Human epidermal growth factor receptor 2, an oncogenic transmembrane glycoprotein, is overexpressed in 15–20% of breast carcinomas. Its protein overexpression and/or gene amplification are closely associated with a poor prognosis and can increase the risk of recurrence. Recent clinical trials have suggested that tumors with strong HER2 expression may increase sensitivity to trastuzumab. Trastuzumab, a 148-kDa humanized monoclonal antibody directed against HER2, is the initial member of the treatment class known as HER2-targeted therapy and is widely used for treating HER2-overexpressing breast cancer. This immunoglobulin G1 (IgG1) kappa was the first treatment to target HER2, a member of the epidermal growth factor receptor family (Dekker 2020).

Its preclinical efficacy was intensive until clinical studies further defined its effect. In 1998, trastuzumab was approved as a first-line single agent for patients with metastatic breast cancer and was later approved in combination with paclitaxel after the landmark Phase III trials in 2001 (DiPeri et al. 2023). Due to such a specific and strong primary effect, guidelines recommend trastuzumab as a first-line treatment option in five different HER2-positive biologic scenarios, with ongoing efforts to minimize the cardiotoxic effects that may accompany it (Ignatov et al. 2019; Sharifi and O’Regan 2019; Alkaya Yıldız and Erkan 2024).

The pertuzumab epitope targets HER2’s dimerization subdomain II. It is a type 1 humanized monoclonal antibody and received breakthrough designation from the US FDA in 2013 (Kirmiziay et al. 2024). Pertuzumab was granted market approval in 2013 by the US FDA for the treatment of HER2-positive metastatic breast cancer. The FDA granted pertuzumab priority review because it effectively extended life expectancy by 16 months. Pertuzumab binds to subdomain II of HER2, prevents the formation of HER2 heterodimers, and exhibits no antibody-dependent cytotoxic effect (Acibuca et al. 2023). By dimerizing HER3 under the mediation of TACE, PTEN, or PI3K, pertuzumab inhibits the domain and thus can prevent the recurrence of tumors following the success of PERJETA IV (Güney and Sayin 2023). The Phase III APHINITY trial was designed to determine whether PERJETA was effective in combination with trastuzumab and chemotherapy in patients with HER2-positive early breast cancer (EBC). The trial involved more than 4,800 patients from 500 centers in 45 countries, including nearly 400 individuals from China. In the study, patients with HER2-positive EBC received surgery followed by chemotherapy and PERJETA plus trastuzumab, or chemotherapy combined with trastuzumab and a placebo. Data showed that after a median follow-up of 4 years, 93.0% of the PERJETA group survived without developing invasive disease compared to 89.7% of the control group (Sharma et al. 2021). Compared with patients taking trastuzumab and chemotherapy alone, the side effects of those receiving the PERJETA regimen were consistent with previous observations. The researchers confirmed that adding PERJETA to trastuzumab and chemotherapy for HER2-positive early breast cancer can prevent disease relapse (Huang 2024).

Since the launch of the technology, progress in this field has involved the preparation, evaluation, clinical testing, and reverse translational studies of different antibody models, used either as naked antibodies or conjugated to chemotherapeutic agents against breast and gastric cancer. Among the first results of this research, ado-trastuzumab emtansine emerged as a potent antibody–drug conjugate and was the first to be used in breast cancer patients. Its clinical success helped raise interest in other antibody conjugates. Cooperation with the same institution has also been valuable in selecting targeted chemotherapy prodrugs and antibody-assisting agents, affiliated with a biotechnology company that has produced effective antibody–drug conjugates against other cancer-related antigens. Results from ongoing reverse translational studies using T-DM1 models will most likely provide a basis for developing other antibody–drug conjugates for different cancer types (Botea 2024).

Ado-trastuzumab emtansine is an antibody–drug conjugate consisting of the HER2-binding monoclonal antibody trastuzumab, a linker–payload, and the microtubule inhibitor-derived maytansinoid emtansine. Its favorable clinical profile indicates that T-DM1 is an optimal therapeutic option both for heavily pretreated breast cancer patients and for those receiving first-line treatment (Zbancioc 2024).

Lapatinib is another TKI/EGFR HER1/HER2 inhibitor that blocks HER1 and HER2 protein kinases by reversibly binding to the receptors’ adenosine triphosphate (ATP)-binding pocket. In the USA, lapatinib combined with capecitabine was approved in 2007. In some regions, it is used as monotherapy in advanced HER2-positive breast cancer that overexpresses HER2 and has progressed through chemotherapy, trastuzumab, and other novel agents. Currently, lapatinib is being studied in clinical trials for early breast cancer. Furthermore, lapatinib may concentrate in brain metastases, exhibiting preferential activity that can circumvent CNS lesions in patients with HER2-positive advanced breast cancer. These distinctive features make lapatinib promising for the treatment of HER2-positive brain metastases of breast cancer (Yamaoka et al. 2016).

In laboratory studies, lapatinib combined with trastuzumab showed significant antiproliferative properties compared with either single-agent therapy in various experimental HER2+ breast cancer cell lines. In addition, lapatinib can target and eradicate HER2-positive macrometastases in distal organs by targeting and eradicating inducible head and neck or breast cancer cell line models using in vitro selection. With an appropriate dose and distribution, administration of lapatinib delayed tumor growth, reduced established lung metastases, and induced substantial apoptosis in lung macrometastases in mice. This promising approach not only provides ancillary preclinical evidence for using lapatinib as part of adjuvant therapy – which could help reduce or eliminate micro- and macrometastases of HER2 cancers, thereby delaying local relapses or distant organ metastases – but also points to another potential means of increasing the response rate to standard adjuvant therapy (Al-hussaniy 2022). Noninvasive imaging further indicates that lapatinib may exert antimetastatic activity by delaying the metastatic process and targeting early macrometastatic sites in distant organs. Furthermore, lapatinib might also neutralize the precancerous stem cell niche before solid tumor establishment, rendering pre-established macrometastases more treatment responsive, thereby improving responses to subsequent standard adjuvant therapy (Gámez-Chiachio et al. 2022; Stanowicka-Grada and Senkus 2023).

The majority of HER2-positive breast cancer patients significantly benefit from the combined use of anti-HER2-targeted therapies with standard chemotherapy. However, one-third of adjuvant therapy patients fail treatment and develop metastases, indicating primary resistance to trastuzumab. The mechanisms involved in the development of resistance are poorly understood. HER2 overexpression in breast cancer, along with the subsequent activation of multiple signaling cascades, has been suggested as a predictive factor for resistance to trastuzumab therapy (Anon 2023). All these cascades involving angiogenesis, extracellular matrix degradation, cell survival, proliferation, migration, and invasion are tightly interconnected. To identify more valuable predictive factors, tumors of resistant patients were examined. These patients present significantly more basal-like tumors as well as higher lymph node involvement. If it were possible to analyze tumor tissue before the start of therapy to understand the development of a specific type of resistance, patients could receive targeted therapy to prevent the emergence of resistant cells a priori. The profile of resistant cells could help guide the selection of an optimal combined treatment strategy (Trapani et al. 2021).

The onset of resistance is a major problem associated with anti-HER2 therapies. Because cytokine/chemokine signaling in the tumor microenvironment has previously been shown to thwart therapy, a model was generated to determine whether perturbation of tumor–immune intercommunication could prevent the onset of de novo resistance. This work indicates that tumors with high stromal cell content, presumably including many immune effector cells, are most often refractory to anti-HER2 therapy. Stromal immune cells activate and release cytokines/chemokines that stimulate HER2 pathway output to high levels, thereby conferring resistance. These findings suggest that the early addition of a stromal immune-tempering agent to an anti-HER2 regimen – rather than adding it only at the time of progression – might delay the onset of resistance by prolonging the time required for activated cytokines/chemokines to be released during therapy response, as well as the time required for HER2 signaling rounds to expand dedicated resistance clones (Trapani et al. 2021).

The success of trastuzumab in the treatment of HER2-overexpressing breast and gastric cancer patients has encouraged clinicians to establish new treatment strategies targeting the HER2 pathway to increase its therapeutic impact. Ongoing preclinical and clinical studies have shown that trastuzumab likely does not achieve saturation of the HER2 pathway in vivo, and HER2-targeting agents can be combined in different ways to increase pathway downregulation. Moreover, given the increasing evidence of treatment failure due to PTEN loss, HER3 stimulation, or mutations in downstream pathways, combined treatment strategies must also account for these mechanisms and the tumor microenvironment. A neoadjuvant Phase II clinical trial demonstrated that adding lapatinib to trastuzumab can increase the fraction of patients achieving a pathologic complete response (Al-hussaniy et al. 2023; Namiq and Sulaiman 2023).

Dual HER2 blockade with lapatinib and trastuzumab has increasingly demonstrated therapeutic activity in combination with chemotherapy in adjuvant, neoadjuvant, and metastatic breast cancer settings. In a meta-analysis of clinical trials, the addition of lapatinib to trastuzumab increased the rate of pathologic complete response and reduced mastectomy rates, with an increased risk of toxicity but no increased risk of surgical complications. Recently, two adjuvant Phase III trials evaluated the addition of 1 year of lapatinib to 1 year of trastuzumab; however, these studies did not demonstrate a clear benefit of dual HER2 blockade. Due to study design differences – such as variation in dose, timing of initial trastuzumab administration, and inclusion of specific patient subpopulations – the impact of dual HER2 blockade remains under investigation (Cheong and Ho 2021).

Standard chemotherapy regimens are widely used for adjuvant therapy, for metastatic disease, and for the treatment of HER2-overexpressing and endocrine therapy-resistant breast cancer (Al-Hussaniy et al. 2023a). However, with the notable exceptions of anthracyclines in the adjuvant setting and taxanes in the adjuvant and first- and/or second-line settings, many chemotherapeutic agents, whether used as single agents or in combination regimens, show limited efficacy in cancer therapy, particularly for metastatic disease. High levels of HER2 expression have been associated with resistance to certain chemotherapy drugs, including tamoxifen, cisplatin, paclitaxel, and endocrine therapy (Al-Hussaniy et al. 2023b). This resistance may be primarily attributed to different signaling pathways activated by the combination of HER2 with chemotherapeutic agents (Haki et al. 2024).

Although taxanes do not directly inhibit HER2, they are believed to exert parallel effects on mitotic microtubule dynamics, thereby preventing the completion of mitosis. This contributes to their partial impact on targeting the mitotic spindle (Al-Kuraishy et al. 2022; Sirhan et al. 2022; Anon 2024).

The use of trastuzumab is associated with a risk of cardiotoxicity. Unlike anthracyclines, trastuzumab-induced cardiotoxicity is typically reversible and not dose-dependent, but it is primarily attributed to the inhibition of HER2 signaling in cardiomyocytes, which plays a vital role in cellular repair and survival via the neuregulin-1/ErbB4–HER2 pathway (Kurmanji et al. 2024). Disruption of this pathway leads to myocardial dysfunction, especially when trastuzumab is combined with anthracyclines, increasing the risk of left ventricular systolic dysfunction and heart failure. Risk factors for cardiotoxicity include older age, preexisting cardiovascular disease, hypertension, and cumulative exposure to cardiotoxic agents. Strategies to reduce cardiotoxicity include baseline and periodic cardiac monitoring using echocardiography or MUGA scans, cardiac biomarkers such as troponin I and BNP, and the avoidance of anthracycline-based regimens when possible. Cardioprotective agents such as ACE inhibitors (e.g., enalapril) and beta-blockers (e.g., carvedilol) have demonstrated efficacy in preserving left ventricular function and preventing cardiotoxic events(Al-Hussaniy et al. 2025), particularly in high-risk patients (Al-Hussaniy et al. 2022). Adjusting treatment regimens, using trastuzumab biosimilars or subcutaneous formulations, and managing modifiable cardiovascular risk factors are additional approaches that help mitigate cardiac complications. With appropriate risk assessment and preventive strategies, the therapeutic benefits of trastuzumab can be safely maximized while minimizing its impact on cardiac health (Al-Hussaniy et al. 2022; Anon 2022).

Cases of interstitial lung disease have been reported with an increased frequency in trastuzumab-treated patients, although its cause has not been clearly established. Risk factors include concomitant chemotherapy and a history of interstitial pneumonitis. Chest X-rays should be performed if symptoms occur, and discontinuation of trastuzumab should be considered for patients who develop interstitial lung disease (Prabha et al. 2017).

Trastuzumab, the cornerstone of HER2-targeted therapy, is generally well tolerated but poses a notable risk of cardiotoxicity. Pertuzumab contributes additional risks, including diarrhea, febrile neutropenia, and fatigue. Antibody–drug conjugates such as ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) introduce further complexities, with toxicities related to their cytotoxic payloads. T-DM1 is associated with thrombocytopenia and hepatotoxicity, while T-DXd carries a significant risk of interstitial lung disease (ILD), a potentially fatal complication that mandates vigilant respiratory monitoring.

Tyrosine kinase inhibitors (TKIs), including lapatinib and neratinib, are frequently associated with gastrointestinal disturbances such as diarrhea and hepatotoxicity. Notably, neratinib-induced diarrhea can be severe and persistent, requiring prophylactic loperamide and dose adjustments.

Furthermore, emerging HER2-directed agents – such as tucatinib and zanidatamab – have shown more favorable safety profiles in early studies, particularly regarding CNS penetration and tolerability, but long-term data remain limited(Abdullah et al. 2024).