雌激素受体阳性HER2阴性乳腺癌与其他亚型相比，发病比例最高，晚期患者容易对内分泌治疗耐药，即使联合CDK4/6抑制剂也是如此。根据目前的临床实践，治疗第一周期通常无法区分对药物有效和无效的患者。长期以来，影像检查一直是评定肿瘤疗效以及指导临床决策必不可少的工具，也常被用于估计无进展生存，这是此情况下不完美但被广泛采用的总生存替代指标。虽然如此，影像检查难以实时动态观察等局限性促使人们寻求替代和补充的方法。循环肿瘤DNA长期动态监测是近年来出现的新方法，可以通过微创血液检测解决这些局限性，并且用于指导治疗方案决策。循环肿瘤DNA是肿瘤细胞释放到血液循环的一部分游离DNA，过去主要被用于早期乳腺癌，因为体内循环肿瘤DNA一旦被检测出，可以提示复发转移风险高。晚期乳腺癌已经发生复发转移，循环肿瘤DNA已经到处都是，检测是否还有意义？

　　2025年7月4日，欧洲肿瘤内科学会官方期刊《肿瘤学年鉴》在线发表法国综合癌症中心联盟的PADA-1研究事后分析报告，首次对雌激素受体阳性HER2阴性晚期乳腺癌CDK4/6抑制剂联合内分泌治疗早期循环肿瘤DNA的预后意义进行评定。

  • PADA-1 (NCT03079011): PAlbociclib and Circulating Tumor DNA for ESR1 Mutation Detection
  • Official Title: Randomized, Open Label, Multicentric Phase III Trial to Evaluate the Safety and Efficacy of Palbociclib in Combination With HT Driven by ctDNA ESR1 Mutation Monitoring in ER+, HER2-negative Metastatic Breast Cancer Patients

　　该多中心非盲随机对照三期临床研究于2017年3月22日至2019年1月31日从法国83家医院入组年龄≥18岁、美国东部肿瘤学协作组体力状态评分0～2的雌激素受体阳性HER2阴性晚期乳腺癌女性1017例，给予哌柏西利＋芳香化酶抑制剂一线治疗并通过循环肿瘤DNA分析监测血液ESR1突变水平。随后，279例血液ESR1突变水平升高，其中病情尚未进展且签署知情同意书的172例按1∶1随机分组进行治疗：88例改用氟维司群＋哌柏西利，84例继续芳香化酶抑制剂＋哌柏西利。

　　本次事后分析对其中369例患者治疗前以及治疗早期（中位28天）对应血浆样本游离DNA进行497个基因检测，其中治疗前出现循环肿瘤DNA突变334例（91%），治疗第二周期出现突变279例（76%）。

　　单因素分析表明，治疗前循环肿瘤DNA水平具有预后价值：
  • 等位基因平均变异率每增加1%
  • 进展或死亡风险增加7%（风险比：1.07，95%置信区间：1.05～1.09，P<0.001）
  • 总死亡风险增加8%（风险比：1.08，95%置信区间：1.05～1.11，P<0.001）
  • 驱动体细胞突变数量每增加1%
  • 进展或死亡风险增加13%（风险比：1.13，95%置信区间：1.07～1.19，P<0.001）
  • 总死亡风险增加16%（风险比：1.16，95%置信区间：1.07～1.24，P<0.001）


　　多因素分析表明，治疗早期循环肿瘤DNA变化也与结局相关：
  • 两个时间点等位基因平均变异率都>0.5%且驱动体细胞突变数量每增加1%
  • 进展或死亡风险增加39%（风险比：1.39，95%置信区间：1.27～1.53，P<0.001）
  • 总死亡风险增加51%（风险比：1.51，95%置信区间：1.35～1.68，P<0.001）
  • 两个时间点等位基因平均变异率都增加且驱动体细胞突变数量每增加1%
  • 进展或死亡风险增加31%（风险比：1.31，95%置信区间：1.19～1.44，P<0.001）
  • 总死亡风险增加10%（风险比：1.10，95%置信区间：1.02～1.18，P=0.02）


　　将循环肿瘤DNA的治疗前特征结合治疗前后变化特征，建立循环肿瘤DNA风险评分，根据多因素模型分析，具有独立于实体肿瘤疗效评价标准的预后能力，对于111例患者（30%）组成的测试集，循环肿瘤DNA风险评分高低相比：
  • 进展或死亡风险增加86%（风险比：1.86，95%置信区间：1.16～2.97，P=0.009）
  • 总死亡风险增加高达310%（风险比：4.10，95%置信区间：1.93～8.72，P<0.001）


　　将循环肿瘤DNA风险评分结合临床风险评分，与单用临床风险评分相比：
  • 无进展生存C指数：64.7%比59.3%（标准差：2.5比2.2，P=0.027）
  • 总生存C指数：70.0%比60.3%（标准差：3.4比4.2，P=0.035）


　　因此，该前瞻研究事后分析结果表明，对于雌激素受体阳性HER2阴性晚期乳腺癌，CDK4/6抑制剂哌柏西利＋内分泌治疗早期循环肿瘤DNA的变化可预测无进展生存和总生存，循环肿瘤DNA风险评分可改进传统的实体肿瘤疗效评价标准和临床风险评分，提倡临床实践将循环肿瘤DNA作为预后生物标志物。

晚期乳腺癌内分泌治疗预后早知道
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Ann Oncol. 2025 Jul 4. IF: 65.4

Prognostic significance of early on-treatment evolution of circulating tumor DNA in advanced ER+/HER2- breast cancer.

Mamann A, Pradat Y, Bidard FC, Delaloge S, Cabel L, Faull I, Marques S, Bachelot T, Dalenc F, De La Motte Rouge T, Pistilli B, Samaniego J, Frenel JS, Levy C, Ferrero JM, Sabatier R, Ladoire S, Chakiba C, Hardy AC, Lemonnier J, Mahi Y, Andre F, Cournede PH, Michiels S, Bernard E.

CentraleSupélec, Université Paris-Saclay, Gif-sur-Yvette, France; Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif, France; Gustave Roussy, Villejuif, France; Gustave Roussy, Université Paris-Saclay, France; Paris-Saclay University, Saint-Cloud, France; Institut Curie, Saint-Cloud, France; Guardant Health, Europe; Unicancer, Paris, France; Centre Léon Bérard, Lyon, France; Cancer Research Center Toulouse, Toulouse, France; Oncopole Claudius Regaud, Toulouse, France; Paul Sabatier University, Toulouse, France; Centre Eugène Marquis, Rennes, France; Institut de Cancerologie de L’Ouest, Saint-Herblain, France; Nantes Université, Inserm, Nantes, France; Centre Francois Baclesse, Caen, France; Centre Antoine Lacassagne, Nice, France; Institut Paoli Calmettes, Aix-Marseille Université, Marseille, France; Centre Georges Francois Leclerc, Dijon, France; Institut Bergonié, Bordeaux, France; Centre Armoricain d’Oncologie, Plérin, France.

HIGHLIGHTS
  • In 369 ER+/HER2- breast cancer patients, 91% had circulating tumor DNA (ctDNA) mutations at baseline and 76% at cycle 2 of treatment.
  • Baseline and dynamic ctDNA metrics independently predicted progression-free survival and overall survival.
  • A ctDNA-based risk model stratified patients in low- and high- risk groups, independent from RECIST.
  • Integrating ctDNA features with clinical variables improved survival discrimination.

BACKGROUND: Patients with advanced estrogen receptor-positive, HER2-negative (ER+/HER2-) breast cancer commonly develop resistance to treatment with hormone therapy and cyclin-dependent kinases 4/6 (CDK4/6) inhibitors. Responders cannot be distinguished from non-responders after the first cycle of treatment under current practice. We assessed circulating tumor DNA (ctDNA) measures at early time-points as prognostic markers.

PATIENTS AND METHODS: Paired plasma samples were collected at baseline and early on-treatment (median 28 days) from 369 patients with advanced ER+/HER2- breast cancer treated in the PADA-1 trial with hormone therapy and a CDK4/6 inhibitor. Cell-free DNA was profiled with a 497-gene panel (Guardant360 LDT).

RESULTS: Baseline ctDNA levels including the mean variant allele frequency (VAF) (progression-free survival [PFS] HR = 1.07 [1.05, 1.09] P<0.001, overall survival [OS] HR = 1.08 [1.05, 1.11] P<0.001) and the number of driver somatic mutations (PFS HR = 1.13 [1.07, 1.19], P<0.001 and OS HR = 1.16 [1.07, 1.24], P<0.001) were prognostic. Early on-treatment ctDNA dynamics were also associated with outcomes, including the number of driver somatic mutations with VAF>0.5% at both timepoints (PFS HR = 1.39 [1.27,1.53] P<0.001 and OS HR = 1.51 [1.35,1.68] P<0.001) and the number of driver somatic mutations with a VAF increase (PFS HR = 1.31 [1.19,1.44] P<0.001 and OS HR = 1.10 [1.02,1.18] P=0.02). A ctDNA-based risk model incorporating baseline and dynamic ctDNA features was independently prognostic from RECIST in multivariable models (Test set: OS HR = 4.10 [1.93,8.72], P<0.001, PFS HR = 1.86 [1.16,2.97], P=0.009). The integration of ctDNA features into a clinical model improved survival discrimination for PFS (C-index 64.7% [s.d. 2.5] for a ctDNA & clinical model vs. 59.3% [s.d. 2.2] for a clinical only model, p=0.027) and for OS (C-index 70.0% [s.d 3.4] vs. 60.3% [s.d. 4.2], p=0.035).

CONCLUSIONS: Early on-treatment evolution of ctDNA is prognostic for both PFS and OS in advanced ER+/HER2- breast cancer. A ctDNA-based risk model improves upon traditional RECIST and clinical parameters, advocating for ctDNA as a prognostic biomarker in clinical practice.

KEYWORDS: ER+/HER2- advanced breast cancer, circulating tumor DNA, on-treatment dynamics, survival analysis, prognostic model, risk score

DOI: 10.1016/j.annonc.2025.06.015