晚期乳腺癌一线治疗主动换药时机

　　目前，对于激素受体阳性HER2阴性乳腺癌转移患者，当肿瘤进展时更换治疗方案已经成为标准。临床研究的肿瘤进展定义根据RECIST标准，而临床实践则根据其他指标，其中许多指标未被RECIST纳入，例如更细微的影像学变化、体检发现、肿瘤标志物升高或癌症相关症状加重。因此，在临床上，即使影像学显示病情稳定，如果出现症状进展，也可以考虑更换治疗方案；或者，即使出现无症状寡转移进展，也可继续使用相同的治疗方案。这些方法体现了控制肿瘤相关症状、维持生活质量以及应对慢性疾病的核心目标，因为患者需要寻求多种治疗选择。

　　许多激素受体阳性HER2阴性乳腺癌由于雌激素受体编码基因ESR1继发突变而对芳香化酶抑制剂产生耐药，加之口服选择性雌激素受体降解剂（SERD）对ESR1突变乳腺癌具有治疗优势，这些发现促使多项研究探索SERD治疗的最佳起始时机。例如，SERENA-6是首个前瞻采用外周血液循环肿瘤DNA监测临床进展前继发耐药突变的全球注册研究，并据此指导激素受体阳性晚期乳腺癌患者的治疗方案调整。在一线治疗期间，若出现ESR1突变，则将芳香化酶抑制剂改换为口服SERD卡米司群，并继续用CDK4/6抑制剂，中期分析显示，患者无进展生存显著改善。

• SERENA-6 (NCT04964934): Phase III Study to Assess AZD9833+ CDK4/6 Inhibitor in HR+/HER2-MBC With Detectable ESR1m Before Progression

• Official Title: A Phase III, Double-blind, Randomised Study to Assess Switching to AZD9833 (a Next Generation, Oral SERD) + CDK4/6 Inhibitor vs Continuing Aromatase Inhibitor (Letrozole or Anastrozole)+ CDK4/6 Inhibitor in HR+/HER2-MBC Patients With Detectable ESR1Mutation Without Disease Progression During 1L Treatment With Aromatase Inhibitor+ CDK4/6 Inhibitor- A ctDNA Guided Early Switch Study

• Sponsor: AstraZeneca

　　2026年7月14日，英国《柳叶刀》肿瘤学分册在线发表SERENA-6研究ESR1突变监测汇总结果、无进展生存和安全性数据更新、再次无进展生存更长时间随访最终分析以及不同治疗方案ESR1突变循环肿瘤DNA动态变化探索性分析，从而对这一新的治疗策略进行全面阐述。

　　该随机分组双盲安慰剂对照三期临床研究于2021年6月30日至2024年6月14日从23个国家或地区264家医院和癌症中心入组女性（无论是否绝经）或男性、年龄≥18岁、雌激素受体阳性HER2阴性局部晚期或远处转移乳腺癌、芳香化酶抑制剂联合CDK4/6抑制剂一线治疗至少6个月、美国东部肿瘤学协作组（ECOG）体力状态评分0或1的患者，每2至3个月对循环肿瘤DNA进行ESR1突变检测，同时进行常规临床评定。循环肿瘤DNA存在ESR1突变且尚未发现放射学进展的患者按1比1随机分组，采用区组随机化方法（按疾病部位、ESR1突变检测时间、从开始用芳香化酶抑制剂联合CDK4/6抑制剂至随机分组的时间以及CDK4/6抑制剂进行分层）分别口服卡米司群（75毫克，每天1次）联合CDK4/6抑制剂（原剂量）或继续口服芳香化酶抑制剂（阿那曲唑1毫克或来曲唑2.5毫克，每天1次）联合CDK4/6抑制剂（原剂量）治疗。哌柏西利和瑞波西利的给药方案为：每28天每天口服1次连续21天然后停药7天；阿贝西利的给药方案为：每28天每天口服2次。SERENA-6研究样本量旨在确保主要终点（研究者根据RECIST1.1标准评定的无进展生存）和关键次要终点（研究者评定的再次无进展生存，即从随机分组至首次后续治疗后疾病进展或死亡的时间）都有足够的统计学效力。对于已发生首次疾病进展的患者，每8至12周进行扫描以评定再次无进展生存。本次数据截止时更新的无进展生存分析为描述性分析，疗效分析纳入全部随机分组的患者（意向治疗分析）。

　　该研究共筛查3325例患者，其中3256例患者一线治疗期间进行至少1次ESR1基因突变检测，截至筛查结束时，共有548例患者的ESR1基因突变检测结果阳性。其中315例患者（女性312例占99%；白人199例占63%，亚裔73例占23%，黑人或非洲裔美国人6例占2%，其他种族、未报告种族或种族数据缺失37例占12%）被随机分为2组：卡米司群联合CDK4/6抑制剂组157例，芳香化酶抑制剂联合CDK4/6抑制剂组158例。

　　数据截至2026年1月2日，中位随访23.5个月（四分位17.9至32.1），卡米司群联合CDK4/6抑制剂组与芳香化酶抑制剂联合CDK4/6抑制剂组相比：

• 无进展生存：中位16.8个月比9.2个月（95%置信区间：14.7～19.4、7.2～9.7）

• 进展或死亡风险：减少55%（风险比：0.45，95%置信区间：0.34～0.59，名义P<0.0001）与中期分析结果一致

• 再次无进展生存：中位25.7个月比19.1个月（95%置信区间：20.4～30.3、16.8～21.0）

• 进展或死亡风险：减少37%（风险比：0.63，95%置信区间：0.46～0.86，P=0.0037）

• 未化疗或抗体缀合药物治疗生存：中位22.6个月比18.7个月（95%置信区间：19.3～30.9、15.8～22.1）

• 死亡风险：减少36%（风险比：0.64，95%置信区间：0.47～0.87，名义P=0.0038）

• 总生存：中位41.2个月比40.2个月（95%置信区间：35.5～未达、36.5～43.3）

• 死亡风险：减少13%（风险比：0.87，95%置信区间：0.57～1.30）

• 总体健康状况和生活质量恶化风险：减少52%（风险比：0.48，95%置信区间：0.31～0.76，名义P<0.0001）

• 3～4级中性粒细胞减少发生率：27%比17%

• 3～4级中性粒细胞计数下降发生率：23%比19%

• 严重不良事件报告率：15%比19%

　　研究者认为有3例死亡可能与治疗相关（卡米司群联合CDK4/6抑制剂组猝死1例可能与卡米司群相关，芳香化酶抑制剂联合CDK4/6抑制剂组脓毒症1例可能与阿贝西利相关、肠梗阻1例可能与来曲唑相关）。

　　值得注意的是对照组158例发生再次无进展生存事件患者仅有8例由于病情迅速恶化而未进行后续治疗，这表明该组患者经过筛选，病情进展相对缓慢。

　　因此，该研究结果表明，对于雌激素受体阳性HER2阴性局部晚期或远处转移乳腺癌芳香化酶抑制剂联合CDK4/6抑制剂联合治疗期间患者，在放射学进展之前检测到ESR1突变时，改换卡米司群联合CDK4/6抑制剂与继续芳香化酶抑制剂联合CDK4/6抑制剂相比，可带来持续的无进展生存获益，并转化为再次无进展生存的统计学显著改善。这些结果进一步支持在检测到ESR1突变后，就将内分泌治疗方案从芳香化酶抑制剂改换为卡米司群，并继续用全球批准的任何一种CDK4/6抑制剂，以延长一线治疗的获益。

　　对此，美国哈佛大学德纳法伯研究院和意大利米兰大学欧洲癌症研究院的学者发表同期评论：晚期乳腺癌改换治疗方案应该立刻还是以后？

　　上述来自不同临床终点的研究结果应该如何指导临床实践？值得注意的是，SERENA-6研究提出两个重要问题：口服SERD的优越性和靶向分子进展，但是并未比较检测到ESR1突变时改换至卡米司群治疗与临床或影像学进展时开始口服SERD治疗的比较，如此设计将比较研究组与对照组继续原治疗并在疾病进展时开始用卡米司群治疗的无进展生存。

　　由于目前晚期乳腺癌患者可选择的治疗方案众多，人们越来越关注将再次无进展生存作为评定特定治疗方案的终点指标。不过，由于缺乏标准定义，且缺乏与统一二线治疗方案的交叉比较，再次无进展生存的解读仍然困难。事实上，SERENA-6研究的卡米司群组再次无进展生存中位时间反而长于再次后续治疗中位时间（25.7个月比21.7个月），该差异反映再次无进展生存定义的局限性。此外，在进行再次无进展生存分析期间，研究组患者在随机分组后可能接受两种不同的药物治疗，而对照组患者仅接受一种新的不同药物治疗，这可能导致再次无进展生存差异被夸大，从而使研究组获益。在该情况下，未化疗或抗体缀合药物治疗生存可能代表更好的终点，考虑到这些药物的给药方式及其副作用，对于患者而言可能是有价值的衡量标准，但是由于中位生存仅延长3.9个月，临床影响很难知道，而且此类决定很大程度上取决于患者和临床医生的偏好和选择。

　　延缓生活质量恶化是至关重要的患者获益。不过，方法学问题也使数据解读更困难，包括卡米司群相关光幻觉和芳香化酶抑制剂相关关节痛缓解可能导致研究参与者功能性地揭盲、总体健康状况和生活质量恶化的快速出现以及20周后问卷调查的依从性低。

　　关于成本分析应该如何影响人群临床实践，目前仍然存在争议，因为根据CDK4/6抑制剂初始治疗和预设二线治疗方案的随机化设计相比，根据ESR1突变出现时的随机化无法代表整个一线治疗人群的分布情况。在SERENA-6研究中，不计药物成本，要预防2年时发生1例无进展生存事件，需要筛查18例患者并治疗5例，假设ESR1突变发生率为35%（其中80%不伴影像学进展），从治疗开始到检测到ESR1突变的中位时间为22个月，每位患者需进行4.5次检测，每次检测费用为5000美元，那么循环肿瘤DNA检测的估计成本高达40.5万美元。

　　SERENA-6研究标志着液体活检迈向临床实践指导和疾病进展预测新时代的关键一步，该研究的设计经验对于帮助临床医生为患者取得最佳治疗效果至关重要。

Lancet Oncol. 2026 Jul 14. IF: 33.7

Switching to camizestrant at ESR1 mutation emergence before disease progression during first-line treatment of hormone receptor-positive advanced breast cancer (SERENA-6): extended analysis of a double-blind, placebo-controlled, randomised, phase 3 trial.

Turner NC, Mayer EL, Park YH, Janni W, Ma C, Cristofanilli M, Bianchini G, Kalinsky K, Iwata H, Chia S, Brufsky AM, Fasching PA, Nowecki Z, Pascual J, Karadurmus N, Gal-Yam E, Chung WP, Im SA, Zambelli A, Dalenc F, Oliveira M, Ishiguro H, Huang CS, Klinowska T, Fox S, Morrow C, Robert L, Huang-Bartlett C, Bidard FC.

Royal Marsden Hospital, London, UK; AstraZeneca, Cambridge, UK; Dana-Farber Cancer Institute, Boston, MA, USA; Washington University School of Medicine, Saint Louis, MO, USA; Weill Cornell Medicine/NewYork-Presbyterian Brooklyn Methodist Hospital, New York, NY, USA; Winship Cancer Institute, Atlanta, GA, USA; UPMC Magee-Women's Hospital, Pittsburgh, PA, USA; AstraZeneca, Gaithersburg, MD, USA; Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Seoul National University Hospital, Cancer Research Institute, Seoul National University, Seoul, Korea; Universitatsklinikum Ulm, Ulm, Germany; University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany; IRCCS Ospedale San Raffaele, Milan, Italy; IRCCS Istituto Clinico Humanitas, Milan, Italy; Nagoya City University, Nagoya, Japan; Saitama Medical University International Medical Center, Hidaka, Japan; BC Cancer Agency, Vancouver, BC, Canada; Narodowy Instytut Onkologii im Marii Sklodowskiej-Curie, Warsaw, Poland; Hospital Universitario Virgen de la Victoria, IBIMA, Málaga, Spain; Vall d'Hebron University Hospital, Barcelona, Spain; AstraZeneca, Barcelona, Spain; Gülhane Training and Research Hospital, University of Health Sciences, Ankara, Turkey; Sheba Medical Center, Tel-Hashomer, Israel; National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, China; National Taiwan University Hospital, Taipei, Taiwan, China; Oncopole Claudius Regaud, IUCT, Toulouse, France; Institut Curie, Paris, France.

BACKGROUND: SERENA-6 is, to our knowledge, the first global registrational study to use prospective circulating tumour DNA (ctDNA) monitoring to identify the emergence of an acquired resistance mutation before clinical progression and then direct a change in therapy in patients with hormone receptor-positive advanced breast cancer. Switching to camizestrant from aromatase inhibitor with continued cyclin-dependent kinase (CDK) 4/6 inhibitor at ESR1 mutation emergence during first-line therapy significantly improved progression-free survival at interim analysis. We report comprehensive results from ESR1 mutation surveillance in SERENA-6, updated progression-free survival, final analysis of second progression-free survival with longer follow-up, and an exploratory analysis of ESR1 mutation ctDNA dynamics on treatment to give a comprehensive report of this new treatment strategy.

METHODS: This double-blind, placebo-controlled, randomised, phase 3 trial was conducted at 264 hospitals and cancer centres in 23 countries and enrolled women with any menopausal status, or men, aged 18 years or older who were receiving first-line treatment with aromatase inhibitor plus CDK4/6 inhibitor for at least 6 months for oestrogen receptor-positive, HER2-negative locally advanced or metastatic breast cancer. Patients were required to have an Eastern Cooperative Oncology Group performance status score of 0 or 1. Eligible patients were enrolled and had ctDNA tested for ESR1 mutation every 2-3 months, coinciding with routine clinical assessments, using the Guardant360 CDx assay. Patients with an ESR1 mutation in ctDNA and without radiological progression were randomly assigned (1:1) using block randomisation (stratified by disease site, time of ESR1 mutation detection, time from initiation of aromatase inhibitor plus CDK4/6 inhibitor to randomisation, and CDK4/6 inhibitor) to switch to camizestrant (75 mg orally once daily) with continued CDK4/6 inhibitor (orally at the same dose) or to continue receiving aromatase inhibitor (anastrozole 1 mg or letrozole 2.5 mg orally once daily) plus CDK4/6 inhibitor (orally at the same dose as was received during ESR1 mutation surveillance phase). Palbociclib and ribociclib were dosed, orally, once daily for 21 days and then 7 days with no treatment in 28-day cycles, while abemaciclib was dosed, orally, twice daily every day in 28-day cycles. The SERENA-6 sample size was determined to ensure sufficient power for both the primary endpoint (investigator-assessed according to RECIST 1.1 progression-free survival) and the key secondary endpoint of investigator-assessed second progression-free survival (time from randomisation to disease progression after first subsequent therapy or death). For patients who had experienced a first progression, scans to assess second progression-free survival were conducted every 8-12 weeks. Updated progression-free survival analysis at this data cutoff was descriptive. Efficacy analyses included all randomly assigned patients (intention to treat). This study is registered with ClinicalTrials.gov, NCT04964934, and is ongoing.

FINDINGS: From June 30, 2021, to June 14, 2024, 3325 patients were screened and 3256 patients received at least one ESR1 mutation test during first-line therapy and 548 patients had a positive ESR1 mutation test by the time of screening closure. 315 patients (312 [99%] female; 199 [63%] White, 73 [23%] Asian, six [2%] Black or African American, 37 [12%] other, not reported, or with missing race data) were randomly assigned: 157 to camizestrant plus CDK4/6 inhibitor and 158 to aromatase inhibitor plus CDK4/6 inhibitor. After a median follow-up of 23.5 months (IQR 17.9-32.1; data cutoff Jan 2, 2026), median progression-free survival was 16.8 months (95% CI 14.7-19.4) with camizestrant plus CDK4/6 inhibitor versus 9.2 months (7.2-9.7) with aromatase inhibitor plus CDK4/6 inhibitor (hazard ratio [HR] 0.45 [95% CI 0.34-0.59]; nominal p<0.0001); consistent with previous interim analysis. Median second progression-free survival was 25.7 months (95% CI 20.4-30.3) with camizestrant plus CDK4/6 inhibitor versus 19.1 months (16.8-21.0) with aromatase inhibitor plus CDK4/6 inhibitor; HR 0.63 (0.46-0.86; p=0.0037). The most common grade 3-4 adverse events were neutropenia (42 [27%] patients in the camizestrant plus CDK4/6 inhibitor group vs 27 [17%] patients in the aromatase inhibitor plus CDK4/6 inhibitor group) and neutrophil count decreased (35 [23%] vs 30 [19%] patients), while serious adverse events were reported in 24 (15%) versus 29 (19%) patients. There were three deaths considered by the trial investigator to be possibly related to treatment (camizestrant plus CDK4/6 inhibitor group: sudden death, possibly related to camizestrant; aromatase inhibitor plus CDK4/6 inhibitor group: sepsis, possibly related to abemaciclib, and ileus, possibly related to letrozole).

INTERPRETATION: Switching to camizestrant plus CDK4/6 inhibitor at ESR1 mutation emergence, versus continuing aromatase inhibitor plus CDK4/6 inhibitor, resulted in sustained progression-free survival benefit that translated into a statistically significant improvement in second progression-free survival. These results further support switching endocrine treatment to camizestrant from aromatase inhibitor upon detection of ESR1 mutation, with continuation of any of the globally approved CDK4/6 inhibitor, to extend first-line treatment benefit.

FUNDING: AstraZeneca

PMID: 42442380

DOI: 10.1016/S1470-2045(26)00287-1

Lancet Oncol. 2026 Jul 14. IF: 33.7

Now or later? Switching therapies in metastatic breast cancer.

Valenza C, Regan MM, Burstein HJ.

Dana-Farber Cancer Institute, Boston, MA, USA; Harvard University, Boston, MA, USA; European Institute of Oncology, IRCCS, Milan, Italy; University of Milan, Milan, Italy.

In contemporary management of patients with hormone receptor-positive, HER2-negative metastatic breast cancer, it is standard to switch therapies at tumour progression, defined by RECIST criteria in clinical trials, and by other measures (many, ironically, considered non-measurable by RECIST) in clinical practice, including subtler radiological changes, findings on examination, rising tumour markers, or increased symptoms related to cancer. Accordingly, in the clinic, a treatment change can be considered for symptomatic progression despite radiologically stable disease, or the same treatment might be continued beyond asymptomatic oligoprogression. These approaches reflect the core goals of controlling tumour-related symptoms, preserving quality of life, and navigating a chronic disease where patients will pursue multiple therapeutic options.

PMID: 42442379

DOI: 10.1016/S1470-2045(26)00332-3

来源：SIBCS

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