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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.
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Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer. The systemic antitumor therapy of advanced NSCLC has undergone renovations of chemotherapy, targeted therapy and immunotherapy, which results in greatly improved survival for patients with advanced NSCLC. Immune checkpoint inhibitors (ICIs), especially targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), has changed the treatment paradigm of NSCLC. ICIs have become the standard treatment for advanced NSCLC without epidermal growth factor receptor(EGFR) mutation or anaplastic lymphomakinase(ALK) translocation in the first- or second-line setting, and for locally advanced NSCLC following concurrent radiotherapy and chemotherapy. ICIs are also promising in adjuvant/neoadjuvant therapy. More and more ICIs have been approved domestically for the treatment of NSCLC. Led by the NSCLC expert committee of Chinese Society of Clinical Oncology (CSCO), this consensus was developed and updated based on thoroughly reviewing domestic and foreign literatures, clinical trial data, systematic reviews, experts' discussion and the consensus(2019 version). This consensus will aid domestic clinicians in the treatment of NSCLC with ICIs. .
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Non-small cell lung cancer (NSCLC) is the most common pathological type of lung cancer, most NSCLC patients are at advanced stage at the time of diagnosis. For patients without sensitive driven-oncogene mutations, chemotherapy is still the main treatment at present, the overall prognosis is poor. Improving outcomes and obtaining long-term survival are the most urgent needs of patients with advanced NSCLC. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors (ICIs), especially targeting programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1), have made a breakthrough in the treatment of NSCLC, beneficial to patients' survival and changed the treatment pattern for NSCLC. It shows more and more important role in the treatment of NSCLC. Led by NSCLC expert committee of Chinese society of clinical oncology (CSCO), relevant experts in this field were organized. On the basis of referring to domestic and foreign literature, systematically evaluating the results of Chinese and foreign clinical trials, and combining the experiences of the experts, the experts group reached an agreement to develop this consensus. It will guide domestic counterparts for better application of ICIs to treat NSCLC.
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Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the standard treatment for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, most of patients will develop resistance to TKIs treatment due to the emergence of the T790M mutation. The third-generation EGFR-TKI is highly selective and efficient for activating mutants (EGFR sensitive mutations) and resistance mutant (T790M+ ). This review summarizes the mechanism and clinical efficacy of the third-generation EGFR-TKI in NSCLC patients.
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With the advances in molecular detection technology and the emergence of various targeted agents, we have entered the era of precision medicine across the whole process of cancer diagnosis and treatment. Tyrosine kinase inhibitors targeting epidermal growth factor receptor gene mutation, the most common driver, have been developed from the first generation to the third generation, improving the survival and life quality of patients with advanced non-small cell lung cancer. It is critically important how to rank these targeted agents and arrange combination therapies, and this review will focus on the strategies of the third-generation EGFR-TKI in the context of precision medicine.
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Early diagnosis and screening are of great significance for improving the prognosis of patients with lung cancer. Low-dose helical computed tomography (LDCT) reduces lung cancer mortality by about 20％, making it the most effective screening tool. However, high false-positive rates, costs, and potential harms highlight the need for complementary biomarkers. The diagnostic performance of biomarkers such as noninvasive autoantibody and plasma/serum microRNA (miRNA) were shown in several studies, making them approved for early diagnosis in our country, Europe and the United States, and their role in screening is being explored in ongoing studies.
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<p><b>OBJECTIVE</b>To evaluate the impact of histology on efficacy of pemetrexed in Chinese non-small cell lung cancer (NSCLC) patients. This report summarized the results of two clinical trials of pemetrexed in Chinese patients with advanced NSCLC in 2nd line setting and maintenance setting after 1st line (JMID study and Chinese subgroup from JMEN study) treatment.</p><p><b>METHODS</b>For the Chinese JMID study (second-line), Chinese patients with locally advanced or metastatic (stage IIIA, IIIB or IV) NSCLC who had prior chemotherapy were enrolled. The study was designed to investigate the noninferiority of pemetrexed (500 mg/m(2), day 1 of each 21-day cycle) to docetaxel (75 mg/m(2), day 1 of each 21-day cycle) in terms of overall survival (OS). For the global JMEN study (maintenance), patients initially diagnosed with IIIB or IV NSCLC, those who had not progressed after completing at least four cycles of platinum-based chemotherapy were enrolled to test for the superiority of pemetrexed (500 mg/m(2), day 1 of each 21-day cycle) over placebo with progression free survival (PFS) as primary endpoint.</p><p><b>RESULTS</b>In JMID study, the OS was similar between the pemetrexed group (Pem group) and docetaxel group (Doc group). Retrospective histological subtype analysis showed survival benefits (both OS and PFS) numerically of non-squamous patients over squamous patients in the Pem group (OS: HR 0.74, 95% CI 0.45-1.21, P = 0.2267, median 11.7 vs. 9.7 months; PFS: HR 0.77, 95% CI 0.44-1.34, P = 0.3585, median 3.0 vs. 1.7 months). In the Chinese subgroup of JMEN study, the median PFS in the Pem group for squamous and nonsquamous patients was 4.2 and 1.5 months for squamous patients, the median OS in the Pem group for squamous and nonsquamous patients was 22.5 and 6.2 months for squamous patients. In JMEN China subgroup analysis, the HR on histology was not analyzed due to the small sample size. In terms of safety profile, drug-related grade 3 or 4 hematological toxicities (leukocytopenia and neutropenia) events occurring after second-line treatment were significantly lower in the Pem group than in the Doc group (both P < 0.001). Similarly in patients receiving pemetrexed maintenance after first-line treatment, incidences of toxicity events were low.</p><p><b>CONCLUSIONS</b>Consistent with global results, in Chinese NSCLC patients, histology has an impact on the efficacy of pemetrexed, in which non-squamous histology predicts a positive outcome for patients treated with pemetrexed. In terms of overall safety, pemetrexed is better than docetaxel with a lower incidence of adverse events and anticipates manageable safety profile in NSCLC patients. Based on consistent Chinese data from the two studies, pemetrexed is recommended as a standard chemotherapy regime in both second-line and maintenance setting after first-line treatment for Chinese non-squamous NSCLC patients.</p>
Subject(s)
Humans , Antineoplastic Agents , Therapeutic Uses , Carcinoma, Non-Small-Cell Lung , Drug Therapy , Pathology , China , Disease-Free Survival , Glutamates , Therapeutic Uses , Guanine , Therapeutic Uses , Lung Neoplasms , Drug Therapy , Pathology , Pemetrexed , Treatment OutcomeABSTRACT
Chemokines are a group of small molecules that cause the directed migration of cells. In lung cancer, chemokines involve in the regulation of tumor cell growth, angiogenesis, anti-tumor immunity and remote metastasis, which provides a novel therapeutic target for lung cancer.
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<p><b>BACKGROUND AND OBJECTIVE</b>The transport of nucleoside transmembrane mediated by equilibrative nucleoside transporter (ENT) plays an important role in regulating various cellular functions, and the ENT gene may be candidate gene of tumors. The aim of this study is to investigate the association between the single nudcleotide polymorphism (SNP) of ENT3 and the hereditary susceptibility of lung cancer.</p><p><b>METHODS</b>A case-control study was performed involved in 351 lung cancer patients and 207 cancer-free controls from Chinese population in Shanghai pulmonary hospital. The rs10999776 (C>T) polymorphism was determined by using Real-time PCR with AllGlo probes. The frequency distribution of genotypes and allele between lung cancer and controls groups was analyzed by chi-square test. The association between polymorphism in the ENT3 gene with the risk of lung cancer was estimated by computing odds ration (OR) and 95%CI.</p><p><b>RESULTS</b>The genotype (CC, TC, IT) and allele distribution of the ENT3 SNP in the patients with lung cancer was not significantly different compared with that in controls (P > 0.05). Compared with never-smokers with wild homozygous genotype, smokers with T allele (TC+TT) had increased risk of lung cancer (OR = 2.848, 95% CI: 1.536-4.879, P = 0.005), and those with pack-years of smoking more than 30 had higher risk (OR = 3.076, 95% CI: 2.308-6.741, P = 0.001). And the risk of squamous cell carcinoma significantly increased in smokers, especially those with T allele (TC+TI) genotype (OR = 6.066, 95% CI: 2.884-12.758, P < 0.001). The genotype with smoking conditions had no significant effect on adenocarcinoma (all P > 0.05).</p><p><b>CONCLUSION</b>The results suggested rs10999776 polymorphism may implicate in the risk of squamous cell carcinoma in Chinese population which may interact with smoking-exposure.</p>
Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Genetic Predisposition to Disease , Lung Neoplasms , Genetics , Nucleoside Transport Proteins , Genetics , Polymorphism, Single Nucleotide , SmokingABSTRACT
Objective:To construct superparamagnetic iron oxide nanoparticles targeting tumor angiogenesis and evaluate their potential value as contrast agent in magnetic resonance imaging (MRI) .Methods:Ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles targeting tumor angiogenesis were prepared by using co-precipitation chemical method. Cyclic RGD(cRGD) containing the sequence of Arg-Gly-Asp were conjugated USPIO nanoparticles by using chemical conjugative method to prepare superparamagnetic imaging agent targeting tumor angiogenic vessles. The physical and chemical properties of cRGD-USPIO nanoparticles were detected. The specific binding capabilities of cRGD-USPIO and USPIO to human lung adenocarcinoma cells (A549) and human umbilical vein endothelial cells (HUVEC) were tested by Prussian blue staining. A549 xenografts were established in nude mice, then USPIO and cRGD-USPIO were injected though tail vein, and the MRI signal enhancement effect of cRGD-USPIO was evaluated.Results:We successfully prepared the cRGD-USPIO nanoparticles. Its core diameter was 5-10 nm and the average diameter was (43.97±10.10) nm and the quality saturation magnetic intensity was 59.94 A·m~2·kg~(-1). Cell-binding test suggested that cRGD-USPIO group showed strengthened positive staining. In vivo MRI experiments showed that signals of tumor were significantly reduced in cRGD-USPIO group than that in USPIO group (P<0.01). Conclusion:The constructed cRGD-USPIO nanoparticles can be developed as a potential tumor-specific MRI contrast agent for the early diagnosis of cancer.
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Objective:To evaluate the relationship between erlotinib-induced skin rash and clinical outcome and explore the effective way to prevent skin rash. Methods:The data from 76 non-small cell lung cancer(NSCLC) patients who experienced erlotinib-induced skin rash from Dec 2005 to Sep 2008 were collected. All the patients were confirmed with NSCLC by pathological and cytological examination and received erlotinib 150 mg/d till they had progressive disease or intolerable adverse reaction. The severity of skin rash was recorded and graded according to National Cancer Institute-Common Toxicity Criteria (NCI-CTC). The therapeutic outcome of skin rash was observed. Results:The skin rash develops as early as 3 days after commencement of erlotinib therapy, with median onset at 8 days. Twenty-seven (35.5%) patients experienced grade 1 skin rash, 44 patients (57.9%) had grade 2 and 5 cases (6.6%) had grade 3 skin rash. A statistically significant correlation was observed between skin rash and erlotinib therapy. The disease-controlling rate was 63.0% for grade 1 skin rash patients including 5 cases with partial remission and 12 cases with stable disease and 91.8% for grade 2/3 skin rash patients including 32 cases with partial remission and 13 cases with stable disease (P<0.05). The median time to progression(TTP) and median overall survival(OS) were prolonged in patients experienced grade 2/3 skin rash compared with those in patients with grade 1 skin rash (TTP: 5.1 months vs 9.7 months, P<0.01; OS: 10.0 months vs 14.6 months, P<0.01). The skin rash was alleviated in 60 out of 76 patients (78.9%). Conclusion:Skin rash is a potent surrogate marker of favorable outcome in patients who received erlotinib treatment. It was tolerable to most patients. Appropriate therapy may be useful in decreasing the severity of skin rash.
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Objective:To construct RNA interference plasmid specific for integrin β1 gene, and to explore the effects of inhibition of integrin β1 protein expression on the biological behavior of non-small cell lung carcinoma(NSCLC) cells. Methods:Genomic sequences of integrin β1 gene was retrieved from GenBank, and cDNA encoding small hairpin RNA(shRNA) for integrin β1 was designed and named as 17-2. A non-specific sequence was designed as negative control and named as N. The cDNA was synthesized and inserted into plasmids pUC19. Recombinant plasmids were then transformed into competent E.coli. The positive clones were selected and recombinant plasmids were extracted.The two shRNA vectors were transfected into NSCLC cell line PC-9/AB2 mediated by lipofectAMINE 2000. The stably transfec-ted cell clones were selected by G418 screening. Fluorescence microscope, real-time fluorescent quantitative (RFQ)-PCR, and Western blotting were performed to examine integrin β1 mRNA and protein expressions.Cell scratch test and adhesion test were used to detect the influences of silencing integrin β1 on cell migration and adhesion capacity. Results:The stably transfected 17.2 cell clones and N cell clones were screened by G418. The green fluorescence-staining cells were observed in full-field under fluorescence microscope. The level of integrin β1 was significantly down-regulated in 17-2 group compared with N group and primary PC-9/AB2 cells.Scratch test and adhesion test showed that the migration and adhesion capacity of PC-9/AB2 cells was significantly reduced after silencing integrin β1. Conclusion:This study successfully constructed integrin β1 specific shRNA expression vector. The expression of integrin β1 was significantly silenced in NSCLC cells transfected with that vecton. Silencing integrin β1 can significantly reduce the migration and adhesion capacity of NSCLC cells.
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Objective:To make a prospective study on the effectiveness and safety of toremifene (TOR) combined with novelbine/cisplatin (NP) in the treatment of patients with advanced non-small cell lung cancer (NSCLC) whose first line platinum-based chemotherapy was failure. Methods:Forty-four patients with stage ⅡB-Ⅳ NSCLC, who failed in the first line cisplatin-based chemotherapy from January 2004 to February 2006, were enrolled in this study. All the patients received TOR combined with NP second line chemotherapy for two cycles. The response rate and adverse reaction were evaluated. The survival rate was analyzed.Results:The 44 patients received average 1.8 cycles of chemotherapy (1-3 cycles). The response of 37 patients could be evaluated including 21 patients who received NP regimen before and 16 patients who received platinum-based chemotherapy. After second line therapy, 4 of the 37 patients had partial response (PR), 19 had stable disease (SD), 14 had progressive disease (PD), and no patient had complete response (CR). The total response rate (CR+PR) was 10.8% (4/37). The disease-controlling rate (CR+PR+SD) was 62.2% (23/37). The response rate and disease-controlling rate of squamous cell lung cancer (SCC) were 27.3% (3/12) and 72.7% (8/12), which were significantly higher than adenocarcinoma [0% (0/18) and 44.4% (8/18), P<0.05]. The median survival time was 8.2 months, the median time for SD was 4.0 months (1.0-10.2 months), and the 1-year survival rate was 24.4%. The median survival time and 1-year survival rate of SCC patients had no significant difference compared with adenocarcinoma patients (9.2 vs 7.1 months; 33.3% vs 27.7%, P＝0.72). There was no significant difference in survival rate between male and female patients. One patient stopped therapy for liver function injury (hyperbilirubinemia). The adverse reactions induced by chemotherapy mainly included gastrointestinal reaction, bone marrow suppression, and liver function injury. No serious adverse reaction occurred. Conclusion:The clinical efficacy of second line TOR combined with NP regimen is similar with the first line regimen for NSCLC patients, especially for SCC patients. The frequency of adverse reaction is not increased.
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Individualized therapy is the current trend of treatment in advanced non-small cell lung cancer, the key of individualized therapy is to administrer different treatment options through different biological markers or clinical markers. Currently, biological markers include EGFR protein expression, EGFR mutations, EGFR gene copy, k-ras mutation, EML4-ALK gene fusion, C-MET gene. Clinical markers include rash, pathological types, etc. This article will give a review about those biomarkers.
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Individual therapy is the current trend of treatment in non-small cell lung cancer patient.However, we still face many questions such as what is the individual therapy, why we need individual therapy,which biomarker could be used to guide the individual therapy and how to undergo individual therapy in nonsmall cell lung cancer patient. This article will give a review to answer these questions.
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<p><b>BACKGROUND</b>Pulmonary carcinosarcoma (PCS) is a rare pulmonary mixed malignant tumor. The aim of this study is to explore the clinical characteristics and prognosis of 48 patients with PCS.</p><p><b>METHODS</b>The data of 48 patients with PCS from 1986 to 2004 were analysed retrospectively. Then their prognostic factors were analysed statistically.</p><p><b>RESULTS</b>PCS occurred usually in males over 50 years old, often in the right lungs. The clinical and radiographic characteristics of PCS were similar to primary non-small cell lung cancer. Its diagnosis was mainly verified by postoperative pathologic findings and immunohistochemical staining. The 1-, 3- and 5-year survival rate was 77.1%, 49.5% and 22.7% respectively. The multivariate prognosis analysis and Chi-square test showed that TNM stage was an independent prognostic factor.</p><p><b>CONCLUSIONS</b>TNM stage is an independent prognostic factor for PCS, so it is necessary to operate surgically in early stage to prolong the survival time of patients.</p>
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<p><b>BACKGROUND</b>Recently,mutations in the epidermal growth factor receptor(EGFR) gene were reported to correlate with EGFR tyrosine kinase inhibitor(TKI) response.In this study,relationship between mutations of EGFR in plasma and pleural effusion and responses to gefitinib was investigated in pretreated patients with advanced non-small cell lung cancer(NSCLC).</p><p><b>METHODS</b>The circulating free DNA was isolated from the plasma of 53 cases and pleural effusion of another 10 cases and analysed for EGFR mutations by LightCycle PCR method.Relationship between EGFR mutations and response to gefitinib was analysed with Chi-square test.</p><p><b>RESULTS</b>EGFR mutations were found in 17 of 63 cases(27.0%).EGFR mutations were frequently present in females(P=0.024) and non-smokers(P=0.021).Patients with EGFR mutations had a significantly better response rate compared to that of the wild-type patients(P=0.000).</p><p><b>CONCLUSIONS</b>The EGFR mutations exist in the plasma and the pleural effusion from patients with advanced NSCLC.These mutations can be detected with LightCycle PCR method which is highly specific and sensitive and easy to perform compared with the direct sequencing.It will enable us to get a potential implication in the diagnosis and targeted therapy of NSCLC at late stage.</p>
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Background and purpose:Angiofollicular lymphoid hyperplasia(Castleman's disease,CD) is a rare kind of abnormal disease with lymphoid hyperplasia. We analyzed the clinical data of 21 patients with pathologically-confirmed CD. Methods:Twenty-one cases,including 10 males and 11 females with a mean age of 38.6 years,with CD were collected from January 1971 to December 2007 in this study. The disease was divided into localized type(n=19) and disseminated type(n=2) . The clinical data,CT images and pathological and surgical results were restrospectively analyzed. Results:All cases were categorized as hyaline vascular type. In 19 cases with localized type of CD,the lesion presented as a solitary soft-tissue mass with a mean diameter of 5.2 cm,located at the left and right hilus of the lung(n=3 and 2 respectively) or in the interior lung(n=3) ,in the thoracic wall(n=2) or in the mediastinum(n=9) . Two cases of disseminated type were characterized by many groups of thoracic lymphadenopathy with a mean diameter of 2.3 cm,without other organ involvement. On plain CT scan,the mean CT value was 42 Hu. After contrast administration,obvious homogeneous enhancement was observed in arterial phase with CT value of 112 Hu. The preoperative misdiagnosis by CT was 90.5%. Conclusion:CD have no specifi c CT characteristic,its verifi cation is mainly based on pathologic examination. Surgical resection for localized type of CD is curative,but for disseminated CD,multidisciplinary therapies are recommended.
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<p><b>BACKGROUND</b>At present, it has been known that cyclooxygenase-2 (COX-2) plays a crucial role in invasion, development and metastasis of non-small cell lung cancer (NSCLC). In order to explore whether the expression of COX-2 inhibits the occurrence and development of NSCLC, antisense vector of human COX-2 gene is transfected into COX-2 highly expressing NSCLC cell line H1299 and its effects on proliferation and sensitivity to cisplatin of H1299 are analysed.</p><p><b>METHODS</b>H1299 cells were transfected with antisense vector of human COX-2 gene using LipoVecTM transfecting technique. Transfected cells were selected with Geneticin (G418). The COX-2 mRNA level was examined by using reverse polymerase chain reaction (RT-PCR). The COX-2 protein level was examined by Western Blot. The proliferative status and sensitivity to cisplatin of cells was measured by methabenzthiazuron (MTT) assay.</p><p><b>RESULTS</b>RT-PCR showed a lower COX-2 mRNA level in transfected cells. The level of COX-2 protein was decreased apparently. The proliferative index of the transfected cells decreased significantly (P < 0.05). The IC50 value of cisplatin decreased remarkably in transfected cells (1.8mg/l) compared with that in H1299 cells without transfection (3.8mg/l) (P < 0.05).</p><p><b>CONCLUSIONS</b>Transfection with antisense vector of human COX-2 gene can not only inhibit the proliferation of H1299 cells, but also increase the sensitivity to cisplatin of H1299 cells.</p>
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<p><b>BACKGROUND</b>Multiple drug-resistance to platinum is one of important influencing factors failure to chemotherapy in the treatment of non-small cell lung cancer (NSCLC). To study and explore the effective chemotherapy drugs and chemotherapeutic regimens inhibiting or reversing multiple drug-resistance is the popular problem in lung cancer clinic. The aim of this study is to evaluate the chemotherapeutic response and toxicities of combination of hydroxycamptothecine (HCPT) and ifosfamide (IFO) in patients with relapsed NSCLC after pretreatment with platinum-based regimens.</p><p><b>METHODS</b>Patients with NSCLC, performance status (PS) < or =2, with history of prior platinum-based chemotherapy and without impaired haematopoietic and organ function were eligible. Chemotherapy was administered as follows: HCPT 6-8mg/m² from 1st to 5th day, IFO 1.2mg/m² from the 1st to 3rd day which was recycled every 3 weeks.</p><p><b>RESULTS</b>From June 2002 to December 2003, 69 patients were enrolled and 53 were evaluable for response and all 69 for toxicity. The total response rate was 11.3% (6/53), stable disease was 39.6% (21/53) and progressive disease was 49.1% (26/53). The main side-effect was haematological toxicity, with grade III-IV (G3-4) neutropenia in 12 patients, G3 thrombocytopenia and anemia in 4 and 4 patients respectively. Non-hematological toxicities were negligible. Alopecia rate was 87.0%.</p><p><b>CONCLUSIONS</b>The combination of HCPT and IFO is a tolerable and effective combination regimen to apply in the treatment of cisplatin-pretreated NSCLC patients.</p>