Combination Of Trastuzumab Research Articles

Efficacy and safety of first-line therapy in patients with HER2-positive advanced breast cancer: a network meta-analysis of randomized controlled trials

PurposeThe numerous first-line treatment regimens for human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) necessitate a comprehensive evaluation to inform clinical decision-making. We conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions.MethodsWe systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts from inception to June 1, 2023. NMA was performed to calculate and analyze progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events of grade 3 or higher (≥ 3 AEs).ResultsOut of the 10,313 manuscripts retrieved, we included 28 RCTs involving 11,680 patients. Regarding PFS and ORR, the combination of trastuzumab with tyrosine kinase inhibitors (TKIs) was more favorable than dual-targeted therapy. If only using trastuzumab, combination chemotherapy is superior to monochemotherapy in terms of PFS. It is important to note that the addition of anthracycline did not result in improved PFS. For patients with hormone receptor-positive HER2-positive diseases, dual-targeted combined with endocrine therapy showed better benefit in terms of PFS compared to dual-targeted alone, but it did not reach statistical significance. The comprehensive analysis of PFS and ≥ 3 AEs indicates that monochemotherapy combined with dual-targeted therapy still has the optimal balance between efficacy and safety.ConclusionMonochemotherapy (Docetaxel) plus dual-target (Trastuzumab and Pertuzumab) therapy remains the optimal choice among all first-line treatment options for ABC. The combination of trastuzumab with TKIs (Pyrotinib) demonstrated a significant improvement in PFS and ORR, but further data are warranted to confirm the survival benefit.

Chinese Society of Clinical Oncology (CSCO) Breast Cancer guidelines 2024.

Developing guidelines for the diagnosis and treatment of common cancers in China based on the evidence-based practice, the availability of diagnosis and treatment products, and the up-to-date advances in precision medicine is one of the basic tasks of the Chinese Society of Clinical Oncology Breast Cancer (CSCO BC) Committee. Protocols with high evidence level and good availability are used as the Level I recommendations; protocols with relatively high evidence level but slightly lower expert consensus or with poor availability are used as the Level II recommendations; and protocols that are clinically applicable but with low evidence level are regarded as the Level III recommendations. Based on the findings of clinical research at home and abroad and the opinions of CSCO BC experts, the CSCO BC guidelines determine the levels of recommendations for clinical application. For human epidermal growth factor receptor 2 (HER2)-positive breast cancer, a combination of trastuzumab and pertuzumab regimen were recommended as Level I recommendation for neoadjuvant and first line metastatic breast cancer. Pyrotinib is also recommended as Level I recommendation in first line and second line therapy according to the latest studies conducted in China. Antibody drug conjugates was also recommended for patients with trastuzumab progression. For triple negative breast cancer, immunotherapy in early and metastatic breast cancer was highlighted and listed as new chapters in this version of guideline. For hormone receptor (HR)-positive breast cancer, cyclin dependent kinase 4/6 (CDK4/6) was recommended in different stages, especially in adjuvant therapy. There was also a new chapter for HER2-low breast cancer stratified by HR status. We firmly believe that evidence-based, availability-concerned, and consensus-based guidelines will be more feasible for clinical practice in China and in other countries with similar situations.

Survival after Trastuzumab Therapy in Patients with Locally Advanced or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Cancer: A Meta-Analysis of Randomized Controlled Trials.

In the Trastuzumab for Gastric Cancer study, it was found that trastuzumab combined with doublet chemotherapy (fluoropyrimidine and platinum) was the gold-standard treatment for gastroesophageal adenocarcinoma (GEA) that was locally advanced, unresectable, or metastatic (HER2+). We performed a meta-analysis of randomized phase II/III studies testing trastuzumab in combination or alone. This meta-analysis's findings involved 2048 patients in total. The treatment arm and hormone receptor status were used to stratify the combined HR. Overall, the PFS (Random model) HR [0.80] and 95% confidence intervals (CI) [0.68-0.95] were significantly higher for regimens containing trastuzumab, fluoropyrimidine, and platinum compared to regimens containing fluoropyrimidine and platinum. The results of this meta-analysis provide additional support for trastuzumab's use in treating HER2-positive GEA, particularly in cases where the disease lacks a HER2+ receptor.

Combination chemotherapy with trastuzumab in early-stage breast cancer: a meta-analysis and Bayesian decision analysis of different treatment regimens.

HER2-positive breast cancer is a high-risk malignant tumor, and trastuzumab is an effective targeted therapy drug, but its optimal duration remains uncertain. To compare the efficacy and cost-effectiveness of different durations (6 months, 9 months, 12 months, and 18 months) of trastuzumab combined with chemotherapy in patients with early breast cancer by meta-analysis and Bayesian decision analysis. Randomized controlled trials comparing the effectiveness of different durations of trastuzumab combination chemotherapy in early-stage breast cancer patients were collected by searching multiple databases. Data synthesis was performed using the R software, and a decision tree model was constructed to simulate the expected outcomes and anticipated costs associated with different treatment durations. This study included 9 randomized controlled trials involving 11,328 early-stage breast cancer patients. The meta-analysis results demonstrated that, compared to the control group, trastuzumab combination chemotherapy at different durations significantly improved disease-free survival and overall survival in early-stage breast cancer patients. Among the various treatment durations, it was observed that 12 months of trastuzumab combination chemotherapy, in comparison to other durations, significantly reduced the risk of recurrence and mortality in early-stage breast cancer patients while maintaining a favorable cost-effectiveness ratio. Bayesian decision analysis also confirmed that 12 months of trastuzumab combination chemotherapy is the optimal treatment duration. It is recommended to use 12 months of trastuzumab combination chemotherapy as the standard treatment for early-stage breast cancer patients.

Generation and Characterization of Trastuzumab/Pertuzumab-Resistant HER2-Positive Breast Cancer Cell Lines.

The combination of trastuzumab and pertuzumab as first-line therapy in patients with HER2-positive breast cancer has shown significant clinical benefits compared to trastuzumab alone. However, despite initial therapeutic success, most patients eventually progress, and tumors develop acquired resistance and invariably relapse. Therefore, there is an urgent need to improve our understanding of the mechanisms governing resistance in order to develop targeted therapeutic strategies with improved efficacy. We generated four novel HER2-positive cell lines via prolonged exposure to trastuzumab and pertuzumab and determined their resistance rates. Long-term resistance was confirmed by a significant increase in the colony-forming capacity of the derived cells. We authenticated the molecular identity of the new lines via both immunohistochemistry for the clinical phenotype and molecular profiling of point mutations. HER2 overexpression was confirmed in all resistant cell lines, and acquisition of resistance to trastuzumab and pertuzumab did not translate into differences in ER, PR, and HER2 receptor expression. In contrast, changes in the expression and activity of other HER family members, particularly HER4, were observed. In the same vein, analyses of the receptor and effector kinase status of different cellular pathways revealed that the MAPK pathway may be involved in the acquisition of resistance to trastuzumab and pertuzumab. Finally, proteomic analysis confirmed a significant change in the abundance patterns of more than 600 proteins with implications in key biological processes, such as ribosome formation, mitochondrial activity, and metabolism, which could be relevant mechanisms in the generation of resistance in HER2-positive breast cancer. We concluded that these resistant BCCLs may be a valuable tool to better understand the mechanisms of acquisition of resistance to trastuzumab and pertuzumab-based anti-HER2 therapy.

COST-EFFECTIVENESS OF COMBINATION ANTI-CANCER DRUG THERAPY IN THE MANAGEMENT OF HER2-POSITIVE BREAST CANCER: A META-ANALYSIS

Objective: The objective of this review article is to conduct a basic meta-analysis to determine the cost-effectiveness of the trastuzumab, pertuzumab, and docetaxel (THP) combination compared to the trastuzumab and docetaxel (TH) alone in the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients. The analysis aims to measure the costs involved and the health outcomes of the therapy to identify the most cost-effective treatment option. Methods: The researchers collected costs and quality-adjusted life years data from studies that investigated the cost-effectiveness of different treatment regimens for HER2-positive breast cancer. A meta-analysis was conducted using these data, and a probabilistic sensitivity analysis with 1000 iterations was performed using an Excel spreadsheet. The input data used in the analysis were obtained from four studies deemed appropriate for the meta-analysis. Results: The outputs obtained from the meta-analysis were plotted on an incremental cost-effectiveness ratio (ICER) scatterplot. The ICER scatter plots of the four studies showed that the THP combination was 0% cost-effective at a willingness to pay (WTP) threshold of I$100,000/QALY and 2.38% cost-effective at a WTP of I$200,000/QALY. However, at a higher WTP of I$500,000/QALY, the THP combination was found to be 52.8% cost-effective compared to the TH combination. Conclusion: Based on the findings of this meta-analysis, the THP combination treatment for HER2-positive breast cancer patients is cost-effective compared to the TH combination at a willingness to pay threshold of I$500,000/QALY. However, at lower WTP thresholds, the THP combination may not be cost-effective. These results provide valuable insights for prescribers in identifying and selecting the most cost-effective treatment option among the alternatives available for HER2-positive breast cancer patients.

Optimal choice of neoadjuvant therapy for HER2-positive breast cancer. Analysis of doctors’ preferences in Russian Federation

The development and introduction into widespread practice of anti-HER2 agents has changed the natural course of HER2-positive breast cancer, significantly increasing the chance of cure in early forms and significantly increasing the life expectancy of patients with metastatic disease. The results of clinical trials indicate a significant increase in the frequency of achieving complete pathological regress and improved survival rates when using the combination of trastuzumab + pertuzumab in neoadjuvant therapy for HER2-positive breast cancer, which is reflected in modern national and international guidelines. However, the use of drugs in real clinical practice is associated with a whole range of factors and may differ from standard recommendations. To understand the situation in the Russian Federation, a survey study ‘Therapy of HER2-positive breast cancer’ was conducted. 50 specialists – heads of drug therapy departments and/or their deputies who are directly involved in the development of a treatment plan for patients, were involved in the survey. It allows to reflect the preferences of leading chemotherapists regarding treatment strategies for patients with HER2-positive breast cancer in Russian Federation. This publication highlights the results of a survey on the prescription of neoadjuvant therapy for primary resectable and locally advanced unresectable HER2-positive breast cancer. Most experts prefer to use combinations with pertuzumab. In real clinical practice, 62% of patients receive dual anti-HER2 therapy. In the future, experts are ready to increase the percentage of prescribing pertuzumab for early HER2-positive breast cancer for more 16–20%. Based on the results of large randomized trials, this should improve long-term outcomes in one of the most aggressive forms of breast cancer.

EE528 Analysis of Non-Pharmacological Cost Savings Derived from the Use of Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Injection in Patients with HER2-Positive Breast Cancer in Spain

EE528 Analysis of Non-Pharmacological Cost Savings Derived from the Use of Fixed-Dose Combination of Pertuzumab and Trastuzumab for Subcutaneous Injection in Patients with HER2-Positive Breast Cancer in Spain

CTNI-08. TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER-2 POSITIVE BREAST CANCER (TUTOR): A MULTICENTER PHASE 1 CLINICAL TRIAL

Abstract BACKGROUND 20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), which are frequently tackled with stereotactic radiosurgery (SRS). Tucatinib, an oral HER-2 selective tyrosine kinase inhibitor (TKI), has demonstrated efficacy for HER-2-positive breast cancer in combination with capecitabine and trastuzumab. We hypothesize that a combinatorial approach for HER-2 positive breast cancer BMs (BCBM) will lead to better long-term control of BMs and systemic disease. METHODS This is an in-progress, prospective, single-arm, multicenter, phase 1 clinical trial that aims to determine the safety of combination of tucatinib, capecitabine, and trastuzumab with SRS in patients with HER-2 positive BCBM. Patients with age 18-80 years, ECOG 0-2, normal organ function, and up to 10 newly-diagnosed BMs are enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. The primary endpoint of the study is the maximum tolerated dose (MTD) of tucatinib with SRS. This de-escalation study starts tucatinib at a dose level of 300 mg BID. Dose level -1 is 250 mg BID and level -2 is 200 mg BID. Upto 40 patients will be enrolled based on a 3 + 3 design. We plan to expand the cohort at MTD to 40 patients to assess the safety and efficacy of the combination. Secondary endpoints include efficacy as determined by response rate, intracranial PFS, extracranial PFS, and overall survival. Patients are administered oral tucatinib with SRS, followed by oral tucatinib for two weeks which is the dose-limiting toxicity (DLT) period. This is followed by tucatinib, trastuzumab, and capecitabine until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and any non-hematologic toxicity of grade 3 or greater (excluding alopecia). The trial started enrollment in February 2023. Trial Information: NCT05553522.

Immune microenvironment dynamics of HER2 overexpressing breast cancer under dual anti-HER2 blockade.

The clinical prognosis of the HER2-overexpressing (HER2-OE) subtype of breast cancer (BC) is influenced by the immune infiltrate of the tumor. Specifically, monocytic cells, which are promoters of pro-tumoral immunosuppression, and NK cells, whose basal cytotoxic function may be enhanced with therapeutic antibodies. One of the standards of care for HER2+ BC patients includes the combination of the anti-HER2 antibodies trastuzumab and pertuzumab. This dual combination was a breakthrough against trastuzumab resistance; however, this regimen does not yield complete clinical benefit for a large fraction of patients. Further therapy refinement is still hampered by the lack of knowledge on the immune mechanism of action of this antibody-based dual HER2 blockade. To explore how the dual antibody challenge influences the phenotype and function of immune cells infiltrating the HER2-OE BC microenvironment, we developed in vitro 3D heterotypic cell models of this subtype. The models comprised aggregates of HER2+ BC cell lines and human peripheral blood mononuclear cells. Cells were co-encapsulated in a chemically inert alginate hydrogel and maintained in agitation-based culture system for up to 7 days. The 3D models of the HER2-OE immune microenvironment retained original BC molecular features; the preservation of the NK cell compartment was achieved upon optimization of culture time and cytokine supplementation. Challenging the models with the standard-of-care combination of trastuzumab and pertuzumab resulted in enhanced immune cytotoxicity compared with trastuzumab alone. Features of the response to therapy within the immune tumor microenvironment were recapitulated, including induction of an immune effector state with NK cell activation, enhanced cell apoptosis and decline of immunosuppressive PD-L1+ immune cells. This work presents a unique human 3D model for the study of immune effects of anti-HER2 biologicals, which can be used to test novel therapy regimens and improve anti-tumor immune function.

A novel nanobody-based HER2-targeting antibody exhibits potent synergistic antitumor efficacy in trastuzumab-resistant cancer cells

Human epithelial growth factor receptor-2 (HER2) plays an oncogenic role in numerous tumors, including breast, gastric, and various other solid tumors. While anti-HER2 therapies are approved for the treatment of HER2-positive tumors, a necessity persists for creating novel HER2-targeted agents to resolve therapeutic resistance. Utilizing a synthetic nanobody library and affinity maturation, our study identified four anti-HER2 nanobodies that exhibited high affinity and specificity. These nanobodies recognized three distinct epitopes of HER2-ECD. Additionally, we constructed VHH-Fc and discovered that they facilitated superior internalization and showed moderate growth inhibition. Compared to the combination of trastuzumab and pertuzumab, the VHH-Fc combos or their combination with trastuzumab demonstrated greater or comparable antitumor activity in both ligand-independent and ligand-driven tumors. Most remarkably, A9B5-Fc, which targeted domain I of HER2-ECD, displayed significantly enhanced trastuzumab-synergistic antitumor efficacy compared to pertuzumab under trastuzumab-resistant conditions. Our findings offer anti-HER2 nanobodies with high affinity and non-overlapping epitope recognition. The novel nanobody-based HER2-targeted antibody, A9B5-Fc, binding to HER2-ECD I, mediates promising receptor internalization. It possesses the potential to serve as a potent synergistic partner with trastuzumab, contributing to overcoming acquired resistance.

The Cost-Effectiveness of Pertuzumab for the Treatment of Metastatic HER2+ Breast Cancer in Czechia: A Semi-Markov Model Using Cost States

ObjectivesThis article estimates the cost-effectiveness of adding pertuzumab to the combination of trastuzumab and docetaxel within the first-line treatment for metastatic breast cancer with the amplification of HER2+. MethodsData from Czech clinical practice recorded in the BREAST register are used. A semi-Markov model with states derived based on the treatment phases (first-line medication, no medication, next-line medication, death) is defined to estimate costs from the healthcare payers’ perspective. The benefits are estimated as patient survival until death. The Kaplan–Meier estimates are supplemented by the Cox proportional hazard and the accelerated failure time models to control for patient characteristics. Health-related quality-of-life indicators are derived from relevant literature. ResultsBased on the used data, adding pertuzumab does not result in statistically significantly longer survival while inducing higher treatment costs (€163 360 compared with €90 112 per patient in 2018 prices). Statistically longer survival was not supported by the log-rank test (P = .97), the Cox proportional hazard model, or the accelerated failure time model using the Gompertz distribution. The incremental cost-effectiveness ratio (€87 200) substantially exceeds the willingness to pay for 1 quality-adjusted life-year (€46 500). ConclusionsThis analysis indicates that adding pertuzumab cannot be considered cost-effective in Czechia. However, the observed phenomenon may be attributed to the limited duration of patient follow-up periods at the time of the study’s execution (mean of 20-21 months). Importantly, we find that using states connected to specific treatment phases is appropriate for a retrospective analysis of patient-level clinical data.

Pembrolizumab and trastuzumab in combination with FLOT in the perioperative treatment of HER2-positive, localized esophagogastric adenocarcinoma-a phase II trial of the AIO study group (AIO STO 0321).

Esophagogastric adenocarcinoma (EGA) presents a substantial global health challenge as the number of cases continues to rise. The current standard approach for treating localized EGA involves a combination of triplet chemotherapy, which consists of a platinum compound, a fluoropyrimidine, and a taxane (known as FLOT), followed by surgery. In cases of metastatic EGA with HER2-positive status or in certain studies with localized EGA, the use of HER2-targeted antibodies such as trastuzumab has shown improved responses. Recently, the addition of programmed cell death protein 1 (PD-1) inhibitors, such as pembrolizumab, when combined with 5-FU, platinum-based chemotherapy, and trastuzumab, has demonstrated significant enhancements in response rates for HER2-positive metastatic EGA. However, there is currently insufficient evidence regarding this treatment approach in localized HER2-positive disease. The PHERFLOT study is an open-label, single-arm, multicenter, exploratory phase II trial designed to assess the efficacy, safety, and tolerability of perioperative pembrolizumab, FLOT, and trastuzumab in patients with previously untreated localized HER2-positive EGA. In total, 30 patients will be recruited. The co-primary end points are pathological complete response rate and disease-free survival rate after 2 years. Secondary objectives include safety and tolerability, efficacy in terms of progression-free survival and objective response rate and translational markers, such as blood-based signatures (e.g., immune repertoire changes or emergence of anti-HER2 resistance variants) or microbiota signatures that may correlate with immune activation and therapy response. Recent evidence from phase II clinical trials demonstrated improved efficacy through the addition of trastuzumab to perioperative FLOT. Furthermore, in advanced or metastatic EGA, the combination of trastuzumab, FLOT, and the PD1-inhibitor pembrolizumab significantly improved treatment response. The PHERFLOT study aims to assess the efficacy and safety of this treatment approach in HER2-positive-localized EGA, potentially identifying a promising new perioperative regimen for localized EGA, which then needs to be confirmed within a randomized trial. Furthermore, the accompanying translational program of the study might help to improve the stratification of suitable patients and to identify potential translational targets for future clinical trials. https://clinicaltrials.gov, identifier NCT05504720.

Pruritus related to trastuzumab and pertuzumab in HER2 + breast cancer patients

PurposeThe combination of trastuzumab and pertuzumab (HP) as part of a taxane-based regimen has shown benefit in the adjuvant and metastatic HER2 + breast cancer setting. In the CLEOPATRA trial, pruritus was reported in 11-17.6% of patients. The clinical phenotype and potential treatment strategies for this event have not been reported.MethodsA retrospective review of 2583 patients receiving trastuzumab and pertuzumab for the treatment of HER2 + breast cancer from 11/23/2011 to 6/21/2021 was performed at Memorial Sloan Kettering Cancer Center (MSKCC). Patient demographics, pruritus characteristics, and treatments as documented in the electronic medical record (EMR) were included in this analysis.ResultsOf 2583 pts treated with HP, 122 (4.72%) with pruritus were identified. On average, patients experienced pruritus 319.0 days (8-3171) after initiation of HP. The upper extremities (67.4%), back (29.3%), lower extremities (17.4%), and shoulders (14.1%) were the most commonly affected regions. Grade 1/2 pruritus (97.6%) occurred in most cases. Patients responded primarily to treatment with topical steroids (52.2%), antihistamines (29.9%), emollients (20.9%), and gabapentinoids (16.4%). Of those with pruritus, 4 patients (3.3%) required treatment interruption or discontinuation.ConclusionsPruritus is uncommon in patients on trastuzumab and pertuzumab, generally a chronic condition, with gabapentinoids or antihistamines representing effective therapies.

Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with HR+, HER2+ advanced breast cancer: plain language summary of the monarcHER study.

This article summarizes the results of a study called monarcHER. The study included participants with a certain type of aggressive breast cancer called HR+, HER2+ advanced breast cancer (ABC) that had their disease worsen or return after multiple previous therapies. This summary intends to help you understand the impact of a non-chemotherapy treatment called abemaciclib in people with HR+, HER2+ ABC. When the study was planned, HER2-targeted therapy (ie trastuzumab) was standard treatment and was typically combined with chemotherapy and endocrine therapy (ie fulvestrant). However drug resistance can develop when HER2+ targeted therapy is used for a long time, making it less effective and allowing cancer to grow or spread to other parts of the body. When this happens, few chemotherapy-free options are available. Because of the chemotherapy side effects, this is not desirable. There is an urgent need to develop new, effective, safe, and tolerable treatment options for patients with HR+, HER2+ ABC. The monarcHER study compared the effects of abemaciclib plus trastuzumab with or without fulvestrant compared to the standard of care treatment. Participants were randomly assigned to 1 of 3 groups: Group A (abemaciclib, trastuzumab and fulvestrant), Group B (abemaciclib and trastuzumab), or Group C (trastuzumab and standard of care chemotherapy). The study compared the length of time patients took study treatments without worsening or dying from their breast cancer. This is called the progression free survival (PFS). Participants in Group A had a longer median PFS than those in groups B and C (8.3months, 5.7months and 5.7months respectively). There was no notable difference in PFS between participants in Groups B and C. Additionally, the study looked at the side effects with each treatment group. The most common side effect which is considered severe or lifethreatening was neutropenia, defined as decreased white blood cell levels. Neutropenia may lead to an increased risk of getting infections. However, the percentage of patients experiencing neutropenia was similar in all groups A, B and C (27%, 22% and 26%, respectively). Patients in groups A (79%) and B (78%) who received abemaciclib experienced similar rates of diarrhea. The data from the monarcHER study suggest that the combination of abemaciclib, trastuzumab, and fulvestrant may offer a chemotherapy-free option for patients with HR+, HER2+ ABC who have experienced worsening of disease despite multiple prior therapies.

Does Dual Anti-HER2 Therapy Increase Early Cardiac Toxicity in Comparison with Trastuzumab Alone in Breast Cancer Patients Receiving Adjuvant Radiotherapy? A Multicenter Retrospective Study

Adjuvant trastuzumab in combination with RT has proved its safety in terms of cardiac events. Dual anti-HER2 therapy with pertuzumab is currently standard adjuvant therapy in N+ and high-risk N0 early breast cancer (BC) patients. Our study aims to find if it increases early cardiac toxicity compared with trastuzumab alone in BC patients receiving adjuvant radiotherapy. Operable BC patients who received adjuvant radiotherapy (RT) and trastuzumab with or without pertuzumab between January 2017 and September 2020 in 7 Chinese centers were retrospectively reviewed. The cardiac examination included ultrasonography, electrocardiogram (ECG), NT-proBNP, and cTnI before RT and during follow-up. The cardiac event was any new-onset symptomatic heart disease or abnormality in the cardiac examination after RT. In total, 711 patients with a median age of 52 years were included, of whom 567 (79.7%) patients were treated with trastuzumab-only and 144 (20.3%) patients received dual anti-HER2 therapy. Adjuvant RT was given concurrently in 140/144 (97.2%) of dual anti-HER2 therapy and 562/567 (99.1%) of trastuzumab alone, respectively. With a median follow-up of 11 months, no patients developed symptomatic heart diseases. Among patients with normal baseline, 17 (2.4%), 86 (12.1%), 18 (2.5%) and 14 (7.3%) developed new-onset diastolic dysfunction, left ventricular ejection fraction (LVEF) decline, abnormal ECG, and abnormal NT-proBNP, respectively. No significant difference was found between the trastuzumab-only and dual anti-HER2 cohort in the incidence of all kinds of new-onset cardiac events (all p > 0.1). Multivariate analysis showed that left-sided (vs right-sided) RT significantly increased the risk of ECG abnormality (HR = 2.32, 95% CI 1.62-3.32, p<0.001). Increased age was an independent risk factor for diastolic dysfunction (HR = 1.1, 95% CI 1.02-1.18, p = 0.0098). Dosimetric analysis showed that patients who developed any cardiac events had increased mean heart dose (397.67±251.08 vs 344.87±236.75 cGy, p = 0.032). A significant increase in risk of cardiac events was found in patients with mean heart dose > 450 cGy (HR = 1.55, 95% CI 1.17-2.05, p = 0.0024), V5 > 26% (HR = 1.51, 95% CI 1.09-2.09, p = 0.013), and V30 > 5.5% (HR = 1.49, 95% CI 1.09-2.04, p = 0.0117), respectively. Further analysis was done in the subgroup of patients treated with left-sided RT, internal mammary nodes RT, or anthracyclines, no difference in risk of cardiac events was found between trastuzumab alone and dual anti-HER2 therapy in concurrent with RT (all p > 0.05). Compared with trastuzumab-only, dual anti-HER2 therapy does not increase early cardiac toxicity in combination with adjuvant RT in BC patients. Cardiac radiation exposure remains the primary risk factor associated with early cardiac toxicity.

P70S6K/Akt dual inhibitor DIACC3010 is efficacious in preclinical models of gastric cancer alone and in combination with trastuzumab

The PI3K-Akt-mTOR (PAM) pathway is implicated in tumor progression in many tumor types, including metastatic gastric cancer (GC). The initial promise of PAM inhibitors has been unrealized in the clinic, presumably due, in part, to the up-regulation of Akt signaling that occurs when the pathway is inhibited. Here we present that DIACC3010 (formerly M2698), an inhibitor of two nodes in the PAM pathway, p70S6K and Akt 1/3, blocks the pathway in in vitro and in vivo preclinical models of GC while providing a mechanism that inhibits signaling from subsequent Akt up-regulation. Utilizing GC cell lines and xenograft models, we identified potential markers of DIACC3010-sensitivity in Her2-negative tumors, i.e., PIK3CA mutations, low basal pERK, and a group of differentially expressed genes (DEGs). The combination of DIACC3010 and trastuzumab was evaluated in Her2-positive cell lines and models. Potential biomarkers for the synergistic efficacy of the combination of DIACC3010 + trastuzumab also included DEGs as well as a lack of up-regulation of pERK. Of 27 GC patient-derived xenograft (PDX) models tested in BALB/c nu/nu mice, 59% were sensitive to DIACC3010 + trastuzumab. Of the 21 HER2-negative PDX models, DIACC3010 significantly inhibited the growth of 38%. Altogether, these results provide a path forward to validate the potential biomarkers of DIACC3010 sensitivity in GC and support clinical evaluation of DIACC3010 monotherapy and combination with trastuzumab in patients with HER2- negative and positive advanced GCs, respectively.

Defucosylated Monoclonal Antibody (H2Mab-139-mG2a-f) Exerted Antitumor Activities in Mouse Xenograft Models of Breast Cancers against Human Epidermal Growth Factor Receptor 2.

The clinically approved human epidermal growth factor receptor 2 (HER2)-targeting monoclonal antibodies (mAbs), trastuzumab, and pertuzumab, target domains IV and II, respectively. Trastuzumab is now the standard treatment for HER2-overexpressed breast and gastric cancers, and trastuzumab in combination with pertuzumab showed clinical benefit. However, there still exist patients who do not respond to the therapy. Furthermore, HER2 mutants that cannot be recognized by pertuzumab were found in tumors. Therefore, novel anti-HER2 mAbs and modalities have been desired. In our previous study, we developed a novel anti-HER2 domain I mAb, H2Mab-139 (mouse IgG1, kappa). We herein produced a defucosylated mouse IgG2a type of mAb against HER2 (H2Mab-139-mG2a-f) to enhance antibody-dependent cellular cytotoxicity (ADCC)-mediated antitumor activity. H2Mab-139-mG2a-f exhibits a high binding affinity in flow cytometry with the dissociation constant (KD) determined to be 3.9 × 10-9 M and 7.7 × 10-9 M against HER2-overexpressed Chinese hamster ovary (CHO)-K1 (CHO/HER2) and HER2-positive BT-474 cells, respectively. Moreover, we showed that H2Mab-139-mG2a-f exerted ADCC and complement-dependent cytotoxicity against CHO/HER2 and BT-474 in vitro and exhibited potent antitumor activities in mouse xenograft models. These results indicated that H2Mab-139-mG2a-f exerts antitumor effects against HER2-positive human breast cancers and is useful as an antibody treatment for HER2-positive human cancers.

Pretreatment 18F‐FDG uptake heterogeneity may predict treatment outcome of combined Trastuzumab and Pertuzumab therapy in patients with metastatic HER2 positive breast cancer

ObjectiveIntra-tumoral heterogeneity of 18F‐fluorodeoxyglucose (18F‐FDG) uptake has been proven to be a surrogate marker for predicting treatment outcome in various tumors. However, the value of intra-tumoral heterogeneity in metastatic Human epidermal growth factor receptor 2(HER2) positive breast cancer (MHBC) remains unknown. The aim of this study was to evaluate 18F‐FDG uptake heterogeneity to predict the treatment outcome of the dual target therapy with Trastuzumab and Pertuzumab(TP) in MHBC.MethodsThirty-two patients with MHBC who underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) scan before TP were enrolled retrospectively. The region of interesting (ROI) of the lesions were drawn, and maximum standard uptake value (SUVmax), mean standard uptake value (SUVmean), total lesion glycolysis (TLG), metabolic tumor volume (MTV) and heterogeneity index (HI) were recorded. Correlation between PET/CT parameters and the treatment outcome was analyzed by Spearman Rank Test. The ability to predict prognosis were determined by time‐dependent survival receiver operating characteristic (ROC) analysis. And the survival analyses were then estimated by Kaplan‐Meier method and compared by log‐rank test.ResultsThe survival analysis showed that HI50% calculated by delineating the lesion with 50%SUVmax as threshold was a significant predictor of patients with MHBC treated by the treatment with TP. Patients with HI50% (≥ 1.571) had a significantly worse prognosis of progression free survival (PFS) (6.87 vs. Not Reach, p = 0.001). The area under curve (AUC), the sensitivity and the specificity were 0.88, 100% and 63.6% for PFS, respectively.Conclusion18F-FDG uptake heterogeneity may be useful for predicting the prognosis of MHBC patients treated by TP.

Anthracyclines and trastuzumab associated cardiotoxicity: is the gut microbiota a friend or foe? – a mini-review

Breast cancer (BC) is one of the most prevalent cancers worldwide. Fortunately, BC treatment has taken a huge turn in the last few years. Despite these advances, one of the main issues related to systemic treatment remains the management of its side effects, including cardiotoxicity. In this regard, we highlight the irreversible dose-dependent cardiotoxicity of anthracyclines related to oxidative stress and the reversible cardiotoxicity with trastuzumab, whose mechanism is still poorly understood. Moreover, the combination of anthracyclines and trastuzumab further exacerbate the myocardial damage. More recently, altered gut microbiota composition has been linked to the long-term effects of cancer therapy, including the potential connection between treatment-related microbial changes and cardiotoxicity. Bacteroides spp., Coriobacteriaceae_UGC-002, and Dubosiella have already been reported as bacterial species with deleterious effects on the myocardium, mainly due to the promotion of inflammation. On the other hand, Alloprevotella, Rickenellaceae_RC9, Raoultella planticola, Klebsiella pneumoniae, and Escherichia coli BW25113 can induce cardioprotection, predominantly by increasing anti-inflammatory cytokines, promoting intestinal barrier integrity and early metabolization of doxorubicin. Herein, we explore the role of gut microbiota in the development of cardiotoxicity, as well as future perspectives to decrease the risk of cardiotoxicity associated with BC treatment.