Pontolillo Letizia, Davis Andrew A, Gerratana Lorenzo, Medford Arielle J, Wang Judy, Nicolo' Eleonora, Clifton Katherine, Velimirovic Marko, Warrior Surbhi, Podany Emily, Andreopoulou Eleni, Serafini Mara Serena, Munoz-Arcos Laura, Molteni Elisabetta, Lipsyc-Sharf Marla, Gianni Caterina, Bayou Nadia, Dai Charles S, Giannarelli Diana, Bria Emilio, Ma Cynthia X, Bardia Aditya, Reduzzi Carolina, Cristofanilli Massimo
Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY, USA.
Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy.
NPJ Breast Cancer. 2025 Aug 16;11(1):93. doi: 10.1038/s41523-025-00802-2.
Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) are the mainstay of treatment for hormone receptor positive, HER2 negative (HR + /HER2-) metastatic breast cancer (MBC). However, disease progression is inevitable and unveiling resistance mechanisms is crucial to guide post-CDK4/6i therapeutic strategies. In this study, we retrospectively analyzed a real-world, multi-institutional cohort of patients with HR + /HER2- MBC characterized by circulating tumor DNA (ctDNA) through next-generation sequencing (NGS) before starting second-line treatment. Among 93 patients previously treated with CDK4/6i, PIK3CA (37.6%), ESR1 (46.2%) and TP53 (31.2%) were the most altered genes. Comparing with a CDK4/6i plus ET naïve control cohort, ESR1 (p < 0.001) was significantly associated with first-line exposure. In multivariable analyses, PTEN alterations were independently associated with shorter progression free survival (PFS) (p = 0.008) and overall survival (OS) (p = 0.006), while TP53 (p = 0.031), CCDN1 (p = 0.003) and the ET second-line clinician's choice (p = 0.011) impacted the OS. Moreover, a low-mutant allele frequency was correlated to longer PFS (p = 0.017) and OS (p = 0.038). These findings highlight the prognostic relevance of specific molecular alterations and support the role of genomic profiling in guiding second-line treatment decisions after CDK4/6i therapy. Prospective validation is warranted to confirm the clinical utility of this approach in HR + /HER2 - MBC.
细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6i）联合内分泌治疗（ET）是激素受体阳性、人表皮生长因子受体2阴性（HR + /HER2-）转移性乳腺癌（MBC）的主要治疗方法。然而，疾病进展不可避免，揭示耐药机制对于指导CDK4/6i治疗后的策略至关重要。在本研究中，我们回顾性分析了一个真实世界的多机构队列，该队列中的HR + /HER2- MBC患者在开始二线治疗前通过下一代测序（NGS）对循环肿瘤DNA（ctDNA）进行了特征分析。在93例先前接受过CDK4/6i治疗的患者中，PIK3CA（37.6%）、ESR1（46.2%）和TP53（31.2%）是改变最频繁的基因。与未接受过CDK4/6i联合ET治疗的对照队列相比，ESR1（p < 0.001）与一线治疗暴露显著相关。在多变量分析中，PTEN改变与较短的无进展生存期（PFS）（p = 0.008）和总生存期（OS）（p = 0.006）独立相关，而TP53（p = 0.031）、CCDN1（p = 0.003）和ET二线临床医生的选择（p = 0.011）影响OS。此外，低突变等位基因频率与较长的PFS（p = 0.017）和OS（p = 0.038）相关。这些发现突出了特定分子改变的预后相关性，并支持基因组分析在指导CDK4/6i治疗后二线治疗决策中的作用。需要进行前瞻性验证以确认该方法在HR + /HER2- MBC中的临床实用性。
