Herceptin (trastuzumab)

In vivo, trastuzumab-vincristine conjugates led to remarkable efficacy when compared to two standards of care, with complete tumor regression just 9 days after single administration. This highlights the untapped potential of the chemotherapeutic arsenal toward the development of novel ADC.

We believe that FGFR4 overexpression and complex formation with HER2 can serve as molecular markers to assist clinicians in identifying trastuzumab-resistant tumors. Our results suggest that FGF401 combined with trastuzumab as adjuvant therapy for patients with trastuzumab-resistant breast cancer may be a potential new treatment strategy.

We synthesized Fc-PLG-Mal, conjugated DM1 through a "click" reaction, and subsequently bound the resultant compound with the HER2 antibody trastuzumab...HER2-PLG-DM1 significantly inhibited tumor growth in NCI-N87 tumor-bearing mice, achieving a 90.8% tumor inhibition rate, and displayed dose-dependent effects without significant liver and kidney toxicity. These studies offer an efficient and stable method for the preparation of antibody-coupled drugs.

Tumors with lower IFNG SHAP values exhibited higher IFNG expression and better overall survival, which were linked to more abundant presence of M1 macrophages and activated CD4+ and CD8+ T cells in the tumor microenvironment. The association of the IFNG pathway with overall survival was validated in the trastuzumab arm of the NCCTG-N9831 trial, an independent breast cancer study.

P1/2, N=18, Terminated, BioInvent International AB | Active, not recruiting --> Terminated; After the completion of phase IA, for business reasons it was decided to terminate the study.

P2, N=23, Not yet recruiting, Guangzhou Women and Children's Medical Center

P2, N=73, Not yet recruiting, UNICANCER | Initiation date: Oct 2024 --> Jan 2025

Cardiotoxicity was not associated with DFS or OS. Clinical stage III, Suspension and permanent interruption of treatment regardless of the cause were associated with worse DFS and OS in breast cancer patients.

We aimed to dynamically monitor serum adenosine levels in patients with HER2-positive metastatic breast cancer (MBC) patients and to explore its predictive significance in trastuzumab therapy...The dynamic change of adenosine is a predictive biomarker for monitoring disease progression. The adenosine metabolism-based signature has the potential application in the prognosis of HER2-positive MBC patients.

P1/2, N=40, Recruiting, Centre de recherche du Centre hospitalier universitaire de Sherbrooke

Tumor growth was significantly inhibited by [225Ac]Ac-DOTA-trastuzumab IgG, F(ab')2 or Fab but [225Ac]Ac-DOTA-trastuzumab F(ab')2 was most effective for increasing median survival (46 d vs 22 d for IgG and 29 d for Fab). We conclude that [111In]In- and [225Ac]Ac-DOTA-trastuzumab F(ab')2 exhibited superior properties for theranostic imaging and α-particle RIT of HER2-positive human BC xenografts in NRG mice.

P1/2, N=1, Terminated, Celularity Incorporated | N=52 --> 1 | Trial completion date: Feb 2025 --> Feb 2024 | Active, not recruiting --> Terminated | Trial primary completion date: Feb 2023 --> Feb 2024; for business reasons

P2, N=110, Not yet recruiting, Qilu Hospital of Shandong University

P2, N=175, Active, not recruiting, German Cancer Research Center | Recruiting --> Active, not recruiting

P1, N=40, Recruiting, Baptist Health South Florida | Trial completion date: Nov 2025 --> Feb 2029 | Trial primary completion date: Nov 2024 --> Feb 2028

Specifically, over 50% of patients either do not respond to or develop resistance against trastuzumab.The specific mechanisms of resistance to trastuzumab are currently unclear. This paper aims to review the existing research on the resistance mechanisms of trastuzumab, based on its target, from aspects such as genetic loci, molecular structure, signaling pathways, and the tumor microenvironment and to outline current research progress and new strategies.

Preclinical studies illustrated that tumor regression induced by HER2 antibodies requires T cell involvement, and the combination of immune checkpoint inhibitors with trastuzumab augments HER2-specific T cell responses, promotes immune cell recruitment, and induces the expansion of peripheral memory T cells, which showed synergistic rationales for a combination of pembrolizumab and trastuzumab. The observed synergy between pembrolizumab and trastuzumab highlights a promising treatment avenue that warrants further investigation.

The patient was diagnosed as having stage IV HER2-positive breast cancer, which was treated with a regimen of trastuzumab (8 mg/kg), pertuzumab (first dose: 840 mg; second dose onward: 420 mg) and docetaxel (75 mg/m2) every 3 weeks. After 4 months of chemotherapy, the patient received complete remission. In conclusion, concomitant use of rifampicin and clarithromycin may increase the blood concentration of docetaxel.

P2, N=120, Active, not recruiting, University of California, Irvine | Trial completion date: Jun 2024 --> Jun 2025 | Trial primary completion date: Jun 2024 --> Jun 2025

Trastuzumab with chemotherapy is the standard regimen for HER2-positive GC/GEJC. While, for HER2-negative cases, chemotherapy with or without immune checkpoint inhibitors (ICIs)such as nivolumab or pembrolizumab are regarded as the standard therapy...We will highlight the previous clinical trials of zolbetuximab and provide future perspective of CLDN18.2 targeted therapy. In addition, we will introduce the ongoing development of various CLDN18.2 targeting therapies such as newer monoclonal antibodies, antibody-drug conjugates(ADCs), chimeric antigen receptor T-cell(CAR- T)therapy, and bispecific antibodies.

For HER2-positive tumours, preoperative systemic therapy with trastuzumab may be considered as it demonstrates a significantly higher number of pathological complete remissions and offers the possibility of achiev-ing a higher R0 resection rate. In oligometastatic disease, surgical management of the primary tumour and metastases may be considered in individual cases in patients who respond to systemic therapy. However, an impact on overall survival has only been documented in patients with retroperitoneal involvement and no peritoneal metastases.

This suggests its potential as a viable therapeutic option for trastuzumab-resistant gastric cancers. In summary, compound 10 could be a novel alternative therapeutic strategy for HER2-overexpressing cancers, overcoming the limitations of trastuzumab.

P1/2, N=34, Active, not recruiting, US Oncology Research | N=26 --> 34 | Trial completion date: Jun 2024 --> Jan 2025 | Trial primary completion date: Jun 2024 --> Jan 2025

Treatment included IT delivery of cDC1, 6 times weekly, followed by paclitaxel, 80 mg/m2, intravenously, 12 times weekly...In this nonrandomized clinical trial, the addition of IT cDC1 and trastuzumab/pertuzumab before neoadjuvant chemotherapy was well tolerated with manageable adverse effects. Based on safety and immunogenicity, DL2 was selected for the phase 2 dose. ClinicalTrials.gov Identifier: NCT05325632.

In patients, RAB5A, RAB7A, and GDI2 expression correlates with patient survival and αVβ6 expression predicts relapse following trastuzumab treatment. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates αVβ6-HER2 cross-talk to drive breast cancer invasion but is subverted in trastuzumab-resistant cells to drive αVβ6-independent and HER2-independent tumor progression.

P1, N=123, Active, not recruiting, Genentech, Inc. | N=537 --> 123

Similarly, RT-QPCR demonstrated that SLC6A6 was significantly downregulated in Tra-treated cardiomyocytes in vitro and in vivo. Our study suggests that the differential expression of SLC6A6 in vitro and in vivo models is associated with TIC, which may be a candidate diagnostic gene for the early occurrence and development of TIC and a potential therapeutic target.

The results of in vivo animal experiments also showed that Tra-CM-MSN-PYR significantly inhibited tumor growth. These results indicate that Tra-CM-MSN-PYR has potential application as a targeted therapy for HER2-positive breast cancer in the future.

In patients with pCR who responded to chemotherapy and dual HER2 blockade (TP), the 3-year RFS and brain metastasis-free survival did not differ according to the type of adjuvant anti-HER2 therapy.

Characterizing unresectable, metastatic, or recurrent GC with positive CLDN18.2 expression and evaluating intratumoral heterogeneity and prognostic implications of various therapeutics help advance treatment strategies and develop new therapies for patients with GC.

Here, by performing gene expression profiling in HER2-positive breast cancers from patients receiving adjuvant trastuzumab in the ALTTO clinical trial (NCT00490139), we identify and characterize five molecular subtypes associated with the risk of distant recurrence: immune-enriched, proliferative/metabolic-enriched, mesenchymal/stroma-enriched, luminal, and ERBB2-dependent...Immune-enriched tumors present better survival outcomes, in contrast to mesenchymal/stroma-enriched and proliferative/metabolic-enriched tumors, while luminal and ERBB2-dependent tumors are characterized by low and high rates of pathological complete response, respectively. Of note, these molecular subtypes provide the rationale for treatment approaches leveraging the heterogeneous biology of HER2-positive breast cancer.

These findings might suggest a potential advantage of nab-paclitaxel combined with trastuzumab and pertuzumab compared with the standard regimen in neoadjuvant therapy for patients with HER2-positive early breast cancer, suggesting that this new combination might establish a new standard for neoadjuvant treatment in this patient population.

PIK3CA variants were more frequent in resistant HER2+ BC patients than in responsive patients, with a significant correlation between PIK3CA mutation and a lower pCR rate. PIK3CA variants within exon 9 and 20 (such as Glu545Lys and His1047Tyr respectively) were associated with trastuzumab resistance.

Suppression of EMP3 expression enhanced sensitivity of BC cells to trastuzumab in vitro...Co‑expression of EMP3 and HER2 was positively associated with ER expression (P=0.028) and tended to be associated with nodal metastasis (P=0.085), however this was not significant. Taken together, the present results supported the potential of targeting EMP3 as a novel therapeutic strategy for human BC via co‑expression of HER2 and EMP3.

This study provides initial evidence for trastuzumab's potential therapeutic effects in TNBC, despite low HER2 expression. The observed cytotoxicity, apoptosis induction, and cell cycle modulation in TNBC cells warrant further investigation into trastuzumab's mechanisms of action in HER2-negative contexts and its potential repurposing for TNBC treatment.

Trastuzumab (TZM) is a monoclonal antibody that targets the human epidermal growth factor receptor 2 (HER2) and is clinically used for the treatment of HER2-positive breast tumors...The study demonstrates that FLI is a powerful analytical tool to monitor the delivery of antibodydrugs both in cell cultures and in vivo live systems. Especially, MFLI FRET is a unique imaging modality that can directly quantify target engagement with the potential to elucidate the role of the TME in drug delivery efficacy in intact live tumor xenografts.

Targeting this pathway could overcome resistance and enhance trastuzumab efficacy. Further studies should explore the clinical potential of Hedgehog inhibitors in combination therapies.

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.

Moreover, bioactive Chaga components exerted a synergistic action with cisplatin and with trastuzumab in SK-BR-3 cells by inhibiting both HER2 and HER1 activation and displayed an immunomodulatory effect. Thus, Inonotus obliquus represents a source of triterpenoids that are effective against aggressive BC subtypes and display properties of targeted drugs.

Our findings encourage the exploration of the role of HDAC6 as a prognostic factor and the combinatorial use of HDAC6 selective inhibitors combined with trastuzumab in HER2+ BC, in particular for those patients experiencing drug resistance.

P2, N=45, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

Relapse and metastasis occur in 30-40% of breast cancer patients, even after targeted treatments like trastuzumab for HER2-positive breast cancer...The weighted averaging ensemble approach achieved enhanced performances of 88.46% accuracy, 89.74% precision, 94.59% sensitivity, 73.33% specificity, 92.11% F-Value, 71.07% Mathew's correlation coefficient, and an AUC of 0.903. This framework enables the accurate prediction of relapse and metastasis in HER2-positive breast cancer patients using H&E images and clinical data, thereby assisting in better treatment decision-making.