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Abstract：
BACKGROUND: The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains controversial, with lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6-inhibitors (CDK4/6i) + endocrine therapy (ET) with chemotherapy + ET.
METHODS: We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapy + ET is superior to CDK4/6i + ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples.
RESULTS: Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapy + ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6i + ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6i + ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm.
CONCLUSIONS: The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6i + ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices.
METHODS: We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapy + ET is superior to CDK4/6i + ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples.
RESULTS: Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapy + ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6i + ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6i + ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm.
CONCLUSIONS: The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6i + ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices.
摘要：
背景：具有侵袭性特征的激素受体阳性/HER2阴性转移性乳腺癌（HR+/HER2阴性MBC）的最佳治疗方法仍存在争议，缺乏比较细胞周期蛋白依赖性激酶（CDK）4/6抑制剂（CDK4/6i）+内分泌治疗（ET）与化疗+ET的随机试验。
方法：我们进行了一项开放标签随机II期试验（NCT03227328），以研究对于具有侵袭性特征的HR+/HER2阴性MBC，化疗+ET是否优于CDK4/6i+ET。PAM50内在亚型（IS），免疫学特征，在基线样品上评估基因表达。
结果：在49名随机患者中（中位随访时间：35.2个月），化疗+ET的中位无进展生存期（mPFS）（11.2个月，95%置信区间[CI]：7.7-15.4)在数值上短于mPFS(19.9个月，95％CI：9.0-30.6）与CDK4/6iET（风险比：1.41，95％CI：0.75-2.64）。CDK4/6i+ET下的基底样肿瘤表现出较差的PFS（mPFS：11.4个月，95%CI：3.00-未达到[NR]）和总生存期（OS；mOS：18.8个月，95%CI：18.8-NR）与其他亚型（mPFS：20.7个月，95%CI：9.00-33.4；mOS：NR，95%CI：24.4-NR）。在化疗领域，腔A肿瘤显示较差的PFS（mPFS：5.1个月，95%CI：2.7-NR）比其他IS（mPFS：13.2个月，95%CI：10.6-28.1）。与BC细胞存活和增殖相关的基因/通路与更差的结果相关。与大多数免疫相关基因/特征相反，尤其是CDK4/6i臂。CD24是两组中唯一与较差PFS显著相关的基因。在CDK4/6i组中，三级淋巴结构和较高的肿瘤浸润淋巴细胞也显示出有利的生存趋势。
结论：KENDO试验，虽然过早关闭，进一步增加了支持CDK4/6i+ET用于侵袭性HR+/HER2阴性MBC而非化疗的证据.PAM50是，基因组，和免疫学特征是有希望的生物标志物，以个性化的治疗选择。
方法：我们进行了一项开放标签随机II期试验（NCT03227328），以研究对于具有侵袭性特征的HR+/HER2阴性MBC，化疗+ET是否优于CDK4/6i+ET。PAM50内在亚型（IS），免疫学特征，在基线样品上评估基因表达。
结果：在49名随机患者中（中位随访时间：35.2个月），化疗+ET的中位无进展生存期（mPFS）（11.2个月，95%置信区间[CI]：7.7-15.4)在数值上短于mPFS(19.9个月，95％CI：9.0-30.6）与CDK4/6iET（风险比：1.41，95％CI：0.75-2.64）。CDK4/6i+ET下的基底样肿瘤表现出较差的PFS（mPFS：11.4个月，95%CI：3.00-未达到[NR]）和总生存期（OS；mOS：18.8个月，95%CI：18.8-NR）与其他亚型（mPFS：20.7个月，95%CI：9.00-33.4；mOS：NR，95%CI：24.4-NR）。在化疗领域，腔A肿瘤显示较差的PFS（mPFS：5.1个月，95%CI：2.7-NR）比其他IS（mPFS：13.2个月，95%CI：10.6-28.1）。与BC细胞存活和增殖相关的基因/通路与更差的结果相关。与大多数免疫相关基因/特征相反，尤其是CDK4/6i臂。CD24是两组中唯一与较差PFS显著相关的基因。在CDK4/6i组中，三级淋巴结构和较高的肿瘤浸润淋巴细胞也显示出有利的生存趋势。
结论：KENDO试验，虽然过早关闭，进一步增加了支持CDK4/6i+ET用于侵袭性HR+/HER2阴性MBC而非化疗的证据.PAM50是，基因组，和免疫学特征是有希望的生物标志物，以个性化的治疗选择。
