Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance)

Abstract

Introduction: Surgical resection is curative for some patients with early lung squamous cell carcinoma. Staging and clinical factors do not adequately predict recurrence risk. We sought to validate the discriminative performance of proposed prognostic gene expression signatures at a level of rigor sufficient to support clinical use.

Methods: The two-stage validation used independent core laboratories, objective quality control standards, locked test parameters, and large multi-institutional specimen and data sets. The first stage validation confirmed a signature's ability to stratify patient survival. The second-stage validation determined which signature(s) optimally improved risk discrimination when added to baseline clinical predictors. Participants were prospectively enrolled in institutional (cohort I) or cooperative group (cohort II) biospecimen and data collection protocols. All cases underwent a central review of clinical, pathologic, and biospecimen parameters using objective criteria to determine final inclusion (cohort I: n = 249; cohort II: n = 234). Primary selection required that a signature significantly predict a 3-year survival after surgical resection in cohort I. Signatures meeting this criterion were further tested in cohort II, comparing risk prediction using baseline risk factors alone versus in combination with the signature.

Results: Male sex, advanced age, and higher stage were associated with shorter survival in cohort I and established a baseline clinical model. Of the three signatures validated in cohort I, one signature was validated in cohort II and statistically significantly enhanced the prognosis relative to the baseline model (C-index difference 0.122; p < 0.05).

Conclusions: These results represent the first rigorous validation of a test appropriate to direct adjuvant treatment or clinical trials for patients with lung squamous cell carcinoma.

Trial registration: ClinicalTrials.gov NCT01517971.

Keywords: Clinical prognostic test validation; Early stage NSCLC; Lung squamous cell carcinoma; Prognostic gene expression signature; Surgery.

Conflict of interest statement

Conflict:

F.R.H. reports advisory board participation for Genentech/Roche, BMS, AstraZeneca, Merck, Novartis, Daiichi, Amgen, OncoCyte, Lilly/Loxo, Boehringer-Ingelheim, outside the submitted work;

R.G. reports personal fees from Inivata, Pfizer, AstraZeneca, Genentech, Millennium Pharmaceuticals, AbbVie, F. Hoffman La-Roche, NeoHealth, Janssen, BMS, Eli Lilly, Roche, Nektar, Merck, Celgene, Janssen, Partner Therapeutics, GSK, Jounce, Amgen, Achilles, GenePlus, outside the submitted work;

D.M. reports grants from Bristol-Myers-Squibb, personal fees from Genentech, personal fees from Roche, outside the submitted work;

R.B. reports grants from Genentech, Roche, Merck, Verastem, Epizyme, MedGenome, Siemens, Gritstone, outside the submitted work; In addition, R.B. has 4 patents through the BWH (no royalties to date) and Equity in a new start-up company, Navigation Sciences, outside the submitted work.

Copyright © 2020. Published by Elsevier Inc.

Figures

Figure 1.

Validated signatures and Risk Model Performance in Cohort I. Kaplan-Meier plots of overall survival associated with the three signatures that met primary selection criteria in Cohort I. Insets in each panel describe univariable and multivariable Hazard Ratios (95% C.I.) for the signature, and C-index (95% C.I.) for the multivariable model. A) BWH signature, B) PMH signature and C) UM signature.

Figure 2.

UM signature and Risk Model Performance in Cohort I, for all cases and for subgroups by AJCC 8th edition Stage (IA1, IA2 and IA3 pooled as Stage IA). Kaplan-Meier plots of overall survival based on UM signature predictions for patients in Cohort I. Insets in each panel describe univariable and multivariable Hazard Ratios (95% C.I.) for the UM signature, and C-index (95% C.I.) for the multivariable model. When all cases (n=249) were used, the multivariable Cox analysis included ‘Risk+Age+Gender+Stage’; Cox models of stage-specific subgroups included ‘Risk+Age+Gender’. A) All patients, B) AJCC 8th edition Stage IA, C) AJCC 8th edition Stage IB, D) AJCC 8th edition Stage IIA, E) AJCC 8th edition Stage IIB and F) AJCC 8th edition Stage IIIA.

Figure 3.

UM signature and Risk Model Performance in Cohort II, for all cases and for subgroups by AJCC 8th edition Stage (IA1, IA2 and IA3 pooled as Stage IA). Kaplan-Meier plots of overall survival based on UM signature predictions for patients in Cohort II. Insets in each panel describe univariable and multivariable Hazard Ratios (95% C.I.) for the UM signature, and C-index (95% C.I.) for the multivariable model. When all cases (n=234) were used, the multivariable Cox analysis included ‘Risk+Age+Gender+Stage’; Cox models of stage-specific subgroups included ‘Risk+Age+Gender’. A) All patients, B) AJCC 8th edition Stage IA, C) AJCC 8th edition Stage IB, D) AJCC 8th edition Stage IIA, E) AJCC 8th edition Stage IIB and F) AJCC 8th edition Stage IIIA.