Journal of Thoracic Oncology:
doi: 10.1097/JTO.0000000000000167
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Germline Egfr T790m Mutation Found in Multiple Members of a Familial Cohort
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The acquisition of the EGFR T790M point mutation is the most common mechanism of resistance to EGFR tyrosine kinase inhibitors whereas de novo EGFR T790M mutations are rare. This report describes the findings of molecular analysis on synchronous lung tumors of a 44-year-old never smoker with no family history of lung cancer, who had genetic testing that led to the identification of a germline EGFR T790M mutation. The subsequent genetic testing of her unaffected relatives revealed two additional EGFR T790M germline carriers: her daughter, and mother who was diagnosed with metastatic lung adenocarcinoma after the initial test. Further analysis demonstrated that the proband’s tumors were well-differentiated primary lung adenocarcinoma, with concurrent somatic mutations (EGFR exon 19 deletion, EGFR L858R, EGFR T790M, and ARID1A, which was recently found in lung adenocarcinoma). The presence of germline EGFR T790M is clinically linked to lung adenocarcinoma development and found in about half of all patients harboring baseline EGFR T790M in their tumor specimens before treatment. The authors recommended these patients be tested for germline EGFR T790M and suggested prospective studies on germline EGFR T790M mutation carriers to gain insights on the clinical significance of the mutation. According to the authors, their patients with germline EGFR T790M mutations showed bilateral ground-glass opacities and pulmonary nodules on radiographs. Two of four patients had indolent disease whereas the other two had more aggressive metastatic disease and died from their disease after chemotherapy. Evaluation of the concurrent somatic mutations and the germline carriers would help understand the oncogenic development from germline mutation carrier to clinically evident malignancy, which may ultimately help develop therapeutic interventions for this cohort. (p. 554)

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Hereditary Lung Cancer Syndrome Targets Never Smokers with Germline Egfr Gene T790m Mutations
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This report describes the investigation of hereditary lung cancer in a 29-year-old female patient and her family pedigree, in addition to literature review to summarize the current knowledge of this familial form of lung cancer. The proband, with a smoking history of 0.1 pack-years, has adenocarcinoma, preneoplastic and preinvasive lesions, harboring L858R mutation in exon 21 and a germline T790M mutation. Relevant history of five generations of her family and blood samples from members of three generations were collected for the T790M mutation testing. Combining proband’s family pedigree with the literature, 19 of a total of 29 mutation carriers developed lung cancer. Tumors arising in T790M germline carriers, all of who had non–small-cell lung cancer, were with one or more adenocarcinomas, ground-glass and solid nodular lesions, and associated with preinvasive lesions. Of the 22 tumors tested, 73% had T790M germline mutation in addition to a second activating mutation. The findings also revealed a highly significant association between never smokers and lung cancer cases in germline T790M carriers (p = 3.2E-07). The authors also conducted analysis to detect EGFR and germline T790M mutations in Japanese patients using paired normal and tumor tissues from 627 patients with resected non–small-cell lung cancer before tyrosine kinase inhibitors or other therapies. Thirty-three percent of samples were positive for EGFR mutation whereas none of 627 samples were positive for germline T790M mutations. Without adjusting for ethnicity, the prevalence of germline T790M mutation in the general population is estimated to be less than one in 7500. From the findings on the proband and family pedigree, germline T790M mutation is a major cancer predisposition gene, with an estimated 31% risk for lung cancer in never-smoker carriers, which is greater than in heavy smokers with or without the mutation. The median age of the cancer cases was about 63 years, they were predominantly women, in both lung cancers with sporadic EGFR mutations and for germline T790M cases. Unaffected carriers with this mutation are at higher risk for developing lung cancer regardless of smoking status and should be closely monitored including low-dose computed tomography scans. (p. 456)

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Comparison of Clinical Outcomes After Gefitinib and Erlotinib Treatment in Non–Small-Cell Lung Cancer Patients Harboring an Epidermal Growth Factor Receptor Mutation in Either Exon 19 or 21
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Data comparing the efficacy and safety of erlotinib and gefitinib are limited in patients with advanced non–small-cell lung cancer (NSCLC) harboring EGFR mutations. In this study, the authors retrospectively reviewed data and compared the clinical outcomes of 317 patients with recurrent or metastatic stage IIIB/IV NSCLC, who had exon 19 deletion or L858R mutation in exon 21, and were treated with gefinitib (n = 228) or erlotinib (n = 147). Gefitinib- and erlotinib-treated patients were pair-matched on sex, smoking history, Eastern Cooperative Oncology Group performance status and EGFR mutation types. The study population, with a median age of 58 years, consisted of 63.6% never smokers, 98.3% adenocarcinoma, and 90.9% with good Eastern Cooperative Oncology Group status (0, 1). No significant difference was observed between gefitinib- and erlotinib-treated groups in overall response rates (p = 0.575), disease control rates (p = 0.305), and median progression-free survival (p = 0.056). Gefitinib and erlotinib were given as first-line treatment in 26% of 242 patients. In these patients, no significant difference between the two groups was found in overall response rates (p = 0.431) and median progression-free survival (p = 0.507). The authors concluded that, taken together, similar efficacy from gefitinib and erlotinib treatments was demonstrated in advanced NSCLC with EGFR mutations. (p. 506)

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Next-Generation Sequencing Reveals a Novel Nsclc Alk F1174v Mutation and Confirms Alk G1202r Mutation Confers High-Level Resistance to Alectinib (Ch5424802/Ro5424802) in Alk-Rearranged Nsclc Patients Who Progressed on Crizotinib
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This brief report described the finding of a novel acquired secondary mutation in the anaplastic lymphoma kinase (ALK) gene, namely ALK F1174V in an ALK-rearranged (ALK+) non–small-cell lung cancer (NSCLC) patient, who was resistant to crizotinib after a prolonged partial response. The discovery was achieved using comprehensive next-generation sequencing (NGS). The patient is currently in a phase II trial for crizotinib-resistant ALK+ NSCLC patients receiving alectinib treatment, a more potent ALK inhibitor in clinical development. In addition, a second ALK+ NSCLC patient was reported to harbor a previously described secondary acquired mutation, ALK G1202R, using comprehensive NGS. This patient was also enrolled in the same phase II trial as the aforementioned patient and received alectinib treatment. However, ALK G1202R was shown to confer high-level resistance to alectinib with disease progression, validating in vitro findings in a patient for the first time. This report demonstrated that comprehensive genomic profiling using targeted NGS provides insights into resistant tumor population and additional underlying genetic abnormalities apart from secondary acquired mutations (S45 deletion in CTNNB1, and loss of CDKN2A/B and ARFRP1 amplification in parallel with ALK F1174V and ALK G1202R, respectively). This would help guide treatment decisions in crizotinib-resistant ALK+ NSCLC patients using second-generation ALK inhibitors and other novel therapeutic intervention. (p. 549)

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Prognostic Impact of Paraneoplastic Cushing’s Syndrome in Small-Cell Lung Cancer
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Paraneoplastic Cushing’s syndrome (CushingPS) is rare but severe in small-cell lung cancer (SCLC). The authors conducted a 14-year retrospective study to assess the impact of CushingPS in SCLC regarding presentation, response to treatment and survival, as well as to determine potential treatment strategy for the disease at different stages. Of 383 SCLC patients, CushingPS was found in 23, other paraneoplastic syndrome (OtherPS) in 56, and 304 had no paraneoplastic syndrome (NoPS). In comparison with patients with OtherPS and NoPS, CushingPS patients had more extensive disease (82.6%, p = 0.005), more than two metastatic sites (63%; p ≤0.001), a higher World Health Organization performance status (2–4) (73.9%; p = 0.006), greater weight loss of 10% or more (47.8%; p ≤0.001), reduced objective response (47.6%, p = 0.04) and poorer sensitivity (19%, p = 0.01) to first-line therapy. CushingPS patients had a median survival of 6.6 months versus 9.2 months (OtherPS) and 13.1 months (NoPS) (p ≤ 0.001). It was also shown that the NoPS group with World Health Organization performance status of 3 to 4 exhibited similar extensive disease, response and sensitivity to first-line treatment, and survival to the CushingPS group. CushingPS patients demonstrated no objective response to second-line treatment on relapse (p = 0.005). To conclude, CushingPS is a prognostic factor of death with a hazard ratio of 2.31 (p ≤ 0.001). It is correlated to extensive tumors in SCLC patients with poor performance status and dramatic weight loss. Their lowered objective response and sensitivity to first-line therapy and nonresponsiveness to second-line therapy indicate early palliative care at first-line treatment and only palliative care at relapse. (p. 497)

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Research Watch

A Correlative Mild Trial Study: Plasma mirna Signature Classifier in Computed Tomography Lung Cancer Screening

In search of complementary biomarkers to potentially reduce the false-positive rates of low-dose computed tomography (LDCT) for lung cancer screening, the authors conducted a retrospective study on the diagnostic performance of a noninvasive plasma microRNA signature classifier (MSC) in plasma samples collected from smokers (n = 939) in the randomized Multicenter Italian Lung Detection trial. Quantitative reverse-transcriptase polymerase chain reaction–based assay for MSC was used to examine samples from lung cancer patients and disease-free participants in LDCT arm (n = 652) and observation arm (n = 287). A blinded validation study was used to analyze diagnostic performance of MSC. The results demonstrated 87% sensitivity and 81% specificity using MSC to detect lung cancer in both arms, with 88% and 80%, respectively, in the LDCT arm. MSC also showed 99% and 99.86% of negative predictive value for detection and death from the disease, respectively. In addition to better sensitivity and similar specificity to LDCT alone (79% and 81%, respectively), MSC plus LDCT reduced LDCT false-positive rate by fivefold (19.4%–3.7%). A significant correlation with survival was also observed in MSC risk groups (p < 0.001). Taken together, the findings demonstrated the predictive, diagnostic, and prognostic value of MSC with the potential of reducing the false-positive rate of LDCT.

Sozzi G, Boeri M, Rossi M, et al. Clinical utility of a plasma-based miRNA signature classifier within computed tomography lung cancer screening: a correlative MILD Trial Study. J Clin Oncol 2014; doi:10.1200/jco.2013.50.4357.

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Lux-Lung 6 Trial: Afatinib Improves Progression-Free Survival in Asian Patients With Egfr-Mutation–Positive Advanced Nsclc Compared With Gemcitabine/Cisplatin as First-Line Treatment

Studies have demonstrated a survival benefit from afatinib, an irreversible inhibitor of the ErbB family, when compared with pemetrexed and cisplatin as first-line treatment in EGFR-mutation–positive advanced non–small-cell lung cancer (NSCLC) patients. In the phase III LUX-Lung 6 trial, Wu et al. set out to compare afatinib with the widely used chemotherapy regimen in Asia, gemcitabine plus cisplatin, as first-line in treatment-naive Asian patients with stage IIIB/IV NSCLC harboring EGFR mutation. The primary endpoint was progression-free survival. In the 364 randomized patients, the afatinib arm showed significantly longer median survival (11.0 months) versus the gemcitabine plus cisplatin arm (5.6 months; p < 0.0001). Objective response was observed in 66.9% versus 23.0% of patients, respectively, (odds ratio = 7.28, p < 0.0001). Rash or acne, diarrhea, and stomatitis or mucositis were the most common treatment-related grade 3 or 4 toxicity in the afatinib arm versus vomiting, neutropenia, and leucopenia in the gemcitabine plus cisplatin arm. Treatment-related severe adverse events occurred in 6.3% of the afatinib group versus 8.0% of the gemcitabine plus cisplatin group. Taken together, this study demonstrated that first-line afatinib improves progression-free survival and objective response rate, with a tolerable safety profile versus the gemcitabine plus cisplatin regimen in Asian patients with EGFR-positive advanced NSCLC.

Wu YL, Zhou C, Hu C-P, et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014;15:213–222.

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Lume-Lung 1: Docetaxel Plus Nintedanib versus Docetaxel Plus Placebo in Previously Treated Non–Small-Cell Lung Cancer Patients

The phase III, double-blind, randomized controlled trial, LUME-Lung 1, aimed to evaluate the efficacy and safety of adding nintedanib to docetaxel as a second-line treatment for patients with stage IIIB/IV recurrent non–small-cell lung cancer progressing after first-line chemotherapy. The primary endpoint was progression-free survival and the key secondary endpoint was overall survival. After a median follow-up of 7.1 months, the docetaxel plus nintedanib arm achieved a significantly improved progression-free survival of 3.4 months versus 2.7 months in the docetaxel plus placebo arm (p = 0.0019). The addition of nintedanib to docetaxel significantly improved overall survival in patients with adenocarcinoma, whose disease progressed within 9 months after first-line treatment (median 10.9 months versus 7.9 months; p = 0.0073), and in all patients with adenocarcinoma (median 12.6 months versus 10.3 months; p = 0.0359). Diarrhea, reversible rise in alanine aminotransferase and aspartate aminotransferase were more common grade 3 or higher adverse events in the nintedanib combination group. Deaths were reported in the nintedanib combination group (n = 35) and the docetaxel/placebo group (n = 25), possibly unrelated to tumor progression. To conclude, the study indicated that the addition of nintedanib to docetaxel shows survival benefit as a second-line treatment for advanced non– small-cell lung cancer patients with one prior platinum-based treatment, and of adenocarcinoma in particular.

Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomised controlled trial. Lancet Oncol 2014;15:143–155.

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Stereotactic Radiation Therapy Controls Extracentral Nervous System Oligoprogressive Disease in Crizotinib-Treated Alk-Positive Lung Cancer Patients

This study evaluated the safety and durability of using radiotherapeutic local ablative therapy (LAT) to treat extracentral nervous system (eCNS) disease progression in anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC) patients. ALK-positive NSCLC patients treated with crizotinib were classified as having oligoprogressive disease (OPD) when there were four or fewer discrete sites of eCNS progression. Additional LAT courses were given to these patients, who continued on crizotinib until eCNS disease progressed beyond OPD criteria or not suitable for additional LAT. Of 33 patients with progressive disease on crizotinib, 14 met OPD criteria for LAT and received up to three courses of LAT. Local lesion control rates with LAT were 100% (6 months) and 86% (12 months). Single-fraction equivalent dose of more than 25 Gy and 25 Gy or lesser achieved a 12-month local control rate of 100% and 60%, respectively (p = 0.01) with neither acute toxicities nor toxicities that were higher than grade 2. Patients receiving LAT continued to take crizotinib for a median overall time of 28 months versus 10.1 months in those whose disease had progressed and was not suitable for LAT. A prolonged 2-year survival rate was achieved in patients continuing on crizotinib for more than 12 months (72%) versus 12 months or lesser (12%; p < 0.0001). Taken together, LAT is safe and durable in suppressing OPD in ALK-positive NSCLC patients taking crizotinib, which enabled these patients to continue on crizotinib treatment for overall condition and led to improved 2-year survival rates versus those forced to discontinue the drug sooner.

Gan GN, Weickhardt AJ, Scheier B, et al. Stereotactic radiation therapy can safely and durably control sites of extra-central nervous system oligoprogressive disease in anaplastic lymphoma kinase-positive lung cancer patients receiving crizotinib. Internat J Rad Oncol*Biol*Phys, doi:http://dx.doi.org/10.1016/j.ijrobp.2013.11.010.

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News in Brief

A Simple and Accurate Test of Exhaled Breath May Help Detect Early Lung Cancer
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Bousamra and colleagues from the University of Louisville examined exhaled breath from individuals detected with suspicious lung lesions on computed tomography scans. A silicone microprocessor and mass spectrometer was used to test the breath for levels of cancer-specific volatile organic compounds (collectively known as carbonyls). The findings were presented at the 50th Annual Meeting of The Society of Thoracic Surgeons in Orlando, Florida. Increased levels of three or four carbonyls were associated with lung cancers in 95% of patients whereas normal levels of these compounds were associated with benign growth in 80% of patients. The authors also found that increased levels of carbonyl dropped to normal after tumor resection in lung cancer patients. This study suggests that this new approach using exhaled breath, which is simple to be collected and easy for patients, could accurately determine which patients to be sent for invasive biopsy and resection after discovering a suspicious lesion on computed tomography scans.

Photo credit: Pulmonary Pathology http://www.flickr.com/photos/pulmonary_pathology/6327961286/in/photostream/

Copyright © 2014 by the International Association for the Study of Lung Cancer

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