Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP–AMP synthase-stimulator of interferon genes (cGAS–STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.     

PD0325901, an ERK inhibitor,enhances the efficacy of PD-1 inhibitor in non-small cell lung carcinoma

ERK pathway regulated the programmed death ligand-1 (PD-L1) expression which was linked to the response of programmed death-1 (PD-1)/PD-L1 blockade therapy. So it is deducible that ERK inhibitor could enhance the efficacy of PD-1 inhibitor in cancer immunotherapy. In this study, PD0325901, an oral potent ERK inhibitor, strongly enhanced the efficacy of PD-1 antibody in vitro and in vivo models in non-small cell lung carcinoma (NSCLC) cells. Mechanistically, PD0325901 or shRNA-ERK1/2 significantly downregulated the PD-L1 expression in NSCLC cells and increased the CD3⁺ T cells infiltration and functions in tumor tissue. There was a positive correlation between the p-ERK1/2 expression and PD-L1 expression in patients with NSCLC. And the patients with low p-ERK1/2 expression were observed a high response rate of PD-1/PD-L1 blockage therapy. Our results demonstrate that PD0325901, an ERK inhibitor, can enhance the efficacy of PD-1 blockage against NSCLC in vitro and in vivo models. And the combination of ERK inhibitor such as PD0325901 and PD-1/PD-L1 blockage is a promising regimen and encouraged to be further confirmed in the treatment of patients with NSCLC.     

计算机辅助预测EGFR突变的非小细胞肺癌药物敏感性的研究进展

表皮生长因子受体(epidermal growth factor receptor,EGFR)既是非小细胞肺癌(non-small cell lung cancer,NSCLC)的常见驱动基因,也是临床上NSCLC的重要治疗靶标。但EGFR突变导致的耐药性问题严重影响了靶向药物的治疗效果,限制了精准医疗的发展。本文对目前上市的EGFR酪氨酸激酶抑制剂(EGFR-tyrosine kinase inhibitors,EGFR-TKIs)的靶标结合模式进行综述,旨在为新型EGFR-TKIs开发提供理论依据,并回顾总结应用计算机预测EGFR突变体的药物敏感性的研究进展,以期推动发展临床决策的辅助工具来帮助临床医师设计个性化治疗方案。     

Evolution of treatment strategies for oligometastatic NSCLC patients – A systematic review of the literature

BackgroundThe concept of oligometastatic disease (OMD) has expanded the scope of potentially curative therapy for metastatic NSCLC. However, large uncertainties remain regarding its definition and optimal management strategies. We therefore conducted a systematic review to investigate the value of various multimodality treatment concepts.MethodsWe searched the available literature in Pubmed, Medline and EMBASE using the terms “oligomet*”, “synchron*”, “oligorec*”, “metachr*” “NSCLC”, “lung cancer” and “stage IV” and included studies reporting treatment regimens and outcomes on radically treated patients with either “synchronous”, “metachronous” or “mixed” OMD. Only de-novo diagnosis of OMD was considered. The impact of patient and treatment characteristics on overall survival (OS) and time trends in patterns of care were investigated.Results54 studies published between 1987 and 2018 were included. Despite a wide range of OMD definitions, 90.1% of patients were treated for a single metastasis. Systemic therapy was used as backbone treatment for most patients. Although surgery was the preferred local treatment in earlier studies, the use of stereotactic radiotherapy increased rapidly after 2011. No OS difference was observed between surgery or radiotherapy as the treatment of primary tumor or metastases, respectively. A time trend towards improved OS after 2011 could be detected.ConclusionsWhile evidence in favor of radical treatment is emerging, most studies remain retrospective and mainly evaluate patients with singular metastases. While surgery, stereotactic radiotherapy and chemotherapy are the cornerstones of current treatment strategies, future clinical trials need to address the high risk of distant metastases by integrating targeted or immunotherapy.     

Immunotherapy for LELC: Case Report and a Focused Review

Lymphoepithelioma-like carcinoma of the lung (LELC) is a rare, Epstein-Barr virus-associated tumor. LELC occurs mostly in young, Asian nonsmokers. A few hundred cases have been reported, mostly from retrospective Asian studies. Optimal treatment has not been clearly established. Treatment options are based on surgery for early stage and on cisplatin-based chemotherapy as first-line therapy for metastatic disease. Prognosis may seem better than for other types of non–small-cell lung cancer, but it remains poor in advanced disease, with a median survival of 24 months, and new treatments options are still warranted. Immunotherapies are now key players in the treatment of non–small-cell lung cancer. However, few data are available for this rare histologic subgroup. We have reviewed the available data on LELC with a focus on the first few cases reported with a response to a programmed cell death 1 inhibitor.     

Clinical Characteristics,Molecular Phenotyping,and Management of Isolated Adrenal Metastases From Lung Cancer

IntroductionAdrenal gland metastases occur in up to 20% of patients with non–small-lung cancer. In selected cases with limited burden of disease, surgery may be offered to improve patient outcome; furthermore, tissue analysis would provide useful information on genotype of primary and secondary neoplasms.Materials and MethodsWe report our experience in the management of adrenal metastasis by retrospectively reviewing data of 21 consecutive patients treated with curative intent to the primary tumor followed by adrenalectomy in a 15-year time span. Targeted next generation sequencing was performed to compare molecular profile of primary lung cancers and adrenal metastases. Patient overall survival was assessed by Kaplan-Meier method, using adrenalectomy as time zero. Survival rates were compared by log rank test.ResultsNo surgery-related mortality or morbidity was observed. Median survival was 50 months; 5-year overall survival was 34.5% (95% confidence interval, 12%-66%). No significant survival difference was observed with respect to timing of onset (synchronous vs. metachronous) or side (homolateral vs. contralateral) of adrenal metastasis, T or N status of primary lung cancer, mutational asset, and histologic type. Mutations in TP53 genes were found in 61% and 85% of primary and metastatic tumors, respectively. In 3 of 15 cases, we found differences between molecular mutation patterns in primary lung cancer and corresponding adrenal metastasis.ConclusionsAdrenalectomy is a safe and effective approach in selected cases. Discordance between primary and secondary tumor mutational profile was found in 20% of assessable patients.     

Efficacy and Safety of Ceritinib (450 mg/d or 600 mg/d) With Food Versus 750-mg/d Fasted in Patients With ALK Receptor Tyrosine Kinase (ALK)–Positive NSCLC: Primary Efficacy Results From the ASCEND-8 Study

IntroductionIn an earlier report of the ASCEND-8 study (open-label, phase I, three-arm study, treatment-naive patients and pre-treated patients with advanced/metastatic NSCLC), it was shown that ceritinib 450 mg with food had comparable exposure and better gastrointestinal tolerability than 750-mg fasted.MethodsHere, we report efficacy and updated safety data from primary efficacy analysis of the ASCEND-8 study. Key secondary endpoints were overall response rate and duration of response, assessed by blinded independent review committee (BIRC) using Response Evaluation Criteria in Solid Tumors 1.1.ResultsIn total, 306 patients were randomized to ceritinib 450-mg fed (n = 108) or 600-mg fed (n = 87) or 750-mg fasted (n = 111), of which 304 patients were included in safety analysis and 198 treatment-naive patients (ALK receptor tyrosine kinase [ALK]–positive by immunohistochemistry) were included in the efficacy analysis (450-mg fed [n = 73], 600-mg fed [n = 51], and 750-mg fasted [n = 74]). The BIRC-assessed overall response rate was 78.1% (95% confidence interval [CI]: 66.9–86.9), 72.5% (95% CI: 58.3–84.1), and 75.7% (95% CI: 64.3–84.9), respectively; and the median duration of response (months) by BIRC was not estimable (NE) (95% CI: 11.2–NE), 20.7 (95% CI: 15.8–NE), and 15.4 (95% CI: 8.3–NE), respectively. Based on the safety analysis (n = 304), the 450-mg fed arm showed the highest median relative dose intensity (100% versus 78.5% versus 83.7%), lowest proportion of patients with dose reductions (24.1% versus 65.1% versus 60.9%), and lowest proportion of patients with gastrointestinal toxicities (75.9% versus 82.6% versus 91.8%).ConclusionCeritinib at a dose of 450 mg with food compared to 750-mg fasted showed consistent efficacy and less gastrointestinal toxicity.     

Long Non-Coding RNA NANCI/NKX2-1 Duplex Impacts Prognosis in Stage I Non-Small-Cell Lung Cancer

BackgroundNANCI, an intergenic long non-coding RNA (lncRNA) is essential for buffering NKX2-1 expression during embryonic development and in adult tissue. We analyzed NANCI and NKX2-1 in human lung embryonic samples and adult lung tissues and evaluated their potential as prognostic markers in stage I non-small cell lung cancer (NSCLC).Methods and resultsNANCI and NKX2-1 expression was assessed by TaqMan assays in 18 human embryonic samples from 8 to 13 weeks, 59 non-tumoral (NT) lung tissue samples, and 98 stage I NSCLC tumor samples. NANCI and NKX2-1 expression in embryonic and NSCLC samples were downregulated in comparison to adult NT tissue. Patients with low expression of NANCI had shorter disease-free survival (DFS) and overall survival (OS) than those with high levels (47.6 vs 69.3 months, P = 0.032 and 57.7 vs 77.6 months, P = 0.021, respectively). When the expression levels of NANCI and NKX2-1 were evaluated in combination, four groups were identified (high NANCI/high NKX2-1, low NANCI/high NKX2-1, high NANCI/low NKX2-1 and low NANCI/low NKX2-1) with differential impact on DFS (P = 0.042) and OS (P = 0.024). Interestingly, the high NANCI/high NKX2-1 duplex group had longer DFS and OS than the other three groups (71.25 vs 46.3 months, P = 0.009 and 81.3 vs 56.1 months, P = 0.004, respectively). In the multivariate analysis, the high NANCI/high NKX2-1 duplex was identified as an independent prognostic factor for longer DFS (HR 0.346, 95% CI, 0.169–0.709; P = 0.004) and OS (HR 0.309, 95% CI, 0.121–0.786; P = 0.014).ConclusionsNANCI and the NANCI-NKX2-1 duplex impacts prognosis in stage I NSCLC patients.     

新辅助化疗对局部晚期非小细胞肺癌患者临床疗效和手术切除率的影响

目的 探讨局部晚期非小细胞肺癌(NSCLC)患者手术前进行新辅助化疗的临床效果以及对患者的手术和生存情况的影响.方法 66例Ⅲ期NSCLC患者,其中36例患者在手术前进行2个周期全身化疗,为观察组;其余30例患者确诊后直接进行手术,为对照组.对2组患者的手术切除情况、手术相关指标、生存率以及T淋巴细胞亚群等指标进行收集整理.结果 新辅助化疗的有效率为58.3％,其中有13例患者病情下调,病情下调率为36.1％.观察组患者的手术切除率显著高于对照组(P＜0.05);在手术时,2组患者的术中出血量和手术时间均存在统计学差异,其中观察组均显著低于对照组(P＜0.05).术后随访3年,观察组和对照组患者的1年生存率、2年生存率和3年生存率分别是83.3％和60.0％、75.0％和50.0％、63.9％和40.0％,2组患者差异具有统计学意义(P＜0.05).手术前观察组患者的CD4+和CD4 +/CD8+显著高于对照组(P＜0.05).结论 在手术前进行新辅助化疗对NSCLC患者手术切除率以及生存率等情况都有提高的效果,可能与提高患者免疫水平和降低术中出血量有关.