Abstract
BackgroundPalliative 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.MethodsResected 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.ResultsFrom 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.ConclusionsUsing 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.
Highlights
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)
The response rate to pemetrexed was significantly higher in patients with non-squamous versus squamous NSCLC in the first-line pivotal trial [9], still more than 20% of patients with squamous NSCLC had a response to pemetrexed while the response rate was merely ~ 30% in patients with non-squamous histology [11]
Of the 91 surgically resected samples of the primary tumour, 68 (74.7%) samples were suitable for further processing into Tissue microarrays (TMA)
Summary
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). Despite the changing treatment landscape with increasing use of molecular targeted agents and immunotherapy, pemetrexed-based chemotherapy is still widely used as standard treatment in patients with advanced nonsquamous non-small-cell lung cancer [6, 7]. The response rate to pemetrexed was significantly higher in patients with non-squamous versus squamous NSCLC in the first-line pivotal trial [9], still more than 20% of patients with squamous NSCLC had a response to pemetrexed while the response rate was merely ~ 30% in patients with non-squamous histology [11] These findings highlight the need for predictive molecular markers for pemetrexed-based treatment
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