An epidermal growth factor receptor-targeting immunotoxin based on IgG shows potent antitumor activity against head and neck cancer.

The epidermal growth factor receptor (EGFR) is an important target for cancer therapies. Many head and neck cancer (HNC) cells have been reported to overexpress EGFR; therefore, anti-EGFR therapies have been attempted in patients with HNC. However, its clinical efficacy is limited owing to the development of drug resistance. In this study, we developed an EGFR-targeting immunotoxin consisting of a clinically proven anti-EGFR IgG (cetuximab; CTX) and a toxin fragment (LR-LO10) derived from Pseudomonas exotoxin A (PE) using a novel site-specific conjugation technology (peptide-directed photo-crosslinking reaction), as an alternative option. The immunotoxin (CTX-LR-LO10) showed specific binding to EGFR and properties of a typical IgG, such as stability, interactions with receptors of immune cells, and pharmacokinetics, and inhibited protein synthesis via modification of elongation factor-2. Treatment of EGFR-positive HNC cells with the immunotoxin resulted in apoptotic cell death and the inhibition of cell migration and invasion. The efficacy of CTX-LR-LO10 was evaluated in xenograft mouse models, and the immunotoxin exhibited much stronger tumor suppression than CTX or LR-LO10. Transcriptome analyses revealed that the immunotoxins elicited immune responses and altered the expression of genes related to its mechanisms of action. These results support the notion that CTX-LR-LO10 may serve as a new therapeutic agent targeting EGFR-positive cancers.

[Retracted] Galectin­3 blockade suppresses the growth of cetuximab­resistant human oral squamous cell carcinoma.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the colony formation assay data shown in Fig. 4C on p. 6 were strikingly similar to data appearing in different form in other articles written by different authors at different research institutes, which had already been published. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 24: 685, 2021; DOI: 10.3892/mmr.2021.12325].

Efficacy of recombinant human epidermal growth factor plus sodium hyaluronate eye drops in diabetic dry eye post-cataract surgery.

BACKGROUND: Dry eye syndrome (DES) after diabetic cataract surgery can seriously affect the patient's quality of life. Therefore, effective alleviation of symptoms in patients with this disease has important clinical significance. AIM: To explore the clinical effect of recombinant human epidermal growth factor (rhEGF) plus sodium hyaluronate (SH) eye drops on DES after cataract surgery in patients with diabetes. METHODS: We retrospectively evaluated 82 patients with diabetes who experienced DES after cataract surgery at Tianjin Beichen Hospital, Affiliated Hospital of Nankai University between April 2021 and April 2023. They were classified into an observation group (42 cases, rhEGF + SH eye drops) and a control group (40 cases, SH eye drops alone), depending on the different treatment schemes. The thera-peutic efficacy, dry eye symptom score, tear film breakup time (TFBUT), basic tear secretion score [assessed using Schirmer I test (SIt)], corneal fluorescein staining (FL) score, tear inflammatory markers, adverse reactions during treatment, and treatment satisfaction were compared between the two groups. RESULTS: Therapeutic efficacy was higher in the observation group compared with the control group. Both groups showed improved TFBUT and dry eye, as well as improved SIt and FL scores after treatment, with a more pronounced improvement in the observation group. Although no marked differences in adverse reactions were observed between the two groups, treatment satisfaction was higher in the observation group. CONCLUSION: rhEGF + SH eye drops rendered clinical benefits to patients by effectively ameliorating dry eye and visual impairment with favorable efficacy, fewer adverse reactions, and high safety levels. Thus, this treatment should be promoted in clinical practice.

EGFR-TKIs - induced cardiotoxicity in NSCLC: incidence, evaluation, and monitoring.

The advent of targeted drug therapy has greatly changed the treatment landscape of advanced non-small cell lung cancer(NSCLC), but the cardioxic side effects of targeted drug anti-cancer therapy seriously affect the prognosis of NSCLC, and it has become the second leading cause of death in cancer patients. Therefore, early identification of the cardiotoxic side effects of targeted drugs is crucial for the prevention and treatment of cardiovascular diseases. The cardiotoxic side effects that may be caused by novel targeted drugs epidermal growth factor receptor inhibitors, including thromboembolic events, heart failure, cardiomyopathy, arrhythmia and hypertension, are discussed, and the mechanisms of their respective adverse cardiovascular reactions are summarized, to provide useful recommendations for cardiac management of patients with advanced lung cancer to maximize treatment outcomes for lung cancer survivors. Clinicians need to balance the risk-benefit ratio between targeted therapy for malignant tumors and drug-induced cardiotoxicity, and evaluate and monitor TKIs-induced cardiotoxicity through electrocardiogram, cardiac imaging, biomarkers, etc., so as to remove the susceptibility risk factors as soon as possible and provide a reference for the clinical use of such drugs in the treatment of malignant tumors.

A case of Ph+ acute lymphoblastic leukemia and EGFR mutant lung adenocarcinoma synchronous overlap: may one TKI drug solve two diseases?

BACKGROUND: Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) refers to ALL patients with t(9;22) cytogenetic abnormalities, accounting for about 25% of ALL. Lung adenocarcinoma (LUAD) is the most common pathological type of non-small-cell lung cancer, which has a frequency of approximately 45% cases with mutations in EGFR. Both Ph+ ALL and EGFR mutant LUAD are involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway. Although the second primary hematological malignancy after the treatment of solid tumors is common in clinics, the synchronous multiple primary malignant tumors of hematological malignancy overlap solid tumors are uncommon, even both tumors involved in the pathogenesis of the abnormal activation of the tyrosine kinase pathway are extremely rare. CASE PRESENTATION: An 84-year-old man with fatigue and dizziness was diagnosed with Ph+ ALL. Meanwhile, a chest CT indicated a space-occupying lesions, characterized by the presence of void, in the right lower lope with the enlargement of mediastinal lymph node and right pleural effusion. After a few weeks, the patient was diagnosed with LUAD with EGFR exon 19 mutation. Both tyrosine kinase inhibitors (TKI) (Flumatinib) and EGFR-TKI (Oxertinib) was used for the patients, and finally have controlled both diseases. CONCLUSION: As far as we know, we for the first time reported a case of Ph+ ALL and EGFR mutant LUAD synchronous overlap, of which pathogenesis is related to abnormal tyrosine kinase activation. This patient was successfully treated with two different TKIs without serious adverse events.

B7-H3 enhances colorectal cancer progression by regulating HB-EGF via HIF-1α.

Background: B7-H3 (or CD276) represents an important costimulatory molecule expressed in many malignant solid tumors, including colorectal cancer (CRC). The receptor of B7-H3 is not known, and the intracellular function of B7-H3 remains obscure. Herein, we report that B7-H3 upregulated the epidermal growth factor heparin-binding epidermal growth factor (HB-EGF), likely by regulating hypoxia-inducible factor 1α (HIF-1α) and thereby promoting the progression of CRC. Methods: Lentiviral transfection was performed on CRC cells to establish stable low-B7-H3 expression cells. A mechanistic analysis with an Agilent human gene expression profiling chip was conducted on them. Clinical data and specimens were collected to detect the connection between B7-H3 and HB-EGF in CRC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the messenger RNA (mRNA) level of B7-H3, HB-EGF, and HIF-1α. Chromatin immunoprecipitation (ChIP) quantitative real-time PCR was conducted. The protein level of HIF-1α and the phosphatidylinositide 3-kinases (PI3K)-protein kinase B (AKT) pathway were detected by western blot. HIF-1α was recovered by lentiviral transfection, and the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis ability were detected. Results: B7-H3 promoted tumor progression through HB-EGF and the PI3K-AKT pathway. As B7-H3 was downregulated, HB-EGF levels were significantly reduced simultaneously, a growth trend that was shown by both CRC cell lines and cancer tissues. In addition, B7-H3 and HB-EGF had significant associations with tumor-node-metastasis (TNM) stage and lymph node metastasis in 50 CRC patients. The binding ability of HIF-1α to the HB-EGF promoter region was significantly decreased in the shB7-H3 RKO group. Western blot revealed that PI3K, AKT, and mammalian target of rapamycin (mTOR) protein amounts and p-AKT and p-mTOR phosphorylation were also downregulated in shB7-H3 RKO cells, suggesting that B7-H3 may regulate HIF-1α via PI3K-AKT signaling. After recovery of the HIF-1α level by lentiviral transfection, the HB-EGF mRNA levels, proliferation, invasion, and angiogenesis in CRC cells recovered as well. Conclusions: B7-H3 may transmit intracellular signals through PI3K-AKT-mTOR-HIF-1α signaling, upregulating HB-EGF. As the final transcription factor of the pathway, HIF-1α regulates the transcription of the HB-EGF gene, thereby promoting HB-EGF expression, which eventually mediates cell proliferation, invasion, and angiogenesis and promotes the progression of CRC.

Best practices for achieving consensus in HER2-low expression in breast cancer: current perspectives from practising pathologists.

AIMS: Human epidermal growth factor receptor 2 (HER2) expression is an important biomarker in breast cancer (BC). Most BC cases categorised as HER2-negative (HER2-) express low levels of HER2 [immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridisation not amplified (ISH-)] and represent a clinically relevant therapeutic category that is amenable to targeted therapy using a recently approved HER2-directed antibody-drug conjugate. A group of practising pathologists, with expertise in breast pathology and BC biomarker testing, outline best practices and guidance for achieving consensus in HER2 IHC scoring for BC. METHODS AND RESULTS: The authors describe current knowledge and challenges of IHC testing and scoring of HER2-low expressing BC and provide best practices and guidance for accurate identification of BCs expressing low levels of HER2. These expert pathologists propose an algorithm for assessing HER2 expression with validated IHC assays and incorporate the 2023 American Society of Clinical Oncology and College of American Pathologist guideline update. The authors also provide guidance on when to seek consensus for HER2 IHC scoring, how to incorporate HER2-low into IHC reporting and present examples of HER2 IHC staining, including challenging cases. CONCLUSIONS: Awareness of BC cases that are negative for HER protein overexpression/gene amplification and the related clinical relevance for targeted therapy highlight the importance of accurate HER2 IHC scoring for optimal treatment selection.

Comparing the Effectiveness of Afatinib and Osimertinib for Patients With PD-L1-positive EGFR-mutant Non-small Cell Carcinoma.

Background/Aim: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs, and information on the comparison between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC is scarce. Patients and Methods: We retrospectively analyzed data of patients with PD-L1-positive EGFR-mutant NSCLC to compare the effectiveness of afatinib and osimertinib. Results: A total of 177 patients were included in the study. The Cox proportion hazard model was adjusted for age, sex, performance status, EGFR mutation status, PD-L1 expression level, and brain metastasis, revealing that there was no significant difference in risk for progression [hazard ratio (HR)=0.99, 95% confidence interval (CI)=0.64-1.53] or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib. Conclusion: In conclusion, the EGFR-TKI treatment duration and overall survival after the treatment with afatinib or osimertinib were similar in patients with PD-L1-positive EGFR-mutant NSCLC in the present study.

Clinical impact of EGFR and KRAS mutations in surgically treated unifocal and multifocal lung adenocarcinoma.

Background: Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma (KRAS) are the two most common oncogenic drivers in lung adenocarcinoma, and their roles still need further exploration. Here we aimed to compare the clinical impact of EGFR and KRAS mutations on disease progression in resected unifocal and multifocal lung adenocarcinoma. Methods: Clinicopathologic and genomic data were collected for patients who underwent resection of lung adenocarcinoma from 2008 to 2022 at Stanford University Hospital. Retrospective review was performed in 241 patients whose tumors harbored EGFR (n=150, 62.2%) or KRAS (n=91, 37.8%) mutations. Clinical outcome was analyzed with special attention to the natural history of secondary nodules in multifocal cases wherein the dominant tumor had been resected. Results: We confirm that compared with EGFR mutations, patients with KRAS mutations had more smokers, larger tumor size, higher TNM stage, higher positron emission tomography (PET)/computed tomography (CT) standard uptake value max, higher tumor mutation burden, and worse disease-free survival and overall survival on univariate analysis. For patients with multifocal pulmonary nodules, the median follow-up of unresected secondary nodules was 55 months. Secondary nodule progression-free survival (SNPFS) was significantly worse for patients with KRAS mutations than those with EGFR mutations (mean 40.3±6.6 vs. 67.7±6.5 months, P=0.004). Univariate analysis showed tumor size, tumor morphology, pathologic TNM stage, and KRAS mutations were significantly associated with SNPFS, while multivariate analysis showed only KRAS mutations were independently associated with worse SNPFS (hazard ratio 1.752, 95% confidence interval: 1.017-3.018, P=0.043). Conclusions: Resected lung adenocarcinomas with KRAS mutations have more aggressive clinicopathological features and confer worse prognosis than those with EGFR mutations. Secondary pulmonary nodules in multifocal cases with dominant KRAS-mutant tumors have more rapid progression of the secondary nodules.

Neoadjuvant aumolertinib monotherapy for EGFR-mutant lung squamous cell carcinoma: a case report.

Background: Lung cancer is the malignant tumor with high incidence and mortality in China, and more than 30% of non-small cell lung cancer (NSCLC) patients are in the locally advanced stage at the first-time diagnosis. Currently, neoadjuvant epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) combined with radical surgery is effective in the treatment of unresectable stage III EGFR-mutated NSCLC (NSCLCm), and related studies are gradually increasing. But the feasibility of neoadjuvant EGFR-TKI combined with radical surgery for unresectable stage III EGFR-mutant lung squamous cell carcinoma (LUSQm) remains controversial. Case Description: This report presented a successful case of neoadjuvant target-therapy with aumolertinib, the third-generation EGFR-TKI, combined with radical surgery for a stage IIIA LUSQm female patient. After four cycles (28 days/cycle) of neoadjuvant target-therapy, the tumor had a partial response on imaging evaluation and pathological evaluation after surgery showed complete tumor response. The neoadjuvant target-therapy was well tolerated. All adverse events (AEs) that occurred during the treatment were grade I, including decreased platelets, impaired liver function, and diarrhea. The patient was instructed to continue taking Aumolertinib for 3 years after surgery. At the cut-off date of April 1, 2024, the patient had no recurrence after 20 months of treatment. Conclusions: The result of patient treatment demonstrated the potential feasibility of neoadjuvant Aumolertinib monotherapy for locally advanced LUSQm. The report provides some support for neoadjuvant target-therapy for LUSQm.

Patient-reported outcomes for the phase 3 FURLONG study of furmonertinib versus gefitinib as first-line therapy for Chinese patients with locally advanced or metastatic EGFR mutation-positive non-small cell lung cancer.

Background: Furmonertinib showed superior efficacy compared with gefitinib as first-line therapy in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) in the FURLONG study. Here we present prespecified secondary endpoints of patient-reported outcomes (PRO). Methods: In this multicentre, double-blind, double-dummy, randomised phase 3 study, patients were 1:1 randomly assigned to receive furmonertinib 80 mg once daily or gefitinib 250 mg once daily. PROs assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30 and Quality-of-Life Questionnaire Lung Cancer 13 were analysed using a mixed model for repeated measures and time-to-event analyses. A difference in score of 10 points or more was deemed clinically relevant. Findings: Three hundred and fifty-seven patients (furmonertinib group, n = 178; gefitinib group, n = 179) received at least one dose of the study drug, all of whom completed at least one PRO assessment. Statistically significant difference of overall score changes from baseline favoured furmonertinib in physical functioning (between-group difference 2.14 [95% CI 0.25-4.04], p = 0.027), nausea/vomiting (-1.56 [95% CI -2.62 to -0.49], p = 0.004), appetite loss (-2.24 [95% CI -4.26 to -0.23], p = 0.029), diarrhoea (-3.36 [95% CI -5.19 to -1.54], p < 0.001), alopecia (-2.62 [95% CI -4.54 to -0.71], p = 0.007), and pain in other parts (-4.55 [95% CI -7.37 to -1.74], p = 0.002), but not reached clinical relevance. Time to deterioration in physical functioning (hazard ratio 0.63 [95% CI 0.42-0.94], p = 0.021), cognitive functioning (0.73 [95% CI 0.54-0.98], p = 0.034), nausea/vomiting (0.64 [95% CI 0.41-0.99], p = 0.042), appetite loss (0.63 [95% CI 0.43-0.92], p = 0.016), diarrhoea (0.63 [95% CI 0.46-0.85], p = 0.002), dyspnoea (0.72 [95% CI 0.53-0.98], p = 0.034), cough (0.67 [95% CI 0.44-1.00], p = 0.049), dysphagia (0.54 [95% CI 0.35-0.83], p = 0.004), and alopecia (0.62 [95% CI 0.42-0.90], p = 0.012) was longer with furmonertinib versus gefitinib. Interpretation: In patients with locally advanced or metastatic EGFR mutation-positive NSCLC, furmonertinib showed improved scores and delayed deterioration in several functioning and symptoms compared to gefitinib. Funding: Shanghai Allist Pharmaceutical Technology Co., Ltd and the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer.

More than 1.9 million new colorectal cancer (CRC) cases and 935000 deaths were estimated to occur worldwide in 2020, representing about one in ten cancer cases and deaths. Overall, colorectal ranks third in incidence, but second in mortality. More than half of the patients are in advanced stages at diagnosis. Treatment options are complex because of the heterogeneity of the patient population, including different molecular subtypes. Treatments have included conventional fluorouracil-based chemotherapy, targeted therapy, immunotherapy, etc. In recent years, with the development of genetic testing technology, more and more targeted drugs have been applied to the treatment of CRC, which has further prolonged the survival of metastatic CRC patients.

Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer.

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance. Human epidermal growth factor receptor 2 (HER2) is one of the most important targets in targeted therapy for gastric cancer. Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer. The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified. However, monoclonal antibodies, due to their large molecular weight, inability to penetrate the blood-brain barrier, and drug resistance, lead to decreased therapeutic efficacy, so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer. Small-molecule tyrosine kinase inhibitors, such as lapatinib and pyrrotinib, have the advantages of small molecular weight, penetrating the blood-brain barrier and high oral bioavailability, and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future. Antibo-drug conjugate, such as T-DM1 and T-DXd, can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing, and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab. Therefore, after more detailed stratification of gastric cancer patients, various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Retrospective clinical study analysis of skin adverse reactions related to epidermal growth factor receptor inhibitors.

Background: Epidermal growth factor receptor inhibitors (EGFRIs) represent a cornerstone in the targeted therapy of malignant tumors. While effective, dermatological adverse events (dAEs) associated with EGFRIs pose a significant challenge, often necessitating treatment discontinuation due to their severity and potential to impede the continuity of cancer therapy. Despite extensive research, the specific mechanisms and predictors of these adverse events remain poorly understood, particularly in diverse populations. This gap in knowledge underscores the need for targeted studies to better predict and manage these events, enhancing patient outcomes and adherence to life-saving therapies. Methods: This observational study was conducted at The First Affiliated Hospital of Guangxi Medical University, covering cancer patients treated with EGFRIs from 2020 to 2022. We analyzed clinical data including patient demographics, treatment specifics, and the development and timing of dAEs. The study employed SPSS 26.0 software for data analysis, focusing on the incidence of dAEs and factors influencing their occurrence. We used Kaplan-Meier and Cox regression methods to establish a predictive model for dAEs, tracking their onset and impact on treatment continuity. Results: In our study of 120 patients treated with EGFR inhibitors at The First Affiliated Hospital of Guangxi Medical University, we found a high prevalence of dAEs, with 84.2% of patients experiencing such effects. The most common manifestations were papulopustular rashes, observed as pustules in 52.5% and papules in 57.4% of cases, followed by nail lesions in 62.4% of patients, oral or other mucosal ulcers in 34.7%, and hair changes in 26.7%. The median incubation time (MIT) for dAEs was 5 weeks. We identified drug type, ethnicity, and occupation as statistically significant risk factors (P<0.05 for all) that influenced the MIT, which the Cox regression model further identified as protective factors. Nomograms were developed to assess the risk of dAEs, although it is important to note that these models have only been internally validated, lacking external validation data at this stage. Conclusions: The study highlights the high incidence of EGFRIs-associated dAEs, with specific dermatological manifestations posing significant challenges in cancer therapy. The identification of drug type, ethnicity, and occupation as influential factors on the MIT for dAEs informs clinical decisions. Our prediction model serves as a practical tool for evaluating the risk of developing dAEs over time, aiming to optimize patient management and mitigate treatment interruptions.

Case report: Disitamab vedotin combined with immunotherapy demonstrated excellent efficacy in scrotal Paget's disease with Her-2 overexpression.

Background: Extramammary Paget's disease (EMPD) is a rare epithelial malignancy, and approximately 30%-40% of EMPD patients overexpress human epidermal growth factor receptor 2 (Her-2). Currently, there are no established standard treatments for advanced EMPD while anti-Her-2 therapy is recommended for Her-2-positive cases. Case presentation: Here, we report a 51-year-old male diagnosed with advanced Her-2-positive EMPD, presenting with numerous lymph node metastases. This patient received disitamab vedotin (an antibody-drug conjugate, targeting Her-2) combined with serplulimab as first-line treatment. After seven cycles of combination therapy, the patient tolerated the treatment well and the lymph node lesions continued to shrink. However, the patient developed immunotherapy-related pneumonia following the eighth treatment. Hormone therapy was administered while all the anti-tumor therapies were halted. After the pneumonia improved, the patient underwent positron emission tomography-computed tomography, revealing a complete response to his tumor. To consolidate the effect, he received another five cycles of disitamab vedotin monotherapy as maintenance therapy, without experiencing any adverse events. To date, the patient has remained in good health without any recurrence 10 months after drug discontinuance. Conclusion: Disitamab vedotin combined with immunotherapy demonstrated a long-term clinical benefit in advanced Her-2-positive EMPD. For rare solid tumors with Her-2 overexpression, disitamab vedotin combined with immunotherapy might offer a viable therapeutic choice.

Real-World Treatment Patterns and Clinical Outcomes Among Patients with Metastatic or Unresectable EGFR-Mutated Non-Small Cell Lung Cancer Previously Treated with Osimertinib and Platinum-Based Chemotherapy.

INTRODUCTION: For patients with epidermal growth factor receptor-mutated (EGFRm) locally advanced/metastatic non-small cell lung cancer (mNSCLC) whose disease has progressed on or after osimertinib and platinum-based chemotherapy (PBC), no uniformly accepted standard of care exists. Moreover, limited efficacy of standard treatments indicates an unmet medical need, which is being addressed by ongoing clinical investigations, including the HERTHENA-Lung01 (NCT04619004) study of patritumab deruxtecan (HER3­DXd). However, because limited information is available on real-world clinical outcomes in such patients, early-phase trials of investigational therapies lack sufficient context for comparison. This study describes the real-world clinical characteristics, treatments, and outcomes for patients with EGFRm mNSCLC who initiated a new line of therapy following previous osimertinib and PBC, including a subset matched to the HERTHENA-Lung01 population. METHODS: This retrospective analysis used a US database derived from deidentified electronic health records. The reference cohort included patients with EGFRm mNSCLC who had initiated a new line of therapy between November 13, 2015 and June 30, 2021, following prior osimertinib and PBC. A subset of patients resembling the HERTHENA-Lung01 population was then extracted from the reference cohort; this matched subset was optimized using propensity score (PS) weighting. Endpoints were real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). Confirmed real-world objective response rate (rwORR; partial/complete response confirmed ≥ 28 days later) was calculated for the response-evaluable subgroups of patients (with ≥ 2 response assessments spaced ≥ 28 days apart). RESULTS: In the reference cohort (N = 273), multiple treatment regimens were used, and none was predominant. Median rwPFS and rwOS were 3.3 and 8.6 months, respectively; confirmed rwORR (response evaluable, n = 123) was 13.0%. In the matched subset (n = 126), after PS weighting, median rwPFS and rwOS were 4.2 and 9.1 months, respectively; confirmed rwORR (response evaluable, n = 57) was 14.1%. CONCLUSION: The treatment landscape for this heavily pretreated population of patients with EGFRm mNSCLC is fragmented, with no uniformly accepted standard of care. A high unmet need exists for therapeutic options that provide meaningful improvements in clinical benefit.

Erlotinib or Gefitinib for Treating Advanced Epidermal Growth Factor Receptor Mutation-Positive Lung Cancer in Aotearoa New Zealand: Protocol for a National Whole-of-Patient-Population Retrospective Cohort Study and Results of a Validation Substudy.

BACKGROUND: Starting in 2010, the epidermal growth factor receptor (EGFR) kinase inhibitors erlotinib and gefitinib were introduced into routine use in Aotearoa New Zealand (NZ) for treating advanced lung cancer, but their impact in this setting is unknown. OBJECTIVE: The study described in this protocol aims to understand the effectiveness and safety of these new personalized lung cancer treatments and the contributions made by concomitant medicines and other factors to adverse outcomes in the general NZ patient population. A substudy aimed to validate national electronic health databases as the data source and the methods for determining patient eligibility and identifying outcomes and variables. METHODS: This study will include all NZ patients with advanced EGFR mutation-positive lung cancer who were first dispensed erlotinib or gefitinib before October 1, 2020, and followed until death or for at least 1 year. Routinely collected health administrative and clinical data will be collated from national electronic cancer registration, hospital discharge, mortality registration, and pharmaceutical dispensing databases by deterministic data linkage using National Health Index numbers. The primary effectiveness and safety outcomes will be time to treatment discontinuation and serious adverse events, respectively. The primary variable will be high-risk concomitant medicines use with erlotinib or gefitinib. For the validation substudy (n=100), data from clinical records were compared to those from national electronic health databases and analyzed by agreement analysis for categorical data and by paired 2-tailed t tests for numerical data. RESULTS: In the validation substudy, national electronic health databases and clinical records agreed in determining patient eligibility and for identifying serious adverse events, high-risk concomitant medicines use, and other categorical data with overall agreement and κ statistic of >90% and >0.8000, respectively; for example, for the determination of patient eligibility, the comparison of proxy and standard eligibility criteria applied to national electronic health databases and clinical records, respectively, showed overall agreement and κ statistic of 96% and 0.8936, respectively. Dates for estimating time to treatment discontinuation and other numerical variables and outcomes showed small differences, mostly with nonsignificant P values and 95% CIs overlapping with zero difference; for example, for the dates of the first dispensing of erlotinib or gefitinib, national electronic health databases and clinical records differed on average by approximately 4 days with a nonsignificant P value of .33 and 95% CIs overlapping with zero difference. As of May 2024, the main study is ongoing. CONCLUSIONS: A protocol is presented for a national whole-of-patient-population retrospective cohort study designed to describe the safety and effectiveness of erlotinib and gefitinib during their first decade of routine use in NZ for treating EGFR mutation-positive lung cancer. The validation substudy demonstrated the feasibility and validity of using national electronic health databases and the methods for determining patient eligibility and identifying the study outcomes and variables proposed in the study protocol. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000998549; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368928. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/51381.

Management of oligometastatic and oligoprogressive epidermal growth factor receptor mutated non-small cell lung cancer patients: state of the art of a combined approach.

Recently, the development of targeted therapy approaches such as those based on tyrosine kinase inhibitor (TKI) greatly improved the clinical outcomes of patients affected by oncogene addicted advanced non-small cell lung cancer (NSCLC). Similarly, the improvement of radiation therapy techniques has permitted to deliver high radiation doses to a limited number of metastatic target lesions (oligopersistent or oligoprogressive), with limited high-dose normal tissue exposure that leads to low severe toxicity rates. The aim of this narrative review was to provide an overview of the currently established definition of oligometastatic and oligoprogressive disease, to define first line and subsequent lines targeted therapies and the role of consolidative non-invasive local ablative treatments (LATs) in these settings. The potential benefit of local treatment (LT) such as radiotherapy (RT) or surgery might be represented by an overall reduction of switching to subsequent systemic treatments lowering the risk of further systemic dissemination. Further randomized clinical trials will clarify the role of LT and their correct timing in relation to systemic targeted therapies.

Urine Epidermal Growth Factor and Kidney Function Decline in Middle-Aged Adults.

Rationale & Objective: The diagnosis and prognostication of chronic kidney disease (CKD) largely rely on glomerular measures that may not reflect tubular damage. We investigated the associations of urine kidney tubule biomarkers with estimated glomerular filtration rate (eGFR) change among middle-aged adults, when chronic diseases typically emerge. Study Design: An observational cohort study. Setting & Participants: A total of 1,145 participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study without CKD, hypertension, or cardiovascular disease at the year 20 visit. Exposures: Seven different biomarkers of tubular health: urine epidermal growth factor (EGF), alpha-1-microglobulin (α1m), interleukin-18, kidney injury molecule-1, monocyte chemoattractant protein-1, uromodulin, and chitinase-3-like protein 1. Outcomes: Ten-year eGFR change and incident reduced eGFR (new onset of eGFR < 60 mL/min/1.73 m2). Analytical Approach: We examined associations of tubular health biomarkers with 10-year eGFR change and incident reduced eGFR with linear mixed models and interval-censored proportional hazards regression models, respectively. Both minimally and fully adjusted models were controlled for urine creatinine levels. Results: The mean age of participants was 44.8 ± 3.7 years, with 39% African American and 56% female. The average 10-year change in eGFR was -18.6 mL/min/1.73 m2 (95% CI, -19.4 to -17.8). In contrast to the other tubular biomarkers, which showed conflicting results, EGF demonstrated strong, consistent associations with both kidney outcomes. Each 1-standard deviation (SD) higher EGF was associated with a 2.37 mL/min/1.73 m2 (95% CI, 0.64-4.10) smaller 10-year decrease in eGFR and a 42% (95% CI, 4%-64%) lower risk of incident reduced eGFR in the fully adjusted model. Limitations: Observational design, measurements of eGFR were done only at 5-year intervals during follow-up. Conclusions: In middle-aged, community-dwelling adults without hypertension, cardiovascular disease or CKD, higher urine EGF concentrations are associated with slower eGFR decline, whereas other kidney tubule biomarkers lacked a consistent association with kidney function decline.

Current measures of chronic kidney disease (CKD) rely on markers of glomerular health and function. This approach inadequately captures the role of kidney tubule health, a known histopathological predictor of CKD development. We investigated associations of 7 biomarkers of kidney tubule health with 10-year estimated glomerular filtration rate (eGFR) change and incident reduced eGFR. Among 7 biomarkers, only epidermal growth factor showed persistent and inverse associations with both 10-year eGFR change and incident reduced eGFR. These findings suggest that epidermal growth factor has an association with kidney function changes and might play a protective role in kidney disease development.

Development of neuro-Behcet's disease in a patient with operable HER2-positive breast cancer during neoadjuvant chemotherapy: A case report.

BACKGROUND: Neuro-Behcet's disease (NBD) is a variant of Behcet's disease (BD). To our knowledge, there have been no previous reports on concurrent NBD in breast cancer patients undergoing chemotherapy. CASE PRESENTATION: Our patient had a history of BD and was asymptomatic. She was diagnosed with human epidermal growth factor receptor 2-positive breast cancer by core needle biopsy and was administered neoadjuvant chemotherapy. After four courses, in addition to the aggravation of the existing adverse events, headache, fever, dysarthria, and muscle weakness in the upper left and lower extremities appeared. On admission, she was diagnosed with acute NBD, and steroid therapy was initiated. After her symptoms improved gradually, she was discharged. Then, she underwent mastectomy and axillary lymph node dissection for breast cancer. Trastuzumab and pertuzumab plus tamoxifen were administered postoperatively. Two years postoperatively, no recurrence of breast cancer and NBD was noted. CONCLUSION: When chemotherapy is administered to breast cancer patients with a history of BD, it is necessary to select chemotherapy with as few adverse events as possible and to continue with treatment while paying attention to the risk of NBD.