Xinmin Yu

Salvage treatment with apatinib for advanced non-small-cell lung cancer

Objective No definitive chemotherapeutic regimen has been established in patients with non-small-cell lung cancer (NSCLC) who failed second- or third-line treatment. The aim of this study was to evaluate apatinib, a VEGFR-2 inhibitor, in advanced NSCLC as salvage treatment. Methods We evaluated the efficacy and toxicity of apatinib in patients with previously treated advanced NSCLC from 2014 to 2015 in Zhejiang Cancer Hospital. Survival analysis was performed by the Kaplan–Meier method. Results Forty-two patients were included in the present study. Four patients achieved partial response, and 22 achieved stable disease, representing a response rate of 9.5% and a disease control rate of 61.9%. Median progression-free survival and overall survival were 4.2 and 6.0 months, respectively. The toxicities associated with apatinib were generally acceptable with a total grade 3/4 toxicity of 50%. Conclusion Apatinib appears to have some activity against advanced NSCLC when utilized as salvage treatment.

Re-administration after the failure of gefitinib or erlotinib in patients with advanced non-small cell lung cancer

OBJECTIVE Few treatment options are available for advanced non-small cell lung cancer (NSCLC) patients who have failed of gefitinib or erlotinib treatment in second/third-line treatment. The aim of this study was to investigate the efficacy of re-administration of the same TKI after failure of gefitinib or erlotinib. PATIENTS AND METHODS The clinical data of 33 patients with advanced NSCLC were retrospectively analyzed. All of the patients were given the same TKI treatment after the failure of gefitinib or erlotinib. Survival analysis was evaluated by Kaplan-Meier method. RESULTS Twenty patients (60.6%) were re-administration with gefitinib as the 2(nd) EGFR-TKI, and thirteen patients (39.4%) received erlotinib. One patient (3.0%) showed partial response (PR), 14 (42.4%) achieved stable disease (SD), and 18 (54.5%) had progressive disease (PD). The disease control rate was 45.5% and the median progression-free survival was 1.5 months (95% CI: 0.6-2.3 months). The PFS in patients who got disease control in the prior TKI was 2.2 and 1.2 months in the progression disease cases (P=0.29), the DCR was 54.5% and 27.3% in two group, respectively (P=0.26). CONCLUSIONS Re-administration of TKI seems to be a potential therapeutic option for treatment of selected advanced NSCLC patients after failure of gefitinib or erlotinib, especially for the patients with NSCLC who once responded from the prior TKI treatment.

Clinicopathologic characteristics, genetic variability and therapeutic options of RET rearrangements patients in lung adenocarcinoma.

BACKGROUND RET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer (NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients. PATIENTS AND METHODS For 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases. Thymidylate synthetase (TS) mRNA level was assayed by RT-PCR. Overall survival (OS) was evaluated by Kaplan-Meier method and compared with log-rank test. RESULTS Twelve RET-positive patients were identified by RT-PCR. However, one patient failed the detection of RET rearrangement by FISH and NGS. Totally, 11 patients (1.8%) confirmed with RET rearrangements by three methods, including six females and five males with a median age of 54 years. The presence of RET rearrangements was associated with lepidic predominant lung adenocarcinoma subtype in five of 11 patients. RET rearrangements comprised of nine KIF5B-RET and two CCDC6-RET fusions. Four patients had concurrent gene variability by NGS detection,including EGFR(n=1),MAP2K1 (n=1), CTNNB1 (n=1) and AKT1 (n=1). No survival difference existed between RET-positive and negative patients (58.1 vs. 52.0 months, P=0.504). The median progression-free survival of first-line pemetrexed/platinum regimen was 7.5 months for four recurrent cases. And the level of TS mRNA was lower in RET-positive patients than that in those RET-negative counterparts (239±188×10-4 vs. 394±457×10-4, P=0.019). CONCLUSION The prevalence of RET fusion is approximately 1.8% in Chinese patients with lung adenocarcinoma. RET rearrangements are characterized by lepidic predominance and a lower TS level. RET-rearranged patients may benefit more from pemetrexed-based regimen.

Clinicopathological characteristics and survival of ALK, ROS1 and RET rearrangements in non-adenocarcinoma non-small cell lung cancer patients

ABSTRACT Background: ALK, ROS1 and RET rearrangements represent 3 most frequent fusion genes in non-small cell lung cancer (NSCLC). Rearrangements of these 3 genes exist predominantly in lung adenocarcinoma while rarely in non-adenocarcinoma. Our objective was to explore the frequency, clinicopathological characteristics and survival of ALK, ROS1 and RET rearrangements in non-adenocarcinoma NSCLC patients. Methods: ALK, ROS1 and RET rearrangements were screened by reverse transcriptase polymerase chain reaction (RT-PCR) in patients with completely resected non-adenocarcinoma NSCLC. All positive samples were confirmed with fluorescence in situ hybridization (FISH). Survival analysis was performed with Kaplan-Meier method and log-rank for comparison. Results: A total of 385 patients underwent complete resection, including squamous cell carcinoma (n = 245), adenosquamous carcinoma (n = 85) and large cell carcinoma (n = 55). Twelve of them were identified as harboring fusion genes, including ALK (n = 7), ROS1 (n = 3) and RET (n = 2) rearrangements. The fusion frequencies of adenosquamous, squamous cell and large cell carcinomas were 8.2%, 1.6% and 1.8% respectively. Their median age was 49.5 y and 3 of them had a smoking history. No survival difference existed between fusion gene positive and negative patients (36.7 vs.50.2 months, P = 0.21). Conclusion: The frequencies of ALK, ROS1 and RET rearrangements are low in non-adenocarcinoma NSCLC patients. And their clinical characteristics are similar to those in lung adenocarcinoma. Fusions of the above 3 genes are not prognostic factor for non-adnocarcinoma NSCLC patients.

Mutation and prognostic analyses of PIK3CA in patients with completely resected lung adenocarcinoma.

PIK3CA mutation represents a clinical subset of diverse carcinomas. We explored the status of PIK3CA mutation and evaluated its genetic variability, treatment, and prognosis in patients with lung adenocarcinoma. A total of 810 patients with completely resected lung adenocarcinoma were recruited between 2008 and 2013. The status of PIK3CA mutation and other three genes, that is, EGFR mutation, KRAS mutation and ALK fusion were examined by reverse transcription‐polymerase chain reaction (RT‐PCR). Survival curves were plotted with the Kaplan–Meier method and log‐rank for comparison. Cox proportional hazard model was performed for multivariate analysis. Among the 810 patients, 23 cases of PIK3CA mutation were identified with a frequency of 2.8%. There were 14 men and 9 women with a median age of 61 years. Seventeen tumors revealed concurrent gene abnormalities of EGFR mutation (n = 12), KRAS mutation (n = 3), and ALK fusion (n = 2). Seven patients with EGFR & PIK3CA mutations recurred and administrated of EGFR‐TKIs yielded a median progression free‐survival of 6.0 months. Among four eviromous‐treated patients, stable disease was observed in three patients with a median Progression‐free survival (PFS) of 3.5 months. Patients with and without PIK3CA mutation had different overall survivals (32.2 vs. 49.6 months, P = 0.003). Multivariate analysis revealed that PIK3CA mutation was an independent predictor of poor overall survival (HR = 2.37, P = 0.017). The frequency of PIK3CA mutation was around 2.8% in the Chinese patients of lung adenocarcinoma. PIK3CA mutation was associated with reduced PFS of EGFR‐TKIs treatment and shorter overall survival.

Rare frequency of gene variation and survival analysis in thymic epithelial tumors

Objective Thymic epithelial tumor (TET) is a rare mediastinal neoplasm and little is known about its genetic variability and prognostic factors. This study investigated the genetic variability and prognostic factors of TET. Patients and methods We sequenced 22 cancer-related hotspot genes in TET tissues and matched normal tissues using Ampliseq Ion Torrent next-generation technology. Overall survival was evaluated using Kaplan–Meier methods and compared with log-rank tests. Results A histological analysis of 52 patients with a median age of 52 years showed 15 patients (28.8%) with thymic carcinoma, five with type A thymoma (9.6%), eight with type AB (15.4%), six with type B1 (11.5%), nine with type B2 (17.3%), and nine with type B3 thymoma (17.3%). Three gene mutations were identified, including two with PIK3CA mutation and one with EGFR mutation. The three patients with mutant genes included two cases of thymoma (one with EGFR and the other with PIK3CA mutation) in addition to a case of thymic carcinoma (PIK3CA mutation). The 5-year survival rates were 77.7% in all patients. The 5-year survival rates were 93.3%, 90.0%, 76.9%, and 22.9% corresponding to Masaoka stages I, II, III, and IV (P<0.001). The 5-year survival rates were 100%, 100%, 83.3%, 88.9%, 65.6%, and 60.9% in the histological subtypes of A, AB, B1, B2, and B3 thymomas, and thymic carcinoma, respectively (P=0.012). Conclusion Hotspot gene mutations are rare in TET. PIK3CA and EGFR mutations represent candidate driver genes and treatment targets in TET. Masaoka stage and histological subtypes predict the survival of TET.

Chemotherapy and prognosis in advanced thymic carcinoma patients

OBJECTIVE: The role of chemotherapy in treating advanced thymic carcinoma is unclear. The purpose of the current study was to investigate the efficacy of chemotherapy and the prognostic factors for patients with advanced thymic carcinoma. METHODS: A retrospective review of the medical records of 86 patients treated with chemotherapy for advanced thymic carcinoma was conducted between 2000 and 2012 at our institution. The clinical characteristics, chemotherapy regimens and prognostic factors were analyzed. Survival curves were plotted using the Kaplan–Meier method and the Cox proportional hazard model was used for multivariate analysis. RESULTS: Of the 86 patients, 56 were male and 30 were female. The median survival time was 24.5 months. For the first-line chemotherapy treatment, the objective response rate was 47.7% and the disease control rate was 80.2%. The median progression-free survival for all patients was 6.5 months for first-line chemotherapy. No significant differences in progression-free survival were observed among the different chemotherapy regimens. Multivariate analyses revealed that the prognostic factors for overall survival included performance status (p=0.043), histology grade (p=0.048), and liver metastasis (p=0.047). CONCLUSION: Our results suggest that there is no difference in efficacy between multiagent and doublet regimens. The prognosis of patients with advanced thymic carcinoma can be predicted based on histological grade, liver metastasis and performance status.

Docetaxel-based chemotherapy as second-line regimen for advanced thymic carcinoma

Thymic carcinoma is an uncommon neoplasm. The efficacy of second‐line treatment with docetaxel in advanced thymic carcinoma has not been well studied. Therefore, we conducted a review of the efficacy of docetaxel‐based chemotherapy as a second‐line regimen for advanced thymic carcinoma. Fifteen patients with advanced thymic carcinoma who received second‐line chemotherapy with docetaxel singlet or docetaxel/platinum combination chemotherapy regimens were retrospectively reviewed. There were 11 males and four females, with a median age of 53 years. Squamous cell carcinoma was most common (n = 10), followed by undifferentiated carcinoma (n = 4), and small cell carcinoma (n = 1). Eight patients received docetaxel/platinum combination chemotherapy and seven docetaxel mono‐therapy. Four patients showed partial responses, representing a response rate of 26.7%. The median progression‐free survival and overall survival in the 15 patients were 4.0 (2.8–5.2) and 22.0 (14.6–29.4) months, respectively. There was no difference in progression‐free survival between the docetaxel singlet or docetaxel/platinum combination chemotherapy (3.5 months vs. 4.0 months, P = 0.889). A docetaxel‐based regimen could be a potential therapeutic option as a second‐line chemotherapy for advanced thymic carcinoma.

Mechanisms of primary resistance to EGFR targeted therapy in advanced lung adenocarcinomas

INTRODUCTION Increasing evidence leads to a ratiocination that genetic heterogeneity of the lung adenocarcinoma with EGFR mutations may impact clinical responses and outcomes to EGFR tyrosine kinase inhibitor (TKI) treatments. METHODS We performed genetic profiling of pre-treatment samples of 69 lung adenocarcinoma patients, including tumor FFPE and cell-free DNA (cfDNA), targeting 416 cancer-related genes using next generation sequencing. We analyzed mutation concordance across sample types and investigated potential mechanisms that confer primary resistance to EGFR-TKIs in patients with short progression-free survival (PFS) versus those with long PFS. RESULTS We detected a total of 200 actionable genetic alterations (mean: 2.9 variants/patient, range: 1-7 variants) in tumor FFPE and 140 actionable genetic alterations (mean: 2.0 variants/patient, range: 0-5 variants) in matched cfDNA, respectively. All patients had EGFR TKI-sensitizing mutations, including EGFR Ex19del, L858R, G719S/C, and L861Q. Concurrent TP53 mutations were most commonly observed in 72.5% of patients, followed by EGFR amplification (20.3%), RB1 (10.1%), PIK3CA (7.2%), and MYC (5.8%). For EGFR activating mutations, the concordance rate was 88.2% between cfDNA and FFPE samples. Furthermore, we identified genes that potentially confer primary resistance to EGFR-TKIs including CDC73, SMAD4, RB1 and PIK3CA. We also report signaling pathways enriched in patients with TKI primary resistance. CONCLUSIONS We note the genetic complexity and heterogeneity of EGFR-mutated lung adenocarcinoma and underscore that mutation status is highly concordant between tumor FFPE and cfDNA samples. This study also highlights the alterations that potentially confer primary resistance to EGFR TKI treatments in patients who demonstrated short PFS.

HER2 mutations in Chinese patients with non-small cell lung cancer

Background ERBB2 (HER2) is a driver gene identified in non-small cell lung cancer (NSCLC). The prevalence, clinicopathology, genetic variability and treatment of HER2-positive NSCLC in Chinese population are unclear. Patients and Methods Eight hundred and fifty-nine patients with pathologically confirmed NSCLC were screened for HER2 mutations using Sanger sequencing. Next-generation sequencing (NGS) was performed in positive cases. HER2 amplification was detected with FISH. Overall survival (OS) was evaluated using Kaplan-Meier methods and compared with log-rank tests. Results Twenty-one cases carrying HER2 mutations were identified with a prevalence of 2.4%. HER2 mutations were more frequently encountered in females, non-smokers and adenocarcinoma. NGS was performed in 19 out of 21 patients, The results showed 16 cases with additional genetic aberrations, most commonly associated with TP53 (n = 6), followed by EGFR (n = 3), NF1 (n = 3), KRAS (n = 2) and other mutations. One patient harbored HER2 amplification. Four patients with stage IV received afatinib treatment, and three showed stable disease with a median progression-free survival of 4 months and one patient was diagnosed with progressive disease. Conclusion HER2 mutations represent a distinct subset of NSCLC. NGS showed that HER2 mutations commonly co-existed with other driver genes. Afatinib treatment displayed moderate efficacy in patients with HER2 mutations.