Measuring the expression levels of an enzyme involved in DNA synthesis can help predict the response of lung cancers to certain treatments, a Korean study has shown at the ESMO 2014 Congress in Madrid.

In a randomised phase II study, researchers showed that patients whose lung cancers expressed low levels of an enzyme called thymidylate synthase experienced a greater benefit from treatment with the combination of pemetrexed and cisplatin than those whose tumours expressed high levels.

“Thymidylate synthase is one of the proteins that is targeted by pemetrexed which is the most widely used chemotherapeutic regimen in the treatment of non-squamous NSCLC,” explains study author Professor Myung-Ju Ahn, from the Section of Hematology-Oncology at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

“In this study, we tried to evaluate whether expression of thymidylate synthase is a predictive factor for response to pemetrexed plus cisplatin chemotherapy compared with gemcitabine plus cisplatin in non-squamous cell lung cancer patients.”

In terms of response rate and progression-free survival, the clinical benefits of the pemetrexed combination compared to other regimen were more prominent in those patients who expressed low levels of the molecule, Ahn said.

“This suggests that thymidylate synthase can be used as a predictive biomarker. Furthermore, we also found that low thymidylate synthase expression was associated with prolonged overall survival irrespective of which chemotherapeutic regimen the patients received, suggesting that its expression can also serve as a prognostic biomarker.”

In the study, patients with more than 10% of tumour cells expressing thymidylate synthase were grouped as ‘TS-positive’ and those with 10% or less were grouped as a ‘TS-negative’.

Among 315 patients, the response rate of pemetrexed and gemcitabine were 47.0% and 21.1% in TS- patients, and 40.3% and 39.2% in the TS group.

The median progression-free survival of pemetrexed and gemcitabine combinations were 6.4 and 5.5 months in the TS- group and 5.9 and 5.3 months in the TS group.

The median overall survival in response to treatment with the pemetrexed combination and the gemcitabine combination were not different in the TS- group or in the TS group, however those with TS-negative tumours tended to survive for longer.

The take-home message is that thymidylate synthase could be a useful biomarker in this setting, Ahn says.  

“In non-squamous cell NSCLC, thymidylate synthase-negative patients get more clinical benefit from pemetrexed/cisplatin combination therapy. Furthermore, multivariate analysis of the present study showed that TS negative expression was significantly associated with longer survival, along with younger age and EGFR mutation, suggesting it is a good independent prognostic marker.”

“This study opens the gates for thymidylate synthase (TS)-customized chemotherapy in advanced NSCLC,” commented Dr Rafael Rosell, director of the Cancer Biology and Precision Medicine Program at the Catalan Institute of Oncology, Spain.

“They focus their research on patients with non-squamous NSCLC and show that low-TS expressing patients have a significantly better response and outcome, either with pemetrexed or gemcitabine, in combination with cisplatin.”

“Over-expression of TS could behave as an oncogene and therefore TS could be not only a predictive marker of response to antimetabolite drugs, but also a prognostic marker,” Rosell said.

“Therefore, it could be of interest to see what the relevance of using TS as an overall biomarker could be for predicting chemotherapy outcome. It would be of great interest to gain further insights on the mechanisms of TS up-regulation since a master oncogene, astrocyte elevated gene-1 (AEG-1) has been shown to induce the transcription factor LSF (late SV40 factor) that directly up-regulates TS.” 

Source: ESMO