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- Bergqvist, Michael, et al.
(författare)
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Characteristics and Long-Term OS of Non-Small Cell Lung Cancer Patients Receiving EGFR Tyrosine Kinase Inhibitor Treatment
- 2018
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Ingår i: Journal of Thoracic Oncology. - : Elsevier. - 1556-0864 .- 1556-1380. ; 13:10, s. S419-S419
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are important therapeutic agents in treatment of EGFR mutation-positive non-small cell lung cancer (NSCLC) patients. However, long-term follow-up and knowledge of clinical factors and TKI treatment patterns, which may be associated with longer OS, remains unclear. Using nationwide registry data, the aim was to investigate survival, prognostic factors for OS, and first line TKI treatment pattern of stage IIIB/IV NSCLC patients in Sweden.Method: In this cohort study, data on all patients diagnosed with stage IIIB-IV NSCLC during 2010—2015 from the nationwide Cancer Registry of Sweden were linked with data on dispensed EGFR-TKI drugs, comorbidity, and mortality data from Swedish national health registries. OS was defined as the interval from date of diagnosis until date of death. Survival rates were estimated using the Kaplan-Meier method. Assessment of predictive factors for OS was performed in multivariable Cox regression.Result: Of 9,992 stage IIIB/IV NSCLC patients (mean age 70 years, female 49%), 1419 (14%) received first-line TKI treatment. Overall, 59% of TKI treated patients (median age 68 years) were female, 44% had at least one comorbidity, 85% had adenocarcinoma, and 89% were stage IV. Median follow-up time was 15 months and median OS was 16 months; 1- and 3-years survival rates were 62% and 15%, respectively. Predictors of longer OS were younger age at diagnosis, adenocarcinoma, less advanced clinical stage, and less comorbid disease. Furthermore, patients included in the end of the period had a longer OS compared to earlier. TKI treatment switching/re-challenging, as well as prolonged TKI treatment, also predicted longer OS.Conclusion: This is the first nationwide study on NSCLC patients receiving first-line EGFR TKIs in routine clinical practice in Sweden. In addition to the reported prolonged TKI treatment length and TKI switching/re-challenging during the observation period, improvements and extension of EGFR testing targeting the appropriate NSCLC patient population may further have contributed to the observed relatively long overall survival.
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- Cheng, Chao, et al.
(författare)
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Mosaic chromosomal alterations are associated with increased lung cancer risk : insight from the INTEGRAL-ILCCO cohort analysis
- 2023
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Ingår i: Journal of Thoracic Oncology. - : Elsevier. - 1556-0864 .- 1556-1380.
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Mosaic chromosomal alterations (mCAs) detected in white blood cells represent a type of clonal hematopoiesis (CH) that is understudied compared with CH-related somatic mutations. A few recent studies indicated their potential link with nonhematological cancers, especially lung cancer. Methods: In this study, we investigated the association between mCAs and lung cancer using the high-density genotyping data from the OncoArray study of INTEGRAL-ILCCO, the largest single genetic study of lung cancer with 18,221 lung cancer cases and 14,825 cancer-free controls. Results: We identified a comprehensive list of autosomal mCAs, ChrX mCAs, and mosaic ChrY (mChrY) losses from these samples. Autosomal mCAs were detected in 4.3% of subjects, in addition to ChrX mCAs in 3.6% of females and mChrY losses in 9.6% of males. Multivariable logistic regression analysis indicated that the presence of autosomal mCAs in white blood cells was associated with an increased lung cancer risk after adjusting for key confounding factors, including age, sex, smoking status, and race. This association was mainly driven by a specific type of mCAs: copy-neutral loss of heterozygosity on autosomal chromosomes. The association between autosome copy-neutral loss of heterozygosity and increased risk of lung cancer was further confirmed in two major histologic subtypes, lung adenocarcinoma and squamous cell carcinoma. In addition, we observed a significant increase of ChrX mCAs and mChrY losses in smokers compared with nonsmokers and racial differences in certain types of mCA events. Conclusions: Our study established a link between mCAs in white blood cells and increased risk of lung cancer.
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- Edlund, Karolina, et al.
(författare)
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Prognostic Impact of Tumor Cell Programmed Death Ligand 1 Expression and Immune Cell Infiltration in NSCLC
- 2019
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Ingår i: Journal of Thoracic Oncology. - : Elsevier BV. - 1556-0864 .- 1556-1380. ; 14:4, s. 628-640
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Infiltration of T and B/plasma cells has been linked to NSCLC prognosis, but this has not been thoroughly investigated in relation to the expression of programmed death ligand 1 (PD-L1). Here, we determine the association of lymphocytes and PD-L1 with overall survival (OS) in two retrospective cohorts of operated NSCLC patients who were not treated with checkpoint inhibitors targeting the programmed death 1/PD-L1 axis. Moreover, we evaluate how PD-L1 positivity and clinicopathologic factors affect the prognostic association of lymphocytes.Methods: Cluster of differentiation (CD) 3 (CD3)-, CD8-, CD4-, forkhead box P3 (FOXP3)-, CD20-, CD79A-, and immunoglobulin kappa constant (IGKC)-positive immune cells, and tumor PD-L1 positivity, were determined by immunohistochemistry on tissue microarrays (n = 705). Affymetrix data was analyzed for a patient subset, and supplemented with publicly available transcriptomics data (N = 1724). Associations with OS were assessed by Kaplan-Meier plots and uni- and multivariate Cox regression.Results: Higher levels of T and B plasma cells were associated with longer OS (p = 0.004 and p < 0.001, for CD8 and IGKC, respectively). Highly proliferative tumors with few lymphocytes had the worst outcome. No association of PD-L1 positivity with OS was observed in a nonstratified patient population; however, a significant association with shorter OS was observed in never-smokers (p = 0.009 and p = 0.002, 5% and 50% cutoff). Lymphocyte infiltration was not associated with OS in PD-L1–positive tumors (50% cutoff). The prognostic association of lymphocyte infiltration also depended on the patients’ smoking history and histologic subtype.Conclusions: Proliferation, PD-L1 status, smoking history, and histology should be considered if lymphocyte infiltration is to be used as a prognostic biomarker.
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- Hillerdal, Gunnar, et al.
(författare)
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Treatment of Malignant Pleural Mesothelioma with Carboplatin, Liposomized Doxorubicin, and Gemcitabine A Phase II Study
- 2008
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Ingår i: JOURNAL OF THORACIC ONCOLOGY. - 1556-0864. ; 3:11, s. 1325-1331
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Tidskriftsartikel (refereegranskat)abstract
- Background: Malignant pleural mesothelioma has a poor prognosis and there is limited effect of treatment. The Nordic Mesothelioma groups decided in the year 2000 to investigate a combination or liposomized doxorubicin, carboplatin, and gemcitabine for this disease in a phase II study.Methods: From January 2001, to December 2003, 173 evaluable patients with biopsy-verified malignant mesothelioma were included. Two patients were lost to follow-Lip, but all the others were followed for at least 4 years or until death.Results: Toxicity was fairly low. There were 56 responses (32.4%), of which 2 were complete; the median time to progression was 8.6 months, and the median overall survival was 13 months. Some patients had their responses 4 to 6 months after last treatment. For 116 patients with epitheloid subtype, median Survival was 17 months. A subgroup of these patients with good performance status, early stage, and age 70 years or less, showed a median survival of 22 months.Conclusion: The treatment yields good results with a high number of responses and long survival, and a low toxicity. The long Survival of the epitheloid subgroup with good prognostic factors is as good as or even better than some studies on "radical" Surgery or multimodal treatment, underlining the need of randomized studies to evaluate such treatment options.
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- Hung, Rayjean J., et al.
(författare)
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Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5(p)15.33 TERT-CLPTM1Ll Region
- 2019
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Ingår i: Journal of Thoracic Oncology. - : ELSEVIER SCIENCE INC. - 1556-0864 .- 1556-1380. ; 14:8, s. 1360-1369
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer. Methods: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer. Results: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 x 10(-16)), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 x 10(-16)), and rs4975616 OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 x 10(-14)). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate. Conclusions: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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- Karlsson, Anna, et al.
(författare)
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Gene Expression Profiling of Large Cell Lung Cancer Links Transcriptional Phenotypes to the New Histological WHO 2015 Classification
- 2017
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Ingår i: Journal of Thoracic Oncology. - : ELSEVIER SCIENCE INC. - 1556-0864 .- 1556-1380. ; 12:8, s. 1257-1267
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Large cell lung cancer (LCLC) and large cell neuroendocrine carcinoma (LCNEC) constitute a small proportion of NSCLC. The WHO 2015 classification guidelines changed the definition of the debated histological subtype LCLC to be based on immunomarkers for adenocarcinoma and squamous cancer. We sought to determine whether these new guidelines also translate into the transcriptional landscape of lung cancer, and LCLC specifically.Methods: Gene expression profiling was performed by using Illumina V4 HT12 microarrays (Illumina, San Diego, CA) on samples from 159 cases (comprising all histological subtypes, including 10 classified as LCLC WHO 2015 and 14 classified as LCNEC according to the WHO 2015 guidelines), with complimentary mutational and immunohistochemical data. Derived transcriptional phenotypes were validated in 199 independent tumors, including six WHO 2015 LCLCs and five LCNECs.Results: Unsupervised analysis of gene expression data identified a phenotype comprising 90% of WHO 2015 LCLC tumors, with characteristics of poorly differentiated proliferatiVe cancer, a 90% tumor protein p53 gene (TP53) mutation rate, and lack of well-known NSCLC oncogene driver alterations. Validation in independent data confirmed aggregation of WHO 2015 LCLCs in the specific phenotype. For LCNEC tumors, the unsupervised gene expression analysis suggested two different transcriptional patterns corresponding to a proposed genetic division of LCNEC tumors into SCLC-like and NSCLC-like cancer on the basis of TP53 and retinoblastoma 1 gene (RB1) alteration patterns.Conclusions: Refined classification of LCLC has implications for diagnosis, prognostics, and therapy decisions. Our molecular analyses support the WHO 2015 classification of LCLC and LCNEC tumors, which herein follow different tumorigenic paths and can accordingly be stratified into different transcriptional subgroups, thus linking diagnostic immunohistochemical staining driven classification with the transcriptional landscape of lung cancer.
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| 22. |
- Kerr, Keith M, et al.
(författare)
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Programmed Death-Ligand 1 Immunohistochemistry in Lung Cancer : In what state is this art?
- 2015
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Ingår i: Journal of Thoracic Oncology. - 1556-0864 .- 1556-1380. ; 10:7, s. 985-989
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Tidskriftsartikel (refereegranskat)abstract
- Therapeutic antibodies to programmed death receptor 1 (PD-1) and its ligand PD-L1 show promising clinical results. Anti-PD-L1 immunohistochemistry (IHC) may be a biomarker to select patients more likely to respond to these treatments. However, the development of at least four different therapeutics, each with a different anti-PD-L1 IHC assay, has raised concerns among pathologists and oncologists alike. This article reviews existing data on the IHC biomarker aspects of studies using these drugs in non-small-cell lung cancer (NSCLC) and considers the challenges ahead, should these drug/IHC assay combinations reach routine practice. For each the known biomarker assays in development, there is a different monoclonal IHC antibody clone, produced by one of two diagnostics companies. Each test requires proprietary staining platforms and uses different definitions of a "positive" test for PD-L1 expression, on tumor cells and, in one test, also on tumor infiltrating immune cells. There are still considerable gaps in our knowledge of the technical aspects of these tests, and of the biological implications and associations of PD-L1 expression in NSCLC, considering heterogeneity of expression, dynamic changes in expression, and prognostic implications among other factors. The International Association for the Study of Lung Cancer Pathology Committee raises the prospect of trying not only to harmonize and standardize testing for PD-L1 by IHC, at least at a technical level, but also, ideally, as a predictive marker, to facilitate availability of this test and a promising treatment for patients with NSCLC.
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