Advances in the management of acquired resistance to EGFR-TKI in non-small cell lung cancer

Drugs that specifically target the tyrosine kinase domain of epidermal growth factor receptor(EGFR), such as erlotinib or gefitinib, have exhibited striking efficacy in non-small cell lung cancer(NSCLC) patients harboring activating EGFR mutations. However, acquired resistance inevitably develops and remains a serious barrier for the successful management of patients with this disease. Multiple mechanisms are reportedly involved in the process of acquired resistance, which provide new insights into the management of EGFRtyrosine kinase inhibitor(EGFR-TKI) resistance. Here, we provide an overview of the emerging treatment approaches for patients with EGFR-TKI resistance.     

Duration of immunotherapy – should we continue ad infinitum?

The optimal duration of immunotherapy treatment for cancer patients is unknown. As the survival data from early immunotherapy trials mature we are beginning to appreciate how durable responses can be post‐discontinuation. The purpose of this brief communication is to comment on treatment duration of immunotherapy in patients with melanoma and non‐small cell lung cancer and to provide practice guidance in support of discontinuation.     

Lymphangiosis carcinomatosa independently affects long-term survival of Non-Small Cell Lung Cancer patients

ObjectiveThe significance of postoperatively diagnosed Lymphangiosis Carcinomatosa (L1) as an independent risk factor for long-term survival in Non-Small Cell Lung Cancer (NSCLC) remains controversial. We analyzed the effect of L1 on postoperative survival in stage I, II and III NSCLC-patients.MethodsWe investigated all consecutive patients with NSCLC between January 2012 and December 2019 who underwent an anatomical resection and radical lymphadenectomy at our institute. L1-were compared to L0-patients. All patients received adjuvant chemotherapy in accordance with European guidelines. 3- and 5- year survival rates and median-survival were assessed. To investigate whether L1 is an independent risk factor, we carried out a multivariate cox regression and a pair-match analysis looking at different properties such as TNM.ResultsA total of 641 patients (L0: 74%; L1: 26%) were analyzed. Baseline characteristics were comparable between groups. The mean age was 65.3 ± 10.2 years and 64.9 ± 9.4 years in the L0 and L1-groups respectively (p-value = 0.703). 58.5% of L0-patients were male (L1: 62.7%; p-value = 0.351). Overall survival in the L1-group was significantly shorter compared to the L0-group (L1: 42.3 ± 2.8; L0: 67.6 ± 2.1 months; p-value<0.0001). We confirmed this finding in a pair-matched analysis (L0: 73.9 ± 4.7 months; L1: 42.2 ± 4.2; p-value = 0.009). 3- and 5-year survival were significantly shorter for L1-patients (3-year: L0: 65.9%; L1: 35.9%; p-value<0.0001) (5-year: L0: 34.9%; L1: 7.5%; p-value<0.0001).ConclusionL1 is an independent risk factor for long-term survival of patients with NSCLC. This cohort supports that the L0/L1 status should be included in pathological reports. We suggest to further include L0/L1-status in guideline recommendations for NSCLC patients.     

Clock dial integrated positioning combined with single utility port video-assisted thoracoscopic surgery: a new localization method for lung tumors

BackgroundPreoperative localization of lung tumor mainly consisted of two methods: CT-guided percutaneous localization and electromagnetic navigation bronchoscopy-guided localization. However, these invasive methods could result in serious complications. In order to avoid the adverse effects of preoperative invasive localization, we propose a method of intraoperative noninvasive localization for lung tumors: clock dial integrated positioning (CDIP).MethodsTo retrospectively analyze the clinic data about the application of CDIP for 127 lung tumour patients in single utility port video-assisted thoracoscopic surgery (SUPVATS) between June 2017 and October 2017.ResultsOne hundred and twenty-four cases (97.64%) underwent thoracoscopic surgery, which including 14 lobectomy, 107 partial resection, 2 lobectomy plus partial resection and 1 left pneumonectomy. Three cases (2.36%) underwent thoracoscopic biopsy. The mean operation time and intraoperative bleeding were 47.9±22.1 min and 70.1±40.3 mL, respectively. The mean postoperative hospital stay and chest drain duration were 3.9±2.2 and 3.6±1.8 days, respectively. There were 118 cases of malignant tumors, including adenocarcinoma (n=101), squamous cell carcinoma (n=9), large cell carcinoma (n=2), small cell lung carcinoma (n=3), and metastatic lung carcinoma (n=3). The remaining nine cases were benign tumors, including granuloma (n=3), intrapulmonary lymph node (n=2), sclerosing hemangioma (n=2), and hamartoma (n=2). The incidence of postoperative complications was 10.2%. There was no mortality, secondary operation, or conversion to open procedure due to massive intraoperative bleeding.ConclusionsCDIP combined with SUPVATS is a safe, feasible, and effective method for the localization of lung tumors. This novel method can provide a reliable alternative technique when the marker is dislocated.     

Histone deacetylase 9 downregulation decreases tumor growth and promotes apoptosis in non‐small cell lung cancer after melatonin treatment

Histone deacetylase 9 functions as an oncogene in a variety of cancers, but its role on non‐small cell lung cancer (NSCLC) has not been reported. Melatonin was proven to possess anticancer actions, whereas its effect on NSCLC and underlying mechanisms remains poorly understood. In this study, 337 patients with complete clinicopathologic characteristics who underwent NSCLC surgery were recruited for the study. We found that NSCLC patients with high HDAC9 expression were correlated with worse overall survival and poor prognosis. HDAC9 knockdown significantly reduced NSCLC cell growth and induced apoptosis both in vivo and in vitro. Melatonin application also markedly inhibited cell proliferation, metastasis, and invasion and promoted apoptosis in NSCLC cells. Moreover, RNA‐seq, real‐time quantitative polymerase chain reaction, and western blot analyses showed that melatonin treatment decreased the HDAC9 level in NSCLC cells. A mechanistic study revealed that HDAC9 knockdown further enhanced the anticancer activities of melatonin treatment, whereas HDAC9 overexpression partially reversed the melatonin's anticancer effects. Additionally, the in vivo study found melatonin exerted anti‐proliferative and pro‐apoptotic effects on xenograft tumors which were also strengthened by HDAC9 knockdown. These results indicated that HDAC9 downregulation mediated the anti‐NSCLC actions of melatonin, and targeting HDAC9 may be the novel therapeutic strategy for NSCLC.     

Implementing Genomic Testing for Lung Cancer Into Routine Clinical Practice – The Welsh Experience

AimsOver the last decade there has been a rapid expansion of clinically actionable driver mutations in non-small cell lung cancer (NSCLC), with an unprecedented number of corresponding targeted therapies approved and funded for use in the clinic. Here we summarise the approach taken in Wales to embed a NSCLC biomarker testing pathway within the National Optimal Pathway for Lung Cancer.Materials and methodsThe Welsh Thoracic Oncology Group established a working group tasked with progressing the standardisation of genomic testing. In July 2021, the 10 lung cancer multidisciplinary teams (MDTs) were invited to take part in a national survey of current biomarker testing practices and a retrospective audit of the next generation sequencing (NGS) pathway in Wales was conducted.ResultsSeventy per cent of MDTs completed the survey, which confirmed variability in the approach to testing with respect to timing of requests, patient selection and testing technologies used. Only 43% reported having pathology-initiated reflex testing, but 87% had adopted DNA and RNA NGS testing as their standard-of-care genomic testing strategy. Data from 53 patients with stage III–IV NSCLC with genomic testing requested between October 2020 and May 2021 were analysed in the NGS pathway audit. Forty (75.5%) patients had both DNA and RNA NGS requested, with a median turnaround time from biopsy to results of 26 days (range 19–37 days) and 25 days (range 16–38 days), respectively. The geographical location of MDT did not influence turnaround times and MDTs with reflex testing had shorter biopsy-to-result times. DNA NGS testing was successful in 51 (96.2%) patients; in those who had RNA NGS, testing was successful in 30 (75%) patients.ConclusionSignificant progress has been made within Wales to implement a national biomarker testing pathway, with reflex testing becoming standard of care. However, challenges remain in optimising the quantity and quality of tissue available for testing, together with a need to reduce turnaround times. This will need to be addressed to ensure all eligible patients are tested at the right time in the diagnostic pathway to facilitate optimal treatment strategies and ultimately improve outcomes.