Pulmonary ground-glass nodules (GGNs) include both malignant and benign lesions. Some GGNs become larger, whereas others remain unchanged for years. We have previously reported that smoking history ...and large diameters are predictors for growth. However, the genetic differences among GGNs remain unclear.
GGNs with ground-glass component of ≥50% on a thin-section computed tomography scan that were resected between 2012 and 2014 were evaluated for clinicopathological features and the presence of EGFR/KRAS/ALK/HER2 mutations. ‘Incidence of 2-mm growth’ and ‘Time to 2-mm growth’ were analyzed according to the mutational status.
Among 104 GGNs in 96 patients, this study included 3 atypical adenomatous hyperplasia (AAH), 19 adenocarcinoma in situ (AIS), 27 minimally invasive adenocarcinoma (MIA), and 55 invasive adenocarcinoma (IA). Among the 71 lesions evaluable for growth, 30 GGNs exhibited growth and 5 lesions remained unchanged for ≥2 years before surgery was carried out. We identified mutations or rearrangements in 75% of GGNs (78/104). EGFR mutations were noted in 64% of samples, KRAS in 4%, ALK in 3%, and HER2 in 4%. The remaining 26 quadruple-negative tumors were significantly associated with AAH/AIS (P < 0.01) and no-growth (P < 0.01) compared with driver mutation-positive tumors, whereas EGFR mutation-positive tumors were correlated with MIA/IA (P < 0.01) and growth (P < 0.01) compared with EGFR-negative tumors.
Three fourths of resected GGNs were positive for EGFR, KRAS, ALK, or HER2 mutations. Quadruple-negative tumors were associated with a lack of GGN growth, whereas EGFR mutation-positive tumors displayed a correlation with growth.
The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired ...resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
In cohort A, median progression-free survival (PFS) was 2.1 and 1.3months for T790M-negative and T790M-positive patients, respectively (P=0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20–1.24). Median PFS was 2.1 and 1.3months for patients with a PD-L1 expression level of≥1% or<1%, respectively (P=0.084; hazard ratio of 0.37, 95% confidence interval of 0.10–1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of≥10% and≥50%. The proportion of tumors with a PD-L1 level of≥10% or≥50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8+ TIL density and nonsynonymous mutation burden.
T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.
Epidermal growth factor receptor (EGFR) mutation is predictive for the efficacy of EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer (NSCLC) treatment. We evaluated the ...performance, sensitivity, and concordance between five EGFR tests.
DNA admixtures (n = 34; 1%–50% mutant plasmid DNA) and samples from NSCLC patients 116 formalin-fixed paraffin-embedded (FFPE) tissue, 29 matched bronchofiberscopic brushing (BB) cytology, and 20 additional pleural effusion (PE) cytology samples were analyzed. EGFR mutation tests were PCR-Invader®, peptide nucleic acid-locked nucleic acid PCR clamp, direct sequencing, Cycleave™, and Scorpion Amplification Refractory Mutation System (ARMS)®. Analysis success, mutation status, and concordance rates were assessed.
All tests except direct sequencing detected four mutation types at ≥1% mutant DNA. Analysis success rates were 91.4%–100% (FFPE) and 100% (BB and PE cytology), respectively. Inter-assay concordance rates of successfully analyzed samples were 94.3%–100% (FFPE; kappa coefficients: 0.88–1.00), 93.1%–100% (BB cytology; 0.86–1.00), and 85.0%–100% (PE cytology; 0.70–1.00), and 93.1%–96.6% (0.86–0.93) between BB cytology and matched FFPE.
All EGFR assays carried out comparably in the analysis of FFPE and cytology samples. Cytology-derived DNA is a viable alternative to FFPE samples for analyzing EGFR mutations.
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of metastatic non-small-cell lung cancer (NSCLC) ...was published in 2016. At the ESMO Asia Meeting in November 2017 it was decided by both ESMO and the Chinese Society of Clinical Oncology (CSCO) to convene a special guidelines meeting immediately after the Chinese Thoracic Oncology Group Annual Meeting 2018, in Guangzhou, China. The aim was to adapt the ESMO 2016 guidelines to take into account the ethnic differences associated with the treatment of metastatic NSCLC cancer in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with metastatic NSCLC representing the oncological societies of China (CSCO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), Singapore (SSO) and Taiwan (TOS). The voting was based on scientific evidence, and was independent of both the current treatment practices and the drug availability and reimbursement situations in the six participating Asian countries. During the review process, the updated ESMO 2018 Clinical Practice Guidelines for metastatic NSCLC were released and were also considered, during the final stages of the development of the Pan-Asian adapted Clinical Practice Guidelines.
Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical ...evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261).
Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80mg od (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS).
Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% 27/50; 95% confidence interval (CI) 39–68 and 92% (46/50; 95% CI 81–98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1–15months); at 9months, 75% (95% CI 53–88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population.
Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously.
NCT01802632; NCT02094261
Primary analysis of the phase III study WJTOG 3405 demonstrated superiority of progression-free survival (PFS) for gefitinib (G) in patients treated with the epidermal growth factor receptor ...(EGFR)-tyrosine kinase inhibitor (TKI) gefitinib compared with cisplatin plus docetaxel (CD) as the first-line treatment of stage IIIB/IV or postoperative recurrent EGFR mutation-positive non-small-cell lung cancer. This report presents final overall survival (OS) data.
Patients were randomized between G (250 mg/day orally) and cisplatin (80 mg/m2 intravenously) plus docetaxel (60 mg/m2 i.v.), administered every 21 days for three to six cycles. After the exclusion of 5 patients, 172 patients (86 in each group, modified intention-to-treat population) were included in the survival analysis. OS was re-evaluated using updated data (data cutoff, 30 September 2013; median follow-up time 59.1 months). The Kaplan–Meier method and the log-rank test were used for analysis, and hazard ratios (HRs) for death were calculated using the Cox proportional hazards model.
OS events in the G group and CD group were 68 (79.1%) out of 86 and 59 (68.6%) out of 86, respectively. Median survival time for G and CD were 34.9 and 37.3 months, respectively, with an HR of 1.252 95% confidence interval (CI): 0.883–1.775, P = 0.2070. Multivariate analysis identified postoperative recurrence and stage IIIB/IV disease as independent prognostic factors, with an HR of 0.459 (95% CI: 0.312–0.673, P < 0.001). Median survival time (postoperative recurrence versus stage IIIB/IV disease) were 44.5 and 27.5 months in the G group and 45.5 and 32.8 months in the CD group, respectively.
G did not show OS benefits over CD as the first-line treatment. OS of patients with postoperative recurrence was better than that of stage IIIB/IV disease, even though both groups had metastatic disease.
This study was registered with UMIN (University Hospital Medical Information Network in Japan), number 000000539.
A new adenocarcinoma classification was recently introduced by a joint working group of the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and ...European Respiratory Society (ERS). A distinction is made between pre-invasive lesions, and minimally invasive and invasive adenocarcinoma. The confusing term "bronchioloalveolar carcinoma" is not used any more and new subcategories include adenocarcinoma in situ and minimally invasive adenocarcinoma. Due to a renewed interest in screen-detected nodules and early-stage lung cancers of <2 cm, this classification also has profound implications for thoracic surgeons. In this article, surgical topics are discussed: the role of a minimally invasive approach, especially video-assisted thoracic surgery, limited resection for early-stage lung cancer, the extent of lymph node dissection, the accuracy of intraoperative frozen section analysis, management of multiple lung nodules and prognostic factors in operated patients. Specific key issues are presented based on the current evidence and areas of surgical uncertainty are defined providing a basis for further studies. Thoracic surgeons will play a major role in the application and global introduction of this new adenocarcinoma classification. The remaining controversies regarding the precise diagnosis and management of early-stage lesions will have to be resolved by multidisciplinary and international collaboration.
The clinical implementation of genomic profiling for lung cancer with high-throughput, multiplex tests is warranted to allow prioritization of appropriate therapies for individual patients. We have ...now applied such testing to detect actionable mutations that may inform treatment recommendations in lung cancer.
We prospectively applied amplicon sequencing panels that cover both mutational hotspots in 22 genes related to lung and colon tumorigenesis as well as 72 major variants of ALK, RET, ROS1, and NTRK1 fusion transcripts. We then determined the proportion of patients who received genotype-directed therapy and their overall survival (OS).
Tumor specimens from 110 patients with lung cancer recruited between July 2013 and March 2015 were analyzed. The most common genetic alterations were TP53 mutations in 42 patients, followed by EGFR mutations in 25, STK11 mutations in 12, and KRAS mutations in 10. Potentially actionable mutations were identified in 44 patients including 50% of those with adenocarcinoma and 14% of those with squamous cell carcinoma. The OS of patients with advanced or recurrent cancer who had an actionable mutation and received targeted therapy (median OS not achieved) was significantly longer than that of those with no mutation (18.1 months, P = 0.041) or of those with a mutation not so treated (6.1 months, P = 0.0027).
Multiplex genomic testing was performed on formalin-fixed, paraffin-embedded tumor specimens with a success rate of ≥95%. Such testing can assist physicians in matching patients with approved or experimental targeted treatments.
The University Medical Hospital Information Network (UMIN) Clinical Trials Registry under the identifier UMIN000014782.
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