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Harnessing Clinical Sequencing Data for Survival Stratification of Patients with Metastatic Lung Adenocarcinomas.

ABSTRACT: Purpose:Broad panel sequencing of tumors facilitates routine care of people with cancer as well as clinical trial matching for novel genome-directed therapies. We sought to extend the use of broad panel sequencing results to survival stratification and clinical outcome prediction. Patients and Methods:Using sequencing results from a cohort of 1,054 patients with advanced lung adenocarcinomas, we developed OncoCast, a machine learning tool for survival risk stratification and biomarker identification. Results:With OncoCast, we stratified this patient cohort into four risk groups based on tumor genomic profile. Patients whose tumors harbored a high-risk profile had a median survival of 7.3 months (95% CI 5.5-10.9), compared to a low risk group with a median survival of 32.8 months (95% CI 26.3-38.5), with a hazard ratio of 4.6 (P<2e-16), far superior to any individual gene predictor or standard clinical characteristics. We found that co-mutations of both STK11 and KEAP1 are a strong determinant of unfavorable prognosis with currently available therapies. In patients with targetable oncogenes including EGFR/ALK/ROS1 and received targeted therapies, the tumor genetic background further differentiated survival with mutations in TP53 and ARID1A contributing to a higher risk score for shorter survival. Conclusion:Mutational profile derived from broad-panel sequencing presents an effective genomic stratification for patient survival in advanced lung adenocarcinoma. OncoCast is available as a public resource that facilitates the incorporation of mutational data to predict individual patient prognosis and compare risk characteristics of patient populations.

SUBMITTER: Shen R

PROVIDER: S-EPMC6474404 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Harnessing Clinical Sequencing Data for Survival Stratification of Patients with Metastatic Lung Adenocarcinomas.

Shen Ronglai R Martin Axel A Ni Ai A Hellmann Matthew M Arbour Kathryn C KC Jordan Emmet E Arora Arshi A Ptashkin Ryan R Zehir Ahmet A Kris Mark G MG Rudin Charles M CM Berger Michael F MF Solit David B DB Seshan Venkatraman E VE Arcila Maria M Ladanyi Marc M Riely Gregory J GJ

JCO precision oncology 20190328

<h4>Purpose</h4>Broad panel sequencing of tumors facilitates routine care of people with cancer as well as clinical trial matching for novel genome-directed therapies. We sought to extend the use of broad panel sequencing results to survival stratification and clinical outcome prediction.<h4>Patients and methods</h4>Using sequencing results from a cohort of 1,054 patients with advanced lung adenocarcinomas, we developed OncoCast, a machine learning tool for survival risk stratification and bioma ...[more]

PMID: 31008437

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Project description:Although the most predominant subtype of invasive lung adenocarcinoma has been reported to have clinical significance, a major limitation of this concept is that most tumors are mixed-subtype. Therefore, we aimed to determine the individual prognostic significance of each subtype and also attempted to establish a pathologic index that reflects the pathologic subtypes and overall heterogeneity of lung adenocarcinomas and evaluated its prognostic significance. The individual prognostic impact of each subtype was assessed from the development cohort using the disease-free survival (DFS) curve of a previous large-scale study. Hazard ratios (HRs) from the development cohort were 1, 1.025, 1.059, 1.495, and 1.160 for the lepidic, acinar, papillary, micropapillary, and solid pattern subtype, respectively. Based on the calculated HR of each subtype, four indices representing pathologic heterogeneity were developed. The first and second indices were defined as the sum of the proportions of each subtype multiplied by their HRs, with the addition of either entropy or Gini coefficient, respectively. The third index was calculated as the sum of all subtype percentages multiplied by their HRs. To emphasize heterogeneity, the fourth index was defined as the simple arithmetic sum of the scores of the subtypes multiplied by their HRs. Each subtype was assigned a score of 0 if the subtype was absent and a score of 1 if the subtype was present in a binary fashion. We applied these four pathologic indices to a validation group of 148 patients with comprehensive histologic subtyping for completely resected lung adenocarcinomas. DFS curves were plotted and predictive ability of each pathologic index was evaluated. Among the four pathologic indices, only pathologic index 3 enabled significant patient stratification in the validation cohort according to DFS (P = 0.004) and showed the highest Harrell's C index of 0.691 of all four pathologic indices. In conclusion, we estimated the HR of each subtype and generated four pathologic indices that reflect heterogeneity. One of these, index 3, the pathologic heterogeneity index based on the sum of all subtype percentages multiplied by their HR, possesses good prognostic ability for predicting survival in patients with lung adenocarcinoma.

Dataset Information

Harnessing Clinical Sequencing Data for Survival Stratification of Patients with Metastatic Lung Adenocarcinomas.

Publications

Harnessing Clinical Sequencing Data for Survival Stratification of Patients with Metastatic Lung Adenocarcinomas.

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