CDK4 inhibitors (CDK4/6i), such as palbociclib, ribociclib, and abemaciclib, are approved in combination with hormonal therapy as a front-line treatment for metastatic HR+, HER2- breast cancer. Their targets, CDK4 and CDK6, are cell-cycle regulatory proteins governing the G1–S phase transition across many tissue types. A key challenge remains to uncover biomarkers to identify those patients that may benefit from this class of drugs. Although CDK4/6i addition to estrogen modulation therapy essentially doubles the median progression-free survival, overall survival is not significantly increased. However, in reality only a subset of treated patients respond. Many patients exhibit primary resistance to CDK4/6 inhibition and do not derive any benefit from these agents, often switching to chemotherapy within 6 months. Some patients initially benefit from treatment, but later develop secondary resistance. This highlights the need for complementary or companion diagnostics to pinpoint patients who would respond. In addition, because CDK4 is a bona fide target in other tumor types where CDK4/6i therapy is currently in clinical trials, the lack of target identification may obscure benefit to a subset of patients there as well. This review summarizes the current status of CDK4/6i biomarker test development, both in clinical trials and at the bench, with particular attention paid to those which have a strong biological basis as well as supportive clinical data.

中文翻译：

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乳腺癌中 CDK4/6 抑制剂反应性生物标志物的持续探索

CDK4 抑制剂 (CDK4/6i)，例如 palbociclib、ribociclib 和 abemaciclib，被批准与激素疗法联合作为转移性 HR+、HER2- 乳腺癌的一线治疗。他们的靶标 CDK4 和 CDK6 是细胞周期调节蛋白，控制多种组织类型的 G1-S 相变。一个关键的挑战仍然是发现生物标志物来识别那些可能从此类药物中受益的患者。尽管 CDK4/6i 添加雌激素调节疗法基本上使中位无进展生存期增加了一倍，但总生存期并未显着增加。然而，实际上，只有一小部分接受治疗的患者有反应。许多患者表现出对 CDK4/6 抑制的原发性耐药，并且没有从这些药物中获得任何益处，通常在 6 个月内转为化疗。一些患者最初从治疗中受益，但后来出现继发性耐药。这凸显了补充或伴随诊断的必要性，以查明有反应的患者。此外，由于 CDK4 是其他肿瘤类型的真正靶点，而 CDK4/6i 疗法目前正处于临床试验阶段，因此靶点识别的缺乏也可能掩盖对部分患者的益处。本综述总结了 CDK4/6i 生物标志物测试开发的现状，包括临床试验和实验室，特别关注那些具有强大生物学基础和支持性临床数据的测试。