Human Epidermal Growth Factor Research Articles

A real-world survey on expensive drugs used as first-line chemotherapy in patients with HER2-negative unresectable advanced/recurrent gastric cancer in the stomach cancer study group of the Japan clinical oncology group.

Molecular-targeted drugs and immune checkpoint inhibitors have been developed for various malignant diseases, thereby improving clinical outcomes. However, these drugs are expensive, and few studies have assessed their actual use and costs in Japan. This study aimed to survey the use and costs of first-line chemotherapy for advanced/recurrent gastric cancer (AGC) in real-world settings. The survey included patients with human epidermal growth factor receptor type2 (HER2)-negative AGC who initiated first-line chemotherapy from January 2022 to December 2022 at the participating 92 institutions in the Japan Clinical Oncology Group. Data on the regimens were collected using Google Forms. A regimen that costs >500 000 Japanese yen (JPY) per month was defined as expensive. Data on chemotherapy regimens were collected from 2173 patients at all 92 institutions between March 2023 and May 2023. We analyzed 2113 patients who underwent the chemotherapy with recommended regimens and conditionally recommended regimens according to the Japanese Gastric Cancer Treatment Guidelines sixth edition. The expensive regimens were triplet chemotherapy with fluoropyrimidine (S-1 or capecitabine or 5-fluorouracil/levofolinate), oxaliplatin, and nivolumab. Their monthly costs ranged from 767 648 to 771 046 JPY. Nivolumab-containing regimens cost more than 20 times the price of conventional chemotherapy with fluoropyrimidine and oxaliplatin. These regimens were used in 1416 (67%) of 2113 patients: in 71% of patients aged ≤74years and in 59% of patients aged ≥75years. The regimens with >20-fold cost of conventional chemotherapy were used as first-line chemotherapy in two-thirds of patients and more than half even in the elderly population with HER2-negative AGC. This finding is important for future health economic studies on drug cost-efficacy.

Novel CAR-T Cells Specifically Targeting SIA-CIgG Demonstrate Effective Antitumor Efficacy in Bladder Cancer.

Chimeric Antigen Receptor (CAR) T-cell therapy is a promising cancer treatment method. However, its application in bladder cancer (BC) remains limited, partially because of the absence of appropriate target molecules. Sialylated cancer-derived IgG (SIA-CIgG) is highly expressed in BC and is closely associated with malignant biological behavior. However, its potential as a target for CAR-T cell therapy to treat BC is yet to be established. Here, it is found that SIA-CIgG is highly expressed in most BC samples but displayed limited expression in normal tissues. CAR-T cells specifically targeting SIA-CIgG can effectively lyse BC cells and the cytotoxicity depends on SIA-CIgG expression. Furthermore, SIA-CIgG CAR-T cells demonstrate milder tumor cell lysis and enhanced persistence compared with human epidermal growth factor receptor 2 (HER2) CAR-T cells, which have undergone extensive clinical trials. After repeated tumor antigen challenges, SIA-CIgG CAR-T cells display substantial alterations in both the transcriptome and chromatin accessibility. When combining SIA-CIgG CAR-T cell therapy with FDA-approved drugs to treat BC, the histone deacetylase inhibitor (HDACi), vorinostat, is found to enhance the ablility of CAR-T cells for tumor cell lysis. Therefore, the combination of SIA-CIgG CAR-T cells and vorinostat is promising for BC treatment.

Pre-clinical Evaluation of Karanjin Against DMBA-Induced Breast Cancer in Female Sprague-Dawley Rats Through Modulation of SMAR1 and CDP/CUx genes.

To investigate the chemoprotective potential of karanjin against 7,12-dimethylbenz(α)anthracene (DMBA)-induced breast cancer. Thirty-six female rats were utilized for the study. Breast cancer was induced through a subcutaneous injection of 35mg/kg DMBA. The animals were allocated to six groups. Three groups were allocated for karanjin (50mg/kg, 100mg/kg, and 200mg/kg), and received daily treatment for 20weeks (including 2weeks as pre-treatment). Doxorubicin (4mg/kg) was administered to the standard control group twice a week for 20weeks. The disease control (DC) and normal control (NC) groups received daily treatment with saline. After the treatment, oxidative stress parameters, biochemical parameters, and inflammatory parameters were estimated. CCAAT-displacement protein/cut homeobox (CUP/Cux) and scaffold/matrix attachment region binding protein 1 (SMAR1) expression levels were measured through gene expression analysis. Immunohistochemical (IHC) analysis was performed to estimate the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Tumor growth reduced significantly (P-value < 0.01) in karanjin-treated animals compared to the DC group. Karanjin significantly (P-value < 0.01) regulated the levels of oxidative stress parameters, biochemical parameters, and inflammatory parameters compared to the DC group. Karanjin treatment significantly (P-value < 0.001) regulated the expression levels of SMAR1 and CDP/Cux. A notable reduction in the IHC scores was observed for ER, PR, and HER2 expression in karanjin groups. Karanjin demonstrated chemoprotective activity against DMBA-induced breast cancer in animals potentially through modulation of SMAR1 and CDP/Cux gene expression and reduction of ER, PR and HER2 expression levels.

Efficacy and safety of nanoparticle albumin‑bound paclitaxel compared with solvent‑based paclitaxel in adjuvant therapy for breast cancer: A retrospective study.

The current evidence for the use of nanoparticle albumin-bound paclitaxel (nab-PTX) for adjuvant breast cancer chemotherapy is insufficient. The present study aimed to assess the efficacy and toxicity of nab-PTX in comparison with solvent-based paclitaxel (sb-PTX) in postoperative adjuvant breast cancer treatment. A total of 345 patients were included in the study and separated into nab-PTX (n=289) and sb-PTX (n=56) groups based on the type of taxane used in the adjuvant chemotherapy regimen. The study evaluated the baseline characteristics in both groups and the risk factors for postoperative recurrence of mammary cancer. Furthermore, data concerning disease-free survival (DFS) and adverse effects were obtained and analyzed, and group confounding variables were addressed using 1:2 propensity score matching (PSM). Comparisons before PSM revealed significant differences in baseline characteristics including age, underlying disease, lymph node involvement, vascular invasion, human epidermal growth factor receptor 2 and axillary surgery (P<0.05). Following PSM, there were 90 patients in the nab-PTX group and 56 in the sb-PTX group, with no significant differences in the baseline differences (P>0.05). Before PSM, the 73-month DFS rate was 97.9% in the nab-PTX group compared with 91.1% in the sb-PTX group. However, there were no significant differences between the groups before or after PSM (P=0.15 and P=0.49, respectively). Additionally, Cox regression analysis demonstrated a significantly lower chance of recurrence in patients aged >45 years [hazard ratio (HR), 0.197; 95% confidence interval (CI), 0.052-0.753; P=0.018], whereas underlying disease (HR, 5.352; 95% CI, 1.310-21.854; P=0.019) and lymph node infiltration (HR, 8.930; 95% CI, 1.121-71.161; P=0.039) significantly increased the risk of recurrence. Regarding safety, the sb-PTX group had a significantly greater incidence of anaphylaxis, whereas the nab-PTX group had significantly increased rates of anemia and peripheral neuropathy (P<0.05). In summary, the 73-month DFS rate of the nab-PTX cohort exceeded that of the sb-PTX cohort, but no significant difference was detected between them. Underlying disease, lymph node metastasis and an age of ≤45 years are significant predictors of postoperative recurrence of breast cancer.

Overtreatment and Undertreatment of Early-Stage Breast Cancer in Older Women: Evaluating the POWER Trial

IntroductionRadiation therapy (RT) omission is acceptable in older women with early-stage estrogen receptor + breast cancer treated with breast-conserving surgery (BCS) and adjuvant endocrine therapy (AET). However, RT rates in this population remain high, causing concern for overtreatment. Conversely, patients who omit RT and do not complete a course of AET are at risk of undertreatment. In the Pre-Operative Window of Endocrine Therapy to Inform Radiation Therapy Decisions (POWER) trial, participants receive 90 days of preoperative endocrine therapy to assess tolerance before deciding about RT. This study aimed to determine the rates of undertreatment and overtreatment institutionally and among POWER trial participants. MethodsData were retrospectively collected from medical records of women aged ≥ 65 years diagnosed with invasive, estrogen receptor +/human epidermal growth factor receptor 2- breast cancer, ≤ 3 cm, who had BCS between 2012 and 2022. Patients were categorized as undertreated (BCS alone), overtreated (BCS + RT + AET), or appropriately treated (BCS + RT or BCS + AET). ResultsThe cohort included 478 patients, of whom 62 (12.97%) were undertreated, 202 (42.26%) were overtreated, and 214 (44.77%) were appropriately treated. Appropriately treated patients were more likely to be aged 70-79 years (P < 0.0001) and have high health literacy (P = 0.0003). Of the 37 patients (7.71%) in the POWER trial, more were appropriately treated than patients not in the POWER trial (81.1% versus 44.8%) (P < 0.0001). ConclusionsDespite long-standing guideline changes, RT utilization remains high. This study highlights how a novel patient-centered approach to guide adjuvant therapy decisions may increase the number of appropriately treated patients.

Targeting Grb2 SH3 Domains with Affimer Proteins Provides Novel Insights into Ras Signalling Modulation.

Src homology 3 (SH3) domains play a critical role in mediating protein-protein interactions (PPIs) involved in cell proliferation, migration, and the cytoskeleton. Despite their abundance in the human proteome, the functions and molecular interactions of many SH3 domains remain unknown, and this is in part due to the lack of SH3-domain-specific reagents available for their study. Affimer proteins have been developed as affinity reagents targeting a diverse range of targets, including those involved in PPIs. In this study, Affimer proteins were isolated against both the N- and C-terminal SH3 domains (NSH3 and CSH3) of growth-factor-receptor-bound protein 2 (Grb2), an adapter protein that provides a critical link between cell surface receptors and Ras signalling pathways. Targeting the CSH3 alone for the inhibition of PPIs appeared sufficient for curtailing Ras signalling in mammalian cell lines stimulated with human epidermal growth factor (EGF), which conflicts with the notion that the predominant interactions with Ras activating Son of sevenless (SOS) occur via the NSH3 domain. This result supports a model in which allosteric mechanisms involved in Grb2-SOS1 interaction modulate Ras activation.

Unveiling the Role of HGF/c-Met Signaling in Non-Small Cell Lung Cancer Tumor Microenvironment.

Non-small cell lung cancer (NSCLC) is characterized by several molecular alterations that contribute to its development and progression. These alterations include the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor 2 (HER2), and mesenchymal-epithelial transition factor (c-MET). Among these, the hepatocyte growth factor (HGF)/c-MET signaling pathway plays a crucial role in NSCLC. In spite of this, the involvement of the HGF/c-MET signaling axis in remodeling the tumor microenvironment (TME) remains relatively unexplored. This review explores the biological functions of the HGF/c-MET signaling pathway in both normal and cancerous cells, examining its multifaceted roles in the NSCLC tumor microenvironment, including tumor cell proliferation, migration and invasion, angiogenesis, and immune evasion. Furthermore, we summarize the current progress and clinical applications of MET-targeted therapies in NSCLC and discuss future research directions, such as the development of novel MET inhibitors and the potential of combination immunotherapy.

Screening of a kinase inhibitor library identified novel targetable kinase pathways in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a highly invasive breast cancer subtype that is challenging to treat due to inherent heterogeneity and absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Kinase signaling networks drive cancer growth and development, and kinase inhibitors are promising anti-cancer strategies in diverse cancer subtypes. Kinase inhibitor screens are an efficient, valuable means of identifying compounds that suppress cancer cell growth in vitro, facilitating the identification of kinase vulnerabilities to target therapeutically. The Kinase Chemogenomic Set is a well-annotated library of 187 kinase inhibitor compounds that indexes 215 kinases of the 518 in the known human kinome representing various kinase networks and signaling pathways, several of which are understudied. Our screen revealed 14 kinase inhibitor compounds effectively inhibited TNBC cell growth and proliferation. Upon further testing, three compounds, THZ531, THZ1, and PFE-PKIS 29, had the most significant and consistent effects across a range of TNBC cell lines. These cyclin-dependent kinase (CDK)12/CDK13, CDK7, and phosphoinositide 3-kinase inhibitors, respectively, decreased metabolic activity in TNBC cell lines and promote a gene expression profile consistent with the reversal of the epithelial-to-mesenchymal transition, indicating these kinase networks potentially mediate metastatic behavior. These data identified novel kinase targets and kinase signaling pathways that drive metastasis in TNBC.

A Perspective of PI3K/AKT/mTOR Pathway Inhibitors to Overcome Drug-resistance in Breast Cancer Therapy.

The heterogeneous disease, breast cancer (BC), is a frequently detected cancer today, including hormone receptor-positive (HR+), human epidermal growth factor receptor-2-positive (HER2+), and triple-negative (ER-, PR-, HER2-) BC. Advanced endocrine therapies could improve about 85% HR+ BC patient survival. Still, 20% - 30% of cases of endocrine therapy resistance are observed. For all kinds of breast cancer, drug resistance is a common and dangerous phenomenon, comprised of two types: de novo resistance and acquired resistance (prolonged exposure). According to recent works of literature, the PI3K/AKT/mTOR pathway has become an emerging target for overcoming drug resistance in BC therapy due to its close association with tumour growth and resistance from current therapies. Activation of the PI3K/AKT/mTOR pathway was found to promote multidrug resistance by elevating drugs' outflow. The first orally active PI3K inhibitor, Alpelisib (BYL-719) in fulvestrant combination, was approved for treating HR+/ HER2- metastatic BC. Therefore, utilizing PI3K/mTOR/AKT inhibitors in combination with currently available strategies could be an optimistic approach to overcoming drug resistance and resensitizing drug-resistant tumor cells of BC. Here, in this perspective, BC cancer therapies related to drug resistance, the involvement of PI3K/AKT/mTOR pathway in drug resistance and multi-drug resistance, and the role of PI3K/AKT/mTOR inhibitors in getting rid of drug resistance have been illuminated.

Current and Novel Treatment Options in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer.

Metastatic breast cancer (mBC) remains an incurable disease, and most patients will experience disease progression during their treatment course. Although endocrine therapy remains the mainstay of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative mBC, significant progress has been and continues to be made in the treatment of this BC subtype. The discovery of molecular markers, mutations in key cellular pathways, and genomic signatures have led to the development of novel and targeted agents, such as antibody-drug conjugates, oral selective estrogen receptor downregulators, and inhibitors of the PI3K/AKT/mTOR pathway. This has resulted in significant improvements in the survival and quality of life of patients. With the increasing number of treatment options for patients, appropriate drug sequencing remains a challenge. Treatment discussions should involve patient-physician shared decision making, with consideration of genomic data, previous lines of therapy, side effect profiles, and clinical trial enrollment.

Therapeutic indications for antibody-drug conjugates estimated from HER2 and p53 expressions in endometrial carcinoma

ObjectiveWhile human epidermal growth factor receptor 2 (HER2) is upregulated in endometrial carcinoma—especially in the p53 aberrant type— conventional anti-HER2 therapy is not typically used for this cancer type. Recently, HER2-targeted antibody-drug conjugates have shown antitumor effects against HER2 low-expressing cancers. Therefore, we analyzed the clinicopathological characteristics of HER2-positive endometrial carcinomas including those with low expression, as well as the prognostic significance of p53 and HER2 co-expression. MethodsImmunohistochemistry for HER2 and p53 was performed in 530 patients with endometrial carcinoma; 124 cases (23%) were HER2-positive. ResultsOf the HER2-positive cases, >50% were 1+. A high prevalence of HER2 expression was observed in serous (64%), clear-cell (73%), and mixed (64%) carcinomas. Notably, 19% of endometrioid carcinomas were HER2-positive. HER2 positivity was significantly associated with age ≥60 years, high-grade histological subtype, deep myometrium invasion, stage III/IV, recurrence, and death. Univariate analysis showed that HER2-positive cases had reduced progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.012). However, after adjusting for stage, HER2 positivity was not associated with survival. In the early stage, co-expression of HER2-positive and p53 aberrant types was associated with shorter PFS (p < 0.001) and OS (p < 0.001) compared with at least one negative result. Multivariate analysis of PFS showed HER2 and p53 co-expression (hazard ratio, 1.891; 95% confidence interval, 1.183–5.971, p = 0.008) as an independent prognostic factor. ConclusionsThis study presents detailed clinicopathological characteristics and the prognostic impact of HER2-positivity in endometrial carcinomas. HER2-targeted antibody-drug conjugate therapy may be broadly applicable to endometrial carcinoma.

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.

A Vector Nanoplatform for the Bioimaging of Deep-Seated Tumors.

Today, in preclinical studies, optical bioimaging based on luminescence and fluorescence is indispensable in studying the development of neoplastic transformations, the proliferative activity of the tumor, its metastatic potential, as well as the therapeutic effect of antitumor agents. In order to expand the capabilities of optical imaging, sensors based on the bioluminescence resonance energy transfer (BRET) mechanism and, therefore, independent of an external light source are being developed. A targeted nanoplatform based on HER2-specific liposomes whose internal environment contains a genetically encoded BRET sensor was developed in this study to visualize deep-seated tumors characterized by overexpression of human epidermal growth factor receptor type 2 (HER2). The BRET sensor is a hybrid protein consisting of the highly catalytic luciferase NanoLuc (an energy donor) and a LSSmKate1 red fluorescent protein with a large Stokes shift (an energy acceptor). During the bioimaging of disseminated intraperitoneal tumors formed by HER2-positive SKOV3.ip1cells of serous ovarian cystadenocarcinoma, it was shown that the developed system is applicable in detecting deep-seated tumors of a certain molecular profile. The developed system can become an efficient platform for optimizing preclinical studies of novel targeted drugs.

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.

Rationale for the Initiation, Outcomes, and Characteristics of Chemotherapy Following CDK4/6 Inhibitors in Breast Cancer: A Real-World Cohort Study.

The standard therapy for hormone-receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer includes the use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy. The optimal post-CDK4/6i treatment sequence is unclear. This cohort study evaluated the initiation, characteristics, and outcomes of chemotherapy following CDK4/6i-based treatment. Among the 227 patients who began CDK4/6i therapy, 114 completed it. Seventy-nine female patients received further treatment, including 55 receiving chemotherapy. The average age was 60.1 years. Post-CDK4/6i chemotherapy was typically (69.1%) first-line due to an impending visceral crisis. The median progression-free survival (mPFS) was 3.0 months (range 0.5-18.9), and the median overall survival (mOS) was 8.3 months (0.5-26.1). The median OS from the end of CDK4/6i treatment was 12.4 months (1.5-26.8). In univariate analysis, neither mPFS nor mOS was associated with age, tumor grade, receptor status, Ki67 status, time from diagnosis to CDK4/6i cessation, therapy line, or CDK4/6i type. Dose reduction occurred in 12 patients (21.8%), and chemotherapy was ceased due to adverse events in 8 patients (14.6%). Chemotherapy showed limited benefit regardless of the regimen. The role of chemotherapy may evolve with broader CDK4/6i use in adjuvant treatment.

Prognostic and Predictive Significance of Primary Tumor Localization and HER2 Expression in the Treatment of Patients with KRAS Wild-Type Metastatic Colorectal Cancer: Single-Centre Experience from Serbia.

The treatment of patients with metastatic colorectal cancer (mCRC) is complex and is impacted by the location of the primary tumor (LPT). Our study aims to emphasize the importance of LPT as a prognostic and predictive marker as well as to examine the significance of HER2 overexpression in patients with mCRC, particularly in relation to the response to Epidermal Growth Factor Receptor Antibody treatment (anti-EGFR therapy). In this study, 181 patients with Kirsten RAS (KRAS) wild-type mCRC who received anti-EGFR therapy were included. Among them, 101 had left colon cancer (LCC) and 80 had right colon cancer (RCC). Results demonstrated that patients with KRAS wild-type LCC had better median overall survival (OS) (43 vs. 33 months, p = 0.005) and progression-free survival (PFS) (6 vs. 3 months, p < 0.001) compared to those with RCC. Multivariate analysis identified mucinous adenocarcinoma (p < 0.001), RCC location (p = 0.022), perineural invasion (p = 0.034), and tumors at the resection margin (p = 0.001) as independent predictors of OS, while mucinous adenocarcinoma (p = 0.001) and RCC location (p = 0.004) independently correlated with significantly shorter PFS. In addition, human epidermal growth factor receptor 2 (HER2) positive expression was significantly associated with worse PFS compared to HER2 negative results (p < 0.001). In conclusion, LPT is an important marker for predicting outcomes in the treatment of wild-type mCRC using anti-EGFR therapy, since patients with RCC have a statistically significantly shorter PFS and OS. Further investigation is needed to understand the role of HER2 overexpression in wild-type mCRC, as these patients also exhibit shorter survival.

Muscarinic and nicotinic receptors stimulation by vagus nerve stimulation ameliorates trastuzumab-induced cardiotoxicity via reducing programmed cell death in rats

Despite its efficacy in human epidermal growth factor receptor 2 positive cancer treatment, trastuzumab-induced cardiotoxicity (TIC) has become a growing concern. Due to the lack of cardiomyocyte regeneration and proliferation in adult heart, cell death significantly contributes to cardiovascular diseases. Cardiac autonomic modulation by vagus nerve stimulation (VNS) has shown cardioprotective effects in several heart disease models, while the effects of VNS and its underlying mechanisms against TIC have not been found. Forty adult male Wistar rats were divided into 5 groups: (i) control without VNS (CSham) group, (ii) trastuzumab (4 mg/kg/day, i.p.) without VNS (TSham) group, (iii) trastuzumab + VNS (TVNS) group, (iv) trastuzumab + VNS + mAChR blocker (atropine; 1 mg/kg/day, ip, TVNS + Atro) group, and (v) trastuzumab + VNS + nAChR blocker (mecamylamine; 7.5 mg/kg/day, ip, TVNS + Mec) group. Our results showed that trastuzumab induced cardiac dysfunction by increasing autonomic dysfunction, mitochondrial dysfunction/dynamics imbalance, and cardiomyocyte death including apoptosis, autophagic deficiency, pyroptosis, and ferroptosis, which were notably alleviated by VNS. However, mAChR and nAChR blockers significantly inhibited the beneficial effects of VNS on cardiac autonomic dysfunction, mitochondrial dysfunction, cardiomyocyte apoptosis, pyroptosis, and ferroptosis. Only nAChR could counteract the protective effects of VNS on cardiac mitochondrial dynamics imbalance and autophagy insufficiency. Therefore, VNS prevented TIC by rebalancing autonomic activity, ameliorating mitochondrial dysfunction and cardiomyocyte death through mAChR and nAChR activation. The current study provides a novel perspective elucidating the potential treatment of VNS, thus also offering other pharmacological therapeutic promises in TIC patients.

US Food and Drug Administration Approval Summary: Capivasertib With Fulvestrant for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Locally Advanced or Metastatic Breast Cancer With PIK3CA/AKT1/PTEN Alterations.

The US Food and Drug Administration (FDA) approved capivasertib in combination with fulvestrant for adult patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced, or metastatic breast cancer (MBC) who have received at least one previous endocrine therapy and whose tumors harbor one or more phosphatidylinositol 3-kinase (PIK3CA)/AKT Serine/Threonine Kinase 1 (AKT1)/phosphatase and tensin homolog (PTEN) alterations, as detected by an FDA-approved test. Approval was based on CAPItello-291, a randomized, double-blind, multicenter trial of 708 patients with hormone receptor-positive, HER2-negative advanced or MBC, including 289 patients with PIK3CA/AKT1/PTEN tumor alterations. Patients were randomly assigned 1:1 to receive capivasertib 400 mg twice daily for 4 days per week with fulvestrant versus placebo with fulvestrant. Random assignment was stratified by presence of liver metastases, previous treatment with CDK4/6i, cyclin-dependent kinase four and six (CDK4/6) inhibitors, and geographical region. A statistically significant progression-free survival (PFS) benefit was demonstrated in the overall population (hazard ratio [HR], 0.6 [95% CI, 0.51 to 0.71]); this result was driven by 289 patients in the biomarker-positive population (HR, 0.5 [95% CI, 0.37 to 0.68]). An exploratory analysis of investigator-assessed PFS in the 313 (44%) patients in the biomarker-negative population showed uncertain benefit (HR, 0.78 [95% CI, 0.60 to 1.01]). With capivasertib, more patients had Grade ≥3 toxicities. Key concerns included hyperglycemia (18% all-grade, 2.8% Grade ≥3), cutaneous toxicity (58% all-grade, 17% Grade ≥3), and diarrhea (72% all-grade, 9% Grade ≥3). Capivasertib with fulvestrant was approved for patients whose tumors harbored PIK3CA/AKT1/PTEN alterations. Benefit-risk assessment in this subgroup was favorable based on a statistically significant and clinically meaningful improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in overall survival. By contrast, the benefit-risk was unfavorable in the biomarker-negative population.

Radiation hepatitis after postmastectomy radiation therapy for early breast cancer: difficult to differentiate from drug-induced liver injury caused by abemaciclib.

Abemaciclib (ABM) is recommended for adjuvant endocrine therapy in hormone receptor-positive, human epidermal growth factor receptor type 2-negative early breast cancer (EBC) patients at high risk of recurrence. Here, we present a case of radiation hepatitis challenging to differentiate from drug-induced liver injury during ABM treatment. The patient, a woman in her 40s, underwent right mastectomy, axillary dissection, and postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy for EBC. Subsequently, she received ABM as adjuvant endocrine therapy. Despite suspending ABM due to Grade 3 leukopenia, she developed Grade 3 hepatic dysfunction upon cessation. Based on the dynamic contrast-enhanced computed tomography, we diagnosed the cause of liver dysfunction as radiation hepatitis. Spontaneous improvement allowed us to resume ABM treatment. Clinicians may need to consider radiation hepatitis as a potential cause of hepatic dysfunction in patients who underwent PMRT, along with drug-induced liver injury.

Profiling the Cardiovascular Toxicities of CDK4/6 Inhibitors: A Real-World Pharmacovigilance Study.

Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors are approved for the treatment of human epidermal growth factor receptor 2 (HER-2)-negative, hormone receptor-positive breast cancer. The cardiovascular toxicity of CDK4/6 inhibitors is not well understood. This study aims to profile the cardiac events associated with CDK4/6 inhibitors. Reports from 2015Q1 to 2024Q1 were obtained from the FDA Adverse Event Reporting System (FAERS). Reports identifying palbociclib, ribociclib, and abemaciclib as the primary suspect were examined for cardiovascular toxicity, including hypertension, cardiac failure, cardiomyopathy, arrhythmia, myocardial infarction, and myocarditis. Signal detection was performed using the proportional reporting ratio (PRR), reporting odds ratio (ROR), and information component (IC). A total of 69,139 reports were analyzed. The median time to adverse events was 69 days (interquartile range [IQR], 18-260 days). Of these, 2065 reports documented cardiac adverse events. Ribociclib and QT prolongation were re-confirmed as a signal (PRR 8.43, ROR 8.65, IC025 2.86). Hypertension and cardiac failure were the most frequently reported cardiovascular toxicities. This study demonstrates that the use of CDK4/6 inhibitors is associated with cardiovascular adverse events, such as heart failure and hypertension. Further research is needed to understand the mechanisms and risk factors contributing to the cardiovascular toxicity of CDK4/6 inhibitors.