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Tumor mutational burden in lung cancer: a systematic literature review.

ABSTRACT: Purpose: To assess the association of tumor mutational burden (TMB) with clinical outcomes, other biomarkers and patient/disease characteristics in patients receiving therapy for lung cancer. Results: In total, 4,303 publications were identified; 81 publications were included. The majority of publications assessing clinical efficacy of immunotherapy reported an association with high TMB, particularly when assessing progression-free survival and objective response rate. High TMB was consistently associated with TP53 alterations, and negatively associated with EGFR mutations. High TMB was also associated with smoking, squamous cell non-small cell lung carcinoma, and being male. Methods: A systematic literature review based upon an a priori protocol was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane methodologies. Searches were conducted in EMBASE, SCOPUS, Ovid MEDLINE®, and Emcare (from January 2012 until April 2018) and in two clinical trial registries. Conference abstracts were identified in EMBASE, and in targeted searches of recent major conference proceedings (from January 2016 until April 2018). Publications reporting data in patients receiving therapy for lung cancer that reported TMB and its association with clinical efficacy, or with other biomarkers or patient/disease characteristics, were included. Results are presented descriptively. Conclusion: This systematic literature review identified several clinical outcomes, biomarkers, and patient/disease characteristics associated with high TMB, and highlights the need for standardized definitions and testing practices. Further studies using standardized methodology are required to inform treatment decisions.

SUBMITTER: Willis C

PROVIDER: S-EPMC6859921 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Tumor mutational burden in lung cancer: a systematic literature review.

Willis Connor C Fiander Michelle M Tran Dao D Korytowsky Beata B Thomas John-Michael JM Calderon Florencio F Zyczynski Teresa M TM Brixner Diana D Stenehjem David D DD

Oncotarget 20191112 61

<b>Purpose:</b> To assess the association of tumor mutational burden (TMB) with clinical outcomes, other biomarkers and patient/disease characteristics in patients receiving therapy for lung cancer. <b>Results:</b> In total, 4,303 publications were identified; 81 publications were included. The majority of publications assessing clinical efficacy of immunotherapy reported an association with high TMB, particularly when assessing progression-free survival and objective response rate. High TMB was ...[more]

PMID: 31762941

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Project description:BACKGROUND:Nivolumab plus ipilimumab showed promising efficacy for the treatment of non-small-cell lung cancer (NSCLC) in a phase 1 trial, and tumor mutational burden has emerged as a potential biomarker of benefit. In this part of an open-label, multipart, phase 3 trial, we examined progression-free survival with nivolumab plus ipilimumab versus chemotherapy among patients with a high tumor mutational burden (?10 mutations per megabase). METHODS:We enrolled patients with stage IV or recurrent NSCLC that was not previously treated with chemotherapy. Those with a level of tumor programmed death ligand 1 (PD-L1) expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy; those with a tumor PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. Tumor mutational burden was determined by the FoundationOne CDx assay. RESULTS:Progression-free survival among patients with a high tumor mutational burden was significantly longer with nivolumab plus ipilimumab than with chemotherapy. The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). The objective response rate was 45.3% with nivolumab plus ipilimumab and 26.9% with chemotherapy. The benefit of nivolumab plus ipilimumab over chemotherapy was broadly consistent within subgroups, including patients with a PD-L1 expression level of at least 1% and those with a level of less than 1%. The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy. ical; CheckMate 227 ClinicalTrials.gov number, NCT02477826 .). CONCLUSIONS:Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level. The results validate the benefit of nivolumab plus ipilimumab in NSCLC and the role of tumor mutational burden as a biomarker for patient selection. (Funded by Bristol-Myers Squibb and Ono Pharmaceut

Project description:BackgroundLung cancer is the leading cause of cancer death worldwide. With the growing number of targeted therapies and the introduction of immuno-oncology (IO), personalized medicine has become standard of care in patients with metastatic disease. The development of predictive and prognostic biomarkers is of great importance. Mutational signatures harbor potential clinical value as predictors of therapy response in cancer. Here we set out to investigate particular mutational processes by assessing mutational signatures and associations with clinical features, tumor mutational burden (TMB) and targetable mutations.MethodsIn this retrospective study, we studied tumor DNA from patients with non-small cell lung cancer (NSCLC) irrespective of stage. The samples were sequenced using a 2 megabase (Mb) gene panel. On each sample TMB was determined and defined as the total number of single nucleotide mutations per Mb (mut/Mb) including non-synonymous mutations. Mutational signature profiling was performed on tumor samples in which at least 30 somatic single base substitutions (SBS) were detected.ResultsIn total 195 samples were sequenced. Median total TMB was 10.3 mut/Mb (range 0-109.3). Mutational signatures were evaluated in 76 tumor samples (39%; median TMB 15.2 mut/Mb). SBS signature 4 (SBS4), associated with tobacco smoking, was prominently present in 25 of 76 samples (33%). SBS2 and/or SBS13, both associated with activity of the AID/APOBEC family of cytidine deaminases, were observed in 11 of 76 samples (14%). SBS4 was significantly more present in early stages (I and II) versus advanced stages (III and IV; P = .005).ConclusionIn a large proportion of NSCLC patients tissue panel sequencing with a 2 Mb panel can be used to determine the mutational signatures. In general, mutational signature SBS4 was more often found in early versus advanced stages of NSCLC. Further studies are needed to determine the clinical utility of mutational signature analyses.

Project description:Background and objectivesCancer poses a substantial health and economic burden on patients and caregivers in Canada. Previous reviews have estimated the indirect cost burden as work-related productivity losses associated with cancer. However, these estimates require updating and complementing with more comprehensive data that include relevant dimensions beyond labor market costs, such as patient time, lost leisure time and home productivity losses.MethodsA systematic review of the literature was conducted to identify studies published from 2006 to 2020 that measured and reported the indirect costs borne by cancer patients and their caregivers in Canada, from the patient, caregiver, employer, and societal perspectives. Study characteristics and cost estimation methods were extracted from relevant studies. Costs estimates were reported and converted to 2020 CAD for the following categories: lost earnings, caregiving time costs, home production losses, patient time (leisure), morbidity-, disability-, premature mortality-related costs, friction costs, and overall productivity losses. A quality assessment of individual studies was conducted for included studies using the Newcastle-Ottawa Assessment Tool.ResultsIn total, 3980 studies were identified, of which 18 Canadian studies met the inclusion criteria for review. One-third of the studies used or developed prediction models, 38% enrolled patient cohorts, and 27% used administrative databases. Over one-third of the studies were conducted at a national level (38%). All studies employed the human capital approach to estimate costs, and 16% also used the friction cost approach. Lost earnings were higher among self-employed patients (43% vs 24% among employees) and females ($8200 vs $3200 for males). Caregiver costs ranged from $15,786 to $20,414 per patient per year. Household productivity losses were estimated to be up to $238,904 per household per year. Patient time (leisure) costs were estimated to be between $13,000 and $18,704 per patient per year. Premature annual mortality costs were estimated to be $2.98 billion overall in Quebec. Friction costs incurred by employers were estimated between $6400 and $23,987 per patient per year. Societal productivity losses associated with cancer were estimated between $75 million to $317 million, annually.ConclusionsThis review suggests that the indirect cost burden of cancer is considerable from the patient, caregiver, employer, and societal perspectives. This up-to-date review of the literature provides a comprehensive understanding of the indirect cost burden by including non-labor market activity costs and by examining all relevant perspectives. These results provide a strong case for the government and employers to ensure there are supports in place to help patients and caregivers buffer the impact of cancer so they can continue to engage in productive activities and enjoy leisure time.

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Tumor mutational burden in lung cancer: a systematic literature review.

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Tumor mutational burden in lung cancer: a systematic literature review.

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