JAMA Network Open

Our medical research library holds 11 studies published in JAMA Network Open (2019–2023). Each entry links to the study's record on PubMed and, where there is one, to the publisher's page and a free full text. 11 have an abstract, the authors' own summary as PubMed records it: open "Abstract" to read it.

About the journal

• Publisher: American Medical Association
• Published: 2018 to the present, United States
• Language: English
• ISSN: 2574-3805 (electronic)
• Its record in the NLM Catalog

2020s

• Clinical Outcomes Associated With Pembrolizumab Monotherapy Among Adults With Diffuse Malignant Peritoneal Mesothelioma. M.E. Marmarelis, X. Wang, L. Roshkovan, et al. 2023;6(3):e232526. PubMed · Publisher · Free full text

  Abstract

  Importance: Diffuse malignant peritoneal mesothelioma (DMPM) represents a rare and clinically distinct entity among malignant mesotheliomas. Pembrolizumab has activity in diffuse pleural mesothelioma but limited data are available for DMPM; thus, DMPM-specific outcome data are needed.

  Objective: To evaluate outcomes after the initiation of pembrolizumab monotherapy in the treatment of adults with DMPM.

  Design, Setting, And Participants: This retrospective cohort study was conducted in 2 tertiary care academic cancer centers (University of Pennsylvania Hospital Abramson Cancer Center and Memorial Sloan Kettering Cancer Center). All patients with DMPM treated between January 1, 2015, and September 1, 2019, were retrospectively identified and followed until January 1, 2021. Statistical analysis was performed between September 2021 and February 2022.

  Exposures: Pembrolizumab (200 mg or 2 mg/kg every 21 days).

  Main Outcomes And Measures: Median progression-free survival (PFS) and median overall survival (OS) were assessed using Kaplan-Meier estimates. The best overall response was determined using RECIST (Response Evaluation Criteria in Solid Tumors) criteria, version 1.1. The association of disease characteristics with partial response was evaluated using the Fisher exact test.

  Results: This study included 24 patients with DMPM who received pembrolizumab monotherapy. Patients had a median age of 62 years (IQR, 52.4-70.6 years); 14 (58.3%) were women, 18 (75.0%) had epithelioid histology, and most (19 [79.2%]) were White. A total of 23 patients (95.8%) received systemic chemotherapy prior to pembrolizumab, and the median number of lines of prior therapy was 2 (range, 0-6 lines). Of the 17 patients who underwent programmed death ligand 1 (PD-L1) testing, 6 (35.3%) had positive tumor PD-L1 expression (range, 1.0%-80.0%). Of the 19 evaluable patients, 4 (21.0%) had a partial response (overall response rate, 21.1% [95% CI, 6.1%-46.6%]), 10 (52.6%) had stable disease, and 5 (26.3%) had progressive disease (5 of 24 patients [20.8%] were lost to follow-up). There was no association between a partial response and the presence of a BAP1 alteration, PD-L1 positivity, or nonepithelioid histology. With a median follow-up of 29.2 (95% CI, 19.3 to not available [NA]) months, the median PFS was 4.9 (95% CI, 2.8-13.3) months and the median OS was 20.9 (95% CI, 10.0 to NA) months from pembrolizumab initiation. Three patients (12.5%) experienced PFS of more than 2 years. Among patients with nonepithelioid vs epithelioid histology, there was a numeric advantage in median PFS (11.5 [95% CI, 2.8 to NA] vs 4.0 [95% CI, 2.8-8.8] months) and median OS (31.8 [95% CI, 8.3 to NA] vs 17.5 [95% CI, 10.0 to NA] months); however, this did not reach statistical significance.

  Conclusions And Relevance: The results of this retrospective dual-center cohort study of patients with DMPM suggest that pembrolizumab had clinical activity regardless of PD-L1 status or histology, although patients with nonepithelioid histology may have experienced additional clinical benefit. The partial response rate of 21.0% and median OS of 20.9 months in this cohort with 75.0% epithelioid histology warrants further investigation to identify those most likely to respond to immunotherapy.

• Disparities in Survival Due to Social Determinants of Health and Access to Treatment in US Patients With Operable Malignant Pleural Mesothelioma. A. Alnajar, S.A. Kareff, S.S. Razi, et al. 2023;6(3):e234261. PubMed · Publisher · Free full text

  Abstract

  Importance: Outcomes of localized malignant pleural mesothelioma (MPM) remain poor despite multimodality therapy. It is unclear what role disparities have in the overall survival (OS) of patients with operable MPM.

  Objective: To examine survival disparities associated with social determinants of health (SDOHs) and treatment access in patients with malignant pleural mesothelioma.

  Design, Setting, And Participants: In this observational, retrospective cohort study, patients with MPM diagnosed between January 1, 2004, and December 31, 2017, were identified from the National Cancer Database with a maximum follow-up time of 13.6 years. The analysis was conducted from February 16, 2022, to July 29, 2022. Patients were included if they were diagnosed with potentially resectable clinical stage I to IIIA MPM, had epithelioid and biphasic histologic subtypes, and received chemotherapy. Patients were excluded if they could not receive curative surgery, were 75 years or older, or had metastasis, unknown stage, or tumor extension to the chest wall, mediastinal tissues, or organs.

  Exposures: Chemotherapy alone vs chemotherapy with curative surgery in the form of pleurectomy and decortication or extrapleural pneumonectomy.

  Main Outcomes And Measures: The primary end point was OS. Cox proportional hazards regression models were used to determine hazard ratios (HRs) for OS, including univariable and multivariable models controlling for potential confounders, including demographic, comorbidity, clinical, treatment, tumor, and hospital-related variables, as well as SDOHs.

  Results: A total of 1389 patients with MPM were identified (median [IQR] age, 66 [61-70] years; 1024 [74%] male; 12 [1%] Asian, 49 [3%] Black, 74 [5%] Hispanic, 1233 [89%] White, and 21 [2%] of other race). The median OS was 1.7 years (95% CI, 1.6-1.8). Risk factors associated with worse OS included older age, male sex, Black race, low income, and low educational attainment. Factors associated with greater odds of survival included receipt of surgical therapy, recent year of treatment, increased distance to travel, and treatment at high-volume academic hospitals. The risk factors most strongly associated with poor OS included Black race (HR, 1.96; 95% CI, 1.43-2.69) and male sex (HR, 1.60; 95% CI, 1.38-1.86). Surgical treatment in addition to systemic chemotherapy (HR, 0.70; 95% CI, 0.61-0.81) was independently associated with improved OS, as were chemotherapy initiation (HR, 0.93; 95% CI, 0.87-0.99) and greater travel distance from the hospital (HR, 0.92; 95% CI, 0.86-0.98).

  Conclusions And Relevance: In this retrospective cohort study of patients with operable MPM, there was significant variability in access to care by SDOHs. Addressing disparities in access to multimodality therapy can help ensure equity of care for patients with MPM.

• Germline Variants Incidentally Detected via Tumor-Only Genomic Profiling of Patients With Mesothelioma. O.D. Mitchell, K. Gilliam, D. Del Gaudio, et al. 2023;6(8):e2327351. PubMed · Publisher · Free full text

  Abstract

  Importance: Patients with mesothelioma often have next-generation sequencing (NGS) of their tumor performed; tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS.

  Objective: To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma.

  Design, Setting, And Participants: A series of 161 unrelated patients with mesothelioma from a high-volume mesothelioma program had tumor-only and germline NGS performed during April 2016 to October 2021. Follow-up ranged from 18 months to 7 years. Tumor and germline assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin. Data were analyzed from January to March 2023.

  Main Outcomes And Measures: The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS.

  Results: Of 161 patients with mesothelioma, 105 were male (65%), the mean (SD) age was 64.7 (11.2) years, and 156 patients (97%) self-identified as non-Hispanic White. Most (126 patients [78%]) had at least 1 potentially incidental P/LP germline variant. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 26 patients (16%) carried a P/LP germline variant. Germline P/LP variants were identified in ATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127.

  Conclusions And Relevance: In this case series of 161 patients with mesothelioma, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.

• Comparison of 3 Randomized Clinical Trials of Frontline Therapies for Malignant Pleural Mesothelioma. T. Meirson, F. Pentimalli, F. Cerza, et al. 2022;5(3):e221490. PubMed · Publisher · Free full text

  Abstract

  Importance: Some recently proposed frontline therapies for malignant pleural mesothelioma (MPM) are very costly, yet their impact on quality of life and overall survival of these patients remains arguable. Given the high social toll of this aggressive occupational cancer, it is paramount to establish the real clinical benefit of these treatments.

  Objective: To directly compare and analyze the statistical robustness of the 3 randomized clinical trials (RCTs) of frontline therapies recommended for MPM since 2003.

  Design, Setting, And Participants: This comparative effectiveness study assessed the following phase 3 RCTs: the Mesothelioma Cisplatin Pemetrexed Study (MPS) of cisplatin plus pemetrexed vs cisplatin; the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS) of cisplatin plus pemetrexed plus bevacizumab vs cisplatin plus pemetrexed; and the CheckMate743 (CM743) study of nivolumab plus ipilimumab vs cisplatin plus pemetrexed. Data collection dates for the RCTs ranged from April 1999 to April 2018. Data for this study were analyzed from February to October 2021.

  Main Outcomes And Measures: Patient selection criteria, superiority of the intervention groups, survival-inferred fragility index, and censoring patterns in each RCT.

  Results: A total of 1501 patients were included in the analysis (1170 men [77.9%]; range of median age for treatment groups, 60 [IQR, 19-84] to 69 [IQR, 65-75] years). A virtual comparison of overall survival in MAPS vs the CM743 study showed no statistically significant difference (hazard ratio [HR], 0.97 [95% CI, 0.79-1.20]; P = .79), and the survival-inferred fragility index in the intention-to-treat (ITT) populations was as low as 0.22% of the total sample size in MPS, -0.45% of the total sample size in MAPS, and 0.99% of the total sample size in the CM743 trial. Moreover, reverse restricted mean survival time (RMST) analysis of overall survival using RMST-difference (RMST-D) demonstrated differential censoring in the ITT population of the CM743 trial favoring the control group (0.56 [95% CI, 0.18-0.94]; P = .004) and in the nonepithelioid group (reverse RMST-D, 0.90 [95% CI, 0.001-1.79]; P = .048).

  Conclusions And Relevance: This comparative effectiveness study found no survival benefit in the CM743 trial over MAPS, despite the inclusion of patients with worse prognosis in the latter trial. Moreover, the statistical conclusions of all the examined trials were shown to be extremely fragile, and the findings of differential censoring in the CM743 trial and in the ITT nonepithelial subset raised additional areas of concern. These findings suggest that selection criteria, fragility, and censoring patterns may affect the original conclusions drawn for the respective trials, casting a shadow on the real benefit. This model of analysis lays a rigorous groundwork extendable to trials of all cancer treatments before their registration.

• Lung Cancer Screening in Individuals With and Without Lung-Related Comorbidities. E.M. Metwally, M.P. Rivera, D.D. Durham, et al. 2022;5(9):e2230146. PubMed · Publisher · Free full text

  Abstract

  Importance: Comorbidities characterize the underlying health status of individuals. In the context of lung cancer screening (LCS), lung-related comorbidities may influence the observed benefits and harms.

  Objective: To compare the characteristics of individuals undergoing LCS, the LCS examination result, the cancer detection rate (CDR), and the false-positive rate (FPR) in those with and without lung-related comorbidities.

  Design, Setting, And Participants: A prospective cohort study was conducted in 5 academic and community screening sites across North Carolina from January 1, 2014, to November 7, 2020. Participants included 611 individuals screened for lung cancer who completed a 1-page health history questionnaire.

  Exposures: Presence of at least 1 self-reported lung-related comorbidity, including chronic obstructive pulmonary disease, chronic bronchitis, emphysema, asthma, bronchiectasis, pulmonary fibrosis, silicosis, asbestosis, sarcoidosis, and tuberculosis.

  Main Outcomes And Measures: The LCS examination result was determined from the radiologist's Lung Imaging Reporting and Data System assessment (negative, 1 or 2; positive, 3 or 4). The age-adjusted CDR and FPR were calculated per 100 LCS examinations, using binary logistic regression.

  Results: Among the 611 individuals screened for lung cancer (308 men [50.4%]; mean [SD] age, 64 [6.2] years), 335 (54.8%) had at least 1 lung-related comorbidity. Individuals with vs without lung-related comorbidities were more likely to be female than male (180 of 335 [53.7%] vs 123 of 276 [44.6%]; P = .02), White vs non-White race (275 of 326 [84.4%] vs 193 of 272 [71.0%]; P < .001), and have high school or less education vs greater than a high school education (108 of 231 [46.7%] vs 64 of 208 [30.8%]; P = .001). There were no significant differences in the proportion of positive LCS examinations in those with vs without a lung-related comorbidity at baseline (37 [16.0%] vs 22 [11.1%]; P = .14) or subsequent (40 [12.3%] vs 23 [10.6%]; P = .54) LCS examination. Comparing individuals with vs without lung-related comorbidities, there was no statistically significant difference in the CDR (1.6 vs 1.9 per 100; P = .73) or FPR (13.0 vs 9.3 per 100; P = .16). Of the 17 individuals with lung cancer, 13 patients (76.5%) were diagnosed with stage I lung cancer.

  Conclusions And Relevance: The findings of this study suggest that individuals with self-reported lung-related comorbidities undergoing LCS were more likely to be female, of White race, and have less education than those without lung-related comorbidity. Although no statistically significant differences in the proportion of positive examinations, CDR, or FPR by self-reported lung comorbidities were noted, additional studies with larger numbers of individuals undergoing screening are needed to understand LCS outcomes in those with lung-related comorbidities.

• Assessment of Global Trends in the Diagnosis of Mesothelioma From 1990 to 2017. Z. Zhai, J. Ruan, Y. Zheng, et al. 2021;4(8):e2120360. Historical article PubMed · Publisher · Free full text

  Abstract

  Importance: It is difficult for policy makers and clinicians to formulate targeted management strategies for mesothelioma because data on current epidemiological patterns worldwide are lacking.

  Objective: To evaluate the mesothelioma burden across the world and describe its epidemiological distribution over time and by sociodemographic index (SDI) level, geographic location, sex, and age.

  Design, Setting, And Participants: Annual case data and age-standardized rates of incidence, death, and disability-adjusted life-years associated with mesothelioma among different age groups were obtained from the Global Burden of Disease 2017 database. The estimated annual percentage changes in age-standardized rates were calculated to evaluate temporal trends in incidence and mortality. The study population comprised individuals from 21 regions in 195 countries and territories who were diagnosed with mesothelioma between 1990 and 2017. Data were collected from May 23, 2019, to January 18, 2020.

  Main Outcomes And Measures: Primary outcomes were incident cases, deaths, and their age-standardized rates and estimated annual percentage changes. Secondary outcomes were disability-adjusted life-years and relative temporal trends.

  Results: Overall, 34 615 new cases (95% uncertainty interval [UI], 33 530-35 697 cases) of mesothelioma and 29 909 deaths (95% UI, 29 134-30 613 deaths) associated with mesothelioma were identified in 2017, and more than 70% of these cases and deaths were among male individuals. In 1990, the number of incident cases was 21 224 (95% UI, 17 503-25 450), and the number of deaths associated with mesothelioma was 17 406 (95% UI, 14 495-20 660). These numbers increased worldwide from 1990 to 2017, with more than 50% of cases recorded in regions with high SDI levels, whereas the age-standardized incidence rate (from 0.52 [95% UI, 0.43-0.62] in 1990 to 0.44 [95% UI, 0.42-0.45] in 2017) and the age-standardized death rate (from 0.44 [95% UI, 0.37-0.52] in 1990 to 0.38 [95% UI, 0.37-0.39] in 2017) decreased, with estimated annual percentage changes of -0.61 (95% CI, -0.67 to -0.54) for age-standardized incidence rate and -0.44 (95% CI, -0.52 to -0.37) for age-standardized death rate. The proportion of incident cases among those 70 years or older continued to increase (from 36.49% in 1990 to 44.67% in 2017), but the proportion of patients younger than 50 years decreased (from 16.74% in 1990 to 13.75% in 2017) over time. In addition, mesothelioma incident cases and age-standardized incidence rates began to decrease after 20 years of a complete ban on asbestos use. For example, in Italy, a complete ban on asbestos went into effect in 1992; incident cases increased from 1409 individuals (95% UI, 1013-1733 individuals) in 1990, peaked in 2015 after 23 years of the asbestos ban, then decreased from 1820 individuals (95% UI, 1699-1981 individuals) in 2015 to 1746 individuals (95% UI, 1555-1955 individuals) in 2017.

  Conclusions And Relevance: This cross-sectional study found that incident cases of mesothelioma and deaths associated with mesothelioma continuously increased worldwide, especially in resource-limited regions with low SDI levels. Based on these findings, global governments and medical institutions may consider formulating optimal policies and strategies for the targeted prevention and management of mesothelioma.

• Assessment of Risk of Hereditary Predisposition in Patients With Melanoma and/or Mesothelioma and Renal Neoplasia. S. Gupta, L.A. Erickson, C.M. Lohse, et al. 2021;4(11):e2132615. PubMed · Publisher · Free full text

  Abstract

  Importance: In BAP1 tumor predisposition syndrome, clear cell renal cell carcinoma (RCC) is frequently associated with melanoma and/or mesothelioma, while germline MITF p.E318K alterations are being increasingly reported in melanoma/RCC. Limited data exist on the co-occurrence of melanoma and/or mesothelioma with renal neoplasia and the prevalence of associated germline alterations.

  Objective: To assess the frequency of melanoma and/or mesothelioma co-occurring with renal neoplasia using our institutional nephrectomy registry and to determine the prevalence of BAP1 and MITF alterations within this cohort.

  Design, Setting, And Participants: In this genetic association study, medical records from 8295 patients from 1970 to 2018, renal neoplasia co-occurring with melanoma and/or mesothelioma within a single institutional nephrectomy registry was reevaluated based on contemporary histopathologic criteria and the medical records were reviewed. Data were analyzed from September 2019 to May 2021.

  Main Outcomes And Measures: Identified cases were screened for BAP1 loss using immunohistochemistry; while patients with melanoma and clear cell RCC were screened for MITF p.E318K alterations. Tumors from patients with potential germline alterations were analyzed with comprehensive molecular profiling using a 514-gene next generation sequencing panel.

  Results: Of a total of 8295 patients, 93 (1.1%; 95% CI, 0.9%-1.4%) had melanoma and/or mesothelioma co-occurring with renal neoplasia (cutaneous melanoma, n = 76; uveal melanoma, n = 11; mesothelioma, n = 6). A total of 69 (74.2%) were male; 24 (25.8%) were female; median age at diagnosis of renal neoplasia was 63 years (IQR, 58-70 years) and the median duration of follow-up was 8.5 years (IQR, 5.0-14.6 years). Two patients with clear cell RCC had germline BAP1 alterations in the setting of cutaneous melanoma and mesothelioma. Two patients with hybrid oncocytic tumors had biallelic inactivation of FLCN in a setting of Birt-Hogg-Dubé (BHD) syndrome associated with uveal melanoma and mesothelioma. Tumor-only screening of clear cell RCC associated with cutaneous (n = 53) and uveal melanoma (n = 6) led to the identification of 1 patient with a likely germline MITF p.E318K alteration. After excluding benign renal neoplasia (such as oncocytoma and angiomyolipoma), alterations of BAP1, FLCN, and MITF were identified in 5 of 81 patients (6.2%) with melanoma and/or mesothelioma and renal neoplasia. In contrast to hybrid oncocytic tumors in BHD, no unique genotype-phenotype correlations were seen for clear cell RCC with pathogenic BAP1/ MITF alterations and VHL loss of function variants. Four of 5 cases (80%) met current National Comprehensive Cancer Network criteria for germline testing based on a combination of age, multifocality, histologic findings, and family history.

  Conclusions And Relevance: In this genetic association study, findings support the continued use of these National Comprehensive Cancer Network criteria and suggest more stringent screening may be warranted in this patient population.

• Association of 13 Occupational Carcinogens in Patients With Cancer, Individually and Collectively, 1990-2017. N. Li, Z. Zhai, Y. Zheng, et al. 2021;4(2):e2037530. PubMed · Publisher · Free full text

  Abstract

  Importance: Occupational exposure to carcinogens has been shown to pose a serious disease burden at the global, regional, and national levels. Based on epidemiologic studies and clinical observations, working environment appears to have important effects on the occurrence of human malignant tumors; however, to date, no systematic articles have been published that specifically investigated cancer burden due to occupational exposure in an individual and collective manner.

  Objective: To estimate the degree of exposure and evaluate the cancer burden attributable to occupational carcinogens (OCs) individually and collectively by sex, age, year, and location.

  Design, Setting, And Participants: Cross-sectional study including data on 195 countries from the Global Burden of Diseases, Injuries, and Risk Factors Study from January 1, 1990, to December 31, 2017. Data were analyzed from June 24, 2020, to July 20, 2020.

  Exposures: Thirteen OCs (ie, arsenic, asbestos, benzene, beryllium, cadmium, chromium, diesel engine exhaust, formaldehyde, nickel, polycyclic aromatic hydrocarbons, silica, sulfuric acid, and trichloroethylene).

  Main Outcomes And Measures: The degree and change patterns of exposure as well as the attributable cancer burden, including deaths and disability-adjusted life years (DALYs), by sex, age, year, and location for 13 OCs. The calculation of the population-attributable fraction was based on past exposure in the population and relative risks.

  Results: Based on the GBD 2017 study, 13 OCs attributable to 7 cancer types were included. Most summary exposure values for the 13 OCs, particularly those of diesel engine exhaust (35.6% increase; 95% uncertainty interval [UI], 32.4%-38.5%) and trichloroethylene (30.3% increase; 95% UI, 27.3%-33.5%), increased from 1990 to 2017. Only exposure to asbestos decreased by 13.8% (95% UI, -26.7% to 2.2%). In 2017, 319 000 (95% UI, 256 000-382 000) cancer deaths and 6.42 million (95% UI, 5.15 million to 7.76 million) DALYs were associated with OCs combined, accounting for 61.0% (95% UI, 59.6%-62.4%) of the total cancer deaths and 48.3% (46.3% to 50.2%) of the DALYs. Among the 13 OCs, the 3 leading risk factors for cancer burden were asbestos (71.8%), silica (15.4%), and diesel engine exhaust (5.6%). For most OCs, the attributed cancer outcome was tracheal, bronchial, and lung cancer, which accounted for 89.0% of attributable cancer deaths. China (61 644 cancer deaths), the US (42 848), and Japan (20 748) accounted for the largest number of attributable cancer deaths in 2017; for DALYs, China (1.47 million), the US (0.71 million), and India (0.37 million) were the 3 leading countries.

  Conclusions And Relevance: Results of this study suggest that although OC exposure levels have decreased, the overall cancer burden is continuously increasing.

• Clinical Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Malignant Peritoneal Mesothelioma. K. Raghav, S. Liu, M. Overman, et al. 2021;4(8):e2119934. Letter PubMed · Publisher · Free full text

  Abstract

  This cohort study examines the clinical efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced malignant peritoneal mesothelioma.

• Prevalence of High Tumor Mutational Burden and Association With Survival in Patients With Less Common Solid Tumors. C. Shao, G. Li, L. Huang, et al. 2020;3(10):e2025109. PubMed · Publisher · Free full text

  Abstract

  Importance: Tumor mutational burden (TMB) is a potential biomarker associated with response to immune checkpoint inhibitor therapies. The prognostic value associated with TMB in the absence of immunotherapy is uncertain.

  Objective: To assess the prevalence of high TMB (TMB-H) and its association with overall survival (OS) among patients not treated with immunotherapy with the same 10 tumor types from the KEYNOTE-158 study.

  Design, Setting, And Participants: This retrospective cohort study evaluated the prognostic value of TMB-H, assessed by Foundation Medicine (FMI) and defined as at least 10 mutations/megabase (mut/Mb) in the absence of immunotherapy. Data were sourced from the deidentified Flatiron Health-FMI clinicogenomic database collected up to July 31, 2018. Eligible patients were aged 18 years or older with any of the following solid cancer types: anal, biliary, endometrial, cervical, vulvar, small cell lung, thyroid, salivary gland, mesothelioma, or neuroendocrine tumor. Patients with microsatellite instability-high tumors were excluded from primary analysis. For OS analysis, patients were excluded if immunotherapy started on the FMI report date or earlier or if patients died before January 1, 2012, and patients were censored if immunotherapy was started later than the FMI report date. Data were analyzed from November 2018 to February 2019.

  Main Outcomes And Measures: Overall survival was analyzed using the Kaplan-Meier method and Cox proportional hazards model, adjusting for age, sex, cancer types, practice type, and albumin level.

  Results: Of 2589 eligible patients, 1671 (64.5%) were women, and the mean (SD) age was 63.7 (11.7) years. Median (interquartile range) TMB was 2.6 (1.7-6.1) mut/Mb, and 332 patients (12.8%) had TMB-H (≥10 mut/Mb). Prevalence of TMB-H was highest among patients with small cell lung cancer (40.0%; 95% CI, 34.7%-45.6%) and neuroendocrine tumor (29.3%; 95% CI, 22.8%-36.6%) and lowest was among patients with mesothelioma (1.2%; 95% CI, 0.3%-4.4%) and thyroid cancer (2.7%; 95% CI, 1.2%-5.7%). Adjusted hazard ratio for OS of patients not treated with immunotherapy with TMB-H vs those without TMB-H was 0.94 (95% CI, 0.77-1.13). Comparable results were observed when including patients with high microsatellite instability tumors and calculating OS from first observed antineoplastic treatment date.

  Conclusions And Relevance: These findings suggest that prevalence of TMB-H varies widely depending on tumor type and TMB-H does not appear to be a factor associated with OS among patients across these cancer types treated in the absence of immunotherapy.

2010s

• Application of a Neural Network Whole Transcriptome-Based Pan-Cancer Method for Diagnosis of Primary and Metastatic Cancers. J.K. Grewal, B. Tessier-Cloutier, M. Jones, et al. 2019;2(4):e192597. PubMed · Publisher · Free full text

  Abstract

  Importance: A molecular diagnostic method that incorporates information about the transcriptional status of all genes across multiple tissue types can strengthen confidence in cancer diagnosis.

  Objective: To determine the practical use of a whole transcriptome-based pan-cancer method in diagnosing primary and metastatic cancers and resolving complex diagnoses.

  Design, Setting, And Participants: This cross-sectional diagnostic study assessed Supervised Cancer Origin Prediction Using Expression (SCOPE), a machine learning method using whole-transcriptome RNA sequencing data. Training was performed on publicly available primary cancer data sets, including The Cancer Genome Atlas. Testing was performed retrospectively on untreated primary cancers and treated metastases from volunteer adult patients at BC Cancer in Vancouver, British Columbia, from January 1, 2013, to March 31, 2016, and testing spanned 10 822 samples and 66 output classes representing untreated primary cancers (n = 40) and adjacent normal tissues (n = 26). SCOPE's performance was demonstrated on 211 untreated primary mesothelioma cancers and 201 treatment-resistant metastatic cancers. Finally, SCOPE was used to identify the putative site of origin in 15 cases with initial presentation as cancers with unknown primary of origin.

  Results: A total of 10 688 adult patient samples representing 40 untreated primary tumor types and 26 adjacent-normal tissues were used for training. Demographic data were not available for all data sets. Among the training data set, 5157 of 10 244 (50.3%) were male and the mean (SD) age was 58.9 (14.5) years. Testing was performed on 211 patients with untreated primary mesothelioma (173 [82.0%] male; mean [SD] age, 64.5 [11.3] years); 201 patients with treatment-resistant cancers (141 [70.1%] female; mean [SD] age, 55.6 [12.9] years); and 15 patients with cancers of unknown primary of origin; among the treatment-resistant cancers, 168 were metastatic, and 33 were the primary presentation. An accuracy rate of 99% was obtained for primary epithelioid mesotheliomas tested (125 of 126). The remaining 85 mesotheliomas had a mixed etiology (sarcomatoid mesotheliomas) and were correctly identified as a mixture of their primary components, with potential implications in resolving subtypes and incidences of mixed histology. SCOPE achieved an overall mean (SD) accuracy rate of 86% (11%) and F1 score of 0.79 (0.12) on the 201 treatment-resistant cancers and matched 12 of 15 of the putative diagnoses for cancers with indeterminate diagnosis from conventional pathology.

  Conclusions And Relevance: These results suggest that machine learning approaches incorporating multiple tumor profiles can more accurately identify the cancerous state and discriminate it from normal cells. SCOPE uses the whole transcriptomes from normal and tumor tissues, and results of this study suggest that it performs well for rare cancer types, primary cancers, treatment-resistant metastatic cancers, and cancers of unknown primary of origin. Genes most relevant in SCOPE's decision making were examined, and several are known biological markers of respective cancers. SCOPE may be applied as an orthogonal diagnostic method in cases where the site of origin of a cancer is unknown, or when standard pathology assessment is inconclusive.

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