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

Autor: Visser S; Department of Pulmonary Medicine, Amphia Hospital, Breda, the Netherlands.; Department of Pulmonary Medicine, Erasmus MC Cancer Institute, P.O. Box 2040, 3000, CA, Rotterdam, The Netherlands.; Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands., Hou J; Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands., Bezemer K; Department of Pulmonary Medicine, Erasmus MC Cancer Institute, P.O. Box 2040, 3000, CA, Rotterdam, The Netherlands., de Vogel LL; Department of Pathology, Erasmus MC, Rotterdam, the Netherlands., Hegmans JPJJ; Department of Pulmonary Medicine, Erasmus MC Cancer Institute, P.O. Box 2040, 3000, CA, Rotterdam, The Netherlands., Stricker BH; Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands., Philipsen S; Department of Cell Biology, Erasmus MC, Rotterdam, the Netherlands., Aerts JGJV; Department of Pulmonary Medicine, Amphia Hospital, Breda, the Netherlands. j.aerts@erasmusmc.nl.; Department of Pulmonary Medicine, Erasmus MC Cancer Institute, P.O. Box 2040, 3000, CA, Rotterdam, The Netherlands. j.aerts@erasmusmc.nl.
Jazyk: angličtina
Zdroj: BMC cancer [BMC Cancer] 2019 May 14; Vol. 19 (1), pp. 440. Date of Electronic Publication: 2019 May 14.
DOI: 10.1186/s12885-019-5645-x
Abstrakt: 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.
Databáze: MEDLINE
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