HER2-positive Breast Cancer Patients Research Articles

EXTH-63. FOCUSED ULTRASOUND HYPERTHERMIA MEDIATED CONTROL OF THERMAL RESPONSIVE CAR T CELL ACTIVITY IN BREAST CANCER BRAIN METASTASIS

Abstract HER2-targeted therapies are promising treatment options for metastatic breast cancer and have improved the median overall survival. However, breast cancer brain metastasis (BCBM), observed in up to 50% of HER2-positive breast cancer patients, remains a clinical challenge. While Chimeric Antigen Receptor (CAR) T cell therapy is promising therapeutic strategy to address the unmet need in treating BCBM, improving its effectiveness and safety is critical for clinical translation. We hypothesized that spatially and temporally controlled activity of CAR-T cells with a thermal gene switch (TS) under MRI-guided focused ultrasound (MRgFUS) would potentiate anti-tumor responses in difficult-to-treat BCBM. To test our hypothesis, we developed a closed-loop controlled MR-thermometry (MRTI) based FUS system (MRgFUS) and αHER2 CAR-T cells engineered with TS expressing the reporter gene firefly luciferase (TS.Fluc) or bi-specific engager on NKG2D ligands (TS.BTE) upon MRgFUS-hyperthermia (41.5°C). In vivo quantification of TS activity from intratumorally delivered TS.Fluc αHER2 CAR-T cells in HER2+ BCBM mice model (HER2+ MDA-MB-468 in NSG mice with primary human CAR-T cells) followed by pulsed MRgFUS-hyperthermia resulted in a ~10-fold increase in luminescent activity compared to unheated mice. To assess longitudinal activation, we quantified TS activity with a second sonication 4 days post the initial FUS treatment. Prior to the second sonication, TS.Fluc expression had returned to baseline levels, while following it robust TS.Fluc expression was observed again, demonstrating that MRgFUS can activate engineered T cells with TS in brain tumors with high spatiotemporal control. Subsequently we investigated the therapeutic efficacy of intratumorally delivered TS.BTE αHER2 CAR T cells in mixed tumor model of heterogeneous HER2 MDA-MB-468 (75% HER2+) and observed significant tumor regression of HER2- tumor cells in the treated group compared to controls, demonstrating the potential of the proposed strategy to noninvasively drive the local production of key transgenes and potentiate anti-tumor responses in difficult-to-treat BCBM.

Cost minimization analysis of treatments for metastatic HER2-positive breast cancer in Peru: Fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injections

The main objective of this study is to determine whether the employment of fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC; and Phesgo as brand name) to treat metastatic HER2-positive breast cancer patients would minimize costs compared to the traditional treatment of separate intravenous doses of pertuzumab and trastuzumab in Peru. To achieve this, we used EsSalud (the social security health insurance) data and assessed it through a mixed strategy, which consisted of a quantitative and a qualitative approach. The first one aimed to calculate the direct (non-drug consumables, drugs, and healthcare professionals) and indirect costs of both treatments to develop a comparison, whilst the second aimed to validate information and internalize the procedure in an EsSalud context. Overall, we found that the usage of PH FDC SC would be cost saving in EsSalud’s context. Specifically, we found three main advantages. Firstly, PH FDC SC generates a savings of 62% in non-drug consumables, which helps alleviate the healthcare system budget constraint. Secondly, its adoption frees up 61 hours of treatment and observation time for a single patient per year, which in turn increases the attention capacity of the healthcare system in terms of nursing hours and chemotherapy couches. Thirdly, the reduction of clinic time supposes an advantage for the patient in the form of increased productivity and well-being. Hence, the adoption of this drug would improve the quality of life of patients while reducing costs and pressure on the healthcare system. This is aligned with the strategy of prioritizing the appropriate breast cancer treatment within the National Cancer Care Plan. In this regard, we also found that the savings produced from switching from the traditional intravenous treatment to the subcutaneous one would allow EsSalud to afford full annual costs of 2 additional treatments, but without increasing their budget. This would cover 7% of the gap of 29 patients who do not have access to full treatment.

Efficacy and Safety Profile of Different Schedules of Adjuvant Trastuzumab Therapy among Patients with HER2-Positive Breast Cancer: Real-World Experience from a Tertiary Cancer Center in South India

One year of adjuvant trastuzumab is the standard of care for HER2-positive breast cancer. In low–middle income countries, delivery of 1-year trastuzumab is challenging due to significant financial burden. Evidence for shorter durations of adjuvant trastuzumab is gaining popularity in this regard. In this study, we compared the effectiveness and safety of 1 year versus shorter durations of adjuvant trastuzumab practiced in our center. In total, 312 patients were included in this analysis. The median age was 52 years. More than two-thirds of patients (67.6%) had stage 2 disease and majority were hormone-receptor-positive (62.5%). The median follow-up duration was 50 months. The 4-year disease-free survival was 97.3%. The 4-year disease-free survival for shorter durations of adjuvant trastuzumab was 98% compared with 96.7% in 1-year trastuzumab therapy group. In univariate analysis, stage at diagnosis was the only factor which had statistically significant association with disease-free survival. In multivariate analysis, none of the variables were found to be predictive of survival. Two patients (0.6%) had significant left ventricular ejection fraction decline.Shorter durations of adjuvant trastuzumab have comparable 4-year disease-free survival to standard 1-year therapy and is an alternative adjuvant treatment option for HER2-positive breast cancer patients in resource-limited settings.

Evaluation of early cardiotoxicity in HER2-positive breast cancer patients receiving radiotherapy and concurrent trastuzumab.

Overexpression of human epidermal growth factor receptor 2 (HER-2) is associated with aggressive disease in breast cancer. Trastuzumab and radiotherapy are standard treatments for patients with HER-2 + breast cancer, but they may increase the risk of cardiotoxicity. This study aimed to assess early cardiotoxicity in patients receiving radiotherapy (RT) and concurrent trastuzumab. The study included 116 patients with HER-2 + breast cancer who received concurrent treatment with trastuzumab and RT (52 right-side; 64 left-side). Five left ventricular ejection fraction (LVEF) measurements were performed: one before treatment and four subsequent measurements taken at three-month intervals. LVEF was also assessed before (preRT-EF) and after (postRT-EF) radiotherapy. The baseline LVEF was 62.27 ± 5.5%, while the 12-month LVEF was 59.8 ± 5.8% (p < 0.05). In subgroups, post-RT LVEF values ​​were significantly lower than pre-RT LVEF values (p < 0.05). No significant difference was found between the reduction in LVEF for patients receiving 50Gy and 60Gy doses. Moreover, the contribution of regional lymph node irradiation to the decrease in LVEF could not be demonstrated. A positive correlation was found between the total trastuzumab dose and the decrease in LVEF from preRT to postRT. Additionally, a positive correlation was observed between the total taxane dose and the reduction in LVEF from baseline to 9months, both in the overall group and in the left breast cancer group. In our study,it was found that not only trastuzumab but also taxane-based agents could be cardiotoxic. However, no connection was found between RT doses and the decrease in LVEF.

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.

Real-world outcomes of pyrotinib-based therapy for HER2-positive breast cancer with brain metastases: A multicentre, retrospective analysis

ObjectiveThis study was designed to investigate the efficacy and safety of pyrotinib-based therapy for HER2-positive breast cancer with brain metastases (BM) in the real-world setting. MethodsData of HER2-positive breast cancer patients with BM treated with pyrotinib-based therapy from a multicetre, registered, real-world study were analyzed. ResultsAmong 45 female patients, the overall objective response rate (ORR) was 62.2%, higher in 1st/2nd-line than ≥3rd-line (71.0% vs. 42.9%, P=0.072). The objective response rate of intracranial lesions (CNS-ORR) was 71.1 %, with a significantly higher CNS-ORR observed in the 1st or 2nd-line subgroup compared to that of ≥3rd-line subgroup (83.9% vs. 42.9%, P<0.05). By the end of follow-up, 20 patients (44.4%) died, and the 1-year survival rate was 73.3%. The median progression-free survival (PFS) was 9.1 months (95% CI 6.7-11.5). Patients with 1 or 2 BM had a longer median PFS of 12.0 months compared to 7.7 months for those with ≥3 BM (P=0.01). In addition, 1- or 2-line therapy and full dose exposure of pyrotinib of 320mg-400mg/day were associated with improved median PFS (all P>0.05). The median intracranial PFS (CNS-PFS) was 11.4 months (95% CI 7.5-15.3). However, local intervention plus systemic treatment seemed to prolong CNS-PFS compared with systemic treatment alone (13.7 vs. 9.1 months, P=0.128). Diarrhea was most common (88.9%), 24.4% grade 3. ConclusionsThe pyrotinib-based therapy is effective for HER-2 positive breast cancer with BM, especially in 1st- or 2nd-line treatment, with tolerable adverse events. However, insufficient dosing of pyrotinib may impair efficacy outcomes.Micro Abstract: This study is aimed to investigate the efficacy and safety of pyrotinib-based chemotherapy against human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases (BM) in the real-world setting. The clinical outcome data of HER2-positive breast cancer patients with BM treated with pyrotinib-based therapy from a multicenter, registered, real-world study were comprehensively analyzed. Our study showed that the pyrotinib-based therapy could be effective for HER-2-positive breast cancer with BM, especially in first- or second-line treatments, with tolerable adverse events.

Single Vesicle Surface Protein Profiling and Machine Learning-Based Dual Image Analysis for Breast Cancer Detection.

Single-vesicle molecular profiling of cancer-associated extracellular vesicles (EVs) is increasingly being recognized as a powerful tool for cancer detection and monitoring. Mask and target dual imaging is a facile method to quantify the fraction of the molecularly targeted population of EVs in biofluids at the single-vesicle level. However, accurate and efficient dual imaging vesicle analysis has been challenging due to the interference of false signals on the mask images and the need to analyze a large number of images in clinical samples. In this work, we report a fully automatic dual imaging analysis method based on machine learning and use it with dual imaging single-vesicle technology (DISVT) to detect breast cancer at different stages. The convolutional neural network Resnet34 was used along with transfer learning to produce a suitable machine learning model that could accurately identify areas of interest in experimental data. A combination of experimental and synthetic data were used to train the model. Using DISVT and our machine learning-assisted image analysis platform, we determined the fractions of EpCAM-positive EVs and CD24-positive EVs over captured plasma EVs with CD81 marker in the blood plasma of pilot HER2-positive breast cancer patients and compared to those from healthy donors. The amount of both EpCAM-positive and CD24-positive EVs was found negligible for both healthy donors and Stage I patients. The amount of EpCAM-positive EVs (also CD81-positive) increased from 18% to 29% as the cancer progressed from Stage II to III. No significant increase was found with further progression to Stage IV. A similar trend was found for the CD24-positive EVs. Statistical analysis showed that both EpCAM and CD24 markers can detect HER2-positive breast cancer at Stages II, III, or IV. They can also differentiate individual cancer stages except those between Stage III and Stage IV. Due to the simplicity, high sensitivity, and high efficiency, the DISVT with the AI-assisted dual imaging analysis can be widely used for both basic research and clinical applications to quantitatively characterize molecularly targeted EV subtypes in biofluids.

FCGR3A V158F gene polymorphism and trastuzumab response in HER2-positive breast cancer patients

Breast cancer is considered a multifactorial disease, with genetic factors playing an important role in diagnosis and treatment. FCGR3A encodes the receptor for the Fc portion of immunoglobulin G that has been linked to the trastuzumab response. Our study aimed to investigate the association of FCGR3A-V158F gene polymorphism with breast cancer and to evaluate the impact of FCGR3A-V158F gene polymorphism on trastuzumab response in HER2-positive breast cancer patients. The study was conducted on eighty breast cancer patients who were collected from the Department of Oncology at Ain Shams University Hospitals; in addition, twenty age-matched healthy subjects were taken as a healthy control group. Patients were further sub-classified according to their responses. The study showed that there were no statistically significant differences between patients and controls regarding FCGR3A-V158F gene polymorphism genotypes. However, there was a significant association between the concordance of this polymorphism and the response to trastuzumab therapy among the patient’s group. V/V is associated with better treatment response and overall survival (OS) compared to F/V and F/F alleles. Assessment of FCGR3A-V158F gene polymorphism might be useful in making a treatment decision in HER2-positive breast cancer patients.

Changes in blood metabolomes as potential biomarkers for severity and prognosis in doxorubicin-induced heart failure: a study in HER2-positive and HER2-negative breast cancer patients

Abstract Background The use of doxorubicin for breast cancer treatment is often limited due to cardiotoxicity. Doxorubicin was shown to cause the alterations of cardiac metabolome levels in doxorubicin-treated rats. Interestingly, these changes were robustly associated with the development of doxorubicin-induced heart failure. Unfortunately, measurements of cardiac metabolome levels are rarely possible in humans. Hence, non-invasive biomarkers as representatives of doxorubicin-induced heart failure are required in clinical research and practice. Human epidermal growth factor receptor 2 (HER2) is a point of interest in breast cancer treatment. HER2 is associated with tumor aggressiveness. However, it was observed that HER2 protected against systemic oxidative stress and dilated cardiomyopathy. Therefore, we hypothesized that the alterations of blood metabolome levels and cardiac functions following doxorubicin treatment were different between HER2-positive and HER2-negative breast cancer patients. Purpose We determined the potential roles of changes in blood metabolomes as severity and prognostic markers of doxorubicin-induced heart failure. In addition, the changes in blood metabolomes and cardiac parameters following doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients were compared. Methods HER2-positive (n=37) and HER2-negative (n=37) breast cancer patients were enrolled. Echocardiography, heart rate variability, and blood collection were performed at baseline and 2 weeks after completion of doxorubicin treatment in all patients, as well as at 3 months after completion of doxorubicin treatment in HER2-negative breast cancer patients. Blood obtained at all 3 time points was processed for measuring cardiac injury markers. Blood obtained at baseline and 2 weeks after completion of doxorubicin treatment was also processed for measuring oxidative stress in peripheral blood mononuclear cells using flow cytometry and 85 metabolome levels in plasma using mass spectrometry-based targeted metabolomics. Results Cardiac injury and systolic dysfunction at 2 weeks after completion of doxorubicin treatment were comparable between HER2-positive and HER2-negative breast cancer patients. However, only HER2-negative breast cancer patients exhibited increased systemic oxidative stress and cardiac autonomic dysfunction at this time point. Moreover, 33 and 29 blood metabolomes were altered at 2 weeks after completion of doxorubicin treatment in HER2-positive and HER2-negative breast cancer patients, respectively (Figure). Interestingly, the changes in most of these metabolomes were correlated with the changes in cardiac parameters, both at 2 weeks and 3 months after completion of doxorubicin treatment (Figure). Conclusions The changes in blood metabolomes following doxorubicin treatment were dependent on HER2 status, which might be served as severity and prognostic markers of doxorubicin-induced heart failure.

Serum Exosomes Expressing CD9, CD63 and HER2 From Breast-Cancer Patients Decreased After Surgery of the Primary Tumor: A Potential Biomarker of Tumor Burden.

Exosomes are extracellular vesicles produced by both normal and cancer cells. Previous research has demonstrated that circulating exosomes derived from cancer cells may create a niche for future metastasis, distant from the primary tumor. In the present report, circulating exosomes were captured and quantified based on exosome-surface proteins in pre- and post-operative serum of breast cancer patients, focusing on the exosome markers CD9 and CD63, as well as HER2, a therapeutic target for breast cancer. Eight breast cancer patients were recruited, and their pre- and post-operative serum samples were analyzed for CD63 and CD9; or CD9 and human epidermal growth factor receptor-2 (HER2), double-positive exosomes. An ExoCounter with antibody-conjugated beads was used to capture serum-derived exosomes. Sera from patients with tumors larger than 10 mm were used for analysis. The resected breast cancer was also histopathologically analyzed for the presence of HER2. CD63 and CD9 double-positive serum exosomes and CD9 and HER2 double-positive serum exosomes decreased after surgery in breast-cancer patients whose tumors expressed HER2, as determined by histopathological analysis. Serum exosomes expressing CD9, CD63 and HER2 are candidate biomarkers of tumor burden in HER2-positive breast-cancer patients.

Examining cardiac toxicity in HER2-positive breast cancer patients using trastuzumab and its influencing factors at Iran Hospital.

Trastuzumab is primarily utilized in the treatment of patients with human epidermal growth factor receptor 2 (HER2) positive breast cancer. This study aimed to investigate the incidence of cardiac toxicity associated with trastuzumab in HER2-positive breast cancer patients at Iran Hospital in 2023, as well as the factors influencing this toxicity. In this cross-sectional study, 200 patients diagnosed with HER2-positive breast cancer and receiving trastuzumab were included. The criteria for heart failure in this study were defined as an ejection fraction (EF) of less than 50% or a decrease of greater than 10% in EF. Descriptive statistics, the chi-square statistical test, Fisher's exact test, and logistic regression analyses were employed to assess the variables. A p-value of less than 0.05 was deemed statistically significant. The mean age of the participants was 51.5 ± 2.5 years. The odds ratio (OR) for the variable of anthracyclines was 1.3 (95% CI: 1.2-1.4); for opium use, the OR was 2.7 (95% CI: 0.9-8.5); for diabetes, the OR was 2.7 (95% CI: 1.2-5.9); for ischemic heart disease, the OR was 3.5 (95% CI: 1.6-7.7); and for hypertension, the OR was 4.8 (95% CI: 2.1-10.7). The OR for obesity was 1.45 (95% CI: 1.01-2.18), and the OR for age was 1.10 (95% CI: 1.01-1.12). No statistically significant association was found between opium use and cardiotoxicity (p = 0.07). This research contributes to the identification of factors that may predict responses to anthracyclines and the potential for cardiotoxicities. Ultimately, this information could inform the development of more personalized treatment strategies.

HER2-low non-metastatic breast cancer in Qatar-a nationwide retrospective cohort study to evaluate the response to neoadjuvant chemotherapy: a real-world analysis.

Globally, breast cancer is the most prevalent cancer and one of the leading causes of cancer-related death among women. HER2-low breast cancer represents a recently identified molecular category within breast cancer characterized by tumors displaying only slight overexpression of HER2 or lacking gene amplification. To illustrate, HER2-low tumors typically have an IHC (immune histochemistry) score of 1+ or 2+ with negative amplification. Nonetheless, recent findings indicate that even a slight amplification of HER2 could notably influence both therapeutic responses and prognostic outcomes. Our study aims to unveil the impact of HER2-low expression on the response to anthracycline and taxane-based neoadjuvant chemotherapy (NACT) in comparison to the HER2-negative group in non-metastatic breast cancer. This is a retrospective cohort study. All patients' profiles with non-metastatic, HER2-low, and HER2-negative breast cancers who were administered neo-adjuvant chemotherapy and had surgery performed within the period spanning from 1 January 2018 to 30 August 2022 were enrolled. HER2-positive breast cancer patients were excluded. The evaluation of patients' responses was conducted through the examination of surgical pathology reports to compare the two study groups (HER2-low and HER2-negative). The primary objective was evaluating the response to NACT comparing the objective response rate (ORR) in each of the two groups of HER2-low and HER2-negative patients. The total number of patients included was 262 patients; the majority were HER2-low 89% (233/262) vs. 11% (29/262) HER2-negative. An ORR (complete and partial response) to NACT was shown in 71% (185/262) of all patients. The ORR was similar in both groups, 70% (164/233) in the HER2-low group vs. 73% (21/29) in the HER2-negative group, with a statistical difference, OR: 1 (95% CI: 0.8-1), p-value 0.8. Similarly, the pathological complete response (pCR) rate was the same in both study groups at 14%, OR: 0.7 (95% CI: 0.2-3), p-value: 0.6. Interestingly, patients with hormone-positive tumors across both study groups had a higher response rate compared to hormone-negative patients. In the HER2-low cohort, the ORR was higher in patients with hormone-positive tumors in comparison with those with hormone-negative tumors [73% vs. 27%, OR: 0.8 (95% CI:0.8-1), p-value: 0.001]. Comparatively, in the HER2-negative cohort, ORR was also higher in patients with hormone-positive tumors compared to hormone-negative tumors [52% vs. 48%, OR: 2 (95% CI: 1-5), p-value: 0.05]. Subsequently, the ORR of all hormone-positive tumors with a positive outcome (CR or PR) was assessed categorizing the patients based on their HER2 expression. Concerning patients who expressed partial response (N = 115), a statistically significant difference was observed in HER2- low hormone-positive tumors as opposed to HER2-negative hormone-positive tumors [90% vs. 10%, OR: 0.7 (95% CI: 0.5-0.9), p-value: 0.001]. Remarkably, all patients with complete responses were from the HER2-low cohort. Our findings demonstrated a significant influence of HER2-low expression on the response to neoadjuvant chemotherapy among patients with hormone-positive HER2-low breast cancer within the studied cohort. Further studies are needed to evaluate the influence of hormonal expression on the response rate to NACT in the HER2-low patients in our population.

Impact of trastuzumab emtansine (T-DM1) on spleen volume in patients with HER2-positive metastatic breast cancer.

Trastuzumab emtansine (T-DM1) is a novel therapy for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, combining the targeted action of trastuzumab with the cytotoxic effects of emtansine. Although T-DM1 has demonstrated greater efficacy and safety compared to traditional therapies, concerns about hepatotoxicity and spleen-related complications have arisen. We conducted a retrospective study of 64 HER2-positive metastatic breast cancer patients treated with T-DM1 at our institution. Patients underwent computed tomography or magnetic resonance imaging at baseline and during treatment cycles. Spleen volume, portal vein diameter, and laboratory values were compared between baseline and 12months after T-DM1 treatment. Median spleen volume significantly increased from 201cm3 (IQR, 157-275) at baseline to 291cm3 (IQR, 215-420) after 12months of T-DM1 treatment (P<0.001). Spleen enlargement was observed in 87.5% of patients, while no significant alteration was detected in portal vein diameter. The change in spleen volume was positively correlated with changes in serum globulin levels, liver enzymes, and bilirubin levels, but did not impact survival outcomes. T-DM1 therapy in HER2-positive metastatic breast cancer leads to significant spleen enlargement and systemic biochemical changes. Future studies should focus on elucidating the long-term implications of these findings and optimizing monitoring strategies for spleen-related complications.

Enhancing the Safety and Efficacy of Trastuzumab Emtansine (T-DM1) Through Nano-Delivery System in Breast Cancer Therapy.

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate, revolutionizes breast cancer therapy by specifically delivering DM1 to human epidermal growth factor receptor 2 (HER2) overexpressing tumor cells, effectively inhibiting cell division and proliferation. While T-DM1 demonstrates superior efficacy and tolerability, T-DM1-induced thrombocytopenia remains a significant adverse event leading to treatment discontinuation. To address this issue, the study investigates the feasibility of using poly(lactic-co-glycolic acid) (PLGA)nanoparticles as a delivery vehicle to conjugate T-DM1, aiming to alleviate T-DM1-induced thrombocytopenia. The T-DM1-conjugated PLGA nanoparticles (NPs-T-DM1) reduce binding to megakaryocytes without compromising the targeting ability for HER2. Administration of NPs-T-DM1 not only significantly inhibits tumor growth but also reduces damage to megakaryocytes, inhibits T-DM1-induced thrombocytopenia, and remarkably improves the safety of antibody-conjugated drugs. This work presents a promising strategy to enhance the safety and efficacy of T-DM1 in antitumor therapy, offering significant potential for advancing clinical application in HER2-positive breast cancer patients.

Evaluation of Treatment and Recurrence-Free Survival in Patients with Early HER2-Positive Breast Cancer: Real-Life Data Comparing Public and Private Healthcare

Abstract Introduction The present study was designed to compare the treatment provided in private and public health care facilities for women positive for early breast cancer of the human epidermal growth factor receptor 2 (HER2) subtype, who received anti-HER2 therapy in neoadjuvant or adjuvant settings, with an evaluation of the recurrence-free survival (RFS) and pathological complete response (pCR) rates. Materials and Methods The current is a retrospective study carried out at the Instituto Brasileiro de Controle do Cancer (IBCC Oncologia), in the city of São Paulo, Brazil. We included patients treated between 2015 and 2020. Results The study included 472 medical records of early HER2-positive breast cancer patients treated in the public and private health care systems who received neoadjuvant or adjuvant treatments. The pathological complete response (pCR) was related to a lower recurrence rate and a longer recurrence-free survival (RFS). The results showed no statistically significant difference between the public and private health care systems in terms of RFS. Discussion Although the public health care patients were diagnosed with more advanced diseases than the private health care patients, both presented similar survival rates. In spite of the small number of patients evaluated, the dual HER2 blockade did not improve the clinical outcomes. These findings should be confirmed through studies with a larger number of patients and a longer follow-up period.

HER2-targeted therapies for HER2-positive early-stage breast cancer: present and future.

Breast cancer (BC) has the second highest incidence among cancers and is the leading cause of death among women worldwide. The human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 20%-30% of BC patients. The development of HER2-targeted drugs, including monoclonal antibodies (mAbs), tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), has improved the operation rate and pathological remission rate and reduced the risk of postoperative recurrence for HER2-positive early-stage BC (HER2+ EBC) patients. This review systematically summarizes the mechanisms, resistance, therapeutic modalities and safety of HER2-targeted drugs and helps us further understand these drugs and their use in clinical practice for patients with HER2+ EBC.

General Population Mortality Adjustment in Survival Extrapolation of Cancer Trials: Exploring Plausibility and Implications for Cost-Effectiveness Analyses in HER2-Positive Breast Cancer in Sweden.

In economic evaluations of novel therapies, assessing lifetime effects based on trial data often necessitates survival extrapolation, with the choice of model affecting outcomes. The aim of this study was to assess accuracy and variability between alternative approaches to survival extrapolation. Data on HER2-positive breast cancer patients from the Swedish National Breast Cancer Register were used to fit standard parametric distribution (SPD) models and excess hazard (EH) models adjusting the survival projections based on general population mortality (GPM). Models were fitted using 6-y data for stage I and II, 4-y data for stage III, and 2-y data for stage IV cancer reflecting an early data cutoff while maintaining sufficient events for comparison of model estimates with actual long-term outcomes. We compared model projections of 15-y survival and restricted mean survival time (RMST) to 15-y registry data and explored the variability between models in extrapolations of long-term survival. Among 11,224 patients compared with the observed registry 15-y RMST estimates across the disease stages, EH cure models provided the most accurate estimates in patients with stage I to III cancer, whereas EH models without cure most closely matched survival in patients with stage IV cancer, in which cure assumption was less plausible. The Akaike information criterion-averaged model projections varied as follows: -8.2% to +5.3% for SPD models, -4.9% to +5.2% for the EH model without a cure assumption, and -19.3% to -0.2% for the EH model with a cure assumption. EH models significantly reduced between-model variance in the predicted RMSTs over a 50-y time horizon compared with SPD models. EH models may be considered as alternatives to SPD models to produce more accurate and plausible survival extrapolation that accounts for general population mortality. Excess hazard (EH) methods have been suggested as an approach to incorporate background mortality rates in economic evaluation using survival extrapolation.We highlight that EH models with or without a cure assumption can produce more accurate survival projections and significantly reduce between-model variability in comparison with standard parametric distribution models across cancer stages.EH models may be a preferred modeling method to reduce model uncertainty in health economic modeling since models that would otherwise have produced implausible extrapolations are constrained by the EH framework.Reduced uncertainty in economic evaluations will enhance the application of evidence-based health care decision making.

378P Updated data on real-world efficacy and safety of inetetamab-based therapy in HER2-positive metastatic breast cancer patients with prior exposure to trastuzumab

378P Updated data on real-world efficacy and safety of inetetamab-based therapy in HER2-positive metastatic breast cancer patients with prior exposure to trastuzumab

Development and Validation of a Prognostic Nomogram Model for HER2-Positive Male Breast Cancer Patients.

HER2-positive male breast cancer (MBC) is a rare condition that has a poor prognosis. The purpose of this study was to establish a nomogram model for predicting the prognosis of HER2-positive MBC patients. 240 HER2-positive MBC patients from 2004 to 2015 were retrieved from the surveillance, epidemiology, and end results (SEER) database. All HER2-positive MBC patients were divided randomly into training (n = 144) and validation cohorts (n = 96) according to a ratio of 6:4. Univariate and multivariate Cox regression analyses were used to determine the prognostic factors associated with HER2-positive MBC patients. A clinical prediction model was constructed to predict the overall survival of these patients. The nomogram model was assessed by using receiver operating characteristics (ROC) curves, calibration plots and decision curve analysis (DCA). The Cox regression analysis showed that T-stage, M-stage, surgery and chemotherapy were independent risk factors for the prognosis of HER2-positive MBC patients. The model could also accurately predict the Overall survival (OS) of the patients. In the training and validation cohorts, the C indexes of the OS nomograms were 0.746 (0.677-0.815) and 0.754 (0.679-0.829), respectively. Calibration curves and DCA verified the reliability and accuracy of the clinical prediction model. In conclusion, the predictive model constructed had good clinical utility and can help the clinician to select appropriate treatment strategies for HER2-positive MBC patients.

Changes in Mitochondrial Function and Cell Death Patterns in Peripheral Blood Mononuclear Cells during Trastuzumab Treatment Following Doxorubicin Chemotherapy.

Trastuzumab, a monoclonal antibody which works against human epidermal growth factor receptor 2 (HER2), possibly causes cardiotoxicity through mitochondrial dysfunction. The usefulness of isolated peripheral blood mononuclear cells (PBMCs) in the assessment of trastuzumab-induced cardiotoxicity remains uncertain. This study aimed to determine the temporal changes in mitochondrial function, oxidative stress, and cell death in the isolated PBMCs of HER2-positive breast cancer patients during breast cancer treatment and to compare the changes with HER2-negative breast cancer patients who did not receive trastuzumab therapy. Eighteen newly diagnosed HER2-positive breast cancer women who received sequential doxorubicin and trastuzumab were consecutively recruited. Age- and gender-matched controls with HER2-negative breast cancer were selected. Echocardiography was carried out, and blood samples for the study of cardiac biomarkers and PBMCs were collected periodically during treatment. Only one patient in our cohort developed asymptomatic left ventricular dysfunction during trastuzumab treatment. However, trastuzumab following doxorubicin aggravated subclinical cardiac injury, determined by cardiac troponin and echocardiography. Cellular and mitochondrial oxidative stress in isolated PBMCs remained unchanged throughout breast cancer treatment. Regarding mitochondrial respiration, the maximal respiration and spare respiration capacity was significantly increased in controls after doxorubicin treatment but not in patients who received trastuzumab therapy. Moreover, the percentage of apoptosis and necroptosis in isolated PBMCs was dramatically decreased in the control, compared to patients with trastuzumab treatment. In conclusion, trastuzumab caused subtle myocardial injury and impaired mitochondrial respiration and cell viability in isolated PBMCs.