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Open Access 01-12-2019 | NSCLC | Research article

Prediction of response to pemetrexed in non-small-cell lung cancer with immunohistochemical phenotyping based on gene expression profiles

Authors: S. Visser, J. Hou, K. Bezemer, L. L. de Vogel, J. P. J. J. Hegmans, B. H. Stricker, S. Philipsen, J. G. J. V. Aerts

Published in: BMC Cancer | Issue 1/2019

Abstract

Background

Palliative pemetrexed-based chemotherapy remains a standard of care treatment for the majority of patients with advanced non-squamous non-small-cell lung cancer (NSCLC). Currently, no predictive markers for pemetrexed treatment are available.

Methods

Resected tumour samples from pemetrexed-naïve NSCLC patients were collected. Gene expression profiling with respect to predicted sensitivity to pemetrexed classified predicted responders (60%) and non-responders (40%) based on differentially expressed genes encoding for pemetrexed target enzymes. Genes showing a strong correlation with these target genes were selected for measurement of corresponding protein expressions by immunohistochemical (IHC) staining. A semi-quantitative IHC scoring method was applied to construct a prediction model for response to pemetrexed. A retrospective cohort of patients with advanced NSCLC treated with first-line pemetrexed-based chemotherapy was used for external validation.

Results

From ninety-one patients resected tumour samples were collected. The majority of patients had early or locally advanced NSCLC (96.3%). Gene expression profiling revealed five markers, which mRNA levels strongly correlated to pemetrexed target genes mRNA levels: TPX2, CPA3, EZH2, MCM2 and TOP2A. Of 63 (69%) patients IHC staining scores of these markers were obtained, which significantly differed between predicted non-responders and responders (P < 0.05). The optimized prediction model included EZH2 (OR = 0.56, 95% CI 0.35–0.90) and TPX2 (OR = 0.55, 95% CI 0.30–1.01). The model had a sensitivity of 86.8%, specificity of 63.6% and showed a good ability to distinct between responders and non-responders (C-index 0.86).

In the external study population (N = 23) the majority of patients had metastatic NSCLC (95.7%). Partial response (PR) was established in 26.1%. The sensitivity decreased drastically to 33.3%, with a specificity of 82.4% and a C-index of 0.73.

Conclusions

Using external validation this prediction model with IHC staining of target enzyme correlated markers showed a good discrimination, but lacked sensitivity. The role of IHC markers as response predictors for pemetrexed in clinical practice remains questionable.

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Title: Prediction of response to pemetrexed in non-small-cell lung cancer with immunohistochemical phenotyping based on gene expression profiles
Authors: S. Visser
J. Hou
K. Bezemer
L. L. de Vogel
J. P. J. J. Hegmans
B. H. Stricker
S. Philipsen
J. G. J. V. Aerts
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: NSCLC
Lung Cancer
Lung Cancer
NSCLC
Lung Cancer
Published in: BMC Cancer / Issue 1/2019
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-019-5645-x

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