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

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.

• 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
• Journal: BMC cancer (BMC Cancer) Vol. 19 Issue 1 Pg. 440 (May 14 2019) ISSN: 1471-2407 [Electronic] England
• PMID: 31088547 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• Pemetrexed

Topics

• Aged
• Algorithms
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, metabolism)
• Female
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic
• Humans
• Immunohistochemistry
• Lung Neoplasms (drug therapy, genetics, metabolism)
• Male
• Middle Aged
• Models, Theoretical
• Pemetrexed (administration & dosage, therapeutic use)
• ROC Curve
• Retrospective Studies
• Tissue Array Analysis (methods)
• Treatment Outcome