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

TitleA Genomic-Pathologic Annotated Risk Model to Predict Recurrence in Early-Stage Lung Adenocarcinoma.
Publication TypeJournal Article
Year of Publication2021
AuthorsJones GD, Brandt WS, Shen R, Sanchez-Vega F, Tan KSee, Martin A, Zhou J, Berger M, Solit DB, Schultz N, Rizvi H, Liu Y, Adamski A, Chaft JE, Riely GJ, Rocco G, Bott MJ, Molena D, Ladanyi M, Travis WD, Rekhtman N, Park BJ, Adusumilli PS, Lyden D, Imielinski M, Mayo MW, Li BT, Jones DR
JournalJAMA Surg
Date Published2021 Feb 01

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.

Alternate JournalJAMA Surg
PubMed ID33355651
PubMed Central IDPMC7758824
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
R01 CA192399 / CA / NCI NIH HHS / United States
T32 CA009501 / CA / NCI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
Related Faculty: 
Marcin Imielinski, M.D., Ph.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700