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Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Norske artikler - 23 min 8 sek siden
Related Articles

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Nat Commun. 2018 Aug 13;9(1):3221

Authors: Ji X, Bossé Y, Landi MT, Gui J, Xiao X, Qian D, Joubert P, Lamontagne M, Li Y, Gorlov I, de Biasi M, Han Y, Gorlova O, Hung RJ, Wu X, McKay J, Zong X, Carreras-Torres R, Christiani DC, Caporaso N, Johansson M, Liu G, Bojesen SE, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Chen C, Teare MD, Field JK, Kiemeney LA, Lazarus P, Haugen A, Lam S, Schabath MB, Andrew AS, Shen H, Hong YC, Yuan JM, Bertazzi PA, Pesatori AC, Ye Y, Diao N, Su L, Zhang R, Brhane Y, Leighl N, Johansen JS, Mellemgaard A, Saliba W, Haiman C, Wilkens L, Fernandez-Somoano A, Fernandez-Tardon G, van der Heijden EHFM, Kim JH, Dai J, Hu Z, Davies MPA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Doherty J, Goodman GE, Cox A, Taylor F, Woll P, Brüske I, Manz J, Muley T, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd F, Tsao MS, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Zienolddiny S, Duell EJ, Butler LM, Koh WP, Gao YT, Houlston R, McLaughlin J, Stevens V, Nickle DC, Obeidat M, Timens W, Zhu B, Song L, Artigas MS, Tobin MD, Wain LV, Gu F, Byun J, Kamal A, Zhu D, Tyndale RF, Wei WQ, Chanock S, Brennan P, Amos CI

Abstract
Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

PMID: 30104567 [PubMed - in process]

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Norsk publikasjonsliste - 23 min 11 sek siden
Related Articles

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Nat Commun. 2018 Aug 13;9(1):3221

Authors: Ji X, Bossé Y, Landi MT, Gui J, Xiao X, Qian D, Joubert P, Lamontagne M, Li Y, Gorlov I, de Biasi M, Han Y, Gorlova O, Hung RJ, Wu X, McKay J, Zong X, Carreras-Torres R, Christiani DC, Caporaso N, Johansson M, Liu G, Bojesen SE, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Chen C, Teare MD, Field JK, Kiemeney LA, Lazarus P, Haugen A, Lam S, Schabath MB, Andrew AS, Shen H, Hong YC, Yuan JM, Bertazzi PA, Pesatori AC, Ye Y, Diao N, Su L, Zhang R, Brhane Y, Leighl N, Johansen JS, Mellemgaard A, Saliba W, Haiman C, Wilkens L, Fernandez-Somoano A, Fernandez-Tardon G, van der Heijden EHFM, Kim JH, Dai J, Hu Z, Davies MPA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Doherty J, Goodman GE, Cox A, Taylor F, Woll P, Brüske I, Manz J, Muley T, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd F, Tsao MS, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Zienolddiny S, Duell EJ, Butler LM, Koh WP, Gao YT, Houlston R, McLaughlin J, Stevens V, Nickle DC, Obeidat M, Timens W, Zhu B, Song L, Artigas MS, Tobin MD, Wain LV, Gu F, Byun J, Kamal A, Zhu D, Tyndale RF, Wei WQ, Chanock S, Brennan P, Amos CI

Abstract
Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

PMID: 30104567 [PubMed - in process]

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Related Articles

Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.

Nat Commun. 2018 Aug 13;9(1):3221

Authors: Ji X, Bossé Y, Landi MT, Gui J, Xiao X, Qian D, Joubert P, Lamontagne M, Li Y, Gorlov I, de Biasi M, Han Y, Gorlova O, Hung RJ, Wu X, McKay J, Zong X, Carreras-Torres R, Christiani DC, Caporaso N, Johansson M, Liu G, Bojesen SE, Le Marchand L, Albanes D, Bickeböller H, Aldrich MC, Bush WS, Tardon A, Rennert G, Chen C, Teare MD, Field JK, Kiemeney LA, Lazarus P, Haugen A, Lam S, Schabath MB, Andrew AS, Shen H, Hong YC, Yuan JM, Bertazzi PA, Pesatori AC, Ye Y, Diao N, Su L, Zhang R, Brhane Y, Leighl N, Johansen JS, Mellemgaard A, Saliba W, Haiman C, Wilkens L, Fernandez-Somoano A, Fernandez-Tardon G, van der Heijden EHFM, Kim JH, Dai J, Hu Z, Davies MPA, Marcus MW, Brunnström H, Manjer J, Melander O, Muller DC, Overvad K, Trichopoulou A, Tumino R, Doherty J, Goodman GE, Cox A, Taylor F, Woll P, Brüske I, Manz J, Muley T, Risch A, Rosenberger A, Grankvist K, Johansson M, Shepherd F, Tsao MS, Arnold SM, Haura EB, Bolca C, Holcatova I, Janout V, Kontic M, Lissowska J, Mukeria A, Ognjanovic S, Orlowski TM, Scelo G, Swiatkowska B, Zaridze D, Bakke P, Skaug V, Zienolddiny S, Duell EJ, Butler LM, Koh WP, Gao YT, Houlston R, McLaughlin J, Stevens V, Nickle DC, Obeidat M, Timens W, Zhu B, Song L, Artigas MS, Tobin MD, Wain LV, Gu F, Byun J, Kamal A, Zhu D, Tyndale RF, Wei WQ, Chanock S, Brennan P, Amos CI

Abstract
Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.

PMID: 30104567 [PubMed - in process]

Tumor Mutation Burden as a Biomarker in Resected Non-Small-Cell Lung Cancer.

Lungekreft i JCO, NEJM eller The Lancet - 12 timer 23 min siden
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Tumor Mutation Burden as a Biomarker in Resected Non-Small-Cell Lung Cancer.

J Clin Oncol. 2018 Aug 14;:JCO2018781963

Authors: Devarakonda S, Rotolo F, Tsao MS, Lanc I, Brambilla E, Masood A, Olaussen KA, Fulton R, Sakashita S, McLeer-Florin A, Ding K, Le Teuff G, Shepherd FA, Pignon JP, Graziano SL, Kratzke R, Soria JC, Seymour L, Govindan R, Michiels S

Abstract
Purpose The survival benefit with adjuvant chemotherapy for patients with resected stage II-III non-small-cell lung cancer (NSCLC) is modest. Efforts to develop prognostic or predictive biomarkers in these patients have not yielded clinically useful tests. We report findings from the Lung Adjuvant Cisplatin Evaluation (LACE)-Bio-II study, in which we analyzed next-generation sequencing and long-term outcomes data from > 900 patients with early-stage NSCLC treated prospectively in adjuvant landmark clinical trials. We used a targeted gene panel to assess the prognostic and predictive effect of mutations in individual genes, DNA repair pathways, and tumor mutation burden (TMB). Methods A total of 908 unmatched, formalin-fixed, paraffin-embedded, resected lung cancer tumor specimens were sequenced using a targeted panel of 1,538 genes. Stringent filtering criteria were applied to exclude germline variants and artifacts related to formalin fixation. Disease-free survival, overall survival, and lung cancer-specific survival (LCSS) were assessed in Cox models stratified by trial and adjusted for treatment, age, sex, performance score, histology, type of surgery, and stage. Results Nonsynonymous mutations were identified in 1,515 genes in 908 tumor samples. High nonsynonymous TMB (> 8 mutations/Mb) was prognostic for favorable outcomes (ie, overall survival, disease-free survival, and LCSS) in patients with resected NSCLC. LCSS benefit with adjuvant chemotherapy was more pronounced in patients with low nonsynonymous TMBs (≤ 4 mutations/Mb). Presence of mutations in DNA repair pathways, tumor-infiltrating lymphocytes, TP53 alteration subtype, and intratumor heterogeneity was neither prognostic nor predictive. Statistically significant effect of mutations in individual genes was difficult to determine due to high false-discovery rates. Conclusion High nonsynonymous TMB was associated with a better prognosis in patients with resected NSCLC. In addition, the benefit of adjuvant chemotherapy on LCSS was more pronounced in patients with low nonsynonymous TMBs. Studies are warranted to confirm these findings.

PMID: 30106638 [PubMed - as supplied by publisher]

Cause-specific death after surgical resection for early-stage non-small-cell lung cancer.

Norske artikler - ons, 08/15/2018 - 09:30
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Cause-specific death after surgical resection for early-stage non-small-cell lung cancer.

Eur J Cardiothorac Surg. 2018 Jan 01;53(1):221-227

Authors: Bugge AS, Lund MB, Valberg M, Brustugun OT, Solberg S, Kongerud J

Abstract
OBJECTIVES: Surgical resection is the recommended treatment for patients with early-stage non-small-cell lung cancer. However, it is believed that causes other than lung cancer can lead to death following surgical resection. Investigating the risk factors for overall mortality and analysing the specific causes of death may indicate the degree of influence of other causes of death.
METHODS: We assessed individual risk factors affecting overall and cause-specific mortality in a Cox proportional hazards model in a cohort of patients with resected Stage I/II non-small-cell lung cancer (n = 756) from 2007 to 2015 in a tertiary university centre. The follow-up period ranged from 3 days to 9.3 years. Median survival time was 7.3 years (95% confidence interval 6.0-7.9). A few patients died of cardiovascular disease (n = 19) and were included in the group 'other cause'. In a competing risk model, we evaluated the risk factors for specific causes of death in patients dying of lung cancer and dying of non-lung cancer specific conditions.
RESULTS: The overall survival was 94%, 62% and 50% at 1, 5 and 7 years, respectively. At the end of the follow-up period, the risk of having died of, respectively, lung cancer or other causes was 36% and 24%. The cumulative incidence of death of lung cancer increased continuously during the study. Risk factors predicting death of all causes and death of non-small-cell lung cancer were increasing age, severely reduced lung function, Eastern Cooperative Oncology Group Performance Status ≥2, preoperative examination without positron emission tomography/computed tomography, histological tumour diagnosis other than adenocarcinoma and squamous cell carcinoma and increasing disease stage. In patients dying of other causes, age, gender, body mass index, smoking and Eastern Cooperative Oncology Group Performance Status ≥2 affected the mortality rate.
CONCLUSIONS: The probability of having died of lung cancer continued to increase beyond 5 years after the operation. Surveillance of risk factors associated with an increased mortality rate should be considered in the postoperative follow-up examination after lung cancer resection.

PMID: 28950311 [PubMed - indexed for MEDLINE]

Cause-specific death after surgical resection for early-stage non-small-cell lung cancer.

Norsk publikasjonsliste - ons, 08/15/2018 - 09:30
Related Articles

Cause-specific death after surgical resection for early-stage non-small-cell lung cancer.

Eur J Cardiothorac Surg. 2018 Jan 01;53(1):221-227

Authors: Bugge AS, Lund MB, Valberg M, Brustugun OT, Solberg S, Kongerud J

Abstract
OBJECTIVES: Surgical resection is the recommended treatment for patients with early-stage non-small-cell lung cancer. However, it is believed that causes other than lung cancer can lead to death following surgical resection. Investigating the risk factors for overall mortality and analysing the specific causes of death may indicate the degree of influence of other causes of death.
METHODS: We assessed individual risk factors affecting overall and cause-specific mortality in a Cox proportional hazards model in a cohort of patients with resected Stage I/II non-small-cell lung cancer (n = 756) from 2007 to 2015 in a tertiary university centre. The follow-up period ranged from 3 days to 9.3 years. Median survival time was 7.3 years (95% confidence interval 6.0-7.9). A few patients died of cardiovascular disease (n = 19) and were included in the group 'other cause'. In a competing risk model, we evaluated the risk factors for specific causes of death in patients dying of lung cancer and dying of non-lung cancer specific conditions.
RESULTS: The overall survival was 94%, 62% and 50% at 1, 5 and 7 years, respectively. At the end of the follow-up period, the risk of having died of, respectively, lung cancer or other causes was 36% and 24%. The cumulative incidence of death of lung cancer increased continuously during the study. Risk factors predicting death of all causes and death of non-small-cell lung cancer were increasing age, severely reduced lung function, Eastern Cooperative Oncology Group Performance Status ≥2, preoperative examination without positron emission tomography/computed tomography, histological tumour diagnosis other than adenocarcinoma and squamous cell carcinoma and increasing disease stage. In patients dying of other causes, age, gender, body mass index, smoking and Eastern Cooperative Oncology Group Performance Status ≥2 affected the mortality rate.
CONCLUSIONS: The probability of having died of lung cancer continued to increase beyond 5 years after the operation. Surveillance of risk factors associated with an increased mortality rate should be considered in the postoperative follow-up examination after lung cancer resection.

PMID: 28950311 [PubMed - indexed for MEDLINE]

Cause-specific death after surgical resection for early-stage non-small-cell lung cancer.

Related Articles

Cause-specific death after surgical resection for early-stage non-small-cell lung cancer.

Eur J Cardiothorac Surg. 2018 Jan 01;53(1):221-227

Authors: Bugge AS, Lund MB, Valberg M, Brustugun OT, Solberg S, Kongerud J

Abstract
OBJECTIVES: Surgical resection is the recommended treatment for patients with early-stage non-small-cell lung cancer. However, it is believed that causes other than lung cancer can lead to death following surgical resection. Investigating the risk factors for overall mortality and analysing the specific causes of death may indicate the degree of influence of other causes of death.
METHODS: We assessed individual risk factors affecting overall and cause-specific mortality in a Cox proportional hazards model in a cohort of patients with resected Stage I/II non-small-cell lung cancer (n = 756) from 2007 to 2015 in a tertiary university centre. The follow-up period ranged from 3 days to 9.3 years. Median survival time was 7.3 years (95% confidence interval 6.0-7.9). A few patients died of cardiovascular disease (n = 19) and were included in the group 'other cause'. In a competing risk model, we evaluated the risk factors for specific causes of death in patients dying of lung cancer and dying of non-lung cancer specific conditions.
RESULTS: The overall survival was 94%, 62% and 50% at 1, 5 and 7 years, respectively. At the end of the follow-up period, the risk of having died of, respectively, lung cancer or other causes was 36% and 24%. The cumulative incidence of death of lung cancer increased continuously during the study. Risk factors predicting death of all causes and death of non-small-cell lung cancer were increasing age, severely reduced lung function, Eastern Cooperative Oncology Group Performance Status ≥2, preoperative examination without positron emission tomography/computed tomography, histological tumour diagnosis other than adenocarcinoma and squamous cell carcinoma and increasing disease stage. In patients dying of other causes, age, gender, body mass index, smoking and Eastern Cooperative Oncology Group Performance Status ≥2 affected the mortality rate.
CONCLUSIONS: The probability of having died of lung cancer continued to increase beyond 5 years after the operation. Surveillance of risk factors associated with an increased mortality rate should be considered in the postoperative follow-up examination after lung cancer resection.

PMID: 28950311 [PubMed - indexed for MEDLINE]

Theory Meets Practice for Immune Checkpoint Blockade in Small-Cell Lung Cancer.

Lungekreft i JCO, NEJM eller The Lancet - ons, 08/15/2018 - 05:00
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Theory Meets Practice for Immune Checkpoint Blockade in Small-Cell Lung Cancer.

J Clin Oncol. 2016 11 01;34(31):3717-3718

Authors: Riess JW, Lara PN, Gandara DR

PMID: 27601544 [PubMed - indexed for MEDLINE]

Comprehensive Geriatric Assessment-Guided Therapy Does Improve Outcomes of Older Patients With Advanced Lung Cancer.

Lungekreft i JCO, NEJM eller The Lancet - ons, 08/15/2018 - 05:00
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Comprehensive Geriatric Assessment-Guided Therapy Does Improve Outcomes of Older Patients With Advanced Lung Cancer.

J Clin Oncol. 2016 11 20;34(33):4047-4048

Authors: Gajra A, Loh KP, Hurria A, Muss H, Maggiore R, Dale W, Klepin HD, Magnuson A, Lichtman SM, Williams GR, Shahrokhni A, Mohile SG

PMID: 27551131 [PubMed - indexed for MEDLINE]

A Cola to Improve My EGFR TKI Absorption in Metastatic Non-Small-Cell Lung Cancer? No, Thank You, I Prefer Lemonade or Orange Juice Instead.

Lungekreft i JCO, NEJM eller The Lancet - ons, 08/15/2018 - 05:00
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A Cola to Improve My EGFR TKI Absorption in Metastatic Non-Small-Cell Lung Cancer? No, Thank You, I Prefer Lemonade or Orange Juice Instead.

J Clin Oncol. 2016 11 20;34(33):4053-4054

Authors: Singh N, Prasad KT

PMID: 27551118 [PubMed - indexed for MEDLINE]

Implications of Blood-Based T790M Genotyping and Beyond in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.

Lungekreft i JCO, NEJM eller The Lancet - ons, 08/15/2018 - 05:00
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Implications of Blood-Based T790M Genotyping and Beyond in Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer.

J Clin Oncol. 2016 10 01;34(28):3361-2

Authors: Rosell R, Karachaliou N

PMID: 27432918 [PubMed - indexed for MEDLINE]

Moving Programmed Death-1 Inhibitors to the Front Lines in Non-Small-Cell Lung Cancer.

Lungekreft i JCO, NEJM eller The Lancet - tor, 08/09/2018 - 02:00
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Moving Programmed Death-1 Inhibitors to the Front Lines in Non-Small-Cell Lung Cancer.

J Clin Oncol. 2016 09 01;34(25):2953-5

Authors: Gainor JF

PMID: 27382094 [PubMed - indexed for MEDLINE]

Targetable Lung Cancer Brain Metastases: Improved Outcome.

Lungekreft i JCO, NEJM eller The Lancet - tor, 08/09/2018 - 02:00
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Targetable Lung Cancer Brain Metastases: Improved Outcome.

J Clin Oncol. 2016 07 01;34(19):2315

Authors: Chamberlain MC

PMID: 27114601 [PubMed - indexed for MEDLINE]

Is It Time to Reconsider Prophylactic Cranial Radiation in Non-Small-Cell Lung Cancer?

Lungekreft i JCO, NEJM eller The Lancet - tor, 08/09/2018 - 02:00
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Is It Time to Reconsider Prophylactic Cranial Radiation in Non-Small-Cell Lung Cancer?

J Clin Oncol. 2016 07 01;34(19):2314

Authors: Copur MS, Ramaekers R, Clark D, Norvell M, Gauchan D

PMID: 27114597 [PubMed - indexed for MEDLINE]

Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials.

Norske artikler - tir, 08/07/2018 - 10:00
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Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials.

Acta Oncol. 2018 Aug 03;:1-6

Authors: Kristensen A, Solheim TS, Fløtten Ø, Grønberg BH

Abstract
BACKGROUND: Many patients experience toxicity from chemotherapy that may negatively impact their health-related quality of life (HRQoL), but side effects often go undetected by health care personnel. Our aim was to investigate whether hematologic toxicity (HT) was associated with HRQoL impairment, and, consequently, if blood counts could be used to identify patients with the highest need for supportive care during chemotherapy.
MATERIAL AND METHODS: Data from two phase III trials of first-line chemotherapy in advanced non-small-cell lung cancer (NSCLC) were analyzed (n = 873). Blood counts were measured weekly in the treatment period. We categorized patients as having severe (CTCAE grade 3-4) or non-severe (grade 0-2) HT during the first chemotherapy cycle. HRQoL was reported on the EORTC QLQ-C30 and LC13 before and at the end of the cycle. The primary endpoints were changes in global quality of life, fatigue, nausea/vomiting and dyspnea (LC13).
RESULTS: Of the 766 patients with complete data set, 177 (23%) developed severe HT during the first chemotherapy cycle. Changes in fatigue and nausea/vomiting were significantly worse for patients experiencing severe compared to patients with non-severe HT (difference in mean change of 4.9 points; p = .01, and 6.4 points; p = .01, respectively), but this association was limited to neutropenia, not thrombocytopenia or anemia. There were no significant associations between HT and global quality of life or dyspnea (difference in mean change of 2.1 points; p = .28, and 3.3 points; p = .053, respectively).
CONCLUSIONS: Patients developing severe HT had worse changes in two out of four of the primary HRQoL endpoints, but the association was not strong enough to use blood counts to identify patients who need more clinical attention and supportive care during chemotherapy.

PMID: 30074418 [PubMed - as supplied by publisher]

Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials.

Norsk publikasjonsliste - tir, 08/07/2018 - 10:00
Related Articles

Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials.

Acta Oncol. 2018 Aug 03;:1-6

Authors: Kristensen A, Solheim TS, Fløtten Ø, Grønberg BH

Abstract
BACKGROUND: Many patients experience toxicity from chemotherapy that may negatively impact their health-related quality of life (HRQoL), but side effects often go undetected by health care personnel. Our aim was to investigate whether hematologic toxicity (HT) was associated with HRQoL impairment, and, consequently, if blood counts could be used to identify patients with the highest need for supportive care during chemotherapy.
MATERIAL AND METHODS: Data from two phase III trials of first-line chemotherapy in advanced non-small-cell lung cancer (NSCLC) were analyzed (n = 873). Blood counts were measured weekly in the treatment period. We categorized patients as having severe (CTCAE grade 3-4) or non-severe (grade 0-2) HT during the first chemotherapy cycle. HRQoL was reported on the EORTC QLQ-C30 and LC13 before and at the end of the cycle. The primary endpoints were changes in global quality of life, fatigue, nausea/vomiting and dyspnea (LC13).
RESULTS: Of the 766 patients with complete data set, 177 (23%) developed severe HT during the first chemotherapy cycle. Changes in fatigue and nausea/vomiting were significantly worse for patients experiencing severe compared to patients with non-severe HT (difference in mean change of 4.9 points; p = .01, and 6.4 points; p = .01, respectively), but this association was limited to neutropenia, not thrombocytopenia or anemia. There were no significant associations between HT and global quality of life or dyspnea (difference in mean change of 2.1 points; p = .28, and 3.3 points; p = .053, respectively).
CONCLUSIONS: Patients developing severe HT had worse changes in two out of four of the primary HRQoL endpoints, but the association was not strong enough to use blood counts to identify patients who need more clinical attention and supportive care during chemotherapy.

PMID: 30074418 [PubMed - as supplied by publisher]

Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials.

Related Articles

Associations between hematologic toxicity and health-related quality of life during first-line chemotherapy in advanced non-small-cell lung cancer: a pooled analysis of two randomized trials.

Acta Oncol. 2018 Aug 03;:1-6

Authors: Kristensen A, Solheim TS, Fløtten Ø, Grønberg BH

Abstract
BACKGROUND: Many patients experience toxicity from chemotherapy that may negatively impact their health-related quality of life (HRQoL), but side effects often go undetected by health care personnel. Our aim was to investigate whether hematologic toxicity (HT) was associated with HRQoL impairment, and, consequently, if blood counts could be used to identify patients with the highest need for supportive care during chemotherapy.
MATERIAL AND METHODS: Data from two phase III trials of first-line chemotherapy in advanced non-small-cell lung cancer (NSCLC) were analyzed (n = 873). Blood counts were measured weekly in the treatment period. We categorized patients as having severe (CTCAE grade 3-4) or non-severe (grade 0-2) HT during the first chemotherapy cycle. HRQoL was reported on the EORTC QLQ-C30 and LC13 before and at the end of the cycle. The primary endpoints were changes in global quality of life, fatigue, nausea/vomiting and dyspnea (LC13).
RESULTS: Of the 766 patients with complete data set, 177 (23%) developed severe HT during the first chemotherapy cycle. Changes in fatigue and nausea/vomiting were significantly worse for patients experiencing severe compared to patients with non-severe HT (difference in mean change of 4.9 points; p = .01, and 6.4 points; p = .01, respectively), but this association was limited to neutropenia, not thrombocytopenia or anemia. There were no significant associations between HT and global quality of life or dyspnea (difference in mean change of 2.1 points; p = .28, and 3.3 points; p = .053, respectively).
CONCLUSIONS: Patients developing severe HT had worse changes in two out of four of the primary HRQoL endpoints, but the association was not strong enough to use blood counts to identify patients who need more clinical attention and supportive care during chemotherapy.

PMID: 30074418 [PubMed - as supplied by publisher]

CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non-Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3).

Lungekreft i JCO, NEJM eller The Lancet - tir, 08/07/2018 - 01:00
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CNS Efficacy of Osimertinib in Patients With T790M-Positive Advanced Non-Small-Cell Lung Cancer: Data From a Randomized Phase III Trial (AURA3).

J Clin Oncol. 2018 Jul 30;:JCO2018779363

Authors: Wu YL, Ahn MJ, Garassino MC, Han JY, Katakami N, Kim HR, Hodge R, Kaur P, Brown AP, Ghiorghiu D, Papadimitrakopoulou VA, Mok TSK

Abstract
Purpose In patients with epidermal growth factor receptor ( EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC), there is an unmet need for EGFR-tyrosine kinase inhibitors with improved CNS penetration and activity against CNS metastases, either at initial diagnosis or time of progression. We report the first comparative evidence of osimertinib CNS efficacy versus platinum-pemetrexed from a phase III study (AURA3; ClinicalTrials.gov identifier: NCT02151981) in patients with EGFR T790M-positive advanced NSCLC who experience disease progression with prior EGFR-tyrosine kinase inhibitor treatment. Methods Patients with asymptomatic, stable CNS metastases were eligible for enrollment and were randomly assigned 2:1 to osimertinib 80 mg once daily or platinum-pemetrexed. A preplanned subgroup analysis was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiological review. The CNS evaluable for response set included only patients with one or more measurable CNS lesions. The primary objective for this analysis was CNS objective response rate (ORR). Results Of 419 patients randomly assigned to treatment, 116 had measurable and/or nonmeasurable CNS lesions, including 46 patients with measurable CNS lesions. At data cutoff (April 15, 2016), CNS ORR in patients with one or more measurable CNS lesions was 70% (21 of 30; 95% CI, 51% to 85%) with osimertinib and 31% (5 of 16; 95% CI, 11% to 59%) with platinum-pemetrexed (odds ratio, 5.13; 95% CI, 1.44 to 20.64; P = .015); the ORR was 40% (30 of 75; 95% CI, 29% to 52%) and 17% (7 of 41; 95% CI, 7% to 32%), respectively, in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 3.24; 95% CI, 1.33 to 8.81; P = .014). Median CNS duration of response in patients with measurable and/or nonmeasurable CNS lesions was 8.9 months (95% CI, 4.3 months to not calculable) for osimertinib and 5.7 months (95% CI, 4.4 to 5.7 months) for platinum-pemetrexed; median CNS progression-free survival was 11.7 months and 5.6 months, respectively (hazard ratio, 0.32; 95% CI, 0.15 to 0.69; P = .004). Conclusion Osimertinib demonstrated superior CNS efficacy versus platinum-pemetrexed in T790M-positive advanced NSCLC.

PMID: 30059262 [PubMed - as supplied by publisher]

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

Norske artikler - lør, 08/04/2018 - 09:30
Related Articles

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

Int J Epidemiol. 2018 Jul 28;:

Authors: Kachuri L, Saarela O, Bojesen SE, Davey Smith G, Liu G, Landi MT, Caporaso NE, Christiani DC, Johansson M, Panico S, Overvad K, Trichopoulou A, Vineis P, Scelo G, Zaridze D, Wu X, Albanes D, Diergaarde B, Lagiou P, Macfarlane GJ, Aldrich MC, Tardón A, Rennert G, Olshan AF, Weissler MC, Chen C, Goodman GE, Doherty JA, Ness AR, Bickeböller H, Wichmann HE, Risch A, Field JK, Teare MD, Kiemeney LA, van der Heijden EHFM, Carroll JC, Haugen A, Zienolddiny S, Skaug V, Wünsch-Filho V, Tajara EH, Ayoub Moysés R, Daumas Nunes F, Lam S, Eluf-Neto J, Lacko M, Peters WHM, Le Marchand L, Duell EJ, Andrew AS, Franceschi S, Schabath MB, Manjer J, Arnold S, Lazarus P, Mukeriya A, Swiatkowska B, Janout V, Holcatova I, Stojsic J, Mates D, Lissowska J, Boccia S, Lesseur C, Zong X, McKay JD, Brennan P, Amos CI, Hung RJ

Abstract
Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.
Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.
Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.
Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

PMID: 30059977 [PubMed - as supplied by publisher]

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

Norsk publikasjonsliste - lør, 08/04/2018 - 09:30
Related Articles

Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.

Int J Epidemiol. 2018 Jul 28;:

Authors: Kachuri L, Saarela O, Bojesen SE, Davey Smith G, Liu G, Landi MT, Caporaso NE, Christiani DC, Johansson M, Panico S, Overvad K, Trichopoulou A, Vineis P, Scelo G, Zaridze D, Wu X, Albanes D, Diergaarde B, Lagiou P, Macfarlane GJ, Aldrich MC, Tardón A, Rennert G, Olshan AF, Weissler MC, Chen C, Goodman GE, Doherty JA, Ness AR, Bickeböller H, Wichmann HE, Risch A, Field JK, Teare MD, Kiemeney LA, van der Heijden EHFM, Carroll JC, Haugen A, Zienolddiny S, Skaug V, Wünsch-Filho V, Tajara EH, Ayoub Moysés R, Daumas Nunes F, Lam S, Eluf-Neto J, Lacko M, Peters WHM, Le Marchand L, Duell EJ, Andrew AS, Franceschi S, Schabath MB, Manjer J, Arnold S, Lazarus P, Mukeriya A, Swiatkowska B, Janout V, Holcatova I, Stojsic J, Mates D, Lissowska J, Boccia S, Lesseur C, Zong X, McKay JD, Brennan P, Amos CI, Hung RJ

Abstract
Background: Evidence from observational studies of telomere length (TL) has been conflicting regarding its direction of association with cancer risk. We investigated the causal relevance of TL for lung and head and neck cancers using Mendelian Randomization (MR) and mediation analyses.
Methods: We developed a novel genetic instrument for TL in chromosome 5p15.33, using variants identified through deep-sequencing, that were genotyped in 2051 cancer-free subjects. Next, we conducted an MR analysis of lung (16 396 cases, 13 013 controls) and head and neck cancer (4415 cases, 5013 controls) using eight genetic instruments for TL. Lastly, the 5p15.33 instrument and distinct 5p15.33 lung cancer risk loci were evaluated using two-sample mediation analysis, to quantify their direct and indirect, telomere-mediated, effects.
Results: The multi-allelic 5p15.33 instrument explained 1.49-2.00% of TL variation in our data (p = 2.6 × 10-9). The MR analysis estimated that a 1000 base-pair increase in TL increases risk of lung cancer [odds ratio (OR) = 1.41, 95% confidence interval (CI): 1.20-1.65] and lung adenocarcinoma (OR = 1.92, 95% CI: 1.51-2.22), but not squamous lung carcinoma (OR = 1.04, 95% CI: 0.83-1.29) or head and neck cancers (OR = 0.90, 95% CI: 0.70-1.05). Mediation analysis of the 5p15.33 instrument indicated an absence of direct effects on lung cancer risk (OR = 1.00, 95% CI: 0.95-1.04). Analysis of distinct 5p15.33 susceptibility variants estimated that TL mediates up to 40% of the observed associations with lung cancer risk.
Conclusions: Our findings support a causal role for long telomeres in lung cancer aetiology, particularly for adenocarcinoma, and demonstrate that telomere maintenance partially mediates the lung cancer susceptibility conferred by 5p15.33 loci.

PMID: 30059977 [PubMed - as supplied by publisher]