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Last Updated: 09/23/21

Squamous Cell Carcinoma of the Lung: Validation of Molecular Signatures for Prognosis

U01 CA157715

Fred R. Hirsch, MD PhD
University of Colorado, Denver, CO

Dr. Hirsch’s program leveraged the resources of the Squamous Lung Cancer Consortium (SLCC), a group of experienced clinical and biomarker investigators, to validate preexisting gene expression signatures for prognosis of squamous cell carcinoma (SCC), with the goal of bringing the signatures to a more broadly applicable clinical assay. The program’s goal was to use the validated signatures to identify patients with early stage SCC and provide for better selection of candidates for adjuvant therapy.


  • The project team included investigators from the University of Colorado Denver, Mayo Clinic, the University of Michigan, The Brigham and Women’s Hospital, University of California Davis, Washington University St. Louis School of Medicine, Duke University Medical Center, and Princess Margaret Hospital, Toronto.
  • Specimens for these studies were obtained from tissue banks at the participant institutions and from two multi-institutional protocols, ACOSOG Z4031 and CALGB 14202.
  • Statistical support was provided by the Mayo Clinic.


  • Validate previously defined mRNA and miRNA expression signatures for prognosis in early stage SCC and to test the most robust of these signatures in two independent cooperative group clinical trial cohorts
  • Begin validation of genomic variants identified by NCI’s Cancer Genome Atlas Project, assess their prevalence and investigate whether they can supplement the prognostic power of the previously defined signatures
  • Establish a central SCC database including a virtual SCC tissue bank linked to molecular, pathological, and clinical information.


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

Authors: Bueno R, Richards WG, Harpole DH, Ballman KV, Tsao MS, Chen Z, Wang X, Chen G, Chirieac LR, Chui MH, Franklin WA, Giordano TJ, Govindan R, Joshi MB, Merrick DT, Rivard CJ, Sporn T, van Bokhoven A, Yu H, Shepherd FA, Watson MA, Beer DG, Hirsch FR.

Source: J Thorac Oncol. 2020;15(11):1748-1757.

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.

Squamous cell lung cancer: from tumor genomics to cancer therapeutics

Authors: Gandara, D. R., Hammerman, P. S., Sos, M. L., Lara, P. N., Jr., Hirsch, F. R.

Source: Clin Cancer Res 21(10): 2236-2243(2015).

Abstract: Squamous cell lung cancer (SCC) represents an area of unmet need in lung cancer research. For the past several years, therapeutic progress in SCC has lagged behind the now more common non-small cell lung cancer histologic subtype of adenocarcinoma. However, recent efforts to define the complex biology underlying SCC have begun to bear fruit in a multitude of ways, including characterization of previously unknown genomic and signaling pathways, delineation of new, potentially actionable molecular targets, and subsequent development of a large number of agents directed against unique SCC-associated molecular abnormalities. For the first time, SCC-specific prognostic gene signatures and predictive biomarkers of new therapeutic agents are emerging. In addition, recent and ongoing clinical trials, including the Lung-MAP master protocol, have been designed to facilitate approval of targeted therapy-biomarker combinations. In this comprehensive review, we describe the current status of SCC therapeutics, recent advances in the understanding of SCC biology and prognostic gene signatures, and the development of innovative new clinical trials, all of which offer new hope for patients with advanced SCC. Clin Cancer Res; 21(10); 2236-43. (c)2015 AACR. See all articles in this CCR Focus section, "Progress in Lung Cancer."

Fibroblast Growth Factor Receptor 1 and Related Ligands in Small-Cell Lung Cancer

Authors: Zhang, L., Yu, H., Badzio, A., Boyle, T. A., Schildhaus, H. U., Lu, X., Dziadziuszko, R., Jassem, J., Varella-Garcia, M., Heasley, L. E., Kowalewski, A. A., Ellison, K., Chen, G., Zhou,C., Hirsch, F. R.

Source: J Thorac Oncol Epub date 2015/05/29.

Abstract: Small-cell lung cancer (SCLC) accounts for 15% of all lung cancers and has been understudied for novel therapies. Signaling through fibroblast growth factors (FGF2, FGF9) and their high-affinity receptor has recently emerged as a contributing factor in the pathogenesis and progression of non-small-cell lung cancer. In this study, we evaluated fibroblast growth factor receptor 1 (FGFR1) and ligand expression in primary SCLC samples. METHODS: FGFR1 protein expression, messenger RNA (mRNA) levels, and gene copy number were determined by immunohistochemistry (IHC), mRNA in situ hybridization, and silver in situ hybridization, respectively, in primary tumors from 90 patients with SCLC. Protein and mRNA expression of the FGF2 and FGF9 ligands were determined by IHC and mRNA in situ hybridization, respectively. In addition, a second cohort of 24 SCLC biopsy samples with known FGFR1 amplification by fluorescence in situ hybridization was assessed for FGFR1 protein expression by IHC. Spearman correlation analysis was performed to evaluate associations of FGFR1, FGF2 and FGF9 protein levels, respective mRNA levels, and FGFR1 gene copy number. RESULTS: FGFR1 protein expression by IHC demonstrated a significant correlation with FGFR1 mRNA levels (p < 0.0001) and FGFR1 gene copy number (p = 0.03). The prevalence of FGFR1 mRNA positivity was 19.7%. FGFR1 mRNA expression correlated with both FGF2 (p = 0.0001) and FGF9 (p = 0.002) mRNA levels, as well as with FGF2 (p = 0.01) and FGF9 (p = 0.001) protein levels. There was no significant association between FGFR1 and ligands with clinical characteristics or prognosis. In the second cohort of specimens with known FGFR1 amplification by fluorescence in situ hybridization, 23 of 24 had adequate tumor by IHC, and 73.9% (17 of 23) were positive for FGFR1 protein expression. CONCLUSIONS: A subset of SCLCs is characterized by potentially activated FGF/FGFR1 pathways, as evidenced by positive FGF2, FGF9, and FGFR1 protein and/or mRNA expression. FGFR1 protein expression is correlated with FGFR1 mRNA levels and FGFR1 gene copy number. Combined analysis of FGFR1 and ligand expression may allow selection of patients with SCLC to FGFR1 inhibitor therapy.This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.