Efficacy and potential resistance mechanisms of afatinib in advanced non-small cell lung cancer patients with EGFR G719X/L861Q/S768I.

BACKGROUND: Afatinib is the only currently approved EGFR-tyrosine kinase inhibitors for advanced non-small cell lung cancer (NSCLC) patients with EGFR G719X/L861Q/S768I. However, there are limited real-world data concerning the benefits and resistance mechanisms of afatinib in patients with these nonclassical mutations. To fill this gap, the present study was conducted. METHODS: All NSCLC patients treated with afatinib were screened, and patients with EGFR G719X/L861Q/S768I were enrolled into the analysis. Either tumor tissue or blood specimens were detected by the commercial next-generation sequencing (NGS) panels or amplification-refractory mutation system (ARMS)-polymerase chain reaction (PCR) to figure out the mutation genotype. RESULTS: A total of 106 advanced NSCLC patients with EGFR G719X/L861Q/S768I received afatinib treatment. The benefits of afatinib exhibited heterogeneity in different mutation genotypes. Notably, at baseline, NGS testing was performed in 59 patients, and TP53 was the most frequently coexisting mutation. Patients with TP53 mutations obtained fewer survival benefits than those with TP53 wild-type. A total of 68 patients ultimately experienced progression, and 27 patients received NGS testing to clarify the potential resistance mechanisms. EGFR-T790M, CDK4 amplification, FGFR1 amplification, PIK3CA, MET amplification, RET fusions, HER2, and BRAF mutations were identified in three (11.1%), three (11.1%), three (11.1%), three (11.1%), three (11.1%), one (3.7%), one (3.7%), and one (3.7%) of the cases, respectively. Five patients underwent ARMS-PCR testing for detecting EGFR-T790M mutation, and only one patient was T790M-positive. CONCLUSIONS: The present study elucidated the differential benefits of afatinib within different mutation genotypes and first revealed the spectrum of potential resistance mechanisms in patients with EGFR G719X/L861Q/S768I. The results of this study may provide practical clinical information that can guide optimal treatment in this setting.

Tumor-related cytokine release syndrome in a treatment-naïve patient with lung adenocarcinoma: A case report.

BACKGROUND: Cytokine release syndrome (CRS) is defined as systemic inflammation that usually occurs following chimeric antigen receptor T-cell therapy administration; however, it has not been reported in patients with untreated non-small cell lung cancer to date. CASE SUMMARY: A 44-year-old nonsmoking woman presented to the hospital due to fever, palpitation, nausea, and cough for 1 mo and was diagnosed with stage cT3N3M0 (IIIc) adenocarcinoma of the lung. Auxiliary examinations revealed elevated cytokine [tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6] and inflammatory factor levels, which decreased after treatment with corticosteroids and immunoglobulin and when tumor growth was controlled following chemotherapy, radiotherapy, and antiangiogenesis therapy. However, tumor recurrence was observed. After administration of nivolumab as third-line treatment, the patient's condition was transiently controlled; however, CRS-like symptoms suddenly emerged, which led to a resurgence of cytokines and inflammatory factors and rapid death. CONCLUSION: CRS can develop in treatment-naïve lung cancer patients. Patients with tumor-related CRS may be at risk of CRS recurrence, aggravation, and onset of immune checkpoint inhibitor-related adverse events.

Mutational landscape and clonal diversity of pulmonary adenoid cystic carcinoma.

Pulmonary adenoid cystic carcinoma is a rare and indolent lung malignancy, characterized by a protracted but unpredictable growth behavior. Currently, the treatment of PACC relies on surgery and local radiotherapy. However, treatment options for advanced PACC patients are limited. A larger number of studies demonstrated that advanced PACC patients obtained limited benefit from chemotherapy. Moreover, only a few case reports revealed PACC patients were candidates for target therapy. Therefore, there is an urgent need to develop novel therapies. Due to its rareness, its mutational landscape remains largely elusive. In this study, we performed capture-based ultra-deep sequencing on multiregional surgical specimens obtained from 8 PACC patients using a panel consisting of 295 cancer-related genes. Our data revealed distinctive mutational spectrum of PACC, which differed from non-small cell lung cancer and adenoid cystic carcinomas originated from other anatomical sites. PACC, lacking mutations in a majority of non-small cell lung cancer driver genes, has frequent mutations in genes participating in chromatin remodeling and NOTCH signaling pathway. We also elucidated spatial intra-tumoral heterogeneity, which varied among cases. Most mutations in chromatin remodelers were subclonal. Collectively, our findings elucidated molecular signature associated with PACC and highlighted the potential for epigenetic therapy in this disease.

Treatment with EGCG in NSCLC leads to decreasing interstitial fluid pressure and hypoxia to improve chemotherapy efficacy through rebalance of Ang-1 and Ang-2.

AIM: Microvasculature and microenvironment play important roles in proliferation, invasion, metastasis and prognosis in non-small cell lung cancer (NSCLC), which might be altered by many anti-angiogenic drugs. Epigallocatechin-3-gallate (EGCG), a natural anti-angiogenesis agent refined from green tea, was defined to have multiple effects on angiogenesis factors, such as endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and angiopoietins (ANGs). Hypothesizing that EGCG might regulate microvasculature and microenvironment in NSCLC, the effects of EGCG on microvessel density (MVD), expression of Ang-1 and Ang-2, interstitial fluid pressure (IFP), tumor hypoxia, and chemotherapy sensitivity were examined. METHODS AND RESULTS: EGCG treatment of A549 cells in mice bearing xenografts in vivo led to a significant decrease of MVD detected by CD31, and of Ang-2 expression detected by quantum dots double-label immunofluorescence assessment, while Ang-1 decreased with no significance. Decreased IFP was measured by the Wink-in-needle method, while hypoxia was assessed by polarographic electrode and pimonidazole (PIMO) immunohistochemistry. Assuming that these changes would increase response to chemotherapy, tumor growth studies were p[erformed in nude mice with xenografts, which were then treated with EGCG and the chemotherapeutic agent cisplatin. EGCG therapy combined with cisplatin led to synergistic inhibition of tumor growth, compared with administration of each treatment separately (P < 0.001). According to linear regression analysis, IFP was positively correlated with PIMO staining (R(2) = 0.618, P = 0.002), Ang-2 was correlated with MVD (R(2) = 0.423, P = 0.022), IFP (R(2) = 0.663, P = 0.01) and PIMO staining (R(2) = 0.694, P = 0.01). CONCLUSION: IFP and delivery of oxygen might be improved by rebalance of Ang-1/Ang-2 under the treatment of EGCG in NSCLC, which also acts as a sensitizer of chemotherapy. These studies established a new mechanism for using EGCG as an adjuvant chemotherapy agent through modifying microvasculature and microenvironment.

[Misdiagnosis of pancoast cancer: analysis of 26 cases].

OBJECTIVE: To further understand the clinical features and the causes of misdiagnosis of pancoast cancer. METHODS: The data of 26 cases of pancoast cancer from 1999 - 2006 were collected for a retrospective review. The clinical and imaging features, and the causes underlying misdiagnosis were analyzed. RESULTS: There were 24 males and 2 females (mean age 59 ± 6, range 44 - 70 years). The earliest clinical features of pancoast cancer included painful shoulder and back in 25 cases, upper extremity pain, palsy and numbness in 18 cases. Early respiratory symptoms such as cough and sputum were recorded in 5 cases, Horner syndrome in 2 cases, and hoarseness in 1 case. Misdiagnosis was made in 19 of the 26 cases: 13 as periarthritis humeroscapularis, 3 as cervical osteoarthritis and another 3 as pulmonary tuberculosis. CT scanning showed soft tissue masses at the apical segments of the lungs in all the cases (26/26). Three cases were misdiagnosed as "pulmonary tuberculosis" according to the images of X-ray, and another 3 went unnoticed. CONCLUSIONS: Painful shoulder and back were the most common symptoms of pancoast cancer. pancoast cancer was often diagnosed at an advanced stage, and misdiagnosis was common. Thorax CT was the most valuable method for the detection of Pancoast cancer.