PURPOSE To assess the benefits of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advanced EGFR mutation-positive non–small-cell lung cancer. PATIENTS AND METHODS This was a multicenter (17 centers in China), open-label, phase II, randomized controlled trial of erlotinib versus gemcitabine plus cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with stage IIIA-N2 non–small-cell lung cancer with EGFR mutations in exon 19 or 21 (EMERGING). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days; adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75 mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles). Assessments were performed at 6 weeks and every 3 months postsurgery. The primary end point was objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete response, progression-free survival (PFS), overall survival, safety, and tolerability. RESULTS Of 386 patients screened, 72 were randomly assigned to treatment (intention-to-treat population), and 71 were included in the safety analysis (one patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84; P = .092). No pathologic complete response was identified in either arm. Three (9.7%) of 31 patients and zero of 23 patients in the erlotinib and GC chemotherapy arms, respectively, had a major pathologic response. Median PFS was significantly longer with erlotinib (21.5 months) versus GC chemotherapy (11.4 months; hazard ratio, 0.39; 95% CI, 0.23 to 0.67; P < .001). Observed adverse events reflected those most commonly seen with the two treatments. CONCLUSION The primary end point of ORR with 42 days of neoadjuvant erlotinib was not met, but the secondary end point PFS was significantly improved.

Our results suggest that chemotherapy may reduce EGFR mutation frequency in patients with NSCLC, likely the result of a preferential response of subclones with EGFR mutations in tumors with heterogeneous tumor cell populations.

Osteosarcoma is the most common primary bone malignancy, and the lung is the most frequent site of metastasis. The limited understanding of the tumoral heterogeneity and evolutionary process of genomic alterations in pulmonary metastatic osteosarcoma impedes development of novel therapeutic strategies. Here we systematically illustrate the genomic disparities between primary tumors and corresponding pulmonary metastatic tumors by multiregional whole-exome and whole-genome sequencing in 86 tumor regions from 10 patients with osteosarcoma. Metastatic tumors exhibited a significantly higher mutational burden and genomic instability compared with primary tumors, possibly due to accumulation of mutations caused by a greater number of alterations in DNA damage response genes in metastatic tumors. Integrated analysis of the architecture and relationships of subclones revealed a dynamic mutational process and diverse dissemination patterns of osteosarcoma during pulmonary metastasis (6/10 with linear and 4/10 with parallel evolution-ary patterns). All patients demonstrated more significant intertumoral rather than intratumoral heterogeneity between primary tumors and metastatic tumors. Mutated genes were enriched in the PI3K-Akt pathway at both the early and late stages of tumor evolution and in the MAPK pathway at the metastatic stage. Conversely, metastatic tumors showed improved immunogenicity, including higher neoantigen load, elevated PD-L1 expression, and tumor-infiltrating lymphocytes than the corresponding primary tumors. Our study is the first to report the dynamic evolutionary process and temporospatial tumor heterogeneity of pulmonary metastatic osteosarcoma, providing new insights for diagnosis and potential therapeutic strategies for pulmonary metastasis.Significance: High-throughput sequencing of primary and metastatic osteosarcoma provides new insights into the diagnosis of and potential clinical therapeutic strategies for pulmonary metastasis.

Objective. To estimate the prevalence of radiographic and symptomatic knee osteoarthritis (OA) in a remote rural region of northern China, and compare them with those reported in Beijing and with data from the Framingham (Massachusetts) cohort. Methods. A population-based cross-sectional survey was conducted among 1,030 residents of Wuchuan County, Inner Mongolia, age >50 years. Survey participants, mostly farmers reporting heavy physical occupational activity, completed an interviewer-based questionnaire, and bilateral weight-bearing posteroanterior semiflexed knee radiographs were obtained. Results. Whereas the overall prevalence of radiographic knee OA was similar to that demonstrated in the Beijing OA study, men in Wuchuan had approximately double the prevalence of severe radiographic knee OA (prevalence ratio [PR] 2.5, 95% confidence interval [95% CI] 1.6 -3.8) and symptomatic knee OA (PR 1.9, 95% CI 1.3-2.9). Women in Wuchuan also had a higher prevalence of both severe radiographic (PR 1.4, 95% CI 1.0 -2.0) and symptomatic knee OA (PR 1.6, 95% CI 1.2-2.1) compared with their Beijing counterparts. The prevalence of bilateral OA and lateral compartment disease were 2-3 times higher in both Chinese cohorts compared with estimates from the Framingham OA study. Conclusion. The prevalence of symptomatic knee OA in rural areas of China is much higher than reported from urban regions of China or in the Framingham cohort. The higher representation of bilateral and lateral compartment disease in China suggests a unique phenotype to OA. These findings will be useful for guiding the distribution of future health care resources and preventive strategies.

Analysis of circulating tumor DNA (ctDNA) is emerging as a powerful tool for guiding targeted therapy and monitoring tumor evolution in patients with non-small cell lung cancer (NSCLC), especially when representative tissue biopsies are not available. Here, we have compared the ability of four leading technology platforms to detect epidermal growth factor receptor (EGFR) mutations (L858R, exon 19 deletion, T790M and G719X) in ctDNA from NSCLC patients. Two amplification refractory mutation systems (cobas-ARMS and ADx-ARMS), a droplet digital polymerase chain reaction (ddPCR) and a next-generation sequencing (Firefly NGS) platform were included in the comparison. Fifteen EGFR mutations across twenty NSCLC patients were identified. Firefly NGS, cobas-ARMS and ddPCR all displayed superior sensitivity while ADx-ARMS was better suited for the qualitative detection of EGFR mutations with allele frequency higher than 1% in plasma and tissue samples. We observed high coincidence between the plasma and tissue EGFR mutational profiles for three driver mutations (L858R, exon 19 deletion and G719X) that are known targets of first generation EGFR-TKI therapies among patients who relapsed. Discrepancies between tissue and plasma EGFR mutational profiles were mainly attributable to spatial and temporal tumor heterogeneity, mutation inhibition due to therapy response and drug resistance (T790M). This study illustrates the challenges associated with selection of a technology platform for EGFR ctDNA analysis in the context of treatment evaluation and drug resistance detection.