Treatment Of HER2-positive Breast Cancer Research Articles

Clinical efficacy of pyrotinib combined with chemotherapy for neoadjuvant treatment in HER2-positive breast cancer: a single-center study.

This study aimed to evaluate the efficacy of pyrotinib, an orally administered small molecule tyrosine kinase inhibitor, combined with neoadjuvant chemotherapy in treating patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Pyrotinib works by inhibiting the HER2 signaling pathway, thereby preventing tumor cell growth. This single-arm clinical trial aimed to assess the total pathological complete response (tpCR; ypT0/is and ypN0) rate as the primary endpoint. A total of 27 patients were enrolled, each receiving 4-8 cycles of pyrotinib in combination with neoadjuvant chemotherapy. Pyrotinib combined with neoadjuvant chemotherapy demonstrated notable antitumor activity in patients with HER2-positive breast cancer. Among 26 patients, the tpCR rate was 26% (7/26), while the breast pathological complete response rate was 30% (8/26), indicating complete inhibition of the primary tumor in some cases. Notably, patients with HR-negative breast cancer demonstrated a higher tpCR rate compared with those with HR-positive breast cancer. The treatment regimen was well-tolerated. Diarrhea was the most common adverse event, occurring in 92.3% of patients, with 46.2% experiencing grade 3 or higher diarrhea. No severe adverse events or treatment-related fatalities were reported.

Direct medical cost of adjuvant systemic treatment for HER2-positive breast cancer in Vietnam

Context: HER2-positive breast cancer, one of the most aggressive subtypes of breast cancer, is associated with the high cost of HER2-targeted therapies. However, its financial burden in Vietnam has not been fully investigated. Aims: To determine the direct medical costs associated with HER2-positive breast cancer treatment in Vietnam from the perspective of healthcare payers, including social health insurance providers and patients. Methods: A multicenter study was conducted in two tertiary hospitals from January to December 2022. Retrospective patient-level data of 303 HER2-positive breast cancer patients who underwent adjuvant systemic treatment for initial treatment was analyzed. A micro-costing bottom-up approach was used to estimate the direct medical cost per inpatient admission in 2022. All cost calculations are presented as USD values using an exchange rate in 2022. Results: The average cost per inpatient admission was $680.0 ± $431.7. Of these, out-of-pocket costs accounted for approximately 42%. Drug costs were the main driver of total spending (92.9%), followed by hospital beds (2.2%), laboratory tests, and diagnostic imaging (2%). The cost of HER2-targeted therapy was responsible for 82.9% of the total direct medical cost. The average cost per inpatient admission of patients receiving chemotherapy with anti-HER2 agents was seven times higher than that of patients receiving chemotherapy alone ($864.0 vs. $120.6). Factors affecting the cost per inpatient admission were age, residence (urban or rural), occupation, and health insurance reimbursement rate. Conclusions: HER-positive breast cancer treatment imposes a significant financial burden in Vietnam, particularly with regimens containing HER2-targeted therapies. The findings of our study add to the increasing literature on the cost of breast cancer treatment and can contribute to the pharmacoeconomic analysis of HER2-positive breast cancer treatment in Vietnam.

HER2-Positive Breast Cancer Treatment and Resistance.

HER2-positive (+) breast cancer is an aggressive disease with poor prognosis, a narrative that changed drastically with the advent and approval of trastuzumab, the first humanized monoclonal antibody targeting HER2. In addition to another monoclonal antibody, more classes of HER2-targeted agents, including tyrosine kinase inhibitors, and antibody-drug conjugates were developed in the years that followed. While these potent therapies have substantially improved the outcome of patients with HER2+ breast cancer, resistance has prevailed as a clinical challenge ever since the arrival of targeted agents. Efforts to develop new treatment regimens to treat/overcome resistance is futile without a primary understanding of the mechanistic underpinnings of resistance. Resistance could be attributed to mechanisms that are either specific to the tumor epithelial cells or those that emerge through changes in the tumor microenvironment. Reactivation of the HER receptor layer due to incomplete blockade of the HER receptor layer or due to alterations in the HER receptors is one of the major mechanisms. In other instances, resistance may occur due to deregulations in key downstream signaling such as the PI3K/AKT or RAS/MEK/ERK pathways or due to the emergence of compensatory pathways such as ER, other RTKs, or metabolic pathways. Potent new targeted agents and approaches to target key actionable drivers of resistance have already been identified, many of which are in early clinical development or under preclinical evaluation. Ongoing and future translational research will continue to uncover additional therapeutic vulnerabilities, as well as new targeted agents and approaches to treat and/or overcome anti-HER2 treatment resistance.

Evaluating high-sensitivity cardiac troponin I for early detection of treatment-related cardiotoxicity in HER2-positive breast cancer patients

Background: Trastuzumab-related cardiotoxicity is a common adverse effect of HER2-positive breast cancer treatment, especially when combined with anthracyclines. However, to date, no definitive prognostic markers have been found to predict trastuzumab-related cardiotoxicity. Methods: Patients diagnosed with HER2-positive breast cancer, scheduled to receive anthracyclines followed by 12 months of trastuzumab or with pertuzumab, were prospectively followed up for 27 months. Measurements of left ventricular ejection fraction LVEF, high-sesitivity troponin I hs-Tn I, and a full cardiac examination were performed at baseline, after anthracycline treatment, and after four cycles of anti-HER2 agents. Subsequently, LVEF measurement and full cardiac examination were conducted every 3 months until the end of the follow-up. Cardiotoxicity was defined as an absolute decrease in LVEF of ≥15%, or a drop in LVEF of ≥10% from the baseline to <50%. Results: Among 78 patients, cardiotoxicity occurred in 13 (16.7%). A higher risk of cardiotoxicity was linked to hs-Tn I measured after four cycles of anti-HER2 agents (P < 0.001), with a significant cutoff of >84 ng/L. No short-term effects of the anthracycline agents (doxorubicin or epirubicin), were found. However, there was a slightly higher tendency to develop cardiotoxicity (P = 0.046) in patients treated with trastuzumab plus pertuzumab. Conclusion: Hs-Tn I measured after four cycles of trastuzumab in HER2-positive breast cancer patients could be an important predictor of cardiotoxicity induced by chemotherapy followed by anti-HER2 agents, particularly in the first year post-treatment, with a different cutoff value than that used in other cardiac conditions.

Clinicopathological factors as predictors of pathological complete response to neoadjuvant treatment with anti-HER2 treatment in HER2-positive breast cancer

Clinicopathological factors as predictors of pathological complete response to neoadjuvant treatment with anti-HER2 treatment in HER2-positive breast cancer

Evaluation of the safety of T-DXd in the Treatment of HER2-positive breast cancer

Abstract. Breast cancer (BC) is one of the most common diseases in women today, and HER2-positive BC has attracted the attention of researchers. Anti-her2 targeted therapy is an important tool in the treatment of HER2. In recent years, antibody-coupling drugs have entered people's field of vision and triggered a boom, and the research on T-DXd targeted therapy for HER2-positive BC is also gradually advancing and improving. This paper mainly discusses the mechanism of HER2-positive BC, explores the mechanism of action of T-DXd against HER2-positive BC, analyzes the side effects and safety evaluation of T-DXd targeted therapy for adult female patients with HER2-positive BC, and concludes that T-DXd is a relatively safe drug. However, it can be found that the pulmonary interstitial disease after treatment is a serious side effect that should not be ignored. Future studies can focus on discussing the principle of the side effect, ways to reduce the probability of its occurrence and more accurate and safe medication programs.

Hedgehog Pathway Is a Regulator of Stemness in HER2-Positive Trastuzumab-Resistant Breast Cancer.

HER2 overexpression occurs in 20-30% of breast cancers and is associated with poor prognosis. Trastuzumab is a standard treatment for HER2-positive breast cancer; however, resistance develops in approximately 50% of patients within a year. The Hedgehog (Hh) signalling pathway, known for its role in maintaining stemness in various cancers, may contribute to trastuzumab resistance in HER2-positive breast cancer. This study aimed to investigate the role of Hedgehog signalling in maintaining stemness and contributing to trastuzumab resistance in HER2-positive breast cancer cell lines. Trastuzumab-resistant HER2-positive breast cancer cell lines, SKBR3 and HCC1954, were developed through continuous trastuzumab exposure. Cells were treated with GANT61 (Hh inhibitor, IC50:10 µM) or SAG21K (Hh activator, IC50:100 nM) for 24 h to evaluate the Hedgehog signalling response. Stemness marker expression (Nanog, Sox2, Bmi1, Oct4) was measured using qRT-PCR. The combination index (CI) of GANT61 with trastuzumab was calculated using CompuSyn software (version 1.0) to identify synergistic doses (CI < 1). The synergistic concentrations' impact on stemness markers was assessed. Data were analysed using two-way ANOVA and Tukey's post hoc test (p < 0.05). Trastuzumab-resistant cells exhibited increased Hedgehog signalling activity. Treatment with GANT61 significantly downregulated stemness marker expression, while SAG21K treatment led to their upregulation in both SKBR3-R and HCC1954-R cells. The combination of GANT61 and trastuzumab demonstrated a synergistic effect, markedly reducing the expression of stemness markers. These findings indicate that Hedgehog signalling plays a pivotal role in maintaining stemness in trastuzumab-resistant cells, and that the inhibition of this pathway may prevent tumour progression. Hedgehog signalling is crucial in regulating stemness in trastuzumab-resistant HER2-positive breast cancer. Targeting this pathway could overcome resistance and enhance trastuzumab efficacy. Further studies should explore the clinical potential of Hedgehog inhibitors in combination therapies.

Improving treatment outcomes for patients with HER2‑positive breast cancer using neoadjuvant double HER2 blockade

Background. Dual anti-HER2-targeted therapy in breast cancer (BC) significantly increased the rate of pathological complete response (pCR) compared to single blockade when added to chemotherapy. However, limited data exist on the long-term impact on survival of the additional increase in pCR.Aim. To improve recommendations regarding HER2-targeted agents and chemotherapy in the neoadjuvant treatment of BC.Materials and methods. N.N. Petrov National Medical Research Oncology Center, Ministry of Health of Russia took participation in some clinical trials of neoadjuvant treatment of HER2-positive breast cancer, including NeoSphere and NeoALTTO. In multicenter, open-label, phase 2 randomised NeoSphere trial, patients with locally advanced, inflammatory, or early-stage HER2-positive BC were randomly assigned to receive four neoadjuvant cycles of trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m2 from every 3 weeks, increasing to 100 mg/m2 from cycle 2 if tolerated) (group A), pertuzumab (420 mg every 3 weeks) and trastuzumab plus docetaxel (group B), pertuzumab and trastuzumab (group C), or pertuzumab and docetaxel (group D). After surgery, patients received three cycles of FEC. Рatients in group C received four cycles of docetaxel prior to FEC, and trastuzumab 6 mg/kg every 3 weeks to complete 1 years treatment. In NeoALTTO trial from 455 patients 154 patients received lapatinib, 149 – trastuzumab, 152 – combination of lapatinib and trastuzumab.Results. Between 2007, and 2009, 417 patients were randomly assigned to group A (107 patients), group B (n = 107), group C (n = 107), or group D (n = 96). At clinical cutoff, 87 patients had disease progression or died. 5-year progressionfree survival rates were 81 % (95 % confidence interval (CI) 71–87) for group A, 86 % (95 % CI 72–91) for group B, 73 % for group C, and 73 % for group D (95 % CI 0.34–1.40). Disease-free survival rates were consistent with progressionfree survival rates and were 81 % (95 % CI 72–88) for group A, 84 % (95 % CI 72–91) for group B, 80 % (95 % CI 70–86) for group C, and 75 % (95 % CI 64–83) for group D. In NeoALTTO trial patients who achieved pCR had longer progressionfree survival (85 % (95 % CI 76–91)) compared with patients who did not achieve pCR (76 % (95 % CI 71–81)).Conclusion. High levels of progression-free survival and disease-free survival at 5–10-years follow-up show large and overlapping CI, but support the primary endpoint (pCR) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. Additionally, they suggest that pCR could be an early indicator of long-term outcome in early-stage HER2-positive BC.

Poly(Epsilon-Lysine) Dendrons Inhibit Proliferation in HER2-Overexpressing SKBR3 Breast Cancer Cells at Levels Higher than the Low-Expressing MDA-MB-231 Phenotype and Independently from the Presentation of HER2 Bioligands in Their Structure.

Among the known breast cancers, the subtype with HER2 receptors-overexpressing cells is associated with a poor prognosis. The adopted monoclonal antibody Trastuzumab has improved clinical outcomes, but it is associated with drug resistance and relatively high costs. The present work adopted the peptide solid-phase synthesis method to synthesise branched poly(ε-lysine) peptide dendrons with 8 branching arms integrating, at their carboxy terminal molecular root, either an arginine or the HER2 receptor-binding sequence LSYCCK or the scramble sequence CSCLYK. These dendrons were synthesised in quantities higher than 100 mg/batch and with a purity exceeding 95%. When tested with two types of breast cancer cells, the dendrons led to levels of inhibition in the HER2 receptor-overexpressing breast cancer cells (SKBR3) comparable to Trastuzumab and higher than breast cancer cells with low receptor expression (MDA-MB-231) where inhibition was more moderate. Noticeably, the presence of the amino acid sequence LSYCCK at the dendron molecular root did not appear to produce any additional inhibitory effect. This was demonstrated also when the scramble sequence CSCLYK was integrated into the dendron and by the lack of any antiproliferative effect by the control linear target sequence. The specific inhibitory effect on proliferation was finally proven by the absence of cytotoxicity and normal expression of the cell migration marker N-Cadherin. Therefore, the present study shows the potential of poly(ε-lysine) dendrons as a cost-effective alternative to Trastuzumab in the treatment of HER2-positive breast cancer.

Synergistic effect of the sphingosine kinase inhibitor safingol in combination with 2'-nitroflavone in breast cancer.

Sphingosine kinase-1 (SPHK1), the enzyme that catalyzes the synthesis of the pro-oncogenic molecule sphingosine-1-phosphate, is commonly upregulated in breast cancer cells and has been linked with poor prognosis and progression by promoting cell transformation, proliferation, angiogenesis, and metastasis. Therefore, SPHK1-targeting drugs have been proposed for breast cancer treatment, with better antitumor results when they are combined with chemotherapy. Previously, we demonstrated that the synthetic flavonoid 2'-nitroflavone (2'NF) exerted a potent and selective antiproliferative effect in murine HER2-positive LM3 mammary tumor cells. As we found that these cells overexpress SPHK1, we decided to explore the antitumor action of the combination of SPHK inhibitors (safingol or SKI-II) with 2'NF. In vitro assays showed that the combination induced a synergistic antiproliferative effect in LM3 cells. Similar results were obtained when human HER2-positive MDA-MB-453 breast cancer cells were treated with the combination of 2'NF/safingol. We also found that safingol potentiated the 2'NF apoptotic effect in both cell lines. The synergistic antitumor effect was confirmed in vivo in an LM3 syngeneic breast cancer model. Moreover, western blot analysis of tumor lysates revealed that combined treatment increased PARP cleavage and Bax protein levels and decreased anti-apoptotic Bcl-xL and Bcl-2 protein levels. Additionally, mice treated with both compounds showed no histopathological effects on different organ tissues. In summary, these findings suggest that the combination safingol/2'NF can be proposed as a potential therapeutic strategy for HER2-positive breast cancer treatment. KEY MESSAGES: The combination safingol/2'-nitroflavone exerts a synergic antitumor action in vitro. Safingol potentiates 2'-nitroflavone apoptotic effect in breast cancer cells. Safingol enhances the 2'-nitroflavone antitumor activity in vivo in breast cancer.

Cardiotoxicity during neoadjuvant treatment of HER2-positive breast cancer – a case series

Cardiotoxicity during neoadjuvant treatment of HER2-positive breast cancer – a case series

184 (PB172): Evaluation of a Novel and Highly Efficacious Anti-HER2 Antibody-Drug Conjugate for HER2-Positive Breast Cancer Treatment

184 (PB172): Evaluation of a Novel and Highly Efficacious Anti-HER2 Antibody-Drug Conjugate for HER2-Positive Breast Cancer Treatment

276P SHR-A1811 in combination with pyrotinib as neoadjuvant treatment for HER2-positive breast cancer (HER2+ BC): Preliminary results from MUKDEN 07

276P SHR-A1811 in combination with pyrotinib as neoadjuvant treatment for HER2-positive breast cancer (HER2+ BC): Preliminary results from MUKDEN 07

Neratinib plus dasatinib is highly synergistic in HER2-positive breast cancer in vitro and in vivo

BackgroundHER2-targeted therapies have revolutionised the treatment of HER2-positive breast cancer. However, de novo resistance or the emergence of acquired resistance is a persistent clinical problem. Here we report that neratinib, an irreversible pan-HER inhibitor, in combination with the multi-kinase inhibitor dasatinib, currently used to treat certain leukemias, has strong anti-proliferative effects against models of HER2-positive breast cancer that are innately resistant to trastuzumab or have acquired resistance to neratinib. MethodsNeratinib plus dasatinib was examined in a panel of 20 breast cancer cell lines, including HER2-positive, estrogen-receptor-positive, triple negative, and acquired HER2-targeted therapy resistant models. Drug effects on migration and apoptosis induction was evaluated and signaling alterations were determined by reverse phase protein array (RPPA). In vivo efficacy was examined using orthotopically-implanted HCC1954 cells. ResultsSynergy was observed in cell lines innately resistant to trastuzumab, models with acquired resistance to neratinib, and in triple negative breast cancer cell lines. Further investigation showed that neratinib plus dasatinib induced apoptosis and inhibited cell migration to a greater degree than either drug alone. RPPA revealed that the combination caused suppression of key survival signaling through EGFR, Akt, and MAPK inhibition. In vivo, neratinib plus dasatinib was well tolerated and had a prolonged anti-tumor effect against HCC1954 xenografts. ConclusionsThis study provides a strong pre-clinical rationale for the clinical investigation neratinib and dasatinib in HER2+ breast cancer.

LncRNA ZNF649-AS1 promotes trastuzumab resistance and TAM-dependent PD-L1 expression in breast cancer by regulating EXOC7 alternative splicing

BackgroundTrastuzumab resistance is a serious clinical problem in the treatment of HER2-positive breast cancer (BC). The lncRNA ZNF649-AS1 was previously found to promote HER2-positive BC trastuzumab resistance. The study aims to explore the molecular mechanism of ZNF649-AS1 in HER2-positive BC trastuzumab resistance. MethodsTumor tissue and peripheral blood samples were collected from 20 HER2-positive BC patients with trastuzumab-resistant and non-resistant, respectively. Trastuzumab-resistant BC cell lines SKBR-3-TR and BT474-TR were established. RIP was employed to confirm the binding of ZNF649-AS1, PRPF8 and exocyst complex component 7 (EXOC7). RNA expression of EXOC7-L (Full length of EXOC7) and EXOC7-S (Spliceosome of EXOC7) were detected using agarose gel electrophoresis. Expressions of macrophage markers CD68+ CD206+ were measured by flow cytometry. ResultsZNF649-AS1 expression was upregulated in HER2-positive BC trastuzumab resistance. ZNF649-AS1 downregulation inhibited trastuzumab resistance in HER2-positive BC. ZNF649-AS1 regulated EXOC7 alternative splicing by binding with PRPF8. EXOC7-S knockdown suppressed trastuzumab resistance and TAM-dependent PD-L1 expression in HER2-positive BC. EXOC7-S overexpression abolished the effects of ZNF649-AS1 knockdown on trastuzumab resistance and TAM-dependent PD-L1 expression in HER2-positive BC. ConclusionZNF649-AS1 promoted trastuzumab resistance and TAM-dependent PD-L1 expression in HER2-positive BC via promoting alternative splicing of EXOC7 by PRPF8.

PDL1/HER2-Targeted Lipid-Encapsulated Oxygen Nanobubbles Combined with Photodynamic Therapy for HER2+ Breast Cancer Immunotherapy.

Programmed death (PD) 1/PD ligand 1 (PDL1) inhibitors are immune checkpoint inhibitors (ICIs) that may facilitate HER2-positive breast cancer treatment; however, their clinical efficacy remains elusive. Oxygen-enhanced photodynamic therapy (PDT) increases immunogenic cell death (ICD), providing a promising strategy to render the tumor microenvironment more sensitive to the ICIs. Lipid-encapsulated oxygen nanobubbles (Lipo-NBs-O2) obtained using nanobubbles (NBs) water for oxygen delivery in vivo can facilitate enhanced PDT. Here, dual-receptor targeted Lipo-NBs-O2 (DRT@Lipo-NBs-O2) is prepared by modifying Lipo-NBs-O2 with anti-PDL1 scFv and the fusion protein anti-HER2 scFv-tandem-repeat cytochrome c (anti-HER2-nCytc). Copper phthalocyanine is the photosensitizer (PS). DRT@Lipo-PS-NBs-O2 plus near-infrared irradiation leads to robust ICD induction, increasing DC activation and CD8+ T-cell numbers. Modification with anti-PDL1 scFv improves tumor distribution of DRT@Lipo-PS-NBs-O2 and plays the ICI role, invigorating CD8+ T cells and boosting the effects of immunotherapy. Oxygen supplied through DRT@Lipo-PS-NBs-O2 reduces P-glycoprotein expression. Enhanced PDT and Cytc can cause tumor cell death, thereby reducing the immune burden. Under dual receptor targeting and laser local irradiation, tumor cells become subject to the combination effects of PDT, ICD, ICIs, and apoptosis; this effectively suppresses tumor growth and metastasis. Lipo-NBs-O2 affords a combination of oxygen delivery and multidrug therapy to alleviate HER2-positive breast cancer.

Apple polyphenol phloretin inhibits type II glucose transporter and enhances anti-HER2 antibody drug binding as an adjuvant treatment for HER2-positive breast cancer

Apple polyphenol phloretin inhibits type II glucose transporter and enhances anti-HER2 antibody drug binding as an adjuvant treatment for HER2-positive breast cancer

Trastuzumab-functionalized bionic pyrotinib liposomes for targeted therapy of HER2-positive breast cancer

In this study, we prepared a bionic nanosystem of trastuzumab-functionalized SK-BR-3 cell membrane hybrid liposome-coated pyrotinib (Ptb-M-Lip-Her) for the treatment of HER2-positive breast cancer. Transmission electron microscopy, dynamic light scattering, polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting were used to verify the successful preparation of Ptb-M-Lip-Her. In vitro drug release experiments proved that Ptb-M-Lip-Her had a sustained release effect. Cell uptake experiments and in vivo imaging experiments proved that Ptb-M-Lip-Her had good targeting ability to homologous tumor cells (SK-BR-3). The results of cell experiments such as MTT, flow cytometry, immunofluorescence staining and in vivo antitumor experiments showed that Ptb-M-Lip-Her could significantly promote apoptosis and inhibit the proliferation of SK-BR-3 cells. These results clearly indicated that Ptb-M-Lip-Her may be a promising biomimetic nanosystem for targeted therapy of HER2-positive breast cancer.

Cubosomes functionalized with antibodies as a potential strategy for the treatment of HER2-positive breast cancer

Breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) have poor prognosis. Moreover, available chemotherapies cause numerous side effects due to poor selectivity. To advance more effective and safer therapies for HER2-positive breast cancer, we explored the fusion of drug delivery technology and immunotherapy. Our research led to the design of immunocubosomes loaded with panobinostat and functionalized with trastuzumab antibodies, enabling precise targeting of breast cancer cells that overexpress HER2. We characterised the nanostructure of cubosomes using small-angle X-ray scattering (SAXS), cryo-transmission electron microscopy (cryo-TEM), and dynamic light scattering (DLS). Moreover, we confirmed the integrity of the trastuzumab antibodies on the immunocubosomes by Fourier-transform infrared spectroscopy (FTIR) and sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Additionally, we found that panobinostat-loaded immunocubosomes were more cytotoxic, and in an uptake-dependant manner, towards a HER2-positive breast cancer cell line (SKBR3) compared to a cell line representing healthy cells (L929). These results support that the functionalization of cubosomes with antibodies enhances both the effectiveness of the loaded drug and its selectivity for targeting HER2-positive breast cancer cells.

In Vitro Assessment of 177Lu-Labeled Trastuzumab-Targeted Mesoporous Carbon@Silica Nanostructure for the Treatment of HER2-Positive Breast Cancer.

This study assessed the effectiveness of a trastuzumab-targeted 177Lu-labeled mesoporous Carbon@Silica nanostructure (DOTA@TRA/MC@Si) for HER2-positive breast cancer treatment, focusing on its uptake, internalization, and efflux in breast cancer cells. The synthesized PEI-MC@Si nanocomposite was reacted with DOTA-NHS-ester, confirmed by the Arsenazo(III) assay. Following this, TRA was conjugated to the DOTA@PEI-MC@Si for targeting. DOTA@PEI-MC@Si and DOTA@TRA/MC@Si nanocomposites were labeled with 177Lu, and their efficacy was evaluated through in vitro radiolabeling experiments. According to the results, the DOTA@TRA/MC@Si nanocomposite was successfully labeled with 177Lu, yielding a radiochemical yield of 93.0 ± 2.4%. In vitro studies revealed a higher uptake of the [177Lu]Lu-DOTA@TRA/MC@Si nanocomposite in HER2-positive SK-BR-3 cells (44.0 ± 4.6% after 24 h) compared to MDA-MB-231 cells (21.0 ± 2.3%). The IC50 values for TRA-dependent uptake in the SK-BR-3 and BT-474 cells were 0.9 µM and 1.3 µM, respectively, indicating affinity toward HER-2 receptor-expressing cells. The lipophilic distribution coefficients of the radiolabeled nanocomposites were determined to be 1.7 ± 0.3 for [177Lu]Lu-DOTA@TRA/MC@Si and 1.5 ± 0.2 for [177Lu]Lu-DOTA@PEI-MC@Si, suggesting sufficient passive transport through the cell membrane and increased accumulation in target tissues. The [177Lu]Lu-DOTA@TRA/MC@Si nanocomposite showed an uptake into HER2-positive cell lines, marking a valuable step toward the development of a nanoparticle-based therapeutic agent for an improved treatment strategy for HER2-positive breast cancer.