Jul 2026· Critical reviews in oncology/hematology· pp.
105497
· 1 citation· 86 references
Medicine
TL;DR
This work synthesizes current evidence on the signaling architecture underlying targeted therapy across breast cancer subtypes and proposes a four-layer network topology model of resistance integrating receptor tyrosine kinase reprogramming, epigenetic plasticity coupled with tumor microenvironment (TME) co-evolution, to avoid conflating preclinical observations with validated biomarkers.
Abstract
Breast cancer encompasses molecularly distinct subtypes with divergent oncogenic dependencies, each amenable to precision therapeutic intervention. Over the past decade, clinically meaningful advances have reshaped breast cancer management: antibody-drug conjugates (ADCs) have expanded actionable HER2 expression thresholds to include HER2-low and HER2-ultralow populations; cyclin-dependent kinase (CDK) 4/6 inhibitors have become standard-of-care in hormone receptor-positive disease; and immune checkpoint blockade has established durable responses in a defined subset of triple-negative breast cancer (TNBC). Nevertheless, therapeutic resistance remains the central unresolved obstacle to durable benefit. Here, we synthesize current evidence on the signaling architecture underlying targeted therapy across breast cancer subtypes and propose a four-layer network topology model of resistance integrating: (i) canonical pathway reactivation; (ii) receptor tyrosine kinase (RTK) reprogramming; (iii) non-coding RNA (ncRNA) regulatory circuits; and (iv) epigenetic plasticity coupled with tumor microenvironment (TME) co-evolution. We explicitly stratify the discussed mechanisms into three evidence tiers-clinically actionable, plausibly translational, and exploratory-to avoid conflating preclinical observations with validated biomarkers. We critically evaluate FDA-approved and emerging agents within this framework, identify knowledge gaps, and outline future directions-including liquid biopsy-guided adaptive therapy, multi-omic resistance profiling, and biologically rational combination strategies-together with their feasibility constraints related to toxicity, sequencing, cost, and biomarker validation.
ABSTRACT
Recent advances in breast cancer management have transformed treatment across molecular subtypes and expanded the role of precision oncology. Hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-positive (HER2-positive), HER2-low, and triple-negative breast cancer (TNBC) each demonstrate distinct biologic behavior requiring tailored therapeutic strategies. In HR-positive disease, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and next-generation selective estrogen receptor degraders have improved survival, while HER2-directed antibody-drug conjugates (ADCs) have expanded treatment options beyond traditional HER2-positive disease. HER2-low disease has recently emerged as a therapeutically actionable HER2-expression category, addressing a previously limited treatment space. In TNBC, immunotherapy and ADCs have broadened therapeutic options for historically difficult-to-treat disease. Advances in genomic profiling, including next-generation sequencing and circulating tumor DNA testing, allow clinicians to identify biomarkers to guide targeted therapy selection. As treatment complexity increases, APPs play an essential role in implementing precision oncology through patient education, toxicity management, genomic counseling, and clinical trial coordination. This review summarizes current treatment strategies across breast cancer subtypes, highlights emerging therapies, and emphasizes the expanding APP role.
Whitney Tobin· JAAPA : official journal of...· 0 citations
ABSTRACT
Breast cancer remains the most common cancer among women worldwide, characterized by significant molecular heterogeneity. Advances in targeted therapy and immunotherapy have transformed treatment approaches, offering promising new options for patients. Targeted therapies are designed to inhibit the key pathways that drive tumor growth and survival. The cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and other treatments have significantly advanced treatment, delaying progression and extending survival for some subtypes of breast cancer. Nevertheless, targeted therapeutic agents have not yet demonstrated significant clinical efficacy in the treatment of triple-negative breast cancer (TNBC). Meanwhile, immunotherapy has emerged as a complementary approach. Immune checkpoint inhibitors (ICIs) have demonstrated notable efficacy in subsets of TNBC and are under exploration in other breast cancer subtypes, including hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) and HER2-positive disease. Furthermore, innovative strategies such as anticancer vaccines and adoptive T-cell therapy offer potential for prolonged immune engagement and tumor eradication. This review provides an overview of current progress in targeted therapies and immunotherapy for breast cancer, highlighting their mechanisms, clinical utility, and challenges. By integrating knowledge from recent advancements, this review seeks to guide future research and clinical practice toward improved and personalized care for breast cancer patients.
Song Wu, Pangzhou Chen, Wen Zhou et al.· Chinese Medical Journal· 0 citations
Triple-negative breast cancer remains an aggressive and biologically heterogeneous breast cancer subtype. Although the therapeutic landscape has expanded, durable disease control remains clinically challenging in many settings. Existing reviews often organize TNBC therapy by drug class or molecular subtype, which can obscure how treatment response is shaped by interacting biological layers. Here, we review current and emerging therapeutic strategies through a three-layer framework: tumor-cell-intrinsic vulnerabilities, the local immune and stromal microenvironment, and host-level systemic modifiers. We summarize established approaches, including chemotherapy, immune checkpoint blockade, antibody–drug conjugates and PARP inhibition in biomarker-defined settings, and distinguish them from maturing or exploratory strategies such as pathway-directed therapy, epigenetic modulation, anti-vascular combinations, regulated cell-death induction, cellular therapy, vaccines, microbiome-related interventions, liquid biopsy, AI-supported multiomics and adaptive trial designs. This framework integrates evidence level, disease stage, biomarker reliability and patient tolerance into treatment selection for TNBC precision therapy.
Zi-Xun Wang, Xi-Yu Liu, Yu-Xiao Wu et al.· Journal of Hematology & Onco...· 0 citations
Immunotherapy has revolutionized the treatment landscape of breast cancer, particularly for triple-negative breast cancer (TNBC), yet primary and acquired resistance remain formidable obstacles limiting durable clinical benefit. This review provides a comprehensive update on recent advances in breast cancer immunotherapy, with a focused emphasis on the molecular and cellular mechanisms driving treatment resistance and emerging strategies to overcome them. We dissect tumor-intrinsic resistance pathways, including loss of tumor antigens, defects in antigen processing and presentation machinery, insensitivity to interferon-γ signaling, metabolic reprogramming, and epigenetic dysregulation. Tumor-extrinsic mechanisms, such as infiltration of immunosuppressive cells, abnormal angiogenesis, extracellular matrix remodeling, and FGF/FGFR genomic amplification, are highlighted as key barriers to effective immune checkpoint blockade. Emerging evidence implicates novel resistance mediators, including the DUSP22-LGALS1 axis, THSD4-driven T cell exclusion, and the MTDH-SND1 complex impairing antigen presentation, etc. We critically evaluate current strategies to surmount resistance, encompassing combination regimens with chemotherapy, targeted therapies, radiotherapy, and novel immunomodulators. The review also addresses challenges in managing immune-related adverse events, controversies surrounding patient selection biomarkers, and the urgent need for optimized efficacy evaluation systems beyond RECIST criteria. Finally, we discuss future directions, including novel immune checkpoints, microbiome modulation, artificial intelligence-assisted decision-making, and innovative trial designs. By integrating mechanistic insights with clinical evidence, this review provides a framework for understanding and overcoming immunotherapy resistance, advancing the paradigm from "effective" to "precise" immuno-oncology in breast cancer.
Jia-Mei Wang, Yi Zhou, Fei-Fei Li et al.· Critical reviews in oncology...· 0 citations
Breast cancer (BC) remains the leading cause of cancer-related mortality and a major contributor to disease burden among women worldwide. Although PD‑1/PD‑L1‑targeting immune checkpoint inhibitors have become a standard treatment for certain triple‑negative breast cancer subgroups, their use across the broader BC population is limited by intrinsic resistance, an immunosuppressive tumor microenvironment (TME), and treatment‑related adverse effects. The present review offers a comprehensive synthesis of the immunotherapeutic paradigm in BC, spanning ICIs, adoptive cellular therapies (CAR-T, CAR-NK, CAR-M, TIL, TCR-T, and CIK cells), and emerging immune modulators. We critically evaluate pivotal clinical trials, discuss cross-cutting challenges—including biomarker development, therapy resistance, and the practical limitations of cellular products—and highlight rational combinatorial strategies. By contrasting the translational readiness of diverse modalities and outlining a framework for personalized therapy, this review aims to inform future research and clinical practice in harnessing immunity against BC.
Ali Mussa, Mahasin Hamid, M. Talib et al.· Journal of Translational Med...· 0 citations
This review examines the clinical development of palbociclib, ribociclib, and abemaciclib across both early-stage and metastatic settings, revealing clinically meaningful differences in efficacy that challenge the notion of a uniform class effect.
