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Original Investigation
April 9, 2019

Association of Patient Characteristics and Tumor Genomics With Clinical Outcomes Among Patients With Non–Small Cell Lung Cancer Using a Clinicogenomic Database

Author Affiliations
  • 1Foundation Medicine Inc, Cambridge, Massachusetts
  • 2Brigham and Women’s Hospital, Boston, Massachusetts
  • 3Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts
  • 4Flatiron Health Inc, New York, New York
  • 5Stanford University School of Medicine, Stanford, California
  • 6Voyager Therapeutics, Cambridge, Massachusetts
  • 7New York University School of Medicine, New York
  • 8Now with the Food and Drug Administration, Silver Spring, Maryland
JAMA. 2019;321(14):1391-1399. doi:10.1001/jama.2019.3241
Key Points

Question  Can clinical and genomic data obtained in routine clinical care be linked in a Health Insurance Portability and Accountability Act–compliant manner to yield clinically relevant insights?

Findings  A deidentified database of 28 998 patients with cancer, approximately 85% of whom were treated in a community setting, was generated by linking electronic health record–derived longitudinal clinical data with comprehensive tumor genomic profiling. Analysis of 4064 patients with non–small cell lung cancer revealed clinical, genomic, and therapeutic associations that were consistent with prior reports and extended previous observations on evolving community practice patterns.

Meaning  Using data obtained from routine clinical care to generate a validated, multi-institution clinicogenomic database is feasible and can yield novel, clinically meaningful insights.


Importance  Data sets linking comprehensive genomic profiling (CGP) to clinical outcomes may accelerate precision medicine.

Objective  To assess whether a database that combines EHR-derived clinical data with CGP can identify and extend associations in non–small cell lung cancer (NSCLC).

Design, Setting, and Participants  Clinical data from EHRs were linked with CGP results for 28 998 patients from 275 US oncology practices. Among 4064 patients with NSCLC, exploratory associations between tumor genomics and patient characteristics with clinical outcomes were conducted, with data obtained between January 1, 2011, and January 1, 2018.

Exposures  Tumor CGP, including presence of a driver alteration (a pathogenic or likely pathogenic alteration in a gene shown to drive tumor growth); tumor mutation burden (TMB), defined as the number of mutations per megabase; and clinical characteristics gathered from EHRs.

Main Outcomes and Measures  Overall survival (OS), time receiving therapy, maximal therapy response (as documented by the treating physician in the EHR), and clinical benefit rate (fraction of patients with stable disease, partial response, or complete response) to therapy.

Results  Among 4064 patients with NSCLC (median age, 66.0 years; 51.9% female), 3183 (78.3%) had a history of smoking, 3153 (77.6%) had nonsquamous cancer, and 871 (21.4%) had an alteration in EGFR, ALK, or ROS1 (701 [17.2%] with EGFR, 128 [3.1%] with ALK, and 42 [1.0%] with ROS1 alterations). There were 1946 deaths in 7 years. For patients with a driver alteration, improved OS was observed among those treated with (n = 575) vs not treated with (n = 560) targeted therapies (median, 18.6 months [95% CI, 15.2-21.7] vs 11.4 months [95% CI, 9.7-12.5] from advanced diagnosis; P < .001). TMB (in mutations/Mb) was significantly higher among smokers vs nonsmokers (8.7 [IQR, 4.4-14.8] vs 2.6 [IQR, 1.7-5.2]; P < .001) and significantly lower among patients with vs without an alteration in EGFR (3.5 [IQR, 1.76-6.1] vs 7.8 [IQR, 3.5-13.9]; P < .001), ALK (2.1 [IQR, 0.9-4.0] vs 7.0 [IQR, 3.5-13.0]; P < .001), RET (4.6 [IQR, 1.7-8.7] vs 7.0 [IQR, 2.6-13.0]; P = .004), or ROS1 (4.0 [IQR, 1.2-9.6] vs 7.0 [IQR, 2.6-13.0]; P = .03). In patients treated with anti–PD-1/PD-L1 therapies (n = 1290, 31.7%), TMB of 20 or more was significantly associated with improved OS from therapy initiation (16.8 months [95% CI, 11.6-24.9] vs 8.5 months [95% CI, 7.6-9.7]; P < .001), longer time receiving therapy (7.8 months [95% CI, 5.5-11.1] vs 3.3 months [95% CI, 2.8-3.7]; P < .001), and increased clinical benefit rate (80.7% vs 56.7%; P < .001) vs TMB less than 20.

Conclusions and Relevance  Among patients with NSCLC included in a longitudinal database of clinical data linked to CGP results from routine care, exploratory analyses replicated previously described associations between clinical and genomic characteristics, between driver mutations and response to targeted therapy, and between TMB and response to immunotherapy. These findings demonstrate the feasibility of creating a clinicogenomic database derived from routine clinical experience and provide support for further research and discovery evaluating this approach in oncology.