The evolving landscape of HR+/HER2- advanced breast cancer demands a strategic approach to biomarker testing, particularly as patients progress on endocrine therapy.1 Comprehensive genomic profiling has emerged as an essential tool for identifying actionable alterations, including PIK3CA, PTEN, and AKT1 mutations.1,2 The timing of genomic profiling may vary based on individual clinical scenarios, treatment history, and the availability of actionable therapeutic options.
Two primary testing modalities are available, each offering distinct advantages. Tissue-based next-generation sequencing provides comprehensive genomic analysis from tumor samples, while liquid biopsy through circulating tumor DNA (ctDNA) offers a minimally invasive alternative.3 Emerging evidence suggests that plasma-based ctDNA analysis may reveal a broader mutational spectrum than tissue sampling alone, potentially capturing genomic heterogeneity across metastatic sites.3 Liquid biopsy presents several practical advantages, including the ability to monitor disease evolution without requiring tissue procurement, the potential to detect alterations that tissue sampling might miss due to tumor heterogeneity, and the capacity to identify resistance-associated mutations, such as ESR1 alterations, that may emerge during treatment.3 Additionally, ctDNA analysis can provide assessments of genomic instability markers, offering insights into therapy resistance risk and informing treatment selection in real-time.3
Clinical evidence has demonstrated the importance of biomarker-guided patient selection for therapeutic interventions. In one recent trial, patients with confirmed PIK3CA, AKT1, or PTEN alterations experienced clinically meaningful improvements in progression-free survival when treated with pathway-targeted therapy plus fulvestrant, while the benefit in biomarker-negative populations remained uncertain.4 This underscores the role of comprehensive genomic testing in identifying patients most likely to benefit from these targeted approaches.
However, treatment selection following biomarker identification requires careful consideration of the specific alteration detected, prior therapy exposure, patient comorbidities, and individual tolerance for potential adverse events.5 As treatment approaches becomes increasingly personalized, early and comprehensive biomarker testing enables proactive treatment planning and ensures patients have access to the full spectrum of available therapeutic options tailored to their tumor’s molecular characteristics.
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