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Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.

ABSTRACT: Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.

SUBMITTER: Hassan R

PROVIDER: S-EPMC6500142 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.

Hassan Raffit R Morrow Betsy B Thomas Anish A Walsh Tom T Lee Ming K MK Gulsuner Suleyman S Gadiraju Meghana M Panou Vasiliki V Gao Shaojian S Mian Idrees I Khan Javed J Raffeld Mark M Patel Snehal S Xi Liqiang L Wei Jun S JS Hesdorffer Mary M Zhang Jingli J Calzone Kathleen K Desai Arpita A Padiernos Emerson E Alewine Christine C Schrump David S DS Steinberg Seth M SM Kindler Hedy L HL King Mary-Claire MC Churpek Jane E JE

Proceedings of the National Academy of Sciences of the United States of America 20190411 18

Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival follow ...[more]

PMID: 30975761

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Project description:Purpose/objectivesMalignant pleural mesothelioma (MPM) is a rare but aggressive cancer arising from the cells of the thoracic pleura with a poor prognosis. We aimed to develop a model, via interpretable machine learning (ML) methods, predicting overall survival for MPM following radiotherapy based on dosimetric metrics as well as patient characteristics.Materials/methodsSixty MPM (37 right, 23 left) patients treated on a Tomotherapy unit between 2013 and 2018 were retrospectively analyzed. All patients received 45 Gy (25 fractions). The multivariable Cox regression (Cox PH) model and Survival Support Vector Machine (sSVM) were applied to build predictive models of overall survival (OS) based on clinical, dosimetric, and combined variables.ResultsSignificant differences in dosimetric endpoints for critical structures, i.e., the lung, heart, liver, kidney, and stomach, were observed according to target laterality. The OS was found to be insignificantly different (p = 0.18) between MPM patients who tested left- and right-sided, with 1-year OS of 77.3% and 75.0%, respectively. With Cox PH regression, considering dosimetric variables for right-sided patients alone, an increase in PTV_Min, Total_Lung_PTV_Mean, Contra_Lung_Volume, Contra_Lung_V20, Esophagus_Mean, and Heart_Volume had a greater hazard to all-cause death, while an increase in Total_Lung_PTV_V20, Contra_Lung_V5, and Esophagus_Max had a lower hazard to all-cause death. Considering clinical variables alone, males and increases in N stage had greater hazard to all-cause death; considering both clinical and dosimetric variables, increases in N stage, PTV_Mean, PTV_Min, and esophagus_Mean had greater hazard to all-cause death, while increases in T stage and Heart_V30 had lower hazard to all-cause-death. In terms of C-index, the Cox PH model and sSVM performed similarly and fairly well when considering clinical and dosimetric variables independently or jointly.ConclusionsClinical and dosimetric variables may predict the overall survival of mesothelioma patients, which could guide personalized treatment planning towards a better treatment response. The identified predictors and their impact on survival offered additional value for translational application in clinical practice.

Project description:Standard-of-care first-line treatment for metastatic urothelial carcinoma (mUC) is platinum-based chemotherapy (CTx). Maintenance immunotherapy is a treatment option for patients without progressive disease (PD) after induction CTx. IMvigor130 was a randomised, phase 3 study evaluating atezolizumab plus platinum-based CTx (arm A), atezolizumab monotherapy (arm B), or placebo plus platinum-based CTx (arm C) as first-line treatment for mUC. The primary progression-free survival (PFS) analysis showed a statistically significant PFS benefit favouring arm A versus arm C, which did not translate into overall survival (OS) benefit at the final OS analysis. We report exploratory analyses based on response to combination induction treatment (arm A vs arm C) using final OS data. Post-induction OS was analysed for patients without PD during induction (4-6 CTx cycles) who received at least one dose of single-agent atezolizumab/placebo maintenance treatment. Post-progression OS was analysed for patients with PD during induction CTx. Addition of atezolizumab to CTx did not impact OS outcomes, regardless of response to induction CTx, with hazard ratios of 0.84 (95% confidence interval [CI] 0.63-1.10) for patients without PD and 0.75 (95% CI 0.54-1.05) for those with PD during induction CTx. Treatment effects appeared to be greatest for patients treated with cisplatin and for those with PD-L1-high tumours.Patient summaryThe IMvigor130 trial showed that addition of atezolizumab to chemotherapy (CTx) did not improve survival over CTx alone in patients with bladder cancer. Overall, patients whose cancer did not progress during initial treatment tended to live longer than patients whose cancer did progress, but addition of atezolizumab to CTx did not help either group live longer in comparison to CTx alone. However, the results suggest that patients who received a certain CTx drug (cisplatin) or who had high levels of a marker called PD-L1 in their tumour may get the most improvement from addition of atezolizumab to CTx.The IMvigor130 trial is registered on ClinicalTrials.gov as NCT02807636.

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Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.

Publications

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.

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