LGR4 attenuates MGP expression and suppresses EGFR activation-induced triple-negative breast cancer metastasis.

Breast cancer has emerged as the most common cancer globally, with a significant reduction in overall survival rate after metastasis. Compared with other types of breast cancer, triple-negative breast cancer (TNBC) is more prone to metastasize, presenting substantial treatment challenges due to the lack of effective therapies. LGR4, which is highly expressed in breast cancer, has been shown to promote the proliferation and invasion of breast cancer cells. However, its specific role in TNBC remains unclear. In this study, we applied a multi-omics approach to explore the regulatory mechanism of LGR4 in TNBC metastasis. Our findings showed that LGR4 could regulate actin cytoskeletal through EGFR and curtail EGFR activation-induced TNBC metastasis by inhibiting MGP expression. These insights provide new perspectives on the role of LGR4 in breast cancer metastasis.

Beyond tobacco: genomic disparities in lung cancer between smokers and never-smokers.

BACKGROUND: Tobacco use is one of the main risk factors for Lung Cancer (LC) development. However, about 10-20% of those diagnosed with the disease are never-smokers. For Non-Small Cell Lung Cancer (NSCLC) there are clear differences in both the clinical presentation and the tumor genomic profiles between smokers and never-smokers. For example, the Lung Adenocarcinoma (LUAD) histological subtype in never-smokers is predominately found in young women of European, North American, and Asian descent. While the clinical presentation and tumor genomic profiles of smokers have been widely examined, never-smokers are usually underrepresented, especially those of a Latin American (LA) background. In this work, we characterize, for the first time, the difference in the genomic profiles between smokers and never-smokers LC patients from Chile. METHODS: We conduct a comparison by smoking status in the frequencies of genomic alterations (GAs) including somatic mutations and structural variants (fusions) in a total of 10 clinically relevant genes, including the eight most common actionable genes for LC (EGFR, KRAS, ALK, MET, BRAF, RET, ERBB2, and ROS1) and two established driver genes for malignancies other than LC (PIK3CA and MAP2K1). Study participants were grouped as either smokers (current and former, n = 473) or never-smokers (n = 200) according to self-report tobacco use at enrollment. RESULTS: Our findings indicate a higher overall GA frequency for never-smokers compared to smokers (58 vs. 45.7, p-value < 0.01) with the genes EGFR, KRAS, and PIK3CA displaying the highest prevalence while ERBB2, RET, and ROS1 the lowest. Never-smokers present higher frequencies in seven out of the 10 genes; however, smokers harbor a more complex genomic profile. The clearest differences between groups are seen for EGFR (15.6 vs. 21.5, p-value: < 0.01), PIK3CA (6.8 vs 9.5) and ALK (3.2 vs 7.5) in favor of never-smokers, and KRAS (16.3 vs. 11.5) and MAP2K1 (6.6 vs. 3.5) in favor of smokers. Alterations in these genes are comprised almost exclusively by somatic mutations in EGFR and mainly by fusions in ALK, and only by mutations in PIK3CA, KRAS and MAP2K1. CONCLUSIONS: We found clear differences in the genomic landscape by smoking status in LUAD patients from Chile, with potential implications for clinical management in these limited-resource settings.

EGFR-mutated lung cancer as a secondary neoplasm in a patient with Li-Fraumeni syndrome: case report.

Background: Li-Fraumeni syndrome (LFS) is a rare hereditary disorder caused by mutations in the tumor protein p53 (TP53). It causes a predisposition for the development of multiple malignancies, primarily including breast cancers, sarcomas, and central nervous system tumors. There are a few cases reported in the literature of patients with LFS presenting with an epidermal growth factor receptor (EGFR) mutated lung cancer. Still, it has been suggested that there may be an association between the TP53 pathogenic variant and lung cancer with EGFR mutation in somatic cells. Case Description: A 47-year-old non-smoker woman with LFS with a history of multiple tumors, including bilateral breast cancer, pecoma, and sarcoma. In one of her computed tomography, a lesion in the lingula of the lung was detected. It was biopsied, which diagnosed lung adenocarcinoma, and genetic studies detected an EGFR exon 19 deletion. She was treated with a left inferior lobectomy, followed by pemetrexed and cisplatin. Conclusions: The association between TP53 and lung cancer with EGFR mutation has been suggested in case reports. Studies in lung cancer cell lines have shown a link between TP53 mutation and EGFR overexpression. Nonetheless, as more cases are reported, further research is needed to comprehend the interrelation between these two pathologies and the risk posed by LFS to the emergence of EGFR-mutated lung cancer.

EGFR-Tyrosine Kinase Inhibitor Retreatment in Non-Small-Cell Lung Cancer Patients Previously Exposed to EGFR-TKI: A Systematic Review and Meta-Analysis.

We performed a systematic review and meta-analysis to assess the efficacy of EGFR-tyrosine kinase inhibitors (TKI) retreatment in advanced/metastatic non-small-cell lung cancer (NSCLC) patients. We systematically searched PubMed, Embase, Cochrane databases, ASCO, and ESMO websites for studies evaluating EGFR-TKI retreatment in advanced/metastatic NSCLC patients. All analyses were performed using R software (v.4.2.2). We included 19 studies (9 CTs and 10 retrospective cohorts) with a total of 886 patients. In a pooled analysis of all patients during retreatment with TKI, median OS was 11.7 months (95% confidence interval [CI] 10.2-13.4 months) and PFS was 3.2 months (95% CI 2.5-3.9 months). ORR was 15% (95% CI 10-21%) and DCR was 61% (95% CI 53-67%). The subanalysis by generation of TKI in the rechallenge period revealed a slightly better ORR for patients on 3rd generation TKI (p = 0.05). Some limitations include the high heterogeneity of some of the analyses and inability to perform certain subanalyses. Our results unequivocally support the benefit of EGFR-TKI rechallenge in EGFR-mutated NSCLC patients progressing on TKI treatment after a TKI-free interval. These findings may be especially valuable in areas where access to novel therapeutic drugs and clinical trials is limited.

Dermatology-related quality-of-life outcomes in patients with RAS wild-type metastatic colorectal cancer treated with fluorouracil and folinic acid with or without panitumumab (Pmab) maintenance after FOLFOX + Pmab induction: a prespecified secondary analysis of the phase II randomized PanaMa (AIO KRK 0212) trial.

BACKGROUND: The key endpoints for the assessment of the effect of maintenance therapy for metastatic colorectal cancer (mCRC) are survival and quality-of-life outcomes. We aimed to compare dermatology-related quality of life (DRQOL) in patients with RAS wild-type (wt) mCRC treated with fluorouracil and folinic acid (FU/FA) + panitumumab (Pmab) versus FU/FA alone as maintenance therapy after folinic acid, fluorouracil and oxaliplatin + Pmab induction. PATIENTS AND METHODS: The phase II randomized PanaMa (AIO KRK 0212; NCT01991873) trial included 387 patients at 70 community/academic sites in Germany. For this prespecified secondary analysis, DRQOL outcomes were assessed using the Functional Assessment of Cancer Therapy-epidermal growth factor receptor inhibitor (FACT-EGFRI), Dermatology Life Quality Index (DLQI), and Skindex-16 questionnaires at every second cycle of therapy until disease progression/death. RESULTS: At least one DRQOL questionnaire was completed by a total of 310/377 (82%) patients who received induction therapy, and by 216/248 (87%) patients who were randomized and received maintenance therapy. Patients who experienced skin toxicity according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) during induction therapy had significantly worse DRQOL according to all three measures, compared to those who did not [i.e. Skindex-16, mean difference at cycle 2 -12.87; 95% confidence interval (CI) -20.01 to -5.73; P < 0.001]. During maintenance therapy, significantly improved recovery was observed in all DRQOL measures for patients receiving FU/FA, compared to those receiving additional Pmab (i.e. Skindex-16, mean difference at cycle 6 -16.53; 95% CI -22.68 to -10.38; P < 0.001). CONCLUSIONS: In this secondary analysis of a phase II randomized clinical trial, patient-reported DRQOL outcomes correlated with skin toxicity according to NCI-CTCAE during induction therapy. Maintenance therapy with FU/FA + Pmab was associated with deteriorated DRQOL versus FU/FA alone in patients with RAS wt mCRC.

Immunostaining and gene expression of epidermal growth factor receptors (HER1/HER2) in canine cutaneous squamous cell carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is a neoplasm type often diagnosed in dogs. However, studies focused on further investigating its molecular biology, mainly biomarkers to help implementing new therapies, remain scare in the literature. Thus, immunostaining and the gene expression of epidermal growth factor receptors (HER1 and HER2) in canine cSCC presenting different cell differentiation degrees were herein assessed. Thirty-two (32) canine cSCC were selected, classified based on to their cell differentiation degree and subjected to immunohistochemical study to assess HER1 and HER2 immunostaining intensity and distribution. In addition, HER1 and HER2 gene expression was investigated through real-time PCR. Membranous and cytoplasmic immunostaining were observed in both markers. HER2 prevailed in poorly differentiated cSCC; there was positive protein expression correlation between both markers. Mean HER1 gene expression was higher in moderately differentiated, whereas mean HER2 gene expression was higher in poorly differentiated cSCC. Moreover, there was gene expression correlation between markers, regardless of cell differentiation degree. Thus, HER2 protein immunostaining and gene expression were higher in poorly differentiated canine cSCC and it enabled understanding that increase observed in this epidermal growth factor receptor is proportional to this neoplasm's cell differentiation degree in canine species. Results in the current study helped better understanding canine cSCC's molecular biology; however, it is relevant studying other markers aiming to investigate signaling pathways.

Different genetic profiles contribute to worse overall survival in patients with leptomeningeal metastases of non-small-cell lung cancer.

BACKGROUND: To assess the genetic characteristics of central nervous system (CNS) metastases from non-small-cell lung cancer (NSCLC), we gathered the genetic profiles of brain metastases (BM) and leptomeningeal metastases (LM). Our objective was to identify genetic factors contributing to poorer overall survival (OS) in NSCLC patients with LM. METHODS: This study included 25 consecutive patients with BM and 52 patients with LM from Guangdong Sanjiu Brain Hospital. All participants underwent 168-target panel sequencing. RESULTS: Among the 25 patients with BM, TP53 was the most frequently mutated gene (44%), followed by driver genes such as EGFR and BRAF (40% and 20%, respectively). In patients with BM, EGFR_amp and CDK4 were also frequently mutated, with rates of 20% and 16%, respectively. The genetic landscape of patients with LM differed, with the top mutated genes being EGFR, TP53, EGFR_amp, CDKN2A, CCNE1, CDK4, PMS2, and PIK3CA, with mutation rates of 77%, 69%, 31%, 29%, 13%, 13%, 13%, and 12%, respectively. In our study, patients with LM exhibited significantly worse OS compared to those with BM (p = 0.029). The mutation rates of TP53, EGFR_amp, and CDKN2A varied between patients with LM and those with BM, at 69.23% vs. 44%, 30.77% vs. 20%, and 28.85% vs. 12%, respectively. Further exploration revealed that patients with BM with TP53 mutations had a shorter OS than patients without TP53 mutations (p = 0.014). Similarly, patients with LM and TP53 mutations presented with worse OS than those without TP53 mutations (p = 0.0067). LM patients with CDKN2A deletions had worse OS than those without CDKN2A deletions (p = 0.037). Additionally, patients with EGFR_amp had a shorter OS than those without EGFR_amp (p = 0.044). CONCLUSIONS: Patients with LM exhibited significantly worse OS than those with BM. Gene signatures, such as TP53, EGFR_amp, and CDKN2A, may account for shorter outcomes in patients with LM.

Almonertinib and alflutinib show novel inhibition on rare EGFR S768I mutant cells.

PURPOSE: EGFR classical mutations respond well to EGFR tyrosine kinase inhibitors. However, it is uncertain whether currently available EGFR-TKIs are effective against rare EGFR mutations and compound mutations. Herein, the effectiveness of almonertinib and alflutinib, the third-generation tyrosine kinase inhibitors developed in China, on rare EGFR S768I mutations and compound mutations is identified. METHODS: In this study, using CRISPR method, four EGFR S768I mutation cell lines were constructed, and the sensitivity of EGFR to almonertinib and alflutinib was tested, with positive controls being the 1st (gefitinib), 2nd (afatinib), and 3rd (osimertinib) generation drugs. RESULTS: The present results indicate that almonertinib and alflutinib can effectively inhibit cell viability and proliferation in rare EGFR S768I mutations through the ERK or AKT pathways in a time-dependent manner, by blocking the cell cycle and inhibiting apoptosis. CONCLUSIONS: These findings suggest that almonertinib and alflutinib may be potential therapeutic options for non-small cell lung cancer patients with the EGFR S768I mutation.

Experiencia institucional en pacientes con cáncer de pulmón de células no pequeñas con mutaciones de inserción del exón 20 del receptor del factor de crecimiento epidérmico (EGFR)

En el cáncer de pulmón de células no pequeñas (CPCNP) con mutación clásica de EGFR, los inhibidores de la tirosina quinasa (TKI) de EGFR produce mejores resultados que la quimioterapia basada en platino. Sin embargo, la eficacia terapéutica es bastante diferente en pacientes con mutaciones de inserción del exón 20 del EGFR (ex20ins) versus mutaciones comunes. Los pacientes con mutaciones ex20ins son insensibles a los EGFR-TKI y tienen mal pronóstico. Es importante conocer las características demográficas y clínicas en este grupo de pacientes y la prevalencia en nuestra región. Metodología: Revisión retrospectiva, única instituciónal, serie de casos de pacientes con cáncer de pulmón de células no pequeñas con mutaciones de inserción del exón 20 desde 2017-2023. Los pacientes habían recibido terapia de primera línea para enfermedad avanzada y tuvieron estudios de imágenes para evaluar la respuesta. Se registraron los datos demográficos, las características y tratamiento de cada paciente. La respuesta al tratamiento se evaluó utilizando los criterios RECIST v1.1 y la supervivencia global se calculó mediante el método de Kaplan Meier. Resultados: Entre los 15 pacientes identificados con cáncer de pulmón de células no pequeñas con mutaciones de inserción del exón 20 en nuestra institución, la incidencia para la mutación fue del 1.5%. La edad promedio fue de 60 años, el 46,7% eran mujeres, 14 pacientes hispanos y 1 paciente asiático, solo 3 pacientes tenían antecedentes de tabaquismo. El 40% de los pacientes tuvo una escala funcional según el Grupo Cooperativo de Oncología Oriental (ECOG) de 2. El subtipo histológico fue adenocarcinoma en todos los casos. De los 13 (86.7%) pacientes que recibieron tratamiento de primera línea, se les realizaron exploraciones evaluables para determinar la respuesta, 11 progresaron, 1 paciente obtuvo enfermedad estable y otro tuvo respuesta parcial. La mediana de supervivencia global (SG) fue de 5 meses. Conclusiones: Los pacientes con mutaciones de inserción del exón 20 tienen resistencia a los inhibidores de tirosina quinasa, lo cual le confiere un peor pronóstico. Es vital conocer en nuestra región la incidencia de la mutación y las características de los pacientes para ofrecer un diagnóstico y tratamiento oportuno. Nuestros resultados proporcionan un contexto importante para el desarrollo de nuevas terapias que puedan aprobarse en primera línea de tratamiento y no en líneas subsecuentes. (provisto por Infomedic International)

In non-small cell lung cancer (NSCLC) with classical EGFR mutation, EGFR tyrosine kinase inhibitors (TKIs) produce better results than platinum-based chemotherapy. However, therapeutic efficacy is quite different in patients with EGFR exon 20 insertion mutations (ex20ins) versus common mutations. Patients with ex20ins mutations are insensitive to EGFR-TKIs and have poor prognosis. It is important to know the demographic and clinical characteristics in this group of patients and the prevalence in our region. Methodology: retrospective, single institution, case series review of patients with non-small cell lung cancer with exon 20 insertion mutations from 2017-2023. Patients had received first-line therapy for advanced disease and had imaging studies to assess response. Demographics, characteristics, and treatment of each patient were recorded. Treatment response was assessed using RECIST v1.1 criteria and overall survival was calculated using the Kaplan Meier method. Results: Among the 15 patients identified with non-small cell lung cancer with exon 20 insertion mutations at our institution, the incidence for the mutation was 1.5%. The mean age was 60 years, 46.7% were women, and the incidence of the mutation was 1.5%. The average age was 60 years, 46.7% were women, 14 patients were Hispanic and 1 patient was Asian, only 3 patients had a history of smoking. Forty percent of the patients had an Eastern Cooperative Oncology Group (ECOG) functional score of 2. The histologic subtype was adenocarcinoma in all cases. Of the 13 (86.7%) patients who received first-line treatment had evaluable scans to determine response, 11 progressed, 1 patient had stable disease, and 1 patient had a partial response. The median overall survival (OS) was 5 months. Conclusions: Patients with exon 20 insertion mutations have resistance to tyrosine kinase inhibitors, which confers a worse prognosis. It is vital to know in our region the incidence of the mutation and patient characteristics to provide timely diagnosis and treatment. Our results provide an important context for the development of new therapies that can be approved in the first line of treatment and not in subsequent lines. (provided by Infomedic International)

Machine learning-driven prediction of brain metastasis in lung adenocarcinoma using miRNA profile and target gene pathway analysis of an mRNA dataset.

BACKGROUND: Brain metastasis (BM) is common in lung adenocarcinoma (LUAD) and has a poor prognosis, necessitating predictive biomarkers. MicroRNAs (MiRNAs) promote cancer cell growth, infiltration, and metastasis. However, the relationship between the miRNA expression profiles and BM occurrence in patients with LUAD remains unclear. METHODS: We conducted an analysis to identify miRNAs in tissue samples that exhibited different expression levels between patients with and without BM. Using a machine learning approach, we confirmed whether the miRNA profile could be a predictive tool for BM. We performed pathway analysis of miRNA target genes using a matched mRNA dataset. RESULTS: We selected 25 miRNAs that consistently exhibited differential expression between the two groups of 32 samples. The 25-miRNA profile demonstrated a strong predictive potential for BM in both Group 1 and Group 2 and the entire dataset (area under the curve [AUC] = 0.918, accuracy = 0.875 in Group 1; AUC = 0.867, accuracy = 0.781 in Group 2; and AUC = 0.908, accuracy = 0.875 in the entire group). Patients predicted to have BM, based on the 25-miRNA profile, had lower survival rates. Target gene analysis of miRNAs suggested that BM could be induced through the ErbB signaling pathway, proteoglycans in cancer, and the focal adhesion pathway. Furthermore, patients predicted to have BM based on the 25-miRNA profile exhibited higher expression of the epithelial-mesenchymal transition signature, TWIST, and vimentin than those not predicted to have BM. Specifically, there was a correlation between EGFR mRNA levels and BM. CONCLUSIONS: This 25-miRNA profile may serve as a biomarker for predicting BM in patients with LUAD.

Design and Evaluation of a Humanized Anti-EGFR huscFv Antibody Fragment in Combination With Metformin in A549 Cells In Vitro.

BACKGROUND/AIM: The epidermal growth factor receptor (EGFR) is over-expressed in several types of cancer, and monoclonal antibody therapy has been the strategy that has shown the best results. This study focused on the construction of a humanized single chain antibody (huscFv) directed against EGFR (HER1). MATERIALS AND METHODS: The CDR grafting method was used to incorporate murine complementarity determining regions (CDRs) of cetuximab into human sequences. A dot blot assay was used to examine the affinity of the huscFv secreted by HEK293T for EGFR. The inhibitory effect on the viability of A549 cells was evaluated using the WST-1 assay. RESULTS: The incorporation of murine CDRs of cetuximab into human sequences increased the degree of humanness by 16.4%. The increase in the humanization of scFv did not affect the affinity for EGFR. Metformin had a dose-dependent effect, with an IC50 of 46 mM, and in combination with huscFv, the cell viability decreased by 45% compared to the 15% demonstrated by huscFv alone. CONCLUSION: The CDR grafting technique is efficient for the humanization of scFv, maintaining its affinity for EGFR and demonstrating its inhibitory effect when combined with metformin in A549 cells.

A Cross-Sectional Analysis Investigating Pregnant Women's Renal Function and Its Association with Lead and Cadmium Exposures-The DSAN Birth Cohort Study in Recôncavo Baiano, Brazil.

Kidney dysfunction is increasing worldwide and is exacerbated by exposure to toxic metals. Also, pregnancy poses an overload on kidney function. We investigated how blood lead (PbB) and cadmium (CdB) levels were associated with kidney function in pregnant women from Recôncavo Baiano, Brazil, during their second trimester. In this cross-sectional study, the estimated glomerular filtration rate (eGFR) was calculated from serum creatinine and whole blood metal levels were measured by graphite furnace atomic absorption spectrophotometry in 136 volunteers. Sociodemographic data were collected using semi-structured questionnaires. The medians (IQR) of PbB, CdB, and eGFR were 0.85 µg/dL (0.45-1.75), 0.55 µg/L (0.08-0.91), and 121.8 mL/min/1.73 m2 (106.0-127.9), respectively. PbB medians were significantly higher in the eGFR < 90 group at 2.00 µg/dL (0.83, 3.10). After age-adjusted logistic regression, pregnant women with elevated PbB levels had decreased eGFR (OR = 1.82; 95%-CI, 1.14-3.14). However, the participants with elevated PbB levels who reported consuming alcohol during pregnancy or had CdB in the highest tertile had higher odds of reduced eGFR (OR = 2.44; 95%-CI, 1.30-5.47) and (OR = 11.22; 95% CI, 2.53-103.51), respectively. These results suggest that low Pb exposure may affect kidney function in pregnant women and calls for further investigation into toxic metal co-exposures on kidney function during pregnancy in at-risk communities.

MET overexpression correlated with prognosis of EGFR-mutant treatment­naïve advanced lung adenocarcinoma: a real­world retrospective study.

BACKGROUND: About 50-60% treatment-naïve advanced non-small-cell lung cancers were coexistence of epidermal growth factor receptor (EGFR) and mesenchymal epithelial transition (MET) overexpression. However, few studies demonstrated the prognostic value of MET protein expression in untreated EGFR-mutant lung adenocarcinoma (LUAD). METHODS: A total of 235 EGFR-mutant untreated advanced LUAD patients were retrospectively enrolled. MET expression was determined using immunohistochemistry, and MET positivity was defined as 2 + or 3 + using the METmab scoring algorithm. Progression-free survival (PFS) and overall survival (OS) were analysed according to MET expression status. Independent factors predicting prognosis were identified using multivariate Cox regression analyses. RESULTS: Of the 235 patients, 113 (48.1%) harboured exon 19 deletion (19_del), 103 (43.8%) had exon 21 L858R mutations, and 19 (8.1%) had other mutation types, including exon 21 L861Q, exon 18 G719A/C, exon 20 S768I, and L858R/19_del double mutations. MET-positive expression was observed in 192 (81.7%) cases. There was no significant difference in baseline clinicopathological characteristics between MET positivity and MET negativity groups. Patients were stratified by different EGFR mutation subtypes. MET-positive patients in the L858R mutation subgroup had markedly shorter PFS and OS than MET-negative patients (median PFS: 13 versus 27.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.008), but no significant difference was observed in the 19_del subgroup. Multivariate Cox regression analyses indicated that MET positivity was an independent predictor for poor PFS and OS in L858R subgroup (PFS: HR = 3.059, 95% CI 1.552-6.029, p = 0.001; OS: HR = 3.511, 95% CI 1.346-9.160, p = 0.010). Additionally, an inferior survival outcome of MET positivity was observed in the L858R mutation subgroup when treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy as the first-line regimen (median PFS: 13 versus 36.5 months, p < 0.001; median OS: 29 versus not reached, p = 0.012) but not with EGFR-TKI plus platinum doublet chemotherapy. CONCLUSIONS: MET positive expression was an independent predictor of poor outcomes in untreated EGFR L858R mutation advanced LUAD patients treated with first-line EGFR-TKI monotherapy.

The role of angiogenesis inhibitors associated with tyrosine kinase inhibitors in the first-line treatment for EGFR-mutated advanced lung cancer.

Tyrosine kinase inhibitors (TKIs) are the standard treatment for epidermal growth factor receptor mutant (EGFRm) advanced non-small cell lung cancer (NSCLC). Combining TKIs with an angiogenesis inhibitor has shown promise in pre-clinical studies. A systematic search of clinical trials found that combining erlotinib (a first-generation TKI) with bevacizumab or ramucirumab (angiogenesis inhibitors) improved progression-free survival (PFS) in EGFRm advanced NSCLC patients compared to TKI alone. However, no significant benefit in overall survival (OS) was observed in trials. Similar efficacy was seen in patients with specific EGFR mutations. Third generation TKIs were used as second-line therapy for patients with the T790M mutation. The combination treatment was associated with a higher incidence of severe adverse events. Overall, combining erlotinib or another TKI with an angiogenesis inhibitor is a safe and effective alternative for first-line treatment in EGFRm advanced NSCLC, particularly in countries without access to osimertinib and for patients with the EGFR L858R mutation.

Compounds Consisting of Quinazoline, Ibuprofen, and Amino Acids with Cytotoxic and Anti-Inflammatory Effects.

In this research work, a series of 16 quinazoline derivatives bearing ibuprofen and an amino acid were designed as inhibitors of epidermal growth factor receptor tyrosine kinase domain (EGFR-TKD) and cyclooxygenase-2 (COX-2) with the intention of presenting dual action in their biological behavior. The designed compounds were synthesized and assessed for cytotoxicity on epithelial cancer cells lines (AGS, A-431, MCF-7, MDA-MB-231) and epithelial non-tumorigenic cell line (HaCaT). From this evaluation, derivative 6 was observed to exhibit higher cytotoxic potency (IC50) than gefitinib (reference drug) on three cancer cell lines (0.034 µM in A-431, 2.67 µM in MCF-7, and 3.64 µM in AGS) without showing activity on the non-tumorigenic cell line (>100 µM). Furthermore, assessment of EGFR-TKD inhibition by 6 showed a discreet difference compared to gefitinib. Additionally, 6 was used to conduct an in vivo anti-inflammatory assay using the 12-O-tetradecanoylphorbol-3-acetate (TPA) method, and it was shown to be 5 times more potent than ibuprofen. Molecular dynamics studies of EGFR-TKD revealed interactions between compound 6 and M793. On the other hand, one significant interaction was observed for COX-2, involving S531. The RMSD graph indicated that the ligand remained stable in 50 ns.

Primary versus acquired epidermal growth factor receptor Thr790Met mutant non-small cell lung cancer: clinical features and prognoses.

PURPOSE: This study aimed to identify the impact of epidermal growth factor receptor (EGFR) T790M mutations on clinical characteristics and prognosis. METHODS: Retrospective analyses were conducted on the differences on clinicopathological features and prognosis between primary and acquired T790M mutations. Subgroup analyses were performed for primary T790M coexisting with other mutations. RESULTS: Patients with primary T790M mutations showed a 60.53% (23/38) incidence of concurrent L858R mutations, 18.42% (7/38) for 19del mutations and a 21.05% (8/38) occurrence of brain metastases. Conversely, those with acquired T790M mutations demonstrated respective frequencies of 36.53% (61/167), 58.68% (98/167) and 44.31% (74/167), with all comparisons yielding p < 0.05. The median overall survival differed significantly between the two groups, with a duration of 33 months for patients with primary T790M mutations as compared to 48 months for those with acquired mutations (p = 0.030). Notably, among patients with L858R co-mutations, when treated with third-generation EGFR-TKIs, those with acquired T790M mutations experienced a significantly prolonged median time to treatment failure compared to those with primary mutations (17 months vs. 9 months, p = 0.009). CONCLUSION: Patients with primary T790M have unique molecular features and had worse prognosis compared with acquired T790M. Resistance to third-generation EGFR-TKIs seems to be associated with the presence of EGFR co-mutations.

Using Vision Transformer for high robustness and generalization in predicting EGFR mutation status in lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma is a common cause of cancer-related deaths worldwide, and accurate EGFR genotyping is crucial for optimal treatment outcomes. Conventional methods for identifying the EGFR genotype have several limitations. Therefore, we proposed a deep learning model using non-invasive CT images to predict EGFR mutation status with robustness and generalizability. METHODS: A total of 525 patients were enrolled at the local hospital to serve as the internal data set for model training and validation. In addition, a cohort of 30 patients from the publicly available Cancer Imaging Archive Data Set was selected for external testing. All patients underwent plain chest CT, and their EGFR mutation status labels were categorized as either mutant or wild type. The CT images were analyzed using a self-attention-based ViT-B/16 model to predict the EGFR mutation status, and the model's performance was evaluated. To produce an attention map indicating the suspicious locations of EGFR mutations, Grad-CAM was utilized. RESULTS: The ViT deep learning model achieved impressive results, with an accuracy of 0.848, an AUC of 0.868, a sensitivity of 0.924, and a specificity of 0.718 on the validation cohort. Furthermore, in the external test cohort, the model achieved comparable performances, with an accuracy of 0.833, an AUC of 0.885, a sensitivity of 0.900, and a specificity of 0.800. CONCLUSIONS: The ViT model demonstrates a high level of accuracy in predicting the EGFR mutation status of lung adenocarcinoma patients. Moreover, with the aid of attention maps, the model can assist clinicians in making informed clinical decisions.

Characteristics and prognosis of EGFR mutations in small cell lung cancer patients in the NGS era.

PURPOSE: Targeted therapy has not been effective for small cell lung cancer (SCLC) patients. Although some studies have reported on EGFR mutations in SCLC, a systematic investigation into the clinical, immunohistochemical, and molecular characteristics and prognosis of EGFR-mutated SCLCs is lacking. METHODS: Fifty-seven SCLC patients underwent next-generation sequencing technology, with 11 in having EGFR mutations (group A) and 46 without (group B). Immunohistochemistry markers were assessed, and the clinical features and first-line treatment outcomes of both groups were analyzed. RESULTS: Group A consisted primarily of non-smokers (63.6%), females (54.5%), and peripheral-type tumors (54.5%), while group B mainly comprised heavy smokers (71.7%), males (84.8%), and central-type tumors (67.4%). Both groups showed similar immunohistochemistry results and had RB1 and TP53 mutations. When treated with tyrosine kinase inhibitors (TKIs) plus chemotherapy, group A had a higher treatment response rate with overall response and disease control rates of 80% and 100%, respectively, compared to 57.1% and 100% in group B. Group A also had a significantly longer median progression-free survival (8.20 months, 95% CI 6.91-9.49 months) than group B (2.97 months, 95% CI 2.79-3.15), with a significant difference (P = 0.043). Additionally, the median overall survival was significantly longer in group A (16.70 months, 95% CI 1.20-32.21) than in group B (7.37 months, 95% CI 3.85-10.89) (P = 0.016). CONCLUSION: EGFR-mutated SCLCs occurred more frequently in non-smoking females and were linked to prolonged survival, implying a positive prognostic impact. These SCLCs shared immunohistochemical similarities with conventional SCLCs, and both types had prevalent RB1 and TP53 mutations.

Correlation between carcinoembryonic antigen (CEA) expression and EGFR mutations in non-small-cell lung cancer: a meta-analysis.

OBJECTIVES: The purpose of this meta-analysis was to investigate the relationship between serum carcinoembryonic antigen (CEA) expression and epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC). METHODS: Databases such as PubMed, Cochrane, EMBASE and Google Scholar were systematically searched to identify studies assessing the association of serum CEA expression with EGFR mutations. Across 19 studies, 4168 patients were included between CEA expression and EGFR mutations odds ratio (OR) conjoint analysis of correlations. RESULTS: Compared with CEA-negative NSCLC, CEA-positive tumors had an increased EGFR mutation rate (OR = 1.85, 95% confidence interval: 1.48-2.32, P < 0.00001). This association was observed in both stage IIIB/IV patients (OR = 1.60, 95% CI: 1.18-2.15, P = 0.002) and stage I-IIIA (OR = 1.67, 95% CI: 1.01-2.77, P = 0.05) patients. In addition, CEA expression was associated with exon 19 (OR = 1.97, 95% CI: 1.25-3.11, P = 0.003) and exon 21 (OR = 1.51, 95% CI: 1.07-2.12, P = 0.02) EGFR mutations. In ADC pathological type had also showed the correlation (OR = 1.84, 95% CI: 1.31-2.57, P = 0.0004). CONCLUSIONS: This meta-analysis indicated that serum CEA expression was associated with EGFR mutations in NSCLC patients. The results of this study suggest that CEA level may play a predictive role in the EGFR mutation status of NSCLC patients. Detecting serum CEA expression levels can give a good suggestion to those patients who are confused about whether to undergo EGFR mutation tests. Moreover, it may help better plan of the follow-up treatment.

Unveiling the role of MGMT and DAPK hypermethylation in response to anti-EGFR agents: Molecular insights for advancing HNSCC treatment.

BACKGROUND: Epidermal growth factor receptor (EGFR) is frequently activated in head and neck squamous cell carcinoma (HNSCC) and serves as a valuable target for therapy. Despite the availability of the EGFR inhibitors Cetuximab, Afatinib, and Allitinib, there are limited predictive markers for their response. Understanding molecular aberrations in HNSCC could facilitate the identification of new strategies for patient clinical and biological classification, offering novel therapeutic avenues. METHODS: We assessed CCNA1, DCC, MGMT, CDKN2A/p16, and DAPK methylation status in HNSCC cell lines and their association with anti-EGFR treatment response. RESULTS: MGMT methylation status displayed high sensitivity and specificity in distinguishing sensitive and resistant HNSCC cell lines to Afatinib (AUC = 0.955) and Allitinib (AUC = 0.935). Moreover, DAPK methylation status predicted response to Allitinib with high accuracy (AUC = 0.852), indicating their putative predictive biomarker roles. CONCLUSION: These findings hold promise for the development of more personalized and effective treatment approaches for HNSCC patients.