PIK3CA Mutations in Resected Small Cell Lung Cancer.

BACKGROUND: Despite advances in chemotherapy and radiotherapy in recent decades, the prognosis for small cell lung cancer (SCLC) patients is still poor. Targeted therapies in SCLC must be applied systemically to target not only the primary tumor but also metastases. The phosphatidylinositol 3-kinase (PI3K)/AKT pathways play a key regulatory function in the survival, proliferation, energy metabolism and cellular architecture advantages of malignant cells. The phosphatidylinositol 3-kinase catalytic α (PIK3CA) gene, which encodes the p110α catalytic subunit, plays a key role in the activation of AKT downstream signaling and mammary tumor progression. More than 75% of PIK3CA mutations are clustered in the helical (exon 9) and catalytic domains (exon 20). There have been very few studies reporting the PIK3CA mutations status of patients with SCLC who have undergone surgical treatment in mainland China. OBJECTIVES: The aim of the study was to investigate the PIK3CA mutation in SCLC. MATERIAL AND METHODS: Reverse transcription polymerase chain reaction (RT-PCR) and direct sequencing technology was used to detect the PIK3CA mutation in 14 cases of retrospectively collected SCLC patients who underwent surgical treatment at Zhejiang Cancer Hospital, Hangzhou, PRC, between 2002 and 2010. RESULTS: The research revealed no mutations in exons 9 and 20 of the PIK3CA gene. A nucleotide alteration of A1634C (E545A) of exon 9 turned out to be a pseudogene-positive, because the mutation disappeared when near-duplicate detection was employed. CONCLUSIONS: The incidence of PIK3CA mutation is low in SCLC patients, and the pseudogene-positive alteration of A1634C is prone to occur in exon 9 of PIK3CA mutations in human cancers.

Identifying EGFR mutations from SCLC patient plasma by mutant-enriched liquidchip technology.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) such as erlotinib and gefitinib are targeted drugs for the kinase domain of EGFR. They are widely used for the treatment of non-small cell lung cancer (NSCLC). The EGFR exon 19 deletion mutation and the L858R mutation in exon 21 comprise approximately 90% of the somatic mutations in NSCLC patients that respond to EGFR TKI. Several recent studies have also reported that small cell lung cancer (SCLC) patients with EGFR mutations responded to gefitinib. Further study, however, has been limited due to the difficulty obtaining tumor specimens from SCLC patients. OBJECTIVES: The aim of this study was to explore the EGFR mutation status in SCLC patients by plasma analysis. MATERIAL AND METHODS: Plasma samples from SCLC patients were collected for mutant-enriched liquidchip (MEL) analysis to identify the EGFR mutations in exon 19 and 21. RESULTS: The exon 19 deletion mutation was detected in one out of 35 patients (a female non-smoker). No exon 21 mutations were found. CONCLUSIONS: A prevalence of EGFR mutations in SCLC is rare, and occurs most frequently in females and nonsmokers.

Expression and mutation of the c-kit gene and correlation with prognosis of small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive and lethal type of cancer in humans. SCLC is sensitive to chemotherapy and radiotherapy, but long-term survival is low and the majority of patients eventually develop progressive disease. With the success of imatinib mesylate in the treatment of gastrointestinal stromal tumors expressing c-kit, its use in SCLC serves as a novel molecular therapeutic approach. The activity of imatinib mesylate is correlated with the mutation of c-kit gene exons 9 and 11 in gastrointestinal stromal tumors. The incidence of epidermal growth factor receptor mutation in non-small cell lung cancer is higher in China than in the United States of America and European countries. There may be also differences in the incidence of c-kit mutation between China and European countries. At present, no study examining imatinib mesylate treatment for SCLC in China is available. To investigate the expression and mutation of c-kit and the correlation with prognosis of SCLC in China, immunohistochemistry was used to detect the expression of c-kit, and a pyrosequencing assay was used to detect mutations in c-kit exons 9 and 11 of 36 SCLC patients who received surgical treatment at the Zhejiang Cancer Hospital, Hangzhou, China, between 1998 and 2010. All 36 patients were followed up to analyze the correlation between prognosis and expression and mutation of c-kit. The incidence of c-kit-positive expression was 83.3%, including 25.0% weak staining, 22.2% moderate staining and 36.1% strong staining. The overall survival of patients with c-kit strong staining was shorter compared to patients with c-kit not strong staining. No mutation in c-kit exons 9 and 11 was detected. In conclusion, the findings showed that the expression of c-kit is high, and strong staining is a prognostic factor for worse survival.

Mutation status of epidermal growth factor receptor and clinical features of patients with combined small cell lung cancer who received surgical treatment.

The mutation status of epidermal growth factor receptor (EGFR) is correlated with the response of tumors to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), suggesting its usefulness as a biomarker in NSCLC. The incidence of EGFR mutation in NSCLC is higher in China than in the United States and European countries. There have been some case reports concerning cases of gefitinib-responsive small cell lung cancer (SCLC) with EGFR mutations. However, few large studies concerning the mutation status of SCLC patients have been performed. We detected EGFR mutations in exons 19 and 21 of 40 SCLC patients, three of whom had combined SCLC, from the Zhejiang Cancer Hospital using xTAG technology. Only two patients with combined SCLC had an EGFR mutation in exon 19. To determine the EGFR mutation status and clinical features of combined SCLC, we retrospectively analyzed the clinical features of seven patients with combined SCLC who had undergone surgical treatment in Zhejiang Cancer Hospital between 2007 and 2010. EGFR mutations in exons 19 and 21 were detected using the pyrosequencing assay. Of the seven patients with combined SCLCs, 71.4% were male, 71.4% were heavy smokers, most were over 60 years old and 71.4% of the cases were combined adenocarcinoma. Chemotherapy treatment and tumor stage were correlated with survival time. Of the seven cases, one had a mutation in exon 19 of EGFR in both the conventional SCLC and SCLC combined adenocarcinoma components. Combined SCLC commonly occurs in patients who are heavy smokers, male and over 60 years old, and most of the combined type cases are adenocarcinoma. The treatment of combined SCLC may be applied to cases of conventional SCLC. EGFR mutations may therefore occur in combined SCLCs, especially in SCLC combined adenocarcinoma in China.

Identification of serum protein markers for breast cancer relapse with SELDI-TOF MS.

Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to screen serum samples to identify protein markers for early breast cancer relapse. We collected 67 serum samples from patients with breast cancer (24 preoperative; 23 postoperative without breast cancer relapse; 20 postoperative with breast cancer relapse). Eight protein peaks varied between the presurgical group and the postsurgical group without breast cancer relapse; 4 protein peaks were differentially expressed between the postsurgical patients without relapse and patients with relapse. The peak at 3964 m/z dropped after surgery and rebounded after relapse (P < 0.01). These results indicate that there are differences in serum protein expression among the three different groups of patients. SELDI-TOF MS could be used to screen blood samples for the early detection of relapse in primary breast cancer patients. Specifically, protein peak at 3964 m/z is a potential biomarker for the detection of early breast cancer relapse.

Recursive partitioning analysis classification and graded prognostic assessment for non-small cell lung cancer patients with brain metastasis: a retrospective cohort study.

OBJECTIVE: To assess prognostic factors and validate the effectiveness of recursive partitioning analysis (RPA) classes and graded prognostic assessment (GPA) in 290 non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). METHODS: From Jan 2008 to Dec 2009, the clinical data of 290 NSCLC cases with BM treated with multiple modalities including brain irradiation, systemic chemotherapy and tyrosine kinase inhibitors (TKIs) in two institutes were analyzed. Survival was estimated by Kaplan-Meier method. The differences of survival rates in subgroups were assayed using log-rank test. Multivariate Cox's regression method was used to analyze the impact of prognostic factors on survival. Two prognostic indexes models (RPA and GPA) were validated respectively. RESULTS: All patients were followed up for 1-44 months, the median survival time after brain irradiation and its corresponding 95% confidence interval (95% CI) was 14 (12.3-15.8) months. 1-, 2- and 3-year survival rates in the whole group were 56.0%, 28.3%, and 12.0%, respectively. The survival curves of subgroups, stratified by both RPA and GPA, were significantly different (P<0.001). In the multivariate analysis as RPA and GPA entered Cox's regression model, Karnofsky performance status (KPS) ≥ 70, adenocarcinoma subtype, longer administration of TKIs remained their prognostic significance, RPA classes and GPA also appeared in the prognostic model. CONCLUSION: KPS ≥70, adenocarcinoma subtype, longer treatment of molecular targeted drug, and RPA classes and GPA are the independent prognostic factors affecting the survival rates of NSCLC patients with BM.