Abstract:

Breast cancer remains the most prevalent malignancy in women, with a 5-year survival rate less than 20% in advanced stages. The deepening understanding of breast cancer pathogenesis and the emergence of novel therapeutic agents/regimens have progressively extended survival outcomes for advanced breast cancer patients. While therapeutic advancements have driven the formation of treatment consensus, new controversies continue to emerge. This article systematically reviews current consensus and controversies in managing different molecular subtypes of breast cancer based on pivotal 2024 clinical evidence, aiming to provide evidence-based guidance for clinical practice. For first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer, the CLEOPATRA trial established the trastuzumab-pertuzumab-taxane regimen as standard care. However, the PHILA study proposed a new alternative combining trastuzumab, pyrotinib, and taxanes. Subgroup analyses from both trials provide valuable references for differentiated clinical decision-making. In triple-negative breast cancer (TNBC) management, KEYNOTE-355 and TORCHLIGHT trials established chemotherapy combined with programmed death-1 (PD-1) inhibitors as standard therapy for programmed death ligand-1 (PD-L1)-positive patients. Nevertheless, controversies persist regarding patient selection criteria, PD-L1 positivity thresholds, and optimal immunotherapy agents. Early-phase studies of antibody-drug conjugate (ADC)/PD-L1 inhibitor combinations demonstrated unprecedented progression-free survival (PFS) exceeding 12 months in the first-line TNBC treatment, independent of PD-L1 expression, potentially representing the future frontline regimen. For hormone receptor-positive/HER2-negative advanced breast cancer, cyclin-dependent kinase (CDK) 4/6 inhibitor-endocrine therapy combinations remain guideline-endorsed first-line treatment. The SONIA trial challenged conventional paradigms by demonstrating that not all patients required upfront CDK4/6 inhibitors. It also highlighted critical unresolved issues: no standard recommendations exist for post-CDK4/6 inhibitor therapy, though current evidence supports prioritizing targeted therapies for mutation-positive cases or ADC/endocrine therapies for mutation-negative scenarios. Brain metastasis management presents ongoing challenges. Emerging anti-HER2 agents, including tyrosine kinase inhibitor (TKI) and ADC with demonstrated intracranial efficacy, necessitate further investigation into optimal integration strategies with local therapies. ADC dominate therapeutic innovation, with current research prioritizing optimal sequencing strategies amidst expanding ADC options. Future directions should focus on novel drug development, multimodal treatment integration, and personalized precision therapies to prolong patient survival.

Key words: Advanced breast cancer, Consensus, Controversies