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Original Investigation
December 23, 2020

A Genomic-Pathologic Annotated Risk Model to Predict Recurrence in Early-Stage Lung Adenocarcinoma

Author Affiliations
  • 1Thoracic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
  • 3Druckenmiller Center for Lung Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York
  • 4Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 5Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
  • 6Weill Cornell Medicine, New York, New York
  • 7Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 8Department of Pediatrics, Meyer Cancer Center, Weill Cornell Medicine, New York, New York
  • 9Department of Pathology, Weill Cornell Medicine, New York Genome Center, New York
  • 10Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville
JAMA Surg. 2021;156(2):e205601. doi:10.1001/jamasurg.2020.5601
Key Points

Question  Can the integration of genomic and clinicopathologic features predict recurrence better than the TNM system after complete resection of early-stage lung adenocarcinoma (LUAD)?

Findings  In this observational study of 426 patients with LUAD, alterations in SMARCA4 and TP53 and fraction of genome altered were independently associated with relapse-free survival. By integrating genomic and clinicopathologic factors, this prediction model outperformed the TNM-based model (concordance probability estimate, 0.73 vs 0.61) for prediction of relapse-free survival and was externally validated using The Cancer Genome Atlas data set.

Meaning  These findings suggest that integration of genomic and clinicopathologic factors are associated with risk of recurrence in surgically resected LUAD, potentially enriching and increasing accrual to adjuvant therapy clinical trials.

Abstract

Importance  Recommendations for adjuvant therapy after surgical resection of lung adenocarcinoma (LUAD) are based solely on TNM classification but are agnostic to genomic and high-risk clinicopathologic factors. Creation of a prediction model that integrates tumor genomic and clinicopathologic factors may better identify patients at risk for recurrence.

Objective  To identify tumor genomic factors independently associated with recurrence, even in the presence of aggressive, high-risk clinicopathologic variables, in patients with completely resected stages I to III LUAD, and to develop a computational machine-learning prediction model (PRecur) to determine whether the integration of genomic and clinicopathologic features could better predict risk of recurrence, compared with the TNM system.

Design, Setting, and Participants  This prospective cohort study included 426 patients treated from January 1, 2008, to December 31, 2017, at a single large cancer center and selected in consecutive samples. Eligibility criteria included complete surgical resection of stages I to III LUAD, broad-panel next-generation sequencing data with matched clinicopathologic data, and no neoadjuvant therapy. External validation of the PRecur prediction model was performed using The Cancer Genome Atlas (TCGA). Data were analyzed from 2014 to 2018.

Main Outcomes and Measures  The study end point consisted of relapse-free survival (RFS), estimated using the Kaplan-Meier approach. Associations among clinicopathologic factors, genomic alterations, and RFS were established using Cox proportional hazards regression. The PRecur prediction model integrated genomic and clinicopathologic factors using gradient-boosting survival regression for risk group generation and prediction of RFS. A concordance probability estimate (CPE) was used to assess the predictive ability of the PRecur model.

Results  Of the 426 patients included in the analysis (286 women [67%]; median age at surgery, 69 [interquartile range, 62-75] years), 318 (75%) had stage I cancer. Association analysis showed that alterations in SMARCA4 (clinicopathologic-adjusted hazard ratio [HR], 2.44; 95% CI, 1.03-5.77; P = .042) and TP53 (clinicopathologic-adjusted HR, 1.73; 95% CI, 1.09-2.73; P = .02) and the fraction of genome altered (clinicopathologic-adjusted HR, 1.03; 95% CI, 1.10-1.04; P = .005) were independently associated with RFS. The PRecur prediction model outperformed the TNM-based model (CPE, 0.73 vs 0.61; difference, 0.12 [95% CI, 0.05-0.19]; P < .001) for prediction of RFS. To validate the prediction model, PRecur was applied to the TCGA LUAD data set (n = 360), and a clear separation of risk groups was noted (log-rank statistic, 7.5; P = .02), confirming external validation.

Conclusions and Relevance  The findings suggest that integration of tumor genomics and clinicopathologic features improves risk stratification and prediction of recurrence after surgical resection of early-stage LUAD. Improved identification of patients at risk for recurrence could enrich and enhance accrual to adjuvant therapy clinical trials.

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