Study using thymidylate synthase as a predictive and prospective biomarker; Report on a trial with a drug that targets the folate receptor
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 randomized 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." (Cancer Res 2009; 69:8529).
Scan may identify lung cancer patients who will benefit from folate-targeted drug
A non-invasive method for measuring the expression folate receptors on tumour cells can identify which patients with advanced lung cancer are likely to derive greater benefit from combination chemotherapy with the investigational drug vintafolide, researchers report at ESMO 2014.
At the meeting, medical oncologist Dr Rohit Lal from Guy's & St Thomas' NHS Foundation Trust in London, reported results from the phase II TARGET trial, which included 199 patients with non-small cell lung cancer who had already been treated with other drugs, and whose tumours all expressed the folate receptor.
Folic acid and folates are key to the synthesis of DNA and RNA, and abnormalities in folate pathways and folate receptors are involved in many cancers including lung cancer, Lal explains.
Vintafolide is a drug targeted to the folate receptor, and is being developed together with an imaging agent that enables non-invasive imaging of folate receptor expression in tumours.
"Our results show a statistical improvement in overall survival and a promising progression-free survival signal with vintafolide and docetaxel for advanced lung adenocarcinoma patients selected by an imaging biomarker for the folate receptor. These patients also had a higher rate of radiological disease control. More patients treated in the vintafolide combination arm required dose adjustment. The results warrant confirmation in a phase III study," Lal said.
"In this phase II trial, adenocarcinoma patients treated with the vintafolide combination were half as likely to have succumbed from their disease than patients in the docetaxel group. These results will need to be validated in a phase III trial," Lal said.
"Choosing treatments based on tumour biopsy tests is well established. The TARGET trial results show a positive outcome for 2nd-line advanced lung adenocarcinoma patients and may show that by using a scan we can select advanced stage lung cancer patients that may derive a greater benefit from combination chemotherapy."
"This group reports the results of a revolutionary study employing a non-invasive method to detect folate receptor expression in NSCLC cells and the relation to treatment with vintafolide, targeting the folate receptor," Rosell noted. "The preliminary results are promising, indicating that the combination of vintafolide and docetaxel could be effective in advanced lung adenocarcinoma patients selected by imaging tracer for the folate receptor."
