Utility of the 52-Gene Risk Score to Identify Patients with Idiopathic Pulmonary Fibrosis at Greater Risk of Mortality in the Era of Antifibrotic Therapy
verfasst von:
Julia F. Söllner, Stefan Bentink, Christian Hesslinger, Thomas B. Leonard, Megan L. Neely, Nina M. Patel, Thomas Schlange, Jamie L. Todd, Richard Vinisko, Margaret L. Salisbury, on behalf of the IPF-PRO Registry investigators
We investigated whether a 52-gene signature was associated with transplant-free survival and other clinically meaningful outcomes in patients with idiopathic pulmonary fibrosis (IPF) in the IPF-PRO Registry, which enrolled patients who were and were not taking antifibrotic therapy.
Methods
The 52-gene risk signature was implemented to classify patients as being at “high risk” or “low risk” of disease progression and mortality. Transplant-free survival and other outcomes were compared between patients with a low-risk versus high-risk signature.
Results
The 52-gene signature classified 159 patients as at low risk and 86 as at high risk; in these groups, respectively, 56.6% and 51.2% used antifibrotic therapy at enrollment. Among those taking antifibrotic therapy, patients with a low-risk versus high-risk signature were at decreased risk of death, a composite of lung transplant or death, and a composite of decline in DLco % predicted > 15%, lung transplant, or death. Similar results were observed in the overall cohort.
Conclusions
These data suggest that the 52-gene signature can be used in patients with IPF treated with antifibrotic therapy to distinguish patients at higher risk of disease progression and mortality.
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Introduction
Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease [1] characterized by progressive decline in lung function and high mortality, but its rate of progression is variable [2, 3]. Studies using RNA from lung tissue, whole blood, or peripheral blood mononuclear cells (PBMC) have identified gene expression profiles that are associated with faster decline in lung function [4, 5] or shorter transplant-free survival or overall survival time [6‐8]. A study of PBMC gene expression identified a 52-gene signature that predicted transplant-free survival in two cohorts of patients with IPF [6] and this was validated in six independent cohorts using RNA extracted from PBMC or whole blood [9]. The patients in these studies came from the era prior to the approval of the disease-modifying antifibrotic therapies nintedanib and pirfenidone, which have been shown to slow decline in lung function [10, 11] and improve survival [3, 12, 13]. This study investigated whether the 52-gene signature is associated with several clinically meaningful outcomes in patients with IPF who are treated with antifibrotic therapy.
Methods
Study Cohort and Outcomes Assessment
The Idiopathic Pulmonary Fibrosis Prospective Outcomes (IPF-PRO) Registry (ClinicalTrials.gov Identifier: NCT01915511) is a multicenter observational registry of patients with IPF [14]. Patients eligible to participate in the registry were ≥ 40 years of age with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months, did not have malignancy other than skin cancer within the past 5 years, were not on a lung transplant waiting list, and were not participating in a randomized clinical trial. Blood samples were collected at enrollment, and RNA was extracted from whole blood and sequenced as previously described [8]. Participants eligible for this analysis were enrolled between June 2014 and February 2017, had longitudinal outcomes ascertained through December 2019, had blood samples available for sequencing, and had total RNA sequencing that met quality control criteria.
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At enrollment, clinical data from the prior 12 months were collected from patient records, and patients provided blood samples and completed patient-reported outcome questionnaires. Patients were considered as using an antifibrotic drug (nintedanib or pirfenidone) at enrollment if they were taking antifibrotic therapy on the day that the enrollment blood sample was taken. Participants were followed prospectively while receiving usual care, with follow-up data (including vital status, lung transplantation, and pulmonary function) collected approximately every six months.
Composite outcomes included death; death or lung transplant; death, lung transplant, or forced vital capacity (FVC) decline; and death, lung transplant, or diffusing capacity of the lungs for carbon monoxide (DLco) decline. FVC decline and DLco decline were defined as the first instance of an absolute decline in the % predicted value of ≥ 10% or ≥ 15%, respectively, compared to the value at enrollment.
52-Gene Signature “Risk” Status Assessment
As described [9], the 52-gene signature contains 7 increased and 45 decreased genes. Thus, for each patient, the ‘increased ratio’ is calculated by dividing the number of genes with an increased (relative to the cohort geometric mean for the gene) expression by 7, and the ‘decreased ratio’ by dividing the number of genes with decreased expression by 45. Then, an “up score” is derived by obtaining the sum of normalized expression values (subtracted from the cohort geometric mean) of genes with increased expression and multiplying by the increased ratio, and a “down score” derived in a similar manner using the expression values of decreased genes and the decreased ratio. Patients with up scores greater than or equal to and with down scores less than or equal to the cohort median are categorized as at “high risk” of lung transplant or death; other patients are classified as at “low risk.”
Statistical Methods
Patient characteristics at enrollment were summarized as median (Q1, Q3) and the number of events during follow-up was reported as n (%). Cox proportional hazards models adjusted for age, sex, FVC % predicted, and DLco % predicted at enrollment were used to compare the risk of each clinically meaningful composite outcome among patients with a low-risk compared to a high-risk signature. The Kaplan–Meier method was used to generate survival curves to visualize the event-free survival time in the low-risk and high-risk groups. Time to event was compared between patients with a high-risk versus low-risk signature using the log-rank test. Analyses were performed in all patients and in the subgroup of patients using antifibrotic therapy (nintedanib or pirfenidone) at enrollment.
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Results
Among 245 patients included in the analysis cohort, the median age was 70 (65, 75) years, 184 (75.1%) were males, and 134 (54.7%) were using an antifibrotic drug (Table 1). The characteristics of patients using antifibrotic therapy are shown in Online Resource 1. After applying the 52-gene risk signature, 159 patients (64.9%) were identified as at low risk and 86 patients (35.1%) as at high risk. Compared to the high-risk group, patients in the low-risk group had higher FVC and DLco % predicted, and included a greater proportion of females; the low-risk group also had a greater proportion of patients using antifibrotic therapy (Table 1).
Table 1
Patient characteristics at enrollment
All patients (n = 245)
Risk category based on 52-gene signature
Low-risk (n = 159)
High-risk (n = 86)
Age, years
70 (65, 75)
70 (65, 74)
71 (66, 76)
Male
184 (75.1)
114 (71.7)
70 (81.4)
White
236 (96.3)
153 (96.2)
83 (96.5)
FVC % predicted
70.5 (61.2, 80.2)
71.5 (61.4, 82.2)
68.7 (60.9, 77.8)
DLco % predicted
41.1 (32.5, 50.0)
42.6 (33.0, 49.3)
38.4 (31.2, 51.0)
Antifibrotic drug use
134 (54.7)
90 (56.6)
44 (51.2)
Pirfenidone
91 (37.1)
55 (34.6)
36 (41.9)
Nintedanib
43 (17.6)
35 (22.0)
8 (9.3)
Data are median (Q1, Q3) or n (%)
FVC forced vital capacity, DLco diffusing capacity of the lungs for carbon monoxide
In the overall cohort, the median (Q1, Q3) observation time was 2.2 (1.3, 3.1) years. Among the 134 patients using an antifibrotic drug at enrollment, the median (Q1, Q3) observation time was 2.3 (1.2, 3.2) years, during which death occurred in 42 patients; the composite of death or lung transplant in 55 patients; the composite of death, lung transplant, or decline in FVC % predicted > 10% in 80 patients; and the composite of death, lung transplant, or decline in DLco % predicted > 15% in 67 patients. The proportions of patients in each group who experienced components of the composite outcomes are shown in Online Resource 2. Among those using an antifibrotic drug at enrollment, compared to those with a high-risk signature, those with a low-risk signature had a lower risk of death (covariate-adjusted HR 0.49, 95% CI 0.26, 0.95, p = 0.035), the composite of death or lung transplant (covariate-adjusted HR 0.55, 95% CI 0.31, 0.97, p = 0.040), and the composite of death, lung transplant, or decline in DLco % predicted > 15% (covariate-adjusted HR 0.57, 95% CI 0.34, 0.96, p = 0.034). Kaplan–Meier curves are shown in Fig. 1A (death or lung transplant) and Fig. 1B (death, lung transplant, or decline in DLco % predicted > 15%), for participants with low-risk and high-risk signatures who were taking antifibrotic therapy at enrollment. A similar direction and magnitude of effect was observed in unadjusted analyses (Online Resource 3) and among the overall cohort (Online Resources 3 and 4). The risk of the composite of death, lung transplant, or decline in FVC % predicted > 10% was not significantly different between patients with low-risk and high-risk signatures, either in the overall cohort or those taking antifibrotic therapy (Online Resource 3).
Fig. 1
Kaplan–Meier curves for A death or lung transplant and B death, lung transplant, or decline in DLco % predicted > 15% among patients taking antifibrotic therapy at enrollment. P values are from log-rank tests. DLco, diffusing capacity of the lungs for carbon monoxide
×
Discussion
In this analysis of data from a contemporary cohort of patients with IPF, the 52-gene risk signature identified patients at higher risk of disease progression and mortality, including within the group of patients taking antifibrotic therapy at the time of blood collection. To our knowledge, this is the first study to evaluate the utility of the 52-gene signature in predicting these clinically meaningful outcomes in patients with IPF taking antifibrotic therapy.
Evaluating the prognostic value of risk signatures in patients with IPF taking antifibrotic therapies is important, as these therapies modify the course of the disease [10, 11]. Further, a previous study suggested that the 52-gene risk profile may change in response to antifibrotic therapy: while no changes in risk profile were observed among 16 low-risk patients who started antifibrotic treatment after the blood sample was collected, shifts in up scores and down scores were observed among nine high-risk patients who started treatment after sample collection [9]. Those who had a change in 52-gene risk profile showed a significant increase in FVC compared with patients who did not [9].
Identifying patients with IPF who are at higher risk of progression is important for prognostication in clinical practice. In addition, tools that predict progression could enable enrichment of study cohorts for patients at higher risk of short-term progression, enabling clinical trials to be smaller, shorter, and less costly [15‐17]. The results of our study suggest that gene signatures such as the 52-gene signature may be of value as part of an enrichment strategy even among patients treated with antifibrotic therapy. Of note, we have previously reported the lack of association between the 52-gene risk groups and a composite of FVC decline, lung transplant, or death among patients in the IPF-PRO Registry [8], and this observation holds true among patients taking antifibrotic drugs.
The use of a multicenter cohort was a strength of our study, but the cohort was limited to the USA. As in previous analyses of the 52-gene risk signature, the patients were predominantly White. More research is needed into the applicability of the 52-gene risk signature across diverse populations.
To conclude, in a contemporary cohort of patients with IPF taking antifibrotic therapy, the 52-gene risk signature distinguished patients at higher risk of disease progression and mortality.
Acknowledgements
We thank the principal investigators and enrolling centers in the IPF-PRO Registry (listed in Online Resource 5). The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE). The authors did not receive payment for development of this manuscript. Editorial support was provided by Elizabeth Ng and Wendy Morris of Fleishman-Hillard, London, UK, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations.
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Declarations
Competing Interests
Julia F Söllner, Christian Hesslinger, Thomas B Leonard, Nina M Patel, Thomas Schlange, and Richard Vinisko are employees of Boehringer Ingelheim. Stefan Bentink is an employee of Staburo GmbH, which was contracted by Boehringer Ingelheim to conduct some of the analyses presented in this manuscript. Megan L Neely and Jamie L Todd are faculty members of the Duke Clinical Research Institute, which receives funding support from Boehringer Ingelheim Pharmaceuticals, Inc to coordinate the IPF-PRO/ILD-PRO Registry. Jamie L Todd also reports grants paid to her institution from AstraZeneca and CareDx and has participated on advisory boards for Altavant Sciences, Avalyn, Natera, Sanofi, Theravance. Margaret L Salisbury reports grants paid to her institution from the National Institutes of Health; consulting fees from Boehringer Ingelheim, Orinove Inc., Roche; payment for lectures from Boehringer Ingelheim; and reimbursement to attend an investigators’ meeting from Boehringer Ingelheim.
Ethical Approval
The IPF-PRO Registry study obtained ethics approval at the data coordinating center (Duke Clinical Research Institute, Duke Institutional Review Board Protocol Number Pro00046131). The IPF-PRO Registry protocol was approved by the relevant Institutional Review Boards and/or local Independent Ethics Committees prior to enrollment at each site (listed in Online Resource 5).
Consent to Participate
Informed consent was obtained from all individual participants included in the study.
Consent to Publish
Not applicable.
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Utility of the 52-Gene Risk Score to Identify Patients with Idiopathic Pulmonary Fibrosis at Greater Risk of Mortality in the Era of Antifibrotic Therapy
verfasst von
Julia F. Söllner Stefan Bentink Christian Hesslinger Thomas B. Leonard Megan L. Neely Nina M. Patel Thomas Schlange Jamie L. Todd Richard Vinisko Margaret L. Salisbury on behalf of the IPF-PRO Registry investigators
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