Development and validation of a deep transfer learning-based multivariable survival model to predict overall survival in lung cancer.

Background: Numerous deep learning-based survival models are being developed for various diseases, but those that incorporate both deep learning and transfer learning are scarce. Deep learning-based models may not perform optimally in real-world populations due to variations in variables and characteristics. Transfer learning, on the other hand, enables a model developed for one domain to be adapted for a related domain. Our objective was to integrate deep learning and transfer learning to create a multivariable survival model for lung cancer. Methods: We collected data from 601,480 lung cancer patients in the Surveillance, Epidemiology, and End Results (SEER) database and 4,512 lung cancer patients in the First Affiliated Hospital of Guangzhou Medical University (GYFY) database. The primary model was trained with the SEER database, internally validated with a dataset from SEER, and externally validated through transfer learning with the GYFY database. The performance of the model was compared with a traditional Cox model by C-indexes. We also explored the model's performance in the setting of missing data and generated the artificial intelligence (AI) certainty of the prediction. Results: The C-indexes in the training dataset (SEER full sample) with DeepSurv and Cox model were 0.792 (0.791-0.792) and 0.714 (0.713-0.715), respectively. The values were 0.727 (0.704-0.750) and 0.692 (0.666-0.718) after applying the trained model in the test dataset (GYFY). The AI certainty of the DeepSurv model output was from 0.98 to 1. For transfer learning through fine-tuning, the results showed that the test set could achieve a higher C-index (20% vs. 30% fine-tuning data) with more fine-tuning dataset. Besides, the DeepSurv model was more accurate than the traditional Cox model in predicting with missing data, after random data loss of 5%, 10%, 15%, 20%, and median fill-in missing values. Conclusions: The model outperformed the traditional Cox model, was robust with missing data and provided the AI certainty of prediction. It can be used for patient self-evaluation and risk stratification in clinical trials. Researchers can fine-tune the pre-trained model and integrate their own database to explore other prognostic factors.

Profiling Tumor Immune Microenvironment of Non-Small Cell Lung Cancer Using Multiplex Immunofluorescence.

This study attempted to profile the tumor immune microenvironment (TIME) of non-small cell lung cancer (NSCLC) by multiplex immunofluorescence of 681 NSCLC cases. The number, density, and proportion of 26 types of immune cells in tumor nest and tumor stroma were evaluated, revealing some close interactions particularly between intrastromal neutrophils and intratumoral regulatory T cells (Treg) (r2 = 0.439, P < 0.001), intrastromal CD4+CD38+ T cells and CD20-positive B cells (r2 = 0.539, P < 0.001), and intratumoral CD8-positive T cells and M2 macrophages expressing PD-L1 (r2 = 0.339, P < 0.001). Three immune subtypes correlated with distinct immune characteristics were identified using the unsupervised consensus clustering approach. The immune-activated subtype had the longest disease-free survival (DFS) and demonstrated the highest infiltration of CD4-positive T cells, CD8-positive T cells, and CD20-positive B cells. The immune-defected subtype was rich in cancer stem cells and macrophages, and these patients had the worst prognosis. The immune-exempted subtype had the highest levels of neutrophils and Tregs. Intratumoral CD68-positive macrophages, M1 macrophages, and intrastromal CD4+ cells, CD4+FOXP3- cells, CD8+ cells, and PD-L1+ cells were further found to be the most robust prognostic biomarkers for DFS, which were used to construct and validate the immune-related risk score for risk stratification (high vs. median vs. low) and the prediction of 5-year DFS rates (23.2% vs. 37.9% vs. 43.1%, P < 0.001). In conclusion, the intricate and intrinsic structure of TIME in NSCLC was demonstrated, showing potency in subtyping and prognostication.

PD-L1 expression with respect to driver mutations in non-small cell lung cancer in an Asian population: a large study of 1370 cases in China.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) expression with respect to genetic alternations has not been well established in non-small cell lung cancer (NSCLC), especially in the Asian population. METHODS: We reviewed 1370 NSCLC patients from a prospectively maintained database. Immunohistochemistry was performed on tumor cells and tumor-infiltrating lymphocytes (TILs) using the VENTANA (SP142) anti-PD-L1 antibody. The tumor proportion score (TPS) cutoff values were set at ⩾1% and ⩾50%, and the immune proportion score (IPS) cutoff values were set at ⩾1% and ⩾10%. RESULTS: In tumor cells, PD-L1 positivity was observed in 405 (29.6%), 122 (8.9%), and 27 (2.0%) patients with TPS cutoff values at ⩾1% and ⩾50%. Contrastingly, TILs of 1154 (84.2%) and 346 (25.3%) patients stained positive at IPS cutoff values of ⩾1% and ⩾50%, respectively. PD-L1 expression was more common in patients who were mutation-negative irrespective of the TPS cutoff values and tumor size. PD-L1 expression in tumor cells was less frequent in patients harboring EGFR mutations (18.8% TPS ⩾ 1% and 4.6% TPS ⩾ 50%). Conversely, PD-L1 expression was high in the presence of KRAS mutations (47.3% TPS ⩾ 1% and 22.5% TPS ⩾ 50%). Overall, KRAS, BRAF, PICK3A, MET mutations and ROS1 and RET translocations were more frequent, while EGFR and HER2 mutations and ALK translocations were less frequent compared with the overall PD-L1 expression levels. Although the difference between TILs among the PD-L1-positive cases was comparatively small, PD-L1 positivity was less prevalent in EGFR-mutated tumors and more common in those with KRAS mutations, ROS1 translocations, BRAF mutations, or MET mutations. CONCLUSION: Our study showed the heterogeneity in PD-L1 expression with respect to nine major oncogenic drivers in China. Future studies are warranted to further clarify the association between PD-L1 expression and driver mutations in NSCLC.

Efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor mutated, non-small cell lung cancer: systematic review and network meta-analysis.

OBJECTIVE: To compare the efficacy and safety of first line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). DESIGN: Systematic review and network meta-analysis. DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and several international conference databases, from inception to 20 May 2019. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Published and unpublished randomised controlled trials comparing two or more treatments in the first line setting for patients with advanced EGFR mutated NSCLC were included in a bayesian network meta-analysis. Eligible studies reported at least one of the following clinical outcome measures: progression free survival, overall survival, objective response rate, and adverse events of grade 3 or higher. RESULTS: 18 eligible trials involved 4628 patients and 12 treatments: EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed based chemotherapy, pemetrexed free chemotherapy, and combination treatments (afatinib plus cetuximab, erlotinib plus bevacizumab, gefitinib plus pemetrexed based chemotherapy, and gefitinib plus pemetrexed). Consistent with gefitinib plus pemetrexed based chemotherapy (hazard ratio 0.95, 95% credible interval 0.72 to 1.24), osimertinib showed the most favourable progression free survival, with significant differences versus dacomitinib (0.74, 0.55 to 1.00), afatinib (0.52, 0.40 to 0.68), erlotinib (0.48, 0.40 to 0.57), gefitinib (0.44, 0.37 to 0.52), icotinib (0.39, 0.24 to 0.62), pemetrexed based chemotherapy (0.24, 0.17 to 0.33), pemetrexed free chemotherapy (0.16, 0.13 to 0.20), afatinib plus cetuximab (0.44, 0.28 to 0.71), and gefitinib plus pemetrexed (0.65, 0.46 to 0.92). Osimertinib and gefitinib plus pemetrexed based chemotherapy were also consistent (0.94, 0.66 to 1.35) in providing the best overall survival benefit. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab, which caused the most adverse events of grade 3 or higher. Different toxicity spectrums were revealed for individual EGFR-TKIs. Subgroup analyses by the two most common EGFR mutation types indicated that osimertinib was associated with the best progression free survival in patients with the exon 19 deletion, and gefitinib plus pemetrexed based chemotherapy was associated with the best progression free survival in patients with the Leu858Arg mutation. CONCLUSIONS: These results indicate that osimertinib and gefitinib plus pemetrexed based chemotherapy were associated with the best progression free survival and overall survival benefits for patients with advanced EGFR mutated NSCLC, compared with other first line treatments. The treatments resulting in the best progression free survival for patients with the exon 19 deletion and Leu858Arg mutations were osimertinib and gefitinib plus pemetrexed based chemotherapy, respectively. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018111954.

The incidence of lymph node metastasis in patients with different oncogenic driver mutations among T1 non-small-cell lung cancer.

OBJECTIVE: To investigate the incidence and distribution of lymph node metastasis in patients with different gene mutations among pathological T1 non-small-cell lung cancers (NSCLC). METHODS: NSCLC cases resected in our institution between 2016 and 2018 were included. Driver mutation testing was performed in all resected tumor tissues. These patients were grouped by the type of gene mutations. On the basis of protein that mutant-genes encoded involved in the molecular pathway, the genotypes were further classified into four distinct groups: upstream receptor mutant protein (EGFR, HER2 and MET); downstream regulator mutant protein (KRAS and BRAF); fusion mutant protein (ROS1, ALK and RET) and the wild type group. The incidence of lymph node metastasis was compared among different groups. RESULTS: Of the 1052 patients enrolled, the frequency of positive mutations was 68.0%. The incidence of lymph node metastasis were as follows: wild type (19.3%), ROS1 (72.8%), BRAF (55.5%), ALK (44.7%), HER2 (40%), RET (23.1%), KRAS (15.3%), EGFR (15.3%) and MET mutation (0%) (P < 0.001). The incidence of lymph node metastasis was significantly higher in fusion mutant protein group (45.1%) compared with others (wild type 19.3%, downstream regulator mutant protein 19.1%, upstream receptor mutant protein 15.3%, all P < 0.001). Patients with fusion genes also showed higher proportion of vascular invasion and positive lymph node ratio of greater than 0.33 compared to others. CONCLUSION: Different genotypes of NSCLC have different propensity to develop lymph node metastasis. Cases of fusion gene mutations had a higher risk and burden of lymph node metastasis than other genotypes, which may indicate that more intensive treatment or surveillance strategies should be applied for these patients.

The impact of epidermal growth factor receptor mutations on the prognosis of resected non-small cell lung cancer: a meta-analysis of literatures.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation represents a good response to EGFR-tyrosine kinase inhibitor and an advantageous prognostic factor in advanced-stage non-small cell lung cancer (NSCLC). However, the predictive value of EGFR mutation for prognosis in NSCLC patients after complete surgery, which more reflective of natural process, remains controversial. We sought to examine the predictive value of EGFR mutation in NSCLC. Several studies with small sample sizes have been reported but small studies bring bias especially in a postoperative setting. Therefore, we sought to pool all current evidence to show the true effects. METHODS: Electronic databases were used to search the relevant articles. Disease-free survival (DFS), which will be less effected by subsequent treatments after recurrence, was the primary endpoint. The DFS between EGFR mutated and wild-type patients were compared focus on stage I patients who are rarely received adjuvant therapy. Besides, the DFS of patients with 19 exon deletion (19del) and 21 exon L858R mutation (L858R) were compared. A random effects model was used. RESULTS: A total of 19 relevant studies which involved 4,872 cases were enrolled and 2,086 patients were EGFR-mutated. The majority of studies used PCR-based methods to detect EGFR mutations. Through meta-analysis, we observed the DFS of EGFR-mutated patients were similar to wild type patients in overall population (HR 0.93, 95% CI: 0.74 to 1.17). Similar results were observed in stage I subgroup (HR 0.82, 95% CI: 0.50 to 1.33). DFS of 19 del patients were potentially inferior to L858R patients but the difference was not significant (HR 1.38, 95% CI: 0.76 to 2.52). CONCLUSIONS: There was no significant difference in postoperative DFS between EGFR-mutant patients and wild-type with resected NSCLC. In addition, there is still insufficient evidence to support different postoperative treatment strategies (especially for stage I) for both mutated and wild-type patients. However, 19 del may be a negative factor, which may require more strict management. Thus, we strongly encourage reporting specific prognostic impacts of different mutation types.

PD-(L)1 inhibitors vs. chemotherapy vs. their combination in front-line treatment for NSCLC: An indirect comparison.

We comprehensively compared the therapeutic effects and safety of PD-1/L1 antibodies (I), chemotherapy (C) or their combination (I + C) as first-line treatments for advanced NSCLC. Online databases were searched to identify RCTs. Survival outcomes and safety events were pooled by indirect treatment comparison. Main subgroup analyses were conducted according to PD-L1 expression. A total of 11 RCTs involving 6,731 patients were included. Overall, PD-1/L1 inhibitors showed no difference to chemotherapy in PFS (HR 0.90, 0.65-1.24) and OS (HR 0.84, 0.64-1.09), while I + C was superior to chemotherapy both in PFS (HR 0.64, 0.58-0.71) and OS (HR 0.74, 0.62-0.89). I + C also showed advantages over PD-1/L1 in PFS (HR 0.71, 0.51-0.99) but not OS (HR 0.88, 0.64-1.22). In the PD-L1 < 1% subgroup, I + C was beneficial both in OS (HR 0.78, 0.67-0.90) and PFS (HR 0.72, 0.65-0.80) than chemotherapy. In PD-L1 ≥ 50% population, PD-1/L1 had longer OS than chemotherapy (HR 0.71, 0.60-0.84); I + C also had longer OS (HR 0.61, 0.49-0.77) and PFS (HR 0.41,0.34-0.49) than chemotherapy. In indirect analysis (PD-L1 ≥ 50%), I + C was superior to PD-1/L1 in terms of PFS (HR 0.54, 0.35-0.82), but not OS (HR 0.86, 0.65-1.14). Both treatment-related and immune-mediated adverse events occurred most frequently in the combination therapy group. We suggest that a combination regimen is preferable as first-line treatment for NSCLC patients with different PD-L1 expression, in the meanwhile, in cautious of side effects.

Association between certain non-small cell lung cancer driver mutations and predictive markers for chemotherapy or programmed death-ligand 1 inhibition.

This study aimed to analyze the association between driver mutations and predictive markers for some anti-tumor agents in non-small cell lung cancer (NSCLC). A cohort of 785 Chinese patients with NSCLC who underwent resection from March 2016 to November 2017 in the First Affiliated Hospital of Guangzhou Medical University was investigated. The specimens were subjected to hybridization capture and sequence of 8 important NSCLC-related driver genes. In addition, the slides were tested for PD-L1, excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthase (TS) and ß-tubulin III by immunohistochemical staining. A total of 498 (63.4%) patients had at least 1 driver gene alteration. Wild-type, EGFR rare mutation (mut), ALK fusion (fus), RAS mut, RET fus and MET mut had relatively higher proportions of lower ERCC1 expression. EGFR 19del, EGFR L858R, EGFR rare mut, ALK fus, HER2 mut, ROS1 fus and MET mut were more likely to have TS low expression. Wild-type, EGFR L858R, EGFR rare mut and BRAF mut were associated with lower ß-tubulin III expression. In addition, wild-type, RAS mut, ROS1 fus, BRAF and MET mut had higher proportion of PD-L1 high expression. As a pilot validation, 21 wild-type patients with advanced NSCLC showed better depth of response and response rate to taxanes compared with pemetrexed/gemcitabine (31.2%/60.0% vs 26.6%/45.5%). Our study may aid in selecting the optimal salvage regimen after targeted therapy failure, or the chemo-regimen where targeted therapy has not been a routine option. Further validation is warranted.

Erratum: The association between human papillomavirus presence and epidermal growth factor receptor mutations in Asian patients with non-small cell lung cancer.

[This corrects the article DOI: 10.21037/tlcr.2018.03.16.].

The association between human papillomavirus presence and epidermal growth factor receptor mutations in Asian patients with non-small cell lung cancer.

BACKGROUND: The etiology of non-small cell lung cancer (NSCLC) in non-smoker patients remains largely unknown. It has been widely proved that human papillomavirus (HPV) participates in the development of various cancers. Epidermal growth factor receptor (EGFR) mutation patients represent a large portion of non-smokers with NSCLC. We performed this meta-analysis to determine whether HPV infection in NSCLC tissue is associated with EGFR mutations compared with HPV negative controls. METHODS: Online databases were searched up to June 30th 2017. We included studies in which HPV detection was based on polymerase chain reaction (PCR) methods. Random effects model was used in data synthesis and the relative effects were presented as odds ratio (OR) with 95% confidence intervals (CIs). RESULTS: Finally, four eligible studies with a total of 498 patients from Asian countries were identified and included. The general EFGR mutation positive rate was 38.2% among all patients, and the HPV DNA detection rate (HPV subtype being involved: 16, 18, 33 and 58) was 35.3%. The presence of EGFR mutation was significantly higher in HPV-positive patients compared with HPV-negative controls (52% vs. 31%; OR =2.41, 95% CI: 1.21 to 4.77; P=0.012), with moderate heterogeneity among studies (I2=59%; P=0.062). CONCLUSIONS: Our results suggest that HPV infection is associated with EGFR mutations in NSCLC, at least in Asian populations. Further efforts should be made on exploring the potential mechanism and the prognostic character of HPV/EGFR positive NSCLC patient.

The alteration of T790M between 19 del and L858R in NSCLC in the course of EGFR-TKIs therapy: a literature-based pooled analysis.

BACKGROUND: Treatment-naive epidermal growth factor receptor (EGFR) T790M mutation is more inclined to coexist with L858R than with 19 del in non-small cell lung cancer (NSCLC) patients. However, EGFR-tyrosine kinase inhibitors (EGFR-TKIs) might alter this status. We sought to compare the prevalence of T790M upon acquired resistance to EGFR-TKIs between 19 del and L858R by assembling all existing data. METHODS: Electronic databases were comprehensively searched for eligible studies. The primary endpoint was the odds ratio (OR) of T790M mutation in NSCLC co-existing with L858R mutation and 19 del upon resistance to first-generation EGFR-TKIs. A random effects model was used. Stratified analysis was performed based on study type (retrospective and prospective), race (Asians and Caucasians) and sample type (tissue and plasma). RESULTS: A total of 25 studies involving 1,770 patients were included. The overall T790M existent rate was 45.25%. Post-resistance T790M was more frequent in 19 del than in L858R mutated patients (53% vs. 36%; OR 1.87; P<0.001). All outcomes of subgroup and overall analyses were similar. In contrast, we re-analyzed the previous meta-analysis, finding that the pooled rate of pretreatment T790M was 14% and 22% in 19 del and L858R respectively (OR 0.59; P<0.001). The increase of T790M rate was 2.79-fold in 19 del and only 0.63-fold in L858R in the course of EGFR-TKIs therapy. CONCLUSIONS: Opposite to the situation of de novo T790M, it was observed that T790M was more frequent in exon 19 deletion than in L858R among patients with acquired resistance to EGFR-TKIs. The difference in T790M alteration between 19 del and L858R encourages development of detection or treatment strategies for the specific resistance mechanism.

Clinicopathological and prognostic significance of programmed cell death ligand1 (PD-L1) expression in patients with non-small cell lung cancer: a meta-analysis.

OBJECTIVE: Programmed cell death 1 (PD-1) and one of its ligands, PD-L1, are key immune checkpoint proteins. Evidences showed PD-L1 is an emerging biomarker for immunotherapy by anti-PD-1 and anti-PD-L1 antibody in non-small cell lung cancer (NSCLC). To investigate the association of PD-L1 protein expression with clinicopathological features and its impact on survival outcome, we conducted a meta-analysis. METHODS: A comprehensive literature search of electronic databases (up to July 10, 2014) was performed. Correlation between PD-L1 expression and clinicopathological features and overall survival (OS) was analyzed by synthesizing the qualified data. Publication biases were examined. RESULTS: A total of 1,550 NSCLC patients from 9 studies were included. The pooled odds ratios (ORs) indicated high PD-L1 expression was associated with poor tumor differentiation [OR =0.53, 95% confidence interval (CI): 0.39-0.72, P<0.0001]. Whereas, none of other clinicopathological characteristics [gender, smoking status, histological type, invasive depth of tumor, status of lymph node metastasis and tumor node metastasis (TNM) stage] were correlated with PD-L1 expression in current analysis. The combined hazard ratio (HR) for OS showed high expression of PD-L1 impaired the OS in NSCLC (HRpositive/negative =1.47, 95% CI: 1.19-1.83, P=0.0004). CONCLUSIONS: Our meta-analysis indicated PD-L1 protein expression in NSCLC was not associated with common clinicopathological characteristics, except tumor differentiation. It was a poor prognostic biomarker for NSCLC. Further research should be performed to investigate the precise clinicopathological and prognostic significance of PD-L1 in NSCLC under uniform testing standard.

S-1-based versus 5-FU-based chemotherapy as first-line treatment in advanced gastric cancer: a meta-analysis of randomized controlled trials.

To compare the efficacy, prognosis, and toxicity of S-1-based with fluorouracil (5-FU)-based chemotherapy in patients with advanced gastric cancer (AGC) as first-line treatment, we performed this meta-analysis of all eligible randomized controlled trials (RCTs). A comprehensive literature search of electronic databases (up to February 20, 2014) was performed. Additionally, abstracts presented at the American Society of Clinical Oncology (ASCO) conferences held between January 2000 and February 2014 were searched to identify relevant trials. Overall response rate (ORR), time to treatment failure (TTF), overall survival (OS), and grade 3 or 4 toxicities were analyzed. Six RCTs with 2,264 patients of AGC were included. Meta-analysis demonstrated that S-1-based therapy was associated with better OS compared with 5-FU-based therapy (hazard ratio (HR) = 0.80, 95 % confidence interval (CI) 0.80-0.99, P = 0.03). Pooled estimate has showed the trend of superiority of S-1-based therapy in the aspect of ORR (odds ratio (OR) = 1.55, 95 % CI 0.87-2.77, P = 0.14) and TTF (HR = 0.73, 95 % CI 0.53-1.00, P = 0.05), but the difference was not significant. The incidence of toxicities of 5-FU-based regimens was significantly higher for thrombocytopenia (OR = 0.60, 95 % CI 0.42-0.88, P = 0.008) and stomatitis (OR = 0.22, 0, 95 % CI 0.05-0.9, P = 0.03). Based on the published studies, S-1-based therapy was superior to 5-FU-based therapy in OS and safety profile as first-line treatment in AGC. It was prone to improving ORR and TTF, though the difference was not significant. More high-quality randomized controlled trials should be performed to provide more information in comparing these two regimens.

[K-RAS gene mutations in patients with non-small cell lung cancer].

BACKGROUND AND OBJECTIVE: Recent studies indicated that Non-small cell lung cancer (NSCLC) patients with mutant K-RAS failed to benefit from adjuvant chemotherapy, and the cancer did not respond to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). These findings indicated that K-RAS gene status can be a biomarker to predict the sensitivity of EGFR TKIs. The aim of this study is to analyze K-RAS gene mutations with NSCLC patients in Cancer Center of Sun Yet-sen University. METHODS: 52 fresh frozen tumor tissues were collected and K-RAS genes were amplified by PCR. Then PCR amplification fragments were sequenced and analyzed. RESULTS: Somatic mutations in the codon 12 of K-RAS gene in tumors were identified from 2 of 52 (3.8%) patients. There were no relationships among K-RAS gene mutations and gender, pathology, smoking, differentiation and stage. CONCLUSION: The frequency of K-RAS gene mutations with NSCLC in our center is very low and is similar to that in Asia patients, and is lower than that in Caucasian population.

[Efficacy of gefitinib on advanced non-small cell lung cancer in expanded access program (EAP)].

BACKGROUND & OBJECTIVE: Gefitinib is a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, and has been used in treating advanced non-small cell lung cancer (NSCLC). This study was to evaluate the efficacy of Gefitinib on advanced NSCLC, and observe adverse events. METHODS: An open labeled, expanded access program (EAP) was conducted. Pathologically confirmed advanced NSCLC patients who had progressed after systemic chemotherapy or was not suitable for systemic chemotherapy were eligible for this program. Gefitinib (250 mg) was orally administered daily till disease progression or intolerable adverse events developed. RESULTS: From Sep. 2002 to Mar. 2005, 120 patients were enrolled, and 103 of them were assessable for response. The objective response rate was 18.4% (19/103). The disease control rate was 51.5% (53/103). The median survival time was 6 months (0.5-33 months). Adverse events were generally mild (grade I or II), including skin rash (30.1%), dry skin (12.6%), and diarrhea (25.2%). Two (1.9%) patients developed grade III elevation of serum glutamate pyruvate transaminase (SGPT). No grade IV adverse event occurred. CONCLUSION: Gefitinib is effective in treating advanced NSCLC, and the adverse events are mild.

[Tissue microarray analysis of HER2 protein expression in patients with non-small cell lung cancer].

BACKGROUND: Tissue microarray provides a high throughput tool for protein analysis . The aim of this study is to test the expression of HER2 protein in non-small cell lung cancer (NSCLC) by tissue microarray, and analyze the relationship between HER2 protein expression and chemotherapeutic response rate and survival. METHODS: Using tissue microarray, HER2 protein expression was detected in patients with advanced NSCLC by immunohistochemistry. RESULTS: Total 80 patients were enrolled in the study. Only 74 patients could be reviewed for HER2 staining. The response rate to chemotherapy in positive and negative HER2 expression groups was 39.1% and 51.0% respectively (P=0.345). The survival difference was also not significant between the positive and negative HER2 protein expression groups (P= 0.437 ). CONCLUSIONS: The combination of tissue microarray and immunohistochemistry represents a highly feasible technique for examination of HER2 protein expression in NSCLC. There is no significant difference in survival between positive and negative HER2 expression groups. The role of HER2 protein in NSCLC should be further studied.

[Epidermal growth factor receptor mutation in Chinese patients with non-small cell lung cancer].

BACKGROUND & OBJECTIVE: Recent studies showed that somatic mutations in epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain are associated with sensitivity of non-small cell lung cancer(NSCLC) to TK inhibitor gefitinib. The mutations, including in-frame deletions at exon 19 and substitutions at exon 18 or exon 21, cluster around ATP-binding pocket of TK domain. The frequency of mutations are higher in Japanese patients than in American patients. This study was to analyze EGFR mutations in Chinese patients with NSCLC. METHODS: From Jun. to Oct. 2004, fresh specimens of lung cancer and corresponding normal lung tissue were collected from 52 consecutive NSCLC patients (39 men and 13 women) treated in Cancer Center of Sun Yat-sen University. All patients had not received treatment of gefitinib. DNA was extracted from the 52 specimens. Exons 19 and 21 were amplified by polymerase chain reaction (PCR), and sequenced and analyzed from both sense and antisense directions. RESULTS: Somatic mutations in TK domain of EGFR in tumors were identified from 10 of the 52 (19.2%) patients, including 7 cases of in-frame deletion in exon 19 and 3 cases of amino acid substitution in exon 21. Mutation rate was significantly higher in adenocarcinoma, adeno-squamous carcinoma, and bronchioloalveolar cancer than in squamous cell carcinoma [26.1% (6/23), 40.0% (2/5), and 50.0% (2/4) vs. 0 (0/20), P=0.025], and significantly higher in non-smokers than in smokers [41.8% (7/17) vs. 8.6% (3/35), P=0.009]. Mutation rate in women was similar to that in men [23.1% (3/13) vs. 18.0% (7/39), P=0.697]. CONCLUSION: EGFR mutation rate in Chinese NSCLC patients is similar to that in Japanese patients, and is obviously higher than that in Caucasian population.

[Gemcitabine plus cisplatin versus gemcitabine plus vinorelbine in treatment of advanced non-small cell lung cancer (NSCLC)].

BACKGROUND & OBJECTIVE: Although platin-based chemotherapy has become a standard treatment for non-small cell lung cancer (NSCLC), its severe toxicities limit clinical application, and a new replacement is required. The study was to evaluate the efficacy, survival rate and toxicity between the combination of gemcitabine and cisplatin (GP arm) and the combination of gemcitabine and vinorelbine (GN arm) in the treatment of advanced NSCLC. METHODS: Eighty-two patients with locally advanced or metastatic NSCLC were enrolled into this study. 42 patients and 40 patients were randomized into GP group and GN group respectively. The patients' characteristics were similar between the two groups. They were treated with gemcitabine (1 000 mg/m(2) d(1), d(8)) plus cisplatin (80 mg/m(2), d(1)) in GP group, or gemcitabine plus vinorelbine (25 mg/m(2) d(1), d(8)) in GN group. The chemotherapy was repeated every 3 weeks as a cycle. Every patient was treated two cycles at least. RESULTS: An objective response rate of 28.6% was observed in GP arm versus 25% in GN arm (P=0.346). The 1-year survival rate was 64% in GP arm and 66% in GN arm. The median survival time was 9.87 months for GN arm and 8.78 months for GP arm. Nausea and vomiting were the major dose-limiting toxicity. The incidence of grade III/IV nausea and vomiting was significantly higher in the GP arm than in the GN arm (P=0.000). The Leukopenia incidence was similar in two groups (P=0.130). CONCLUSION: The efficacy of GN regimen (platinum-free regimen) was similar to that of GP regimen, but the toxicity of GN regimen is lighter than that of GP regimen.