CDK4/6 inhibitors in invasive lobular carcinoma: Efficacy, resistance patterns, and endocrine partners

BackgroundBreast cancer (BC) remains the most common malignancy in women, with 10-15% being invasive lobular carcinoma (ILC). ILC is typically estrogen receptor (ER) positive, slow-growing, and characterized by multicentricity, multifocality, bilateral involvement, and a distinct metastatic pattern.ObjectivesThis review summarizes recent evidence on CDK4/6 inhibitors combined with endocrine therapy in hormone receptor-positive ILC and explores optimal first-line regimens to overcome resistance.MethodologyA literature search from 2019 to 2025 was conducted in PubMed, Web of Science, and Google Scholar for randomized trials, observational studies, meta-analyses, and translational research on endocrine therapy, CDK4/6 inhibitors, resistance mechanisms, and ILC-specific molecular features. Studies assessing treatment efficacy and resistance pathways were prioritized.ResultsCDK4/6 inhibitors plus endocrine therapy significantly improve progression-free and invasive disease-free survival in HR+/HER2- BC, including ILC. In a pooled FDA analysis of seven phase III trials (<i>n</i> > 4000), combination therapy had an HR of 0.59. In the ILC subgroup (<i>n</i> = 264), median PFS was 16.1 vs 9.2 months (HR 0.58), comparable to the overall population. First-line aromatase inhibitors with CDK4/6 inhibitors enhance overall survival, while fulvestrant combinations benefit endocrine-resistant cases. Early combination therapy is more effective than delayed treatment. Real-world data support these findings.ConclusionCDK4/6 inhibitors with endocrine therapy markedly improve survival in HR+/HER2- BC, yet ILC-focused trials and standardized reporting are limited. Future research should prioritize routine, centralized reporting of ILC subtypes to guide evidence-based, subtype-specific treatment strategies.