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<p>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, <i>PIK3CA</i> (37.6%), <i>ESR1</i> (46.2%) and <i>TP53</i> (31.2%) were the most altered genes. Comparing with a CDK4/6i plus ET naïve control cohort, <i>ESR1</i> (<i>p</i> &lt; 0.001) was significantly associated with first-line exposure. In multivariable analyses, <i>PTEN</i> alterations were independently associated with shorter progression free survival (PFS) (<i>p</i> = 0.008) and overall survival (OS) (<i>p</i> = 0.006), while <i>TP53</i> (<i>p</i> = 0.031), <i>CCDN1</i> (<i>p</i> = 0.003) and the ET second-line clinician’s choice (<i>p</i> = 0.011) impacted the OS. Moreover, a low-mutant allele frequency was correlated to longer PFS (<i>p</i> = 0.017) and OS (<i>p</i> = 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.</p>

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Circulating genomic landscape following cyclin-dependent kinase 4/6 inhibitors exposure in HR + /HER2− metastatic breast cancer: a retrospective multi-institutional Consortium analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月16日

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  • Letizia Pontolillo,
  • Andrew A. Davis,
  • Lorenzo Gerratana,
  • Arielle J. Medford,
  • Judy Wang,
  • Eleonora Nicolo’,
  • Katherine Clifton,
  • Marko Velimirovic,
  • Surbhi Warrior,
  • Emily Podany,
  • Eleni Andreopoulou,
  • Mara Serena Serafini,
  • Laura Munoz-Arcos,
  • Elisabetta Molteni,
  • Marla Lipsyc-Sharf,
  • Caterina Gianni,
  • Nadia Bayou,
  • Charles S. Dai,
  • Diana Giannarelli,
  • Emilio Bria,
  • Cynthia X. Ma,
  • Aditya Bardia,
  • Carolina Reduzzi,
  • Massimo Cristofanilli

摘要

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.