HER2-positive Breast Cancer Research Articles

ENPP1 induces blood-brain barrier dysfunction and promotes brain metastasis formation in HER2-positive breast cancer.

Brain metastasis (BrM) is a devastating end-stage neurological complication that occurs in up to 50% of HER2+ breast cancer patients. Understanding how disseminating tumor cells manage to cross the blood-brain barrier (BBB) is essential for developing effective preventive strategies. We identified the ecto-nucleotidase ENPP1 as specifically enriched in the secretome of HER2+ brain metastatic cells, prompting us to explore its impact on BBB dysfunction and BrM formation. We used in vitro BBB and in vivo premetastatic mouse models to evaluate the effect of tumor-secreted ENPP1 on brain vascular permeability. BBB integrity was analyzed by real-time fluorescence imaging of 20kDa Cy7.5-dextran extravasation and immunofluorescence staining of adherens and tight junction proteins. Pro-metastatic effects of ENPP1 were evaluated in an experimental brain metastatic model. Systemically secreted ENPP1 from primary breast tumors impaired the integrity of BBB with loss of tight and adherens junction proteins early before the onset of BrM. Mechanistically, ENPP1 induced endothelial cell dysfunction by impairing insulin signaling and its downstream AKT/GSK3β/β-catenin pathway. Genetic ablation of ENPP1 from HER2+ brain metastatic cells prevented endothelial cell dysfunction and reduced metastatic burden while prolonging the overall and metastasis-free survival of mice. Furthermore, plasmatic ENPP1 levels correlate with brain metastatic burden and inversely with overall survival. We demonstrated that metastatic breast cancer cells exploit the ENPP1 signaling for cell transmigration across the BBB and brain colonization. Our data implicate ENPP1 as a potential biomarker for poor prognosis and early detection of BrM in HER2+ breast cancer.

2888: Safety of trastuzumab deruxtecan and radiation therapy in HER2-positive breast cancer patients

2888: Safety of trastuzumab deruxtecan and radiation therapy in HER2-positive breast cancer patients

A Non-Canonical p75HER2 Signaling Pathway Underlying Trastuzumab Action and Resistance in Breast Cancer.

Overexpression of HER2 occurs in 25% of breast cancer. Targeting HER2 has proven to be an effective therapeutic strategy for HER2-positive breast cancer. While trastuzumab is the most commonly used HER2 targeting agent, which has significantly improved outcomes, the overall response rate is low. To develop novel therapies to boost trastuzumab efficacy, it is critical to identify the mechanisms underlying trastuzumab action and resistance. We recently showed that the inhibition of breast cancer cell growth by trastuzumab is not through the inhibition of HER2 canonical signaling. Here we report the identification of a novel non-canonical HER2 signaling pathway and its interference by trastuzumab. We showed that HER2 signaled through a non-canonical pathway, regulated intramembrane proteolysis (RIP). In this pathway, HER2 is first cleaved by metalloprotease ADAM10 to produce an extracellular domain (ECD) that is released and the p95HER2 that contains the transmembrane domain (TM) and intracellular domain (ICD). p95HER2, if further cleaved by an intramembrane protease, γ-secretase, produced a soluble ICD p75HER2 with nuclear localization signal (NLS). p75HER2 is phosphorylated and translocated to the nucleus. Nuclear p75HER2 promotes cell proliferation. Trastuzumab targets this non-canonical HER2 pathway via inhibition of the proteolytic cleavage of HER2 by both ADAM10 and γ-secretase. However, p75HER2 pathway also confers resistance to trastuzumab once aberrantly activated. Combination of trastuzumab with ADAM10 and γ-secretase inhibitors completely blocks p75HER2 production in both BT474 and SKBR3 cells. We concluded that HER2 signals through the RIP signaling pathway that promotes cell proliferation and is targeted by trastuzumab. The aberrant HER2 RIP signaling confers resistance to trastuzumab that could be overcome by the application of inhibitors to ADAM10 and γ-secretase.

HER-2 Receptor and αvβ3 Integrin Dual-Ligand Surface-Functionalized Liposome for Metastatic Breast Cancer Therapy.

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer metastasis remains the primary cause of mortality among women globally. Targeted therapies have revolutionized treatment efficacy, with Trastuzumab (Trast), a monoclonal antibody, targeting HER2-positive advanced breast cancer. The tumor-homing peptide iRGD enhances the intratumoral accumulation and penetration of therapeutic agents. Liposomes serve as versatile nanocarriers for both hydrophilic and hydrophobic drugs. Gefitinib (GFB) is a potential anticancer drug against HER2-positive breast cancer, while Lycorine hydrochloride (LCH) is a natural compound with anticancer and anti-inflammatory properties. This study developed TPGS-COOH-coated liposomes co-loaded with GFB and LCH, prepared by the solvent injection method, and surface-functionalized with Trast and iRGD. The dual surface-decorated liposomes (DSDLs) were characterized for their particle size (PS), polydispersity index (PDI), zeta potential (ZP), surface chemistry, surface morphology, and their crystallinity during in-vitro drug release, drug encapsulation, and in-vitro cell line studies on SK-BR-3 and MDA-MB-231 breast cancer cells. The half-maximum inhibitory concentration (IC-50) values of single decorated liposomes (SDLs), iRGD-LP, and Trast-LP, as well as DSDLs (iRGD-Trast-LP) on SK-BR-3 cells, were 6.10 ± 0.42, 4.98 ± 0.36, and 4.34 ± 0.32 μg/mL, respectively. Moreover, the IC-50 values of SDLs and DSDLs on MDA-MB-231 cells were 15.12 ± 0.68, 13.09 ± 0.59, and 11.08 ± 0.48 μg/mL, respectively. Cellular uptake studies using confocal laser scanning microscopy (CLSM) showed that iRGD and Trast functionalization significantly enhanced cellular uptake in both cell lines. The wound-healing assay demonstrated a significant reduction in SDL and DSDL-treated MDA-MB-231 cell migration compared to the control. Additionally, the blood compatibility study showed minimal hemolysis (less than 5% RBC lysis), indicating good biocompatibility and biosafety. Overall, these findings suggest that TPGS-COOH-coated, GFB and LCH co-loaded, dual-ligand (iRGD and Trast) functionalized, multifunctional liposomes could be a promising therapeutic strategy for treating HER2-positive metastatic breast cancer.

Stereotactic radiosurgery for brain metastases from human epidermal receptor 2 positive breast Cancer: an international, multi-center study.

To report patient outcomes and local tumor control rates in a cohort of patients with biopsy-proven HER-2 positive breast cancer treated with stereotactic radiosurgery (SRS) for brain metastases (BM). This international, retrospective, multicenter study, included 195 female patients with 1706 SRS-treated BM. Radiologic and clinical outcomes after SRS were determined and prognostic factors identified. At SRS, median patient age was 55 years [interquartile range (IQR) 47.6-62.0], and 156 (80%) patients had KPS ≥ 80. The median tumor volume was 0.1 cm3 (IQR 0.1-0.5) and the median prescription dose was 16Gy (IQR 16-18). Local tumor control (LTC) rate was 98%, 94%, 93%, 90%, and 88% at six-, 12-, 24-, 36- and 60-months post-SRS, respectively. On multivariate analysis, tumor volume (p = < 0.001) and concurrent pertuzumab (p = 0.02) improved LTC. Overall survival (OS) rates at six-, 12-, 24-, 36-, 48-, and 60-months were 90%, 69%, 46%, 27%, 22%, and 18%, respectively. Concurrent pertuzumab improved OS (p = 0.032). In this patient subgroup, GPA scores ≥ 2.5 (p = 0.038 and p = 0.003) and rare primary tumor histologies (p = 0.01) were associated with increased and decreased OS, respectively. Asymptomatic adverse radiation events (ARE) occurred in 27 (14.0%) and symptomatic ARE in five (2.6%) patients. Invasive lobular carcinoma primary (p = 0.042) and concurrent pertuzumab (p < 0.001) conferred an increased risk for overall but not for symptomatic ARE. SRS affords effective LTC for selected patients with BM from HER-2 positive breast cancer. Concurrent pertuzumab improved LTC and OS but at the same time increased the risk for overall, but not symptomatic, ARE.

Predicting Pathological Characteristics of HER2-Positive Breast Cancer from Ultrasound Images: a Deep Ensemble Approach.

The objective is to evaluate the feasibility of utilizing ultrasound images in identifying critical prognostic biomarkers for HER2-positive breast cancer (HER2 + BC). This study enrolled 512 female patients diagnosed with HER2-positive breast cancer through pathological validation at our institution from January 2016 to December 2021. Five distinct deep convolutional neural networks (DCNNs) and a deep ensemble (DE) approach were trained to classify axillary lymph node involvement (ALNM), lymphovascular invasion (LVI), and histological grade (HG). The efficacy of the models was evaluated based on accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), receiver operating characteristic (ROC) curves, areas under the ROC curve (AUCs), and heat maps. DeLong test was applied to compare differences in AUC among different models. The deep ensemble approach, as the most effective model, demonstrated AUCs and accuracy of 0.869 (95% CI: 0.802-0.936) and 69.7% in LVI, 0.973 (95% CI: 0.949-0.998) and 73.8% in HG, thus providing superior classification performance in the context of imbalanced data (p < 0.05 by the DeLong test). On ALNM, AUC and accuracy were 0.780 (95% CI: 0.688-0.873) and 77.5%, which were comparable to other single models. The pretreatment US-based DE model could hold promise as a clinical guidance for predicting pathological characteristics of patients with HER2-positive breast cancer, thereby providing benefit of facilitating timely adjustments in treatment strategies.

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.

Analysis of Factors Associated With Pathological Complete Response in Patients With HER2-Positive Breast Cancer Receiving Neoadjuvant Chemotherapy

PurposeThis study aimed to examine the impact of the level of HER2 overexpression on pathologic and clinical outcomes in HER2-positive breast cancer (BC) patients treated with neoadjuvant therapy (NAT). MethodsWomen with Stage II or III HER2-positive BC who received anthracycline-taxane-trastuzumab NAT regimens followed by curative-intent surgery were included. Patients were classified according to tumor HER2 expression into HER2-high (immunohistochemistry (IHC) 3+ or fluorescence in situ hybridization (FISH) HER2/CEP17 ratio ≥5 or HER2 copy number ≥10) and HER2-intermediate (IHC 2+ with HER2/CEP17 ratio ≥2 to <5 or copy number ≥4 to <10). Univariate and multivariate logistic regression analyses were performed using HER2 expression as a categorical variable. The primary outcome was pathological complete response (pCR). Estimated 3-year disease-free survival (DFS) and Overall Survival (OS) were secondary outcomes. ResultsAmong 161 patients with HER2-positive BC, 139 (86%) and 22 (14%) were classified as HER2-high and HER2-intermediate, respectively; 105 (65.2%) had hormone receptor (HR)-positive tumors; 72 (45%) achieved a pCR. In the overall population, pCR rates of 18% and 49% were achieved in HER2-intermediate and HER2-high cases, respectively (odds ratio [OR] = 0.23 95% CI 0.07-0.72; P = .007). No pCRs were observed among HR-positive, HER2-intermediate cases. Estimated 3-year DFS was 97.1% versus 89.3% for patients achieving a pCR versus those with residual disease, respectively (P = .0011). ConclusionWe found that patients with HER2-high disease were more likely to achieve pCR after NAT compared to patients with HER2-intermediate BC, a subgroup of patients that may benefit from more personalized NAT strategies.

De-escalation of neoadjuvant taxane and carboplatin therapy in HER2-positive breast cancer with dual HER2 blockade: a multicenter real-world experience in China

BackgroundTCbHP (taxane + carboplatin + trastuzumab + pertuzumab) is the preferred neoadjuvant therapy regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, no consensus exists regarding whether specific populations may be exempt from carboplatin, allowing for de-escalation to the THP (taxane + trastuzumab + pertuzumab) regimen. Additionally, the optimal number of cycles for neoadjuvant THP remains unclear. We compared the efficacy and safety of neoadjuvant TCbHP and THP regimens, providing clinicians with a nuanced perspective to guide their treatment regimen selection.MethodsThis multicenter real-world study included patients with HER2-positive breast cancer undergoing neoadjuvant TCbHP or THP between March 2019 and February 2023. Efficacy was assessed through the pathological complete response (pCR) rate, while safety was evaluated through monitoring adverse events.ResultsAmong 220 patients, 103 received 6 cycles of TCbHP (TCbHP×6), 83 received 6 cycles of THP (THP×6), and 34 received 4 cycles of THP (THP×4). The TCbHP×6 cohort exhibited a 66% pCR rate compared with 53% in the THP×6 cohort (P = 0.072). Subgroup analysis revealed that in patients aged ≤ 50 years, those with hormone receptor (HR)-negative status, and those with clinical stage T2, the pCR rate of the TCbHP×6 regimen was significantly higher than the THP×6 regimen (P < 0.05). The TCbHP×6 cohort reported higher frequencies of any-grade adverse events (99% versus 86.7%) and grade 3–4 events (49.5% versus 12%) than the THP×6 cohort. Propensity score matching identified 27 patient pairs between the THP×6 and THP×4 cohorts, indicating a significantly higher pCR rate for the THP×6 regimen than the THP×4 regimen (63% versus 29.6%, P = 0.029).ConclusionsThe TCbHP×6 regimen is favored for individuals aged ≤ 50 years and those aged > 50, ≤60 years with HR-negative status or clinical stage T2-4. For patients in compromised general condition or lacking the specified indications, the THP×6 regimen emerges as a lower-toxicity alternative with satisfactory efficacy. To ensure treatment efficacy, a minimum of 6 cycles of neoadjuvant THP is required.

Impact of Location of Residence and Distance to Cancer Centre on Medical Oncology Consultation and Neoadjuvant Chemotherapy for Triple-Negative and HER2-Positive Breast Cancer.

Despite consensus guidelines, most patients with early-stage triple-negative (TN) and HER2-positive (HER2+) breast cancer do not see a medical oncologist prior to surgery and do not receive neoadjuvant chemotherapy (NAC). To understand barriers to care, we aimed to characterize the relationship between geography (region of residence and cancer centre proximity) and receipt of a pre-treatment medical oncology consultation and NAC for patients with TN and HER2+ breast cancer. Using linked administrative datasets in Ontario, Canada, we performed a retrospective population-based analysis of women diagnosed with stage I-III TN or HER2+ breast cancer from 2012 to 2020. The outcomes were a pre-treatment medical oncology consultation and the initiation of NAC. We created choropleth maps to assess the distribution of the outcomes and cancer centres across census divisions. To assess the relationship between distance to the nearest cancer centre and outcomes, we performed multivariable regression analyses adjusted for relevant factors, including tumour extent and nodal status. Of 14,647 patients, 29.9% received a pre-treatment medical oncology consultation and 77.7% received NAC. Mapping demonstrated high interregional variability, ranging across census divisions from 12.5% to 64.3% for medical oncology consultation and from 8.8% to 64.3% for NAC. In the full cohort, compared to a distance of ≤5 km from the nearest cancer centre, only 10-25 km was significantly associated with lower odds of NAC (OR 0.83, 95% CI 0.70-0.99). Greater distances were not associated with pre-treatment medical oncology consultation. The interregional variability in medical oncology consultation and NAC for patients with TN and HER2+ breast cancer suggests that regional and/or provider practice patterns underlie discrepancies in the referral for and receipt of NAC. These findings can inform interventions to improve equitable access to NAC for eligible patients.

PAI1 Regulates Cell Morphology and Migration Markers in Trastuzumab-Resistant HER2-Positive Breast Cancer Cells.

HER2-positive breast cancer is a significant cause of mortality. Overcoming trastuzumab resistance requires a deeper understanding of its molecular mechanisms to develop effective therapies. This study investigates the role of plasminogen activator inhibitor-1 (PAI1) in migration and drug resistance in trastuzumab-resistant HER2-positive breast cancer. Trastuzumab resistance poses a significant challenge in clinical management due to its association with aggressive disease behaviour and limited treatment options. This study focuses on PAI1, a key player in the TGF-β signalling pathway, which is implicated in cancer progression and metastasis. Trastuzumab-resistant cell lines (SKBR3 and HCC1954) demonstrated markedly elevated PAI1 expression levels, up to 40-fold compared to parental lines. This elevation was accompanied by increased expression of migration markers such as Col4a1, Fibronectin, ICAM1, Timp2, and Vimentin. Through overexpression and silencing experiments, we observed that modulating PAI1 levels significantly impacts cell morphology, transitioning cells from an epithelial to mesenchymal phenotype. Importantly, combining trastuzumab with aleplasinin, a PAI1 inhibitor, synergistically reduced PAI1 expression in both parental and resistant cell lines. This suggests a potential therapeutic strategy to overcome trastuzumab resistance. These findings emphasise PAI1 as a critical mediator of migration and therapeutic response in HER2-positive breast cancer, offering insights into novel treatment approaches targeting PAI1 to improve clinical outcomes in drug resistance.

Breast Cancer in Young Women: Analysis of Incidence, Clinicopathological Profile and Biological Behaviour in a Tertiary Care Institute from South India

Aims and Objectives: There is an increasing incidence of breast cancer in young women and many of these patients are considered to have more aggressive disease biology. The study aimed to find out the demographic profile, clinicopathological profile, and management details in patients under the age of 40 years treated for breast cancer in a tertiary care institute. Materials and Methods: The study retrospectively analysed all the females with biopsy proven breast cancer treated at our oncology department between January 2012 and December 2018. Patients aged below 40 years were stratified from the total breast cancer patients. The data related to demographic profile, clinical staging, pathological staging, hormonal status and treatment details were collected from medical records for the patients and analysed. Results: A total of 1056 biopsy proven breast cancer patients were treated during the study period. Out of which, the breast cancer patients under the age of 40 years were 161 (15.24%). The mean age at presentation was 33 years. Maximum patients were between the age group of 35 to 40 years (45.4%). Most of the patients were presented with Stage III (44%). Infiltrating Ductal Carcinoma, Grade II was the most common histologic type and grade. ER (Oestrogen Receptor) positivity seen in 49% of patients and PR (Progesterone receptor) Positivity in 49.7% and 46% had HeR2 Positivity. Conclusion: Our study concludes that the incidence of breast cancer patients under the age of 40 years is increasing. These patients tend to have higher grade tumours, Her2 Positive and triple-negative breast cancer. Young patients presenting with breast lumps should undergo all standard screening and diagnostic investigations must be carried out for early diagnosis and proper interventions.

Precision medicine in breast cancer (Review).

Precision medicine in breast cancer is a revolutionary approach that customizes diagnosis and treatment based on individual and tumor characteristics, departing from the traditional one-size-fits-all approach. Breast cancer is diverse, with various subtypes driven by distinct genetic mutations. Understanding this diversity is crucial for tailored treatment strategies that target specific vulnerabilities in each tumor. Genetic testing, particularly for mutations in breast cancer gene (BRCA) DNA repair-associated genes, helps assess hereditary risks and influences treatment decisions. Molecular subtyping guides personalized treatments, such as hormonal therapies for receptor-positive tumors and human epidermal growth factor receptor 2 (HER2)-targeted treatments. Targeted therapies, including those for HER2-positive and hormone receptor-positive breast cancers, offer more effective and precise interventions. Immunotherapy, especially checkpoint inhibitors, shows promise, particularly in certain subtypes such as triple-negative breast cancer, with ongoing research aiming to broaden its effectiveness. Integration of big data and artificial intelligence enhances personalized treatment strategies, while liquid biopsies provide real-time insights into tumor dynamics, aiding in treatment monitoring and modification. Challenges persist, including accessibility and tumor complexity, but emerging technologies and precision prevention offer hope for improved outcomes. Ultimately, precision medicine aims to optimize treatment efficacy, minimize adverse effects and enhance the quality of life for patients with breast cancer.

The burden of systemic therapy administration route in treating HER2-positive breast cancer (for patients, healthcare professionals, and healthcare system): a systematic literature review.

Breast cancer (BC) is one of the leading causes of cancer and is the first cause of death from malignant tumors among women worldwide. New cancer therapies receive regulatory approval yearly and to avoid health disparities in society, the health systems are challenged to adapt their infrastructure, methodologies, and reimbursement policies to allow broad access to these treatments. In addition, listening to patients' voices about their therapy preferences is essential. We aim to investigate the administration route preferences [subcutaneous (SC) or intravenous (IV)] among patients diagnosed with HER2 positive BC and healthcare professionals (HCPs) and to investigate healthcare resources utilization (quality and quantity) for each route of administration (SC or IV) for treating those patients. We conducted a systematic literature review focused on clinical trials and observational and economic studies, using PubMed (MEDLINE), Cochrane Library, Virtual Health Library (VHL), Scientific Electronic Library Online (SciELO), and Latin American and Caribbean Health Sciences Literature (LILACS) databases based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. The literature review included 25 studies in the analysis. Studies have reported that patients and HCPs prefer the SC route of administration to IV because it saves time in terms of chair time, administration, and preparation and is less painful. In addition, SC administration might be a more cost-saving option when analyzing direct and indirect costs. As BC stands as a significant global health concern and the leading cause of cancer-related deaths in women worldwide, understanding and incorporating patient and HCPs preferences in the choice of administration route become paramount. The observed preference for SC administration not only aligns with the imperative of adapting health systems to facilitate broad access to new cancer therapies but also underscores the importance of considering patient experiences and economic implications in shaping treatment strategies. These insights are crucial for healthcare policymakers, clinicians, and stakeholders in optimizing healthcare resources and enhancing the overall quality of BC care.

Machine learning models for differential diagnosing HER2-low breast cancer: A radiomics approach.

To develop machine learning models based on preoperative dynamic enhanced magnetic resonance imaging (DCE-MRI) radiomics and to explore their potential prognostic value in the differential diagnosis of human epidermal growth factor receptor 2 (HER2)-low from HER2-positive breast cancer (BC). A total of 233 patients with pathologically confirmed invasive breast cancer admitted to our hospital between January 2018 and December 2022 were included in this retrospective analysis. Of these, 103 cases were diagnosed as HER2-positive and 130 cases were HER2 low-expression BC. The Synthetic Minority Oversampling Technique is employed to address the class imbalance problem. Patients were randomly split into a training set (163 cases) and a validation set (70 cases) in a 7:3 ratio. Radiomics features from DCE-MRI second-phase imaging were extracted. Z-score normalization was used to standardize the radiomics features, and Pearson's correlation coefficient and recursive feature elimination were used to explore the significant features. Prediction models were constructed using 6 machine learning algorithms: logistic regression, random forest, support vector machine, AdaBoost, decision tree, and auto-encoder. Receiver operating characteristic curves were constructed, and predictive models were evaluated according to the area under the curve (AUC), accuracy, sensitivity, and specificity. In the training set, the AUC, accuracy, sensitivity, and specificity of all models were 1.000. However, in the validation set, the auto-encoder model's AUC, accuracy, sensitivity, and specificity were 0.994, 0.976, 0.972, and 0.978, respectively. The remaining models' AUC, accuracy, sensitivity, and specificity were 1.000. The DeLong test showed no statistically significant differences between the machine learning models in the training and validation sets (Z = 0, P = 1). Our study investigated the feasibility of using DCE-MRI-based radiomics features to predict HER2-low BC. Certain radiomics features showed associations with HER2-low BC and may have predictive value. Machine learning prediction models developed using these radiomics features could be beneficial for distinguishing between HER2-low and HER2-positive BC. These noninvasive preoperative models have the potential to assist in clinical decision-making for HER2-low breast cancer, thereby advancing personalized clinical precision.

Additional statin treatment enhances the efficacy of HER2 blockade and improves prognosis in Rac1-high/HER2-positive breast cancer

The prognosis of HER2-positive breast cancer (BC) has improved with the development of anti-HER2 therapies; however, the problem remains that there are still cases where anti-HER2 therapies do not respond well. We found that the expression of SREBF2, a master transcriptional factor in the mevalonate pathway, was correlated with ERBB2 (HER2) expression and a poor prognosis in HER2-positive BC. The target gene expressions of SREBF2 were associated with higher expression of ERBB2 in HER2-positive BC cells. Statins, anti-hypercholesterolemia drugs that inhibit the mevalonate pathway, enhanced the efficacy of HER2-targeting agents with inducing apoptosis in a geranylgeranylation-dependent manner. Mechanistically, statins specifically inhibited membrane localization of Rac1, a target protein of geranylgeranylation, and suppressed the activation of HER2 downstreams AKT and ERK pathways. Consistently, retrospective analysis showed a longer recurrence-free survival in Rac1-high/HER2-positive BC patients treated with HER2-targeting agents with statins than without statins. Our findings thus suggest that Rac1 expression could be used as a biomarker to stratify HER2-positive BC patients that could benefit from dual blockade, i.e., targeting HER2 with inhibition of geranylgeranylation of Rac1 using statins, thereby opening avenues for precision medicine in a new subset of Rac1-high/HER2-positive BC.

Therapeutic response and outcomes with uncommon breast cancer subtypes in the I-SPY trial 2010-2022.

1 Background: Uncommon histologies are over-represented among high-risk breast cancer (BC) and denote an area with limited trial data and of significant unmet medical need. To better understand trial outcomes in this group and identify signals of tumor responsiveness, we report pathologic complete response (pCR) and early event-free survival (EFS) by disease subtype in the I-SPY2 trial. Additionally, the I-SPY2 trial currently utilizes a combination of tumor molecular signature and receptor status to determine response predictive subtype (RPS) first developed from 987 I-SPY2 patients [Wolf et al, Cancer Cell 2022]. We report disease response rates for those who received what is now known to be optimal RPS guided therapy. Methods: The I-SPY2 platform trial tests novel agents given neo-adjuvantly with a chemotherapy backbone in high-risk BC (HER2 positive, triple negative and high molecular risk estrogen receptor positive BC). Histologic images of research biopsies, local biopsy and surgical pathology reports were reviewed centrally by I-SPY pathologists. Receptor subtype distribution and pCR rates were summarized; and EFS was estimated using the Kaplan Meier method. Association between pCR and EFS was evaluated using the Cox proportional hazard model with significance assessed by the log rank test. Results: 144/2118 (7%) of I-SPY2 participants were identified with metaplastic (60), lobular (55), mucinous (9), micropapillary (8), neuroendocrine (4) and other (8) BCS. Tumor receptor status, pCR rate and EFS by tumor type are shown in the Table. For the full cohort, pCR was associated with better EFS (hazard ratio (95% CI): 0.12 (0.02 - 0.88), p = 0.01). Within metaplastic (metapBC) 11/32 (34%) and 5/28 (18%) patients had a pCR with or without checkpoint blockade, respectively. By RPS group, 9 of 18 (50%) (13 metapBC, 3 other, 2 lobular) in the HER2-Immune+ group who received RPS optimized therapy had a pCR. In this group 6/13 (46%) with metapBC had a pCR. In the HER2+ driven RPS groups, pCR rate in the HER+HER2orBasal was 88% (7/8) and 0% (0/3) in the HER2+Luminal. Conclusions: High pCR rates observed in metapBC and other among subsets of often difficult to treat BC subtypes support novel approaches and provide a roadmap for future study of uncommon BCs. Outcomes were improved when therapy matched RPS vulnerabilities. Participants presenting with uncommon BC subtypes will be prospectively identified in the I-SPY2.2 trial to further develop effective approaches for this group. Clinical trial information: NCT01042379 .[Table: see text]

Combination Therapy of Pyrotinib and Metronomic Vinorelbine in HER2+ Advanced Breast Cancer After Trastuzumab Failure (PROVE): A Prospective Phase 2 Study.

Approximately 50-74% of patients with metastatic HER2-positive breast cancer do not respond to trastuzumab, with 75% of treated patients experiencing disease progression within a year. The combination of pyrotinib and capecitabine has showed efficacy in these patients. This study evaluates the efficacy and safety of pyrotinib combined with metronomic vinorelbine for trastuzumab-pretreated HER2-positive advanced breast cancer patients. In this phase 2 trial, patients aged 18-75 years with HER2-positive advanced breast cancer who had previously failed trastuzumab treatment were enrolled to receive pyrotinib 400mg daily in combination with vinorelbine 40mg thrice weekly. The primary endpoint was progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. From October 21, 2019, to January 21, 2022, 36 patients were enrolled and received at least one dose of study treatment. At the cut-off date, 20 experienced disease progression or death. With a median follow-up duration of 35 months, the median PFS was 13.5 months (95% CI: 8.3-18.5). With all patients evaluated, an ORR of 38.9% (95% CI: 23.1-56.5%) and a DCR of 83.3% (95% CI: 67.2-93.6%) were achieved. The median OS was not reached. Grade 3 adverse events (AEs) were observed in 17 patients, with diarrhea being the most common (27.8%), followed by vomiting (8.3%) and stomachache (5.6%). There were no grade 4/5 AEs. Pyrotinib combined with metronomic vinorelbine showed promising efficacy and an acceptable safety profile in HER2-positive advanced breast cancer patients after trastuzumab failure.

Targeted therapies in HER2-positive breast cancer with receptor-redirected Arazyme-linker-Herceptin as a novel fusion protein.

Targeted treatment of different types of cancers through highly expressed cancer cell surface receptors by fusion proteins is an efficient method for cancer therapy. The HER2 receptor is a member of the tyrosine kinase receptors family, which plays a notable role in breast cancer tumor development. About 25-30% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2). In this study, we evaluated the particulars of a designed recombinant protein formed by HER2-specific Mab Herceptin linked with Arazyme on a HER2-overexpressing breast cancer cell line (SKBR3). Arazyme, a metalloprotease produced by Serratia proteamaculans was fused to the variable area of light and heavy chains of the Herceptin. The cytotoxic assay of the Arazyme-linker-Herceptin in the SKBR3 and MDA-MB-468 cells was evaluated by the MTT and flow cytometry techniques. The Caspase‑3 activity determination and adhesion assay were performed to evaluate the antitumor activity of the Arazyme-linker-Herceptin against SKBR3 cells. Furthermore, RT-PCR was used to measure the expression levels of the Bcl-2, Bax, MMP2, MMP9, and RIP3 genes. The Arazyme-linker-Herceptin showed higher cytotoxicity in SKBR3 cells compared to MDA-MB-468 cells. In addition, flow cytometry results revealed that the Arazyme-linker-Herceptin can significantly induce apoptosis in the HER2-overexpressing breast cancer cell line (SKBR3), which was confirmed by Bax upregulation and the decrease in adhesion of tumor cells and MMP2/MMP9. The findings of this study demonstrated that the Arazyme-linker-Herceptin induced apoptosis and decreased metastatic genes in SKBR3 cells; however, further research is required to confirm the effectiveness of the fusion protein.

Targeting ITGβ3 to Overcome Trastuzumab Resistance through Epithelial-Mesenchymal Transition Regulation in HER2-Positive Breast Cancer.

HER2-positive breast cancer, representing 15-20% of all breast cancer cases, often develops resistance to the HER2-targeted therapy trastuzumab. Unfortunately, effective treatments for advanced HER2-positive breast cancer remain scarce. This study aims to investigate the roles of ITGβ3, and Hedgehog signaling in trastuzumab resistance and explore the potential of combining trastuzumab with cilengitide as a therapeutic strategy. Quantitative gene expression analysis was performed to assess the transcription of EMT (epithelial-mesenchymal transition) markers Slug, Snail, Twist2, and Zeb1 in trastuzumab-resistant HER2-positive breast cancer cells. The effects of ITGβ3 and Hedgehog signaling were investigated. Additionally, the combination therapy of trastuzumab and cilengitide was evaluated. Acquired trastuzumab resistance induced the transcription of Slug, Snail, Twist2, and Zeb1, indicating increased EMT. This increased EMT was mediated by ITGB3 and Hedgehog signaling. ITGβ3 regulated both the Hedgehog pathway and EMT, with the latter being independent of the Hedgehog pathway. The combination of trastuzumab and cilengitide showed a synergistic effect, reducing both EMT and Hedgehog pathway activity. Targeting ITGβ3 with cilengitide, combined with trastuzumab, effectively suppresses the Hedgehog pathway and EMT, offering a potential strategy to overcome trastuzumab resistance and improve outcomes for HER2-positive breast cancer patients.