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.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

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.

Human epidermal growth factor receptor 2 expression level and combined positive score can evaluate efficacy of advanced gastric cancer

BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for high microsatellite instability.AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1(PD-1)inhibitor and chemotherapy.METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2(HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital,Chinese Academy of Medical Sciences between November 2020 and October 2022.All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.RESULTS As of July 1,2023,the objective response rate was 61.9%,and the disease control rate was 96.8%.The median progression-free survival(mPFS)for all patients was 6.3 months.The median overall survival was not achieved.Survival analysis showed that patients with a combined positive score(CPS)≥1 exhibited an extended trend in progression-free survival(PFS)when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment.PFS exhibited a trend for prolongation as the expression level of HER2 increased.Based on PFS,we divided patients into two groups:A treatment group with excellent efficacy and a treatment group with poor efficacy.The mPFS of the excellent efficacy group was 8 months,with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery.The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery.Using good/poor efficacy as the endpoint of our study,univariate analysis revealed that both CPS score(P=0.004)and HER2 expression level(P=0.015)were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC(AGC).Finally,multivariate analysis confirmed that CPS score was a significant influencing factor.CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.

Therapeutic Effect of First-line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI)Combined with Whole Brain Radiotherapy on Patients with EGFR Mutation-positive Lung Adenocarcinoma and Brain Metastases

This study compared the therapeutic effect of first-line epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)with that of EGFR-TKI plus whole brain radiotherapy(WBRT)on patients with EGFR mutation-positive lung adenocarcinoma and brain metastases.A total of 139 patients with lung adenocarcinoma and brain metastases treated with first-line EGFR-TK1therapy from September 2008 to December 2017 were enrolled in this study.The study endpoints were intracranial time to progression(TTP)and overall survival(OS).The effects of clinical pathological parameters and EGFR gene status on the study endpoints were compared.The results showed that the intracranial TTP was significantly longer in EGFR-TKI plus WBRT group than in EGFR-TKI group (median 30.0 vs.18.2 months,χ2=10.824,P=0.001),but no significant difference in the OS was noted between the two groups (median 48.0 vs.41.1 months,χ2=0.012, P=0.912).Also,there was no statistically significant difference in the OS between patients treated with early and late radiotherapy (P=0.849)and between those with asymptomatic and those with symptomatic intracranial metastases (P=0.189).The OS and intracranial TTP of patients with intracranial oligometastases (≤3metastatic sites)were not significantly different from those of patients with multiple intracranial metastases (P=0.104 and P=0.357,respectively),and exon 19 and exon 21 mutations didn't show significant effects on the OS and intracranial TTP of patients (P=0.418 and P=0.386,respectively).In conclusion,there was no statistically significant difference in the OS between the EGFR-TKI alone group and EGFR-TK1 plus WBRT group.However, simultaneous use of WBRT was found to significantly prolong intracranial TTP and improve cerebral symptoms,and thus EGFR-TKI and WBRT combined may be clinically beneficial for patients with EGFR mutation-positive lung adenocarcinoma and brain metastases.

Relationship between molecular changes in epidermal growth factor receptor(EGFR)and anaplastic lymphoma kinase(ALK)mutations in lung adenocarcinoma

Objective This study aimed to analyze the relationship between the mutations in epidermal growth factor receptor(EGFR)and anaplastic lymphoma kinase(ALK)and their impact on the prognosis and treatment of lung adenocarcinoma.Methods A total of 158 cases of lung adenocarcinoma reported between January 2007 and January 2014 were retrospectively analyzed.These tumors were resected using radical pneumonectomy and underwent pathology-based diagnosis at our institution(Inner Mongolia People’s Hospital,Hohhot,China).The tissue sections were evaluated using the updated World Health Organization classification of lung adenocarcinomas(2015 version),with each histological component recorded in 5%increments.The histological subtypes were classified,and any surviving cases were followed up.The reverse transcription-polymerase chain reaction(RT-PCR)and direct DNA sequencing were used to evaluate mutations in exons 18,19,20,and 21 in the EGFR gene,and the echinoderm microtubule-associated protein-like 4 gene-ALK variant(EML4-ALK)fusions were detected using sequencing.Results Our cohort included 25 patients with pre-invasive adenocarcinoma,13 patients with lepidic,66 patients with acinar,13 patients with papillary,and 25 patients with solid infiltrative adenocarcinoma with the remaining cases presenting with a variety of pathological subtypes.The prognosis of each histological subtype was different with the 5-year disease-free survival and 5-year overall survival(OS)of pre-invasion adenocarcinoma at 100%;the 5-year OS of lepidic,acinar,and papillary adenocarcinoma patients was only 84.6%,72.7%,and 76.9%,respectively.The 5-year OS of solid and mucinous adenocarcinomas were 32.0%and 36.4%,respectively.EGFR mutation was detected in 69 cases with a mutation rate of 43.7%and majority of these mutations were found in exons 19(50.6%)and 21(37.9%),with women and non-smokers shown to experience a higher mutation rate(P<0.05).However,histological subtype analysis showed that EGFR mutations were primarily found in adenocarcinomas.Most of these mutations were found in lepidic(53.8%)or acinar adenocarcinomas(50.0%),whereas these mutations were rare in both solid(28.0%)and mucinous adenocarcinoma(27.2%).The fusion mutation rate in the EML4-ALK gene was 5.69%,and was most common in young,nonsmoking patients(P<0.05).Conclusion The prognosis of patients in each lung adenocarcinoma subtype is different,and these outcomes are likely related to mutations in the EGFR and EML4-ALK genes.EGFR mutation rates are higher in lepidic and acinar adenocarcinomas,whereas EML4-ALK gene fusion mutations are more common in solid and mucinous adenocarcinoma.EGFR mutations are more common in female and non-smoking patients,whereas EML4-ALK fusions are more common in young,non-smoking patients.

Epidermal growth factor receptor mutation analysis in cytological specimens and responsiveness to gefitinib in advanced non-small cell lung cancer patients

Background： Epidermal growth factor receptor（EGFR） mutation is the key predictor of EGFR tyrosine kinase inhibitors（TKIs） efficacy in non-small cell lung cancer（NSCLC）. We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.Methods： A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system（ARMS）. We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate（ORR）, disease control rate（DCR） and progression free survival（PFS）.Results： Of all patients, EGFR mutation rate was 28.6%（60/210） by direct sequencing and 45.2%（95/210） by ARMS（P〈0.001） respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR（48.0% vs. 80.9%, P=0.004） and shorter median PFS（7.4 vs. 10.5 months, P=0.009） as compared with that of EGFR mutation positive patients by both detection methods. Conclusions： Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.

High-resolution computed tomography findings independently predict epidermal growth factor receptor mutation status in groundglass nodular lung adenocarcinoma

BACKGROUND For lung adenocarcinoma with epidermal growth factor receptor(EGFR)gene mutation,small molecule tyrosine kinase inhibitors are more effective.Some patients could not obtain enough histological specimens for EGFR gene mutation detection.Specific imaging features can predict EGFR mutation status to a certain extent.AIM To assess the associations of EGFR mutations with high-resolution computerized tomography(HRCT)features in ground-glass nodular lung adenocarcinoma.METHODS This study retrospectively assessed patients with ground-glass nodular lung adenocarcinoma diagnosed between January 2011 and March 2017.EGFR gene mutations in exons 18-21 were detected.The patients were classified into mutant EGFR and wild-type groups,and general data and HRCT image characteristics were assessed.RESULTS Among 98 patients,31(31.6%)and 67(68.4%)had mutated and wild-type EGFR in exons 18-21,respectively.Gender,age,smoking history,location of lesions,morphology,edges,borders,pleural indentations,and associations of nodules with bronchus and blood vessels were comparable in both groups(all P>0.05).Patients with mutant EGFR had larger nodules than those with the wild-type(17.19±6.79 and 14.37±6.30 mm,respectively;P=0.047).Meanwhile,the vacuole/honeycomb sign was more frequent in the mutant EGFR group(P=0.011).The logistic regression prediction model included the combination of nodule size and vacuole/honeycomb sign(OR=1.120,95%CI:1.023-1.227,P=0.014)revealed a sensitivity of 83.9%,a specificity of 52.2%and an AUC of 0.698(95%CI:0.589-0.806;P=0.002).CONCLUSION Nodule size and vacuole/honeycomb features could independently predict EGFR mutation status in ground-glass nodular lung adenocarcinoma.

Gender Does Not Have a Potential Predictive Value for the Presence of Epidermal Growth Factor Receptor Mutation in Lung Adenocarcinoma

Background: Previous studies reported that non-small cell carcinoma patients characterized by female gender, never-smoking status and adenocarcinoma histology were more likely to harbor epidermal growth factor receptor (EGFR) mutations. However, some studies failed to find the relationship between EGFR mutation and gender. Methods: One hundred and eighty-four consecutive patients (90 men and 94 women) of resected lung adenocarcinoma were studied retrospectively. Since the smoking rate is significantly higher in men, we assumed that gender difference might be a seeming factor affected by smoking. Therefore we subdivided the patients into 2 groups: never- and ever-smokers. Results: The number of ever-smokers was 94.44% in men, whereas 8.51% in women. EGFR mutation was positive in 48.9%. For overall patients, EGFR mutation status was associated with gender, pStage, pT status, lepidic dominant histologic subtype, pure/mixed groundglass opacity (GGO) on computed tomography (CT) and smoking status. However, in ever-smokers, EGFR mutation status was associated with lepidic histologic subtype and GGO on CT, but not others including gender. Similar results were also found in never-smokers, and gender was not also related to EGFR mutation in never smokers. Conclusion: The EGFR mutational frequency among men and women was not significantly different when lung adenocarcinoma patients were stratified into never- and ever-smokers.

Associations Between Epidermal Growth Factor Receptor Gene Mutation and Serum Tumor Markers in Advanced Lung Adenocarcinomas: A Retrospective Study

Objective To investigate the associations between epidermal growth factor receptor(EGFR) gene mutations and serum tumor markers in advanced lung adenocarcinomas. Methods We investigated the association between EGFR gene mutations and clinical features, including serum tumor marker levels, in 97 advanced lung adenocarcinomas patients who did not undergo the treatment of EGFR tyrosine kinase inhibitors. EGFR gene mutation was detected by real-time PCR at exons 18, 19, 20, and 21. Serum tumor marker concentrations were analyzed by chemiluminescence assay kit at the same time. Results EGFR gene mutations were detected in 42(43%) advanced lung adenocarcinoma patients. Gender(P=0.003), smoking status(P=0.001), and abnormal serum status of carcinoembryonic antigen(CEA, P=0.028) were significantly associated with EGFR gene mutation incidence. Multivariate analysis showed the abnormal CEA level in serum was independently associated with the incidence of EGFR gene mutation(P=0.046) with an odds ratio of 2.613(95% CI: 1.018-6.710). However, receiver operating characteristic(ROC) curve analysis revealed CEA was not an ideal predictive marker for EGFR gene mutation status in advanced lung adenocarcinoma(the area under the ROC curve was 0.608, P=0.069). Conclusions EGFR gene mutation status is significantly associated with serum CEA status in advanced lung adenocarcinmoas. However, serum CEA is not an ideal predictor for EGFR mutation.

Relationship between epidermal growth factor receptor gene mutation and copy number in Chinese patients with non-small cell lung cancer

Epidermal growth factor receptor(EGFR) gene mutation and copy number are useful predictive markers that guide the selection of non-small cell lung cancer(NSCLC) patients for EGFR-targeting therapy.This study aimed to investigate the correlation between EGFR gene mutation and copy number and clinicopathologic characteristics of Chinese patients with NSCLC.NSCLC specimens collected from 205 patients between November 2009 and January 2011 were selected to detect EGFR gene mutations with real-time polymerase chain reaction(RT-PCR) and to detect EGFR gene copy number with fluorescence in situ hybridization(FISH).EGFR mutations primarily occurred in females,non-smokers,and patients with adenocarinomas(all P < 0.001).Tissues from 128(62%) patients were FISH-positive for EGFR,including 37(18%) with gene amplification and 91(44%) with high polysomy.EGFR gene mutation was correlated with FISH-positive status(R = 0.340,P < 0.001).Multivariate analysis showed that not smoking(OR = 5.910,95% CI = 2.363-14.779,P < 0.001) and having adenocarcinoma(OR = 0.122,95% CI = 0.026-0.581,P = 0.008) were favorable factors for EGFR gene mutation.These results show a high frequency of EGFR FISH positivity in NSCLC tissues from Chinese patients and a significant relevance between EGFR gene mutations and FISH-positive status.Among the FISH-positive samples,EGFR gene mutation occurred more frequently in samples with gene amplification compared to those with high polysomy,suggesting that EGFR mutation and gene amplification should be used as clinical decision parameters to predict response to EGFR-targeting therapy.

JAK3 inhibitor Ⅵ is a mutant specific inhibitor for epidermal growth factor receptor with the gatekeeper mutation T790M

AIM:To identify non-quinazoline kinase inhibitors effective against drug resistant mutants of epidermal growth factor receptor(EGFR).METHODS:A kinase inhibitor library was subjected to screening for specific inhibition pertaining to the in vitro kinase activation of EGFR with the gatekeeper mutation T790 M,which is resistant to small molecular weight tyrosine kinase inhibitors(TKIs) for EGFR in nonsmall cell lung cancers(NSCLCs). This inhibitory effect was confirmed by measuring autophosphorylation of EGFR T790M/L858 R in NCI-H1975 cells,an NSCLC cell line harboring the gatekeeper mutation. The effects of a candidate compound,Janus kinase 3(JAK3) inhibitor Ⅵ,on cell proliferation were evaluated using the MTT assay and were compared between T790M-positive and-negative lung cancer cell lines. JAK3 inhibitor Ⅵ was modeled into the ATP-binding pocket of EGFR T790M/L858 R. Potential physical interactions between the compound and kinase domains of wild-type(WT) or mutant EGFRs or JAK3 were estimated by calculating binding energy. The gatekeeper residues of EGFRs and JAKs were aligned to discuss the similarities among EGFR T790 M and JAKs. RESULTS:We found that JAK3 inhibitor Ⅵ,a known inhibitor for JAK3 tyrosine kinase,selectively inhibits EGFR T790M/L858 R,but has weaker inhibitory effects on the WT EGFR in vitro. JAK3 inhibitor Ⅵ also specifically reduced autophosphorylation of EGFR T790M/L858 R in NCI-H1975 cells upon EGF stimulation,but did not show the inhibitory effect on WT EGFR in A431 cells. Furthermore,JAK3 inhibitor Ⅵ suppressed the proliferationof NCI-H1975 cells,but showed limited inhibitory effects on the WT EGFR-expressing cell lines A431 and A549.A docking simulation between JAK3 inhibitor Ⅵ and the ATP-binding pocket of EGFR T790M/L858 R predicted a potential binding status with hydrogen bonds. Estimated binding energy of JAK3 inhibitor Ⅵ to EGFR T790M/L858 R was more stable than its binding energy to the WT EGFR. Amino acid sequence alignments revealed that the gatekeeper residues of JAK family kinases are methionine in WT,similar to EGFR T790 M,suggesting that TKIs for JAKs may also be effective for EGFR T790 M. CONCLUSION:Our findings demonstrate that JAK3 inhibitor Ⅵ is a gatekeeper mutant selective TKI and offer a strategy to search for new EGFR T790 M inhibitors.

Coexistence of anaplastic lymphoma kinase rearrangement in lung adenocarcinoma harbouring epidermal growth factor receptor mutation:A single-center study

BACKGROUND Accumulating evidences confirm that epidermal growth factor receptor(EGFR)mutation and anaplastic lymphoma kinase(ALK)rearrangement have coexisted in lung adenocarcinoma(LUAD).However,Its biological mechanism,clinicopathological features,and optimization of targeted drugs have not yet been completely elucidated.AIM To explore the clinical profile of LUAD patients with co-mutations of EGFR and ALK genes,with hopes of scientifically guiding similar patients towards selected,targeted drugs.METHODS Two hundred and thirty-seven LUAD patients were enrolled.EGFR mutations were detected by the amplification refractory mutation system-peptide nucleic acid technique,while the expression of ALK rearrangement was screened by the 5′/3′imbalance strategy for reverse transcription followed by quantitative polymerase chain reaction analysis.The clinicopathological features of these patients were analysed retrospectively,and the follow-up data were collected.RESULTS There were six cases with co-mutations of EGFR and ALK genes,which were more common in women,non-smoking and stage IV LUAD patients with bone metastasis,hence a positive rate of 2.53%(6/237).EGFR-tyrosine kinase inhibitors(EGFR-TKIs)were their preferred drugs for targeted therapy in these patients,with progression-free survival ranging from two months to six months.CONCLUSION In Gannan region,the positive rate of co-mutations of EGFR and ALK genes in LUAD patients is relatively high,and the co-mutations are more common in women,non-smoking and stage IV patients with bone metastasis.These patients prefer EGFR-TKIs as their preferred targeted drugs,but the therapeutic effect is not good.EGFR/ALK dual-TKIs may be more effective targeted drugs,which needs further study.

Non-small-cell lung cancer with epidermal growth factor receptor L861Q-L833F compound mutation benefits from both afatinib and osimertinib: A case report

BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs)have been adopted as the standard of care for non-small cell lung cancer(NSCLC)patients harboring EGFR sensitizing mutations.Besides the two common mutations exon 19 deletion and L858R,which together comprise approximately 85%of EGFR mutations in NSCLC,rare EGFR mutations also exist,including point mutations,deletions,and insertions spanning EGFR exons 18-25.However,the responsiveness of uncommon EGFR mutations to EGFR TKIs remains elusive and attracts increasing interest.CASE SUMMARY Herein,we report a 55-year-old male patient with stage IV NSCLC harboring a rare EGFR L833F-L861Q compound mutation in cis.The patient achieved a partial response to first-line treatment with afatinib and a progression-free survival of 10 mo.After afatinib failure,the patient received multiple line treatments with chemotherapy.Upon disease progression,the heavily pretreated patient was treated with osimertinib and bevacizumab,and both lung lesion and brain metastases were stable for more than 3 mo.He had an overall survival of 25 mo.CONCLUSION Our case revealed that both afatinib and the osimertinib+bevacizumab combination demonstrated clinical efficacy in NSCLC harboring an EGFR L833FL861Q compound mutation.The results provide more therapeutic options for patients with rare compound mutations.

Lung adenocarcinoma harboring rare epidermal growth factor receptor L858R and V834L mutations treated with icotinib:A case report

BACKGROUND Epidermal growth factor receptor(EGFR)tyrosine-kinase inhibitors are widely used for the treatment of non-small-cell lung cancer with EGFR mutations.However,patients with rare,even compound EGFR mutations have different responses to EGFR-tyrosine-kinase inhibitors,which bring uncertainty to clinical treatment.CASE SUMMARY A 45-year-old female patient presented with a 3-mo history of cough and white sputum without chest pain.Chest computed tomography revealed lung spaceoccupying lesions and multiple lymphadenectasis.Bronchoscopy and pathology suggested lung adenocarcinoma.Compound variation of EGFR gene(exon 21 L858 R/V834 L)was detected in both tissue and circulating tumor deoxyribonucleic acid samples.As a result of next-generation sequencing and her family’s wishes,the patient was given oral treatment with icotinib hydrochloride(125 mg/d,tid)from March 21,2019 and has achieved stable disease for the last 1 year.CONCLUSION Non-small cell lung adenocarcinoma with EGFR L858 R/V834 L was treated successfully with icotinib,and it may be a new medication treatment option.

Knockdown of HE4 suppresses tumor growth and invasiveness in lung adenocarcinoma through regulation of EGFR signaling

It has been shown that the high expression of human epididymis protein 4(HE4)in most lung cancers is related to the poor prognosis of patients,but the mechanism of pathological transformation of HE4 in lung cancer is still unclear.The current study is expected to clarify the function and mechanism of HE4 in the occurrence and metastasis of lung adenocarcinoma(LUAD).Immunoblotting evaluated HE4 expression in lung cancer cell lines and biopsies,and through analysis of The Cancer Genome Atlas(TCGA)dataset.Frequent HE4 overexpression was demonstrated in LUAD,but not in lung squamous cell carcinoma(LUSC),indicating that HE4 can serve as a biomarker to distinguish between LUAD and LUSC.HE4 knockdown significantly inhibited cell growth,colony formation,wound healing,and invasion,and blocked the G1-phase of the cell cycle in LUAD cell lines through inactivation of the EGFR signaling downstream including PI3K/AKT/mTOR and RAF/MAPK pathways.The first-line EGFR inhibitor gefitinib and HE4 shRNA had no synergistic inhibitory effect on the growth of lung adenocarcinoma cells,while the third-line EGFR inhibitor osimertinib showed additive anti-proliferative effects.Moreover,we provided evidence that HE4 regulated EGFR expression by transcription regulation and protein interaction in LUAD.Our findings suggest that HE4 positively modulates the EGFR signaling pathway to promote growth and invasiveness in LUAD and highlight that targeting HE4 could be a novel strategy for LUAD treatment.

Epidemiology of EGFR Mutation in Adenocarcinoma NSCLC Patients in India: A Systematic Review and Meta-Analysis

Studies reporting the Indian prevalence of Epidermal Growth Factor Receptor (EGFR) mutation are mostly single centers with small sample sizes. This systematic review and meta-analysis summarized the available evidence of EGFR mutation epidemiology in Indian patients with adenocarcinoma (ADC) Non-Small Cell Lung Cancer (NSCLC). We conducted a structured literature search in PubMed, and EMBASE databases from January 2004 through October 2019. The primary outcome of interest was prevalence of EGFR mutation by gender, smoking status, and mutation subtype. The review included 34 studies. EGFR mutation prevalence was 39.5% in patients with ADC, and significantly higher in females, non-smokers, and patients with exon 19 deletions. The EGFR mutation frequency in Indian patients with ADC was higher than reported in Caucasians but at a lower range of that reported in East Asians. These findings support the use of EGFR mutation testing to guide choice of treatment.

EGFR Mutation and FHIT Methylation: Inverse Relationship in Patients with Lung Adenocarcinoma and Tuberculosis

Objective:To investigate the genetic correlations between epithelial growth factor receptor(EGFR)mutation and FHIT methylation in patients diagnosed with lung adenocarcinoma(AC)and pulmonary tuberculosis(TB).Methods:The presence of EGFR mutations and the methylation status of the FHIT gene in patients presenting with AC and TB were analyzed.The correlation between TB status and the observed genetic and epigenetic variations was also examined.Results:Among the 90 patients included in the study,38 exhibited EGFR mutations(14 among those with TB and 24 among those without TB),while 29 exhibited FHIT myelination(19 among those with TB and 10 among those without TB).Furthermore,the protein expression levels of EGFR and FHIT were significantly higher in patients diagnosed solely with AC compared to those presenting with both AC and TB.A robust inverse correlation was identified between TB status and the frequency of EGFR mutation(P<0.001).Moreover,significant associations were observed between TB status and FHIT methylation(P<0.01).Conclusion:The findings suggest a correlation between TB and the prevalence of EGFR mutation and FHIT methylation in the pathogenesis of AC.

Correlation of human epidermal growth factor receptor 2 expression with clinicopathological characteristics and prognosis in gastric cancer

AIM:To investigate human epidermal growth factor receptor 2(HER2) gene amplification and protein expression in Chinese patients with resectable gastric cancer and the association with clinicopathological characteristics and survival.METHODS:One hundred and ninety-seven gastric cancer patients who underwent curative surgery procedures were enrolled into this study.HER2 gene amplification and protein expression were examined using fluorescence in-situ hybridization(FISH) and immunohistochemistry(IHC) analysis on formalin-fixed paraffinembedded gastric cancer samples from all patients.For scoring,Hofmann's HER2 gastric cancer scoring system was adopted.All cases showing IHC3+ or FISH positiv-ity were defined as HER2 positive.Patient clinicopathological data and survival information were collected.Finally,χ 2 statistical analysis was performed to analyze the HER2 positivity rate amongst the subgroups with different clinicopathological characteristics including;gender,age,tumor location,Lauren classification,differentiation,TNM staging,depth of invasion,lymph node metastases and distant metastasis.The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using log rank inspection.RESULTS:According to Hofmann's HER2 gastric cancer scoring criteria,31 cases(15.74%) were identified as HER2 gene amplified and 19 cases(9.64%) were scored as strongly positive for HER2 membrane staining(3+),25 cases(12.69%) were moderately positive(2+) and 153 cases(77.66%) were HER2 negative(0/1+).The concordance rate between IHC and FISH analyses was 88.83%(175/197).Thirty-six cases were defined as positive for HER2 gene amplification and/or protein expression,with 24 of these cases being eligible for Herceptin treatment according to United States recommendations,and 29 of these cases eligible according to EU recommendations.Highly consistent results were detected between IHC3+,IHC0/1 and FISH(73.68% and 95.42%),but low consistency was observed between IHC2+ and FISH(40.00%).The positivity rates in intestinal type and well-differentiated gastric cancer were higher than those in diffuse/mixed type and poorly-differentiated gastric cancer respectively(28.57% vs 13.43%,P = 0.0103;37.25% vs 11.64%,P < 0.0001),but were not correlated with gender,age,tumor location or TNM stage,depth of invasion,lymph node metastases and distant metastasis.In poorly-differentiated gastric cancer patients,those without lymph node metastasis showed a higher HER2 positivity rate than those with lymph node metastasis(26.47% vs 7.14%,P = 0.0021).This association was not present in thosepatients with well-differentiated gastric cancer(28.57% vs 43.33%,P = 0.2832).Within our patient cohort,26 cases were lost to follow-up.The median survival time for the remaining 171 patients was 18 mo.The median survival times of the HER2 positive and negative groups were 17 and 18.5 mo respectively.Overall survival was not significantly different between HER2-positive and negative groups(χ 2 = 0.9157,P = 0.3386),but in patients presenting well-differentiated tumors,the overall survival of the HER2-positive group was significantly worse than that of the HER2-negative group(P = 0.0123).In contrast,patients with poorly differentiated and diffuse/mixed subtype gastric cancers showed no significant differences in overall survival associated with HER2.Furthermore,the median survival time of the HER2 positive group did not show any statistically significant differences when compared to the subgroups of gender,age,tumor location,TNM classification,lymph node metastases and distant metastasis.CONCLUSION:Patients with intestinal type gastric cancer(GC),well-differentiated GC and poorly-differentiated GC without lymph node metastasis,may all represent suitable candidates for targeted therapy using Herceptin.

A CT-based radiomics nomogram for prediction of human epidermal growth factor receptor 2 status in patients with gastric cancer

Objective: To develop and validate a computed tomography(CT)-based radiomics nomogram for predicting human epidermal growth factor receptor 2(HER2) status in patients with gastric cancer.Methods: This retrospective study included 134 patients with gastric cancer(HER2-negative: n=87;HER2-positive: n=47) from April 2013 to March 2018, who were then randomly divided into training(n=94) and validation(n=40) cohorts. Radiomics features were obtained from the CT images showing gastric cancer. Least absolute shrinkage and selection operator(LASSO) regression analysis was utilized for building the radiomics signature. A multivariable logistic regression method was applied to develop a prediction model incorporating the radiomics signature and independent clinicopathologic risk predictors, which were then visualized as a radiomics nomogram. The predictive performance of the nomogram was assessed in the training and validation cohorts.Results: The radiomics signature was significantly associated with HER2 status in both training(P<0.001) and validation(P=0.023) cohorts. The prediction model that incorporated the radiomics signature and carcinoembryonic antigen(CEA) level demonstrated good discriminative performance for HER2 status prediction,with an area under the curve(AUC) of 0.799 [95% confidence interval(95% CI): 0.704-0.894] in the training cohort and 0.771(95% CI: 0.607-0.934) in the validation cohort. The calibration curve of the radiomics nomogram also showed good calibration. Decision curve analysis showed that the radiomics nomogram was useful.Conclusions: We built and validated a radiomics nomogram with good performance for HER2 status prediction in gastric cancer. This radiomics nomogram could serve as a non-invasive tool to predict HER2 status and guide clinical treatment.