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HR阳性阴性早期乳腺癌具有高度异质性,因此需要更深入地了解其生物学特性,以便提供个体化治疗。由于传统预后标志物的预测价值较低,化疗过度或不足是目前面临的最常见挑战之一。根据TAILORx、MINDACT和RxPONDER研究,21基因和70基因表达检测一致表明,对于50岁以上0至3枚淋巴结阳性且基因表达检测评分为中低风险患者,内分泌治疗联合化疗与单用内分泌治疗(芳香化酶抑制剂为主)相比获益相似。不过,这些结果对于年轻患者似乎不太一致。对于50岁以下绝经前女性,只有基因表达检测评分为极低风险且淋巴结阴性患者,内分泌治疗联合化疗与单用内分泌治疗相比获益相似。对于基因表达检测评分为中风险且淋巴结阴性或基因表达检测评分为低风险且淋巴结1期患者,内分泌治疗联合化疗与单用内分泌治疗(他莫昔芬为主)相比,生存获益显著。这些试验仅有大约20%至30%的年轻患者(即使淋巴结阳性病例)接受卵巢功能抑制剂联合芳香化酶抑制剂或他莫昔芬治疗。然而,对于复发风险较高的绝经前女性,内分泌治疗联合卵巢功能抑制剂与单用他莫昔芬相比,已被证实复发风险较低且生存率较高,疗效至少与较旧的化疗方案相似。因此,目前尚不清楚年轻女性化疗获益能否归因于预后良好的化疗所致闭经,尤其对于卵巢储备功能下降的45岁至50岁患者,或者是否源于年轻女性和年老女性的早期乳腺癌生物学显著差异,即使基因表达谱风险特征相似。
根据POETIC研究和荟萃分析,术前短期(2至4周)内分泌治疗后Ki67低表达与高表达患者相比,复发和死亡风险显著较低。因此,西德研究组开展ADAPT-HR+/HER2-和ADAPTcycle研究,将基因表达风险评分与内分泌治疗后Ki67结合,构建可靠且可行的个体化内分泌疗效指标,对HR阳性阴性早期乳腺癌临床高风险患者进行分层,以更好指导术后治疗决策,选择术后治疗方案:化疗、内分泌治疗或内分泌治疗联合CDK4/6抑制剂瑞波西利。ADAPT-HR+/HER2-方案对于21基因复发评分≤25、0至3枚淋巴结阳性且内分泌治疗后Ki67低表达患者生存结局极佳,且与年龄和绝经状态无关;而同组内分泌治疗后Ki67高表达患者高剂量密集化疗效果较差。值得注意的是,内分泌治疗后Ki67高表达且复发评分较高,还被ADAPT-HR+/HER2-研究证实可预测术前化疗后病理完全缓解。
ADAPT-HR+/HER2- (NCT01779206): Adjuvant Dynamic Marker - Adjusted Personalized Therapy Trial Optimizing Risk Assessment and Therapy Response Prediction in Early Breast Cancer
ADAPTcycle (NCT04055493): Adjuvant Dynamic Marker - Adjusted Personalized Therapy Comparing Endocrine Therapy Plus Ribociclib Versus Chemotherapy in Intermediate Risk, HR+/HER2- Early Breast Cancer
2026年4月16日,欧洲肿瘤内科学会官方期刊《肿瘤学年鉴》在线发表西德研究组对ADAPT-HR+/HER2-和ADAPTcycle研究合计7914例患者术前短期内分泌疗效预测指标的分析报告。
两项研究治疗分配依据:术前2至4周标准内分泌治疗后Ki67、21基因复发评分和淋巴结状态。ADAPT-HR+/HER2-研究3675例(年龄≤50岁且绝经前1250例,年龄>50岁或绝经后2425例)患者:如果淋巴结0至1期且21基因复发评分为0至11分、21基因复发评分为12至25分且术前内分泌治疗后Ki67≤10%,那么术后单用内分泌治疗。ADAPTcycle研究4239例(年龄≤50岁1336例,年龄>50岁2903例)患者:如果淋巴结0至1期且21基因复发评分>25分且术前内分泌治疗后Ki67≤10%、21基因复发评分<25分且术前内分泌治疗后Ki67>10%、淋巴结2至3期且21基因复发评分≤25分且术前内分泌治疗后Ki67≤10%,那么随机分入术后化疗组或芳香化酶抑制剂+瑞波西利组。通过多变量逻辑回归模型确定内分泌治疗效果的预测因素。
结果,芳香化酶抑制剂(年龄>50岁或绝经后)与他莫昔芬(年龄≤50岁且绝经前)相比,术前内分泌治疗后Ki67≤10%比例较高:
ADAPT-HR+/HER2-研究:81.4%比40.1%
ADAPTcycle研究:76.7%比34.7%
对于绝经前患者,卵巢功能抑制剂可进一步提高术前内分泌治疗后Ki67≤10%比例。绝经前患者与绝经后患者相比,卵巢功能抑制剂+芳香化酶抑制剂治疗后Ki67≤10%比例相似。
内分泌治疗后Ki67≤10%预测因素包括:
芳香化酶抑制剂(绝经前卵巢功能抑制剂)
年龄>50岁
21基因复发评分
基线Ki67水平较低
雌激素受体(根据免疫组织化学检测)表达较高
HER2(根据21基因检测)表达较高
ADAPT-HR+/HER2-研究术前内分泌治疗后Ki67≤10%与>10%患者相比,5年远处无病生存率显著较高,即使淋巴结0至1期21基因复发评分>25分化疗患者(87.0%比80.7%)并且仅略低于21基因复发评分12至25分患者。
因此,该研究结果表明,虽然HR阳性阴性早期乳腺癌绝经后患者(大多接受芳香化酶抑制剂治疗)与年轻患者相比术前内分泌治疗后Ki67≤10%比例较高,但是接受卵巢功能抑制剂+芳香化酶抑制剂治疗的年轻患者与绝经后患者相比术前内分泌治疗后Ki67≤10%比例相似,这表明治疗才是造成该差异的原因,而非生物学因素。将术前内分泌治疗后Ki67≤10%比例与基因表达检测相结合,可能有助于更多管腔型早期乳腺癌患者避免化疗。
年轻乳腺癌患者的肿瘤更凶险、预后更差,这几乎已经成为临床常识,一度被归咎于生物学差异。但是,西德研究协作组对两项研究将近8000例患者进行分析,用大数据给了我们一个完全不同的剧本:年轻患者疗效差,问题可能不在肿瘤本身,而在我们给的内分泌治疗火力不足。绝经后患者单用芳香化酶抑制剂与年轻患者单用他莫昔芬,内分泌疗效翻倍。当给年轻患者加上卵巢功能抑制剂这个开关,再联合芳香化酶抑制剂,疗效几乎追平绝经后患者。这意味着我们通过优化治疗策略,为年轻患者装上疗效时光机,可能让她们内分泌疗效穿越到绝经后。这背后是深刻的启示:我们常常急于给现象贴标签:年轻所以难治,但是真正的智慧在于追问:是不是我们的方法还没用对?该研究用近乎完美的数据告诉我们,对于HR阳性HER2阴性乳腺癌年轻患者,强化内分泌治疗(卵巢功能抑制剂+芳香化酶抑制剂)是打开疗效穿越之门的钥匙。该研究还提供两个精准的预测指标:一是术后Ki67,二是21基因复发评分。结合这两个指标,医生就能最大程度地找出那些即使不用化疗也能获得极佳生存的患者。该研究的核心并非发现新药,而是重塑临床思路:从根据年龄猜预后,转向根据术前疗效决定术后治疗策略,让避免过度化疗从美好的愿望变成有清晰路标可循的实践路径,这或许就是现代精准医疗送给患者最实在的礼物。
Ann Oncol. 2026 Apr 16. IF: 65.4
Clinical and molecular biomarkers for prediction of endocrine response after short preoperative endocrine therapy in the WSG ADAPT-HR+/HER2- and ADAPTcycle trials (N=7914).
Gluz O, Nitz U, Christgen M, Kuemmel S, Braun M, Thill M, Wuerstlein R, Link T, Aktas B, Lüdtke-Heckenkamp K, Zaiss M, Bjelic-Radisic V, Just M, Veselinovic K, Vincent M, Baehner R, Wujak L, Warm M, Schumacher C, Schem C, Forstbauer H, Krauss K, Hoffmann O, Graeser M, Hartkopf A, Kates R, zu Eulenburg C, Józwiak K, Burmeister S, Schmid P, Kreipe HH, Harbeck N; WSG ADAPT investigators.
West German Study Group, Moenchengladbach, Germany; Ev. Hospital Bethesda, Moenchengladbach, Germany; University Clinics Cologne, Cologne, Germany; Hannover Medical School, Hannover, Germany; Clinics Essen-Mitte, Essen, Germany; Charité - University Medicine Berlin, Berlin, Germany; Rotkreuz Clinics Munich, Munich, Germany; AGAPLESION Markus Hospital, Frankfurt, Germany; LMU University Hospital Munich, Munich, Germany; Carl Gustav Carus Faculty of Medicine and University Hospital, Dresden, Germany; National Center for Tumor Diseases (NCT), Dresden, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany; German Cancer Consortium (DKTK), Dresden, Germany; University Clinics Leipzig, Women's Clinic, Leipzig, Germany; University Hospital of Essen, Essen, Germany; Niels Stensen-Kliniken, Georgsmarienhuette, Germany; Clinic for Interdisciplinary Oncology & Hematology GbR, Freiburg, Germany; Helios University Hospital Wuppertal, University Witten/Herdecke; Wuppertal, Germany; Oncological Specialized Medical Practice Bielefeld, Bielefeld, Germany; University hospital Ulm, Ulm, Germany; Kliniken der Stadt Koln gGmbH, Cologne, Germany; Exact Sciences, Redwood City, California, USA; Municipal Hospital Holweide, Cologne, Germany; St. Elisabeth Hospital, Cologne, Germany; Hospital Jerusalem, Hamburg, Germany; Oncology Practice Network Troisdorf, Troisdorf, Germany; University Witten/Herdecke, Witten, Germany; University Hospital Tuebingen, Tuebingen, Germany; University Medical Center Hamburg, Hamburg, Germany; Brandenburg Medical School Theodor Fontane, Neuruppin, Germany; Queen Mary University of London, London, United Kingdom.
HIGHLIGHTS
ET-response is a robust parameter, as similar ET-response rates were observed in two large phase III trials.
Low post-endocrine Ki67 levels are associated with improved outcomes in N0-1 HR+/HER2- eBC in all RS subgroups
AI use (+OFS), age >50, low RS and baseline Ki67 levels independently predict response to endocrine therapy
Higher estrogen receptor (by IHC) and HER2 mRNA levels are associated with endocrine response
Endocrine response assessment together with gene expression analysis optimizes patient selection for chemotherapy omission
BACKGROUND: Low Ki67 after short preoperative endocrine treatment (ET) indicates a favorable prognosis in HR+/HER2- early breast cancer (eBC). We investigated predictors of ET-response in the WSG ADAPT-HR+/HER2- and ADAPTcycle trials.
PATIENTS AND METHODS: ET-response (Ki67 ≤10%) after 2-4-week standard ET, recurrence score (RS), and nodal status were used for treatment allocation. In ADAPT-HR+/HER2-, clinical high-risk patients received ET-alone if N0-1 and RS 0-11 or RS 12-25 and ET-response. In ADAPTcycle, N0-1 patients with RS>25 and ET-response and those with RS<25 and e.g., ET-non-response, N2-3 patients with RS≤25 and ET-response, were randomized to (neo)adjuvant chemotherapy or aromatase inhibitor (AI)+ribociclib. Predictors of ET-response were identified through multivariable logistic regression models.
RESULTS: 3,675 patients from ADAPT-HR+/HER2- (≤50 years and premenopausal, ≤50y: N=1,250; >50 years or postmenopausal, >50y: N=2,425) and 4,239 from the ADAPTcycle screening cohort (≤50y: N=1,336; >50y: N=2,903) were analyzed. ET-response rates were higher after AI (ADAPT-HR+/HER2-/ADAPTcycle: 81.4%/76.7%) vs. tamoxifen (ADAPT-HR+/HER2-/ADAPTcycle: 40.1%/34.7%) in both age groups, with further improvement by ovarian function suppression (OFS) in premenopausal patients. Premenopausal patients with GnRH+AI had similar ET-response rates as postmenopausal patients. ET-response predictors included AI use (+OFS in premenopausal), age >50y, lower RS and baseline Ki67 levels, and higher expression of estrogen receptor (by immunohistochemistry) and HER2 (by Oncotype DX). In ADAPT-HR+/HER2-, 5-year dDFS in ET-responders was markedly higher vs. non-responders even in chemotherapy-treated N0-1 patients with RS>25 (87.0 vs. 80.7%) and it was only slightly lower vs. RS 12-25 group.
CONCLUSIONS: We observed similar ET-response rates in two large phase III trials. Postmenopausal patients (mostly receiving AI) had higher ET-response rates compared to younger patients. However, young patients with GnRH+AI had ET-response rates comparable to postmenopausal patients, suggesting that therapy rather than biology accounts for the difference. Combining ET-response and gene expression assessment could help more luminal eBC patients avoid chemotherapy.
KEYWORDS: Breast Neoplasms, Biomarkers, Ki-67 Antigen, Prognosis, Logistic Models, Neoadjuvant Therapy
NCT number: NCT01779206, NCT04055493
DOI: 10.1016/j.annonc.2026.04.007
(来源:SIBCS)
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