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

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.

Figure 1.. Oncoprint of the Study Cohort by Pathologic Stage With Annotated Clinicopathologic Variables

Genes are grouped by biological relevance in lung adenocarcinoma. FGA indicates fraction of genome altered; LVI, lymphovascular invasion; Mut/Mb, mutations per megabase; STAS, spread through air spaces; and TMB, tumor mutation burden. ^aP < .05, false-discovery rate, for difference in alteration frequency between stages using Fisher exact test.

Figure 2.. Computational Machine-Learning Prediction Model (PRecur) for Relapse-Free Survival (RFS) Using Integrated Clinicopathologic and Genomic Variables for Risk Stratification

A, Kaplan-Meier plot of 3-year RFS by risk group for the Memorial Sloan Kettering (MSK) cohort (n = 426). B, Kaplan-Meier plot of 3-year RFS by risk group using the PRecur external validation prediction model for the Cancer Genome Atlas lung adenocarcinoma cohort (n = 360). Shaded areas indicate 95% CIs.

Figure 3.. Computational Machine-Learning Prediction Model (PRecur) for Relapse-Free Survival (RFS) Applied to 2 Patient Scenarios

A, Patient with a small, 1.8-cm tumor (pT1bN0M0, stage IA). Three-year RFS curves were predicted by PRecur vs the TNM model for all patients with pT1bN0M0 in our cohort (n = 136). B, Patient with a large, 5.1-cm tumor (pT3N0M0, stage IIB). Three-year RFS curves were predicted by PRecur vs the TNM model for all patients with pT3N0M0 in our cohort (n = 53). FGA indicates fraction of genome altered; L, left; P, posterior; R, right; and TMB, tumor mutation burden.