Comprehensive review of non-invasive-treatment-related cardiovascular toxicity in breast cancer

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  Figure 1. Common cardiovascular toxicity in breast cancer treatment Common cardiovascular toxicities in breast cancer treatment include heart failure, cardiomyopathy, myocarditis, vascular toxicity, hypertension, arrhythmias, pericardial diseases, and valvular heart diseases. Cardiac injury, cardiomyopathy, and heart failure are collectively classified as cancer-therapy-related cardiac dysfunction (CTRCD).

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  Figure 2. Common therapeutic strategies in breast cancer Breast cancer treatment involved in this article includes chemotherapy, targeted therapy, endocrine therapy, immunotherapy, and radiotherapy.

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  Figure 3. Mechanism of DOX cardiovascular toxicity DOX induces cardiovascular toxicity through oxidative stress, mitochondrial dysfunction, and iron overload. It activates ROS, damages DNA, and disrupts mitochondrial function, leading to apoptosis via the PI3K/Akt/mTOR and caspase-3 pathways. DOX also triggers necroptosis through the TNF-α/TNFR1/RIP1/RIP3/MLKL pathway and pyroptosis via the NLRP3/caspase-1 pathway. It disrupts iron metabolism by downregulating ABCB8 and upregulating TFR1, causing iron overload and promoting ferroptosis through lipid peroxidation. Additionally, DOX activates inflammatory pathways, amplifying cardiac damage. TfR, transferrin receptor; PUFA, polyunsaturated fatty acid; GSH, reduced glutathione; GPX4, glutathione peroxidase; GSSG, glutathione disulfide; Lipid-OO∗, lipid peroxides; ABCB8, ATP-binding cassette sub-family B member 8; ROS, reactive oxygen species; IRP, iron response regulatory protein; NAD, nicotinamide adenine dinucleotide; NAM, nicotinamide; NMN, nicotinamide mononucleotide; NMNAT1-3, nicotinamide mononucleotide adenylyltransferase1-3; TBK, TANK-binding kinase; IRF3, interferon regulatory factor 3; AMPK, adenosine monophosphate-activated protein…

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  Figure 4. Mechanism of taxanes cardiovascular toxicity Taxane disrupts cell division by promoting tubulin polymerization, microtubule assembly, and inhibiting depolymerization, leading to cell-cycle arrest and potential cell death. This mechanism involves p53 activation, cyclin-dependent kinase inhibition, and protein kinase modulation. CDK2, recombinant cyclin-dependent kinase 2; p53, tumor protein 53; PCNA, proliferating cell nuclear antigen.

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  Figure 5. Mechanism of trastuzumab cardiovascular toxicity Trastuzumab-induced cardiovascular toxicity arises from the suppression of cardiomyocyte HER2 signaling, which disrupts downstream pathways. This leads to NO production, increased ROS, and inhibition of autophagy, collectively triggering mitochondrial dysfunction. These effects result in decreased ATP production, cytochrome c release, and caspase activation, ultimately impairing myocardial energy metabolism and function. Moreover, trastuzumab disrupts myocardial structure through the MEK/Erk and Src/FAK pathways, potentially involving cMLCK. Immune-mediated cardiomyocyte toxicity may also contribute to its adverse effects. GRB2, growth factor receptor-bound protein 2; PIP3, phosphatidylinositol trisphosphate; eNOS, endothelial nitric oxide synthase; cMLCK, cardiac-specific myosin light-chain kinase; PI3K, phosphoinositide 3-kinase; AKT, Ak transforming factor; mTOR, mammalian target of rapamycin; RAS, Ras GTPase; ERK, extracellular-signal-regulated kinase; BCL, B cell lymphoma.

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  Figure 6. Mechanism of lapatinib-related cardiovascular toxicity Lapatinib shields against TNF-α-induced cardiomyocyte cell demise by triggering AMPK signaling. This cascade involves Ca2+ elevation, CamKK activation, and subsequent AMPK activation. This inhibits lipid and protein synthesis while enhancing fatty acid oxidation via ERRα and PGC-1 activation, ultimately boosting ATP production. AMPK, AMP-activated protein kinase; Akt, protein kinase B; CamKK, calmodulin-dependent kinase kinase; ACC, acetyl-CoA carboxylase; eEF2, eukaryotic elongation factor 2; mTOR, mammalian target of rapamycin; PGC-1, peroxisome proliferator activating receptor gamma coactivator 1α; ERRα, recombinant estrogen-related receptor alpha; LKB1, serine-threonine liver kinase B1.