Immediate Versus Delayed Treatment with EGFR Tyrosine Kinase Inhibitors after First-line Therapy in Advanced Non-small-cell Lung Cancer

Objective： To analyze the outcomes of patients who received TKI immediately after the first-line without progression as maintenance treatment （immediate group） vs. those received delayed treatment upon disease progression as second-line therapy （delayed group）. Methods： The study included 159 no-small-cell lung cancer （NSCLC） patients who received gefitinib or erlotinib as maintenance treatment in the immediate group （85 patients） or as second-line therapy in the delayed group （74 patients）. The primary end point was progression-free survival （PFS）. EGFR mutation status was detected using denaturing high-performance liquid chromatography （DHPLC）. Results： PFS was 17.3 and 16.4 months in the immediate and delayed groups, respectively （hazard ratio [HR], 0.99; 95% Confidence Interval [CI]： 0.69-1.42; P=0.947）. In a subgroup analysis that included only patients with EGFR mutation, however, PFS was significantly longer in the immediate group than in the delayed group （HR, 0.48; 95% CI： 0.27-0.85; P=0.012）. In patients with wild type EGFR, the risk for disease progression was comparable between the two groups （HR, 1.23; 95% CI： 0.61-2.51; P=0.564）. No significant difference was demonstrated between the immediate and delayed group in terms of the overall survival （OS） （26.1 months vs. 21.6 months, respectively; HR=0.53; 95% CI： 0.27 to 1.06; P=0.072）. There was also no difference in the incidence of adverse events between the two groups. Conclusions： EGFR TKI maintenance improves PFS in patients with EGFR mutation. Prospectively designed clinical studies that compare TKI immediate vs. delayed treatment after first-line chemotherapy upon disease progression are needed.

Detection of EGFR-SEPT14 fusion in cell-free DNA of a patient with advanced gastric cancer: A case report

BACKGROUND Gastric cancer is the fifth most diagnosed cancer worldwide and the third most common cause of cancer-related death.In recent decades,increasing application of next-generation sequencing has enabled detection of molecular aberrations,including fusions.In cases where tissue is difficult to obtain,cell-free DNA(cfDNA)is used for detecting mutations to identify the molecular profile of cancer.Here,we report a rare case of EGFR-SEPT14 fusion detected from cfDNA analysis in a patient with gastric cancer.CASE SUMMARY A 49-year-old female diagnosed with advanced gastric cancer in July 2019 received capecitabine and then combination chemotherapy of ramucirumab and paclitaxel,but ascites was detected.The therapy was switched to nivolumab,but disease progression was observed on a positron emission tomography/computed tomography scan in May 2020.Therapy was discontinued,and cfDNA nextgeneration sequencing was immediately evaluated.All genomic variants,including fusions,were analyzed from cfDNA.The following somatic alterations were detected from the patient’s cfDNA:an APC frameshift mutation(NM_000038.5:c.6579del,p.V2194fs)with variant allele frequency of 0.5%,an EGFR amplification with a copy number of 17.3,and an EGFR-SEPT14 fusion with variant allele frequency of 45.3%.The site of the fusion was exon 24 of EGFR fused to exon 10 of SEPT14.The fusion was in-frame and considered to be protooncogenic. Although the patient refused to continue therapy, we suggest thatEGFR-targeted therapies be tried in such future cases.CONCLUSIONThe expanded applications of the cfDNA assay may open a new horizon intreatment of patients with advanced gastric cancer.

Study of the Correlation of EGFR and K-RAS Gene Mutations with Its Protein Expression in Non-small Cell Lung Cancer

OBJECTIVE To investigate gene mutations of epidermal growth factor receptor （EGFR） and K-RAS （Kirsten rat sarcoma viral oncogene） in Chinese patients with non-small cell lung cancer （NSCLC）, and study the correlation with its protein expression and its clinical significance on gefitinib.METHODS Detect the EGFR and K-RAS gene mutations status by gene sequencing and use the method of immunohistochemistry to detect EGFR and K-RAS protein expression.RESULTS The frequency of EGFR mutations was 33%, mainly located in exon 19 and exon 21. The frequency of K-RAS mutations was 5.5%, mainly located in codon 12. There was no case which both had EGFR and K-RAS mutations, suggesting a mutually exclusive relationship between the two. EGFR mutations are more common in adenocarcinomas （particularly those with bronchioloalveolar features）, nonsmokers and females. 16% were detected EGFR positive expression and had no correlation with EGFR mutation （P 〉 0.05）, but had significant correlation with mutation in exon 19 （P 〈 0.05）. The frequency of K-RAS positive expression was 52.5% and had no correlation with K-RAS mutation （P 〉 0.05）. Twelve （8 cases were protein-negative） out of 15 gefitinib-treated NSCLC patients with disease control carry EGFR mutations.CONCLUSION EGFR protein expression has some correlation with exon 19 mutations. Combined detection of EGFR and K-RAS gene mutations can help clinicians to choose patients who may benefit from EGFR tyrosine kinase inhibitor （EGFR-TKI） and to predict the response and prognosis of gefitinib.

Systemic treatment in EGFR-ALK NSCLC patients:second line therapy and beyond

Lung cancer is the most frequently diagnosed cancer and a leading cause of cancer mortality worldwide, with adenocarcinoma being the most common histological subtype. Deeper understanding of the pathobiology of non-small cell lung cancer(NSCLC) has led to the development of small molecules that target genetic mutations known to play critical roles in progression to metastatic disease and to influence response to targeted therapies. The principle goal of precision medicine is to define those patient populations most likely to respond to targeted therapies. However, the cancer genome landscape is composed of relatively few "mountains" [representing the most commonly mutated genes like KRAS, epidermal growth factor(EGFR), and anaplastic lymphoma kinase(ALK)] and a vast number of "hills"(representing low frequency but potentially actionable mutations). Low-frequency lesions that affect a druggable gene product allow a relatively small population of cancer patients for targeted therapy to be selected.

Antitumor activity of aumolertinib, a third-generation EGFR tyrosine kinase inhibitor, in non-small-cell lung cancer harboring uncommon EGFR mutations

Uncommon epidermal growth factor receptor(EGFR) mutations account for 10% 20% of all EGFR mutations in non-small-cell lung cancer(NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors(TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC.Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models(V769-D770insASV and L861Q mutations) and a patientderived xenografts model(H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.

Updates in the management of brain(leptomeningeal) metastasis of lung cancer

Brain(leptomeningeal) metastasis is one of the most common and severe complications of lung cancer. This article interprets expert consensus on the treatment advice for brain(leptomeningeal) metastasis of lung cancer, expounding on its epidemiology, diagnostic standards, efficacy assessment, treatment advice, and other aspects.

Is the EGFR pathway relevant for the pathogenesis but not for treatment of acute myeloid leukemia?

Despite intense research and the development of several new chemotherapeutics,the prognosis for specific subsets of acute myeloid leukemia(AML)has not improved significantly.Thus,the investigation of signaling pathways associated with the pathogenesis and progression of AML has become a source for the discovery of more effective treatments.The epidermal growth factor receptor(EGFR)belongs to the HER family of tyrosine kinase(TK)receptors and is involved in the progression of a variety of solid tumors.Although the expression of members of the HER family appears to be limited to epithelial tissues and derived neoplasms,there is evidence demonstrating their role in hematopoiesis and hematological neoplasms.In AML,preclinical studies and two anecdotal cases of response to EGFR TK inhibitors(TKI)supported the EGFR signaling pathway as a potential therapeutic target.Indeed,the presence of EGFR ligands in the bone marrow microenvironment has been shown to play pathological and regenerative/protective roles in AML.However,data reporting the expression of EGFR in AML remain controversial and the EGFR pathway inhibition in AML patients has demonstrated limited clinical significance.Further studies are required to determine the relevance of the EGFR pathway in AML biology and which patients may benefit from using EGFR TKI or other drugs that target TK receptors.