油门”，让指针飞速旋转。延缓衰老的“好习惯”： 进行运动、食用鱼类（如三文鱼）、接受更高水平的教育，则与拥有更“年轻”的器官状态相关。这些是温柔的“刹车”，帮助我们抵抗时间的冲刷。药物与激素的潜在启示研究还发现了一些药物与器官年轻化之间的有趣关联。例如，常用的止痛药布洛芬(ibuprofen)、保健品氨基葡萄糖(glucosamine)和鱼肝油(cod liver oil)都与肾脏、大脑和胰腺等器官的年轻状态有关。其中一个特别的发现与一种名为Premarin的药物有关，这是一种用于缓解更年期症状的结合雌激素药物。研究显示，在经历了过早绝经的女性中，雌激素治疗与更年轻的免疫系统、肝脏和动脉状态相关。虽然这只是相关性研究，不能直接断定因果关系，但它强有力地提示，激素水平的变化可能在调节特定器官的衰老速度中扮演着重要角色，为未来通过干预内分泌来抗衰老的研究打开了一扇窗。总而言之，这些发现赋予了我们前所未有的“掌控感”。我们的器官年龄，在很大程度上，是我们生活选择的“成绩单”。通过改善生活习惯，我们完全有可能为一个或多个器官“减龄”，从而降低未来患病的风险，延长健康的生命旅程。解码大脑与免疫的长寿密语为了不让这项研究停留在“知其然”的层面，研究人员进一步深挖了“所以然”。他们仔细剖析了那些在衰老模型中权重最高的蛋白质，试图从分子层面解码大脑和免疫系统为何如此重要。大脑衰老的分子指纹在预测大脑年龄的模型中，贡献最大的蛋白质包括：神经丝轻链(Neurofilament light chain, NEFL)：这是神经元轴突（神经细胞的“电线”）受损时会释放到血液中的标志物。它的水平升高，通常意味着神经元的损伤和死亡。髓鞘少突胶质细胞糖蛋白(Myelin oligodendrocyte glycoprotein, MOG)：这是包裹在神经元轴突外的“绝缘层”——髓鞘的关键组成部分。它的变化反映了髓鞘的健康状况。胶质纤维酸性蛋白(Glial fibrillary acidic protein, GFAP)：这是星形胶质细胞（大脑中的一种支持细胞）在应激或损伤时会大量产生的蛋白质。更有趣的是，通过单细胞测序数据分析，研究人员发现，预测大脑衰老的蛋白质中，有近一半（47%）都来源于少突胶质细胞(oligodendrocytes)及其前体细胞。这些细胞的唯一功能就是生产和维护髓鞘。这强有力地表明，大脑的衰老，尤其是在分子层面，与“白质”(white matter)的健康状况（即神经纤维的连接和信号传导效率）息息相关，而不仅仅是传统认为的神经元丢失。长寿的分子机制：一场大脑与免疫的“协同防御”那么，那些预示着长寿的“年轻大脑”和“年轻免疫系统”，又是由哪些蛋白质来定义的呢？当研究人员分析与长寿最相关的蛋白质时，一幅巧妙的生物学画卷徐徐展开。在长寿相关的“年轻大脑”信号中，一种叫做“神经元周围网”(perineuronal net, PNN)的结构扮演了核心角色。PNN就像包裹在特定神经元外的“加固网”或“脚手架”，能够稳定突触连接，保护神经元。而与长寿相关的大脑蛋白质，如BCAN和NCAN，正是PNN的关键组成部分。拥有“年轻大脑”的人，血液中这些PNN蛋白的水平更高，暗示他们的大脑结构可能更稳固、更有韧性。而“年轻免疫系统”的长寿信号则指向了更低的炎症水平。特别是，研究人员发现了一个名为MMP9的蛋白。MMP9是一种由免疫细胞分泌的酶，它的一个重要功能就是降解和重塑包括PNN在内的细胞外基质。在拥有“年轻免疫系统”的人体内，MMP9的水平更低。现在，把这两条线索串联起来：一个“年轻”的、平静的免疫系统，减少了MMP9这类破坏性酶的释放；这反过来又有助于保护和维持大脑中脆弱而重要的PNN结构；一个结构稳定的大脑，其功能自然更具韧性，更能抵抗衰老和疾病的侵袭。这正是“脑-免疫轴”协同作用的生动体现。它告诉我们，长寿或许源于一种全身性的平衡：一个不过度活跃的免疫系统，为大脑提供了一个和平稳定的“内部环境”，让大脑得以保持年轻和健康。未来已在血液中：个性化衰老管理的曙光这篇《自然·医学》的研究，照亮了我们对衰老这一古老谜题的认知。它以海量的数据和巧妙的分析，为我们描绘了一幅前所未有的“人体衰老地图”。这项研究的核心贡献是革命性的：1. 它证明了评估器官特异性生物学年龄的可行性。我们首次能够通过一管血，以一种相对无创、可量化的方式，评估11个关键器官的健康状况。2. 它揭示了大脑和免疫系统在决定健康长寿中的核心地位。多器官的加速衰老是死亡的“催化剂”，而大脑和免疫系统的协同年轻态，则是通往长寿的“VIP通行证”。3. 它为我们提供了可行的干预方向。器官年龄对生活方式高度敏感，这意味着抗衰老不再是遥不可及的梦想，而是可以通过日常选择来实现的科学实践。当然，我们必须清醒地认识到，这还只是研究的开端。这项技术目前还不能直接用于临床诊断。但它所开辟的道路，通向的是一个令人无比兴奋的未来。想象一下，在不远的将来，你的年度体检报告上，除了常规的血脂、血糖指标，还会有一份详细的“器官年龄报告”。医生可以据此告诉你：“你的心脏状态非常好，比同龄人年轻5岁，请继续保持。但你的肝脏年龄偏大，提示你需要注意饮酒和饮食习惯了。”这将是真正的“预防医学”和“个性化健康管理”。我们不再是被动地等待疾病发生，而是在器官功能出现衰退迹象的早期，就主动出击、精准干预。衰老的时钟在我们每个人体内滴答作响，但现在，我们终于有了一面能够窥见其指针的“魔镜”。这面镜子就在我们的血液里。它告诉我们，衰老并非一个不可违抗的统一进程，而是一场我们可以参与、可以影响的，与我们体内每一个器官的“对话”。而在这场对话中，如何让大脑保持睿智，让免疫保持平和，或许就是我们能给自己最宝贵的、抵御时间的礼物。参考文献Oh HS, Le Guen Y, Rappoport N, Urey DY, Farinas A, Rutledge J, Channappa D, Wagner AD, Mormino E, Brunet A, Greicius MD, Wyss-Coray T. Plasma proteomics links brain and immune system aging with healthspan and longevity. Nat Med. 2025 Jul 9. doi: 10.1038/s41591-025-03798-1. Epub ahead of print. PMID: 40634782.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 | 基因密码的“沉默”革命：被忽视的同义突变，竟是疾病的隐形推手？Nature Genetics | 终结无效化疗！一张“基因地图”精准导航，或将为患者避开治疗弯路Cell | 告别“猜谜式”诊断！临床意义未明变异（VUS）研究新范式，系统性破解遗传病变异解读难题Nature | 惊天“内幕”：你肠道里的“叛军”，竟是大脑炎症的幕后黑手？Cell | 绕开“心脏警报”，新一代口服降糖药或将改写糖尿病治疗格局？Science | 颠覆性“体内”CAR-T疗法诞生！一针“编程”免疫细胞，或将终结癌症与自身免疫病！

The ItovebiTM (inavolisib)-based regimen reduced the risk of death by more than 30% in people with PIK3CA-mutated HR-positive, HER2-negative advanced breast cancer, compared with palbociclib and fulvestrant alone1 The PIK3CA mutation is found in approximately 40% of HR-positive advanced breast cancers and is associated with a poor prognosis2,3 New data are being presented in an oral session at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and published in the New England Journal of Medicine1 31 May 2025 - Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today positive final results from the overall survival (OS) analysis of the phase III INAVO120 study. These data showed ItovebiTM (inavolisib), in combination with palbociclib (Ibrance®) and fulvestrant, reduced the risk of death by more than 30% compared with palbociclib and fulvestrant alone. This represents a statistically significant and clinically meaningful improvement in overall survival for people with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, endocrine-resistant, locally advanced or metastatic breast cancer.1 The results are being presented in an oral session at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously published in the New England Journal of Medicine (NEJM).1"For the first time, a PI3K pathway-targeted drug has shown it can help people with this breast cancer subtype live longer," said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. "Itovebi exemplifies our continued commitment to improve survival rates for people with this common PIK3CA mutation, for whom more effective treatment options are needed.” “The landmark data for the inavolisib-based regimen showed not only a doubling in progression-free survival, but importantly that it extended lives and gave people more time without chemotherapy,” said Professor Nicholas Turner, Lead Study Author and Professor of Molecular Oncology at The Institute of Cancer Research, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust, London, United Kingdom. “These results give us confidence that this regimen could become the new standard of care in the first-line setting, having demonstrated a substantial benefit on patient outcomes and quality of life.” The Itovebi-based regimen demonstrated a meaningful OS benefit compared with palbociclib and fulvestrant alone.1 The median OS was 34.0 months (95% CI: 28.4–44.8) for people in the Itovebi arm, compared with 27.0 months (95% CI: 22.8–38.7) in the palbociclib and fulvestrant arm (stratified hazard ratio [HR]=0.67; 95% CI: 0.48–0.94, p-value=0.0190 [boundary=0.0469]).1 The benefit seen in delaying cancer progression was maintained in the updated analysis, with the Itovebi-based regimen showing a consistent improvement in median progression free survival of 17.2 months versus 7.3 months (stratified HR=0.42; 95% CI: 0.32-0.55) in the comparator arm.1 The Itovebi-based regimen also led to a statistically significant improvement in objective response rate (the percentage of patients whose signs of cancer completely disappear or their tumours shrink significantly after treatment) and ad-hoc exploratory analyses showed it substantially delayed time to chemotherapy by approximately two years (stratified HR=0.43; 95% CI: 0.30-0.60).1 No new safety signals were observed at the time of the final OS analysis, with a low discontinuation due to adverse events supporting good tolerability.1 The Itovebi-based regimen is approved in the United States, Switzerland, Canada, Australia, United Arab Emirates and China. In May, it received a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), with a final decision regarding the approval expected from the European Commission in the near future. Data from the INAVO120 study are currently under review with other global health authorities. Beyond INAVO120, Itovebi is currently being investigated in three company-sponsored phase III studies (INAVO121, INAVO122, INAVO123), all in PIK3CA-mutated, locally advanced or metastatic breast cancer in various combinations.4-7 We are exploring additional studies in breast cancer and other tumour types with the hope of providing the benefit of this targeted therapy to more people with PIK3CA mutations. Itovebi is an oral, targeted treatment that has been shown to provide well-tolerated and durable disease control in people with PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer, who often have a poor prognosis and are in urgent need of new treatment options.2,3,8 Itovebi has been designed to help minimise the overall burden and toxicity of treatment and is differentiated from other PI3K inhibitors due to its high potency and specificity for the PI3K alpha isoform versus other isoforms, and unique mechanism of action that facilitates the degradation of mutated PI3K alpha.9,10 The INAVO120 study [NCT04191499] is a phase III, randomised, double-blind, placebo-controlled study evaluating the efficacy and safety of Itovebi™ (inavolisib) in combination with palbociclib and fulvestrant versus placebo plus palbociclib and fulvestrant in people with PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer whose disease progressed during treatment or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for metastatic disease.4 The study included 325 patients, who were randomly assigned to either the investigational or control treatment arm.4 The primary endpoint is progression-free survival, as assessed by investigators, defined as the time from randomisation in the clinical trial to the time when the disease progresses, or a patient dies from any cause.4 Secondary endpoints include overall survival, objective response rate, and clinical benefit rate.4 Beyond INAVO120, Itovebi is currently being investigated in three additional company-sponsored phase III clinical studies in PIK3CA-mutated locally advanced or metastatic breast cancer in various combinations:5-7 in combination with fulvestrant versus alpelisib plus fulvestrant in HR-positive/HER2-negative breast cancer post cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and endocrine combination therapy (INAVO121; NCT05646862). in combination with pertuzumab plus trastuzumab for subcutaneous injection (SC) versus pertuzumab plus trastuzumab for SC and optional physician's choice of endocrine therapy as a maintenance treatment in HER2-positive disease (INAVO122; NCT05894239). in combination with CDK4/6 inhibitor and letrozole versus placebo plus a CDK4/6 inhibitor and letrozole in the first-line setting in PIK3CA-mutated HR-positive/HER2-negative, endocrine-sensitive breast cancer (INAVO123; NCT06790693). HR-positive breast cancer is the most prevalent type of all breast cancers, accounting for approximately 70% of cases.11,12 A defining feature of HR-positive breast cancer is that its tumour cells have receptors that attach to one or both hormones – oestrogen or progesterone – which can contribute to tumour growth. People diagnosed with HR-positive metastatic breast cancer often face the risk of disease progression and treatment side effects, creating a need for additional treatment options.12-14 The PI3K signalling pathway is commonly dysregulated in HR-positive breast cancer, often due to activating PIK3CA mutations, which have been identified as a potential mechanism of intrinsic resistance to standard of care endocrine therapy in combination with cyclin-dependent kinase 4/6 inhibitors.3 Roche has been advancing breast cancer research for more than 30 years with the goal of helping as many people with the disease as possible. Our medicines, along with companion diagnostic tests, have contributed to bringing breakthrough outcomes in human epidermal growth factor 2-positive and triple-negative breast cancers. As our understanding of breast cancer biology rapidly improves, we are working to identify new biomarkers and approaches to treatment for other subtypes of the disease, including oestrogen receptor-positive breast cancer, which is a form of hormone receptor-positive breast cancer, the most prevalent type of all breast cancers.11,12 Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice. For over 125 years, sustainability has been an integral part of Roche’s business. As a science-driven company, our greatest contribution to society is developing innovative medicines and diagnostics that help people live healthier lives. Roche is committed to the Science Based Targets initiative and the Sustainable Markets Initiative to achieve net zero by 2045. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. References [1] Turner NC, et al. INAVO120 Phase III trial final overall survival (OS) analysis of first-line inavolisib (INAVO)/placebo (PBO) + palbociclib (PALBO) + fulvestrant (FULV) in patients (pts) with PIK3CA-mutated, hormone receptor-positive (HR+), HER2-negative (HER2–), endocrine-resistant advanced breast cancer (aBC). Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, 2025 May 30-June 03; Chicago, USA. Abstract #1003. [2] Fillbrunn M, et al. PIK3CA mutation status, progression and survival in advanced HR+/HER2- breast cancer: a meta-analysis of published clinical trials. BMC Cancer. 2022;22(1):1002. [3] Anderson E, et al. A Systematic Review of the Prevalence and Diagnostic Workup of PIK3CA Mutations in HR+/HER2– Metastatic Breast Cancer. Int J Breast Cancer. 2020;2020:3759179. [4] ClinicalTrials.gov. A Study Evaluating the Efficacy and Safety of Inavolisib + Palbociclib + Fulvestrant vs Placebo + Palbociclib + Fulvestrant in Patients With PIK3CA-Mutant, Hormone Receptor-Positive, Her2-Negative, Locally Advanced or Metastatic Breast Cancer (INAVO120) [Internet; cited 2025 May]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT04191499. [5] ClinicalTrials.gov. A Study Evaluating the Efficacy and Safety of Inavolisib Plus Fulvestrant Compared With Alpelisib Plus Fulvestrant in Participants With HR-Positive, HER2-Negative, PIK3CA Mutated, Locally Advanced or Metastatic Breast Cancer Post CDK4/6i and Endocrine Combination Therapy (INAVO121) [Internet; cited 2025 May]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT05646862. [6] ClinicalTrials.gov. A Study to Evaluate the Efficacy and Safety of Inavolisib in Combination With Phesgo Versus Placebo in Combination With Phesgo in Participants With PIK3CA-Mutated HER2-Positive Locally Advanced or Metastatic Breast Cancer (INAVO122) [Internet; cited 2025 May]. Available from: https://classic.clinicaltrials.gov/ct2/show/NCT05894239. [7] ClinicalTrials.gov. A Study Evaluating the Efficacy and Safety of Inavolisib Plus CDK4/​6 Inhibitor and Letrozole vs Placebo + CDK4/​6i and Letrozole in Participants With Endocrine-Sensitive PIK3CA-Mutated, Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer (INAVO123) [Internet; cited 2025 May]. Available from: https://clinicaltrials.gov/study/NCT06790693. [8] Turner NC, et al. Inavolisib-Based Therapy in PIK3CA-Mutated Advanced Breast Cancer. NEJM. 2024;391(17):1584-96. [9] Juric D, et al. A phase I/Ib study of inavolisib (GDC-0077) in combination with fulvestrant in patients (pts) with PIK3CA-mutated hormone receptor-positive/HER2-negative (HR+/HER2–) metastatic breast cancer. Presented at San Antonio Breast Cancer Symposium, 2020 December 7-10; San Antonio, USA. Abstract #P5-17-05. [10] Hong R, et al. GDC-0077 is a selective PI3K alpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies. Cancer Res. 2018;78(4):4-14. [11] National Cancer Institute: Surveillance, Epidemiology and Ends Result Program. Cancer Stat Facts: Female Breast Cancer Subtypes [Internet; cited 2025 May]. Available from: https://seer.cancer.gov/statfacts/html/breast-subtypes.html. [12] Lim E, et al. The natural history of hormone receptor-positive breast cancer. Oncology (Williston Park). 2012;26(8):688-94,696. [13] Tomas R and Barrios CH. Optimal management of hormone receptor positive metastatic breast cancer in 2016. Ther Adv Med Oncol. 2015;7(6):304-20. [14] Galipeau N, et al. Understanding key symptoms, side effects, and impacts of HR+/HER- advanced breast cancer: qualitative study findings. J Patient-Rep Outcomes. 2019;3(1):10. The content above comes from the network. if any infringement, please contact us to modify.