Thymidylate synthase predicts poor response to pemetrexed chemotherapy in patients with advanced breast cancer

Abstract

Pemetrexed is a candidate chemotherapy regimen for anthracycline- and taxane-pretreated advanced breast cancer. However, to the best of our knowledge, no efficient treatment efficacy biomarkers have been identified. In the present study, the potential correlation between thymidylate synthase (TYMS) expression and clinical response to pemetrexed was examined in advanced breast cancer. A retrospective collection was performed by using 77 advanced breast cancer subjects, who received at least three cycles of pemetrexed treatment in the Second Hospital of Shandong University hospital. TYMS expression was detected using immunohistopathological staining. The correlations between TYMS and therapeutic efficacies of different chemotherapy treatment were analyzed. The objective response rate (ORR) and disease control was 31.17 and 64.94%, respectively. Immunohistochemical staining demonstrated that TYMS expression was observed in the cytoplasm and nuclei of breast cancer cells. High TYMS expression was observed in 32 specimens. Elevated TYMS expression was correlated with higher histological grade and lymph node metastasis (P<0.05). Furthermore, significantly higher TYMS expression was observed in treatment-resistant patients than response ones (P<0.05). Patients with low expression level of TYMS exhibit significantly higher ORR. Cox regression analysis indicated that elevated TYMS expression was a detrimental factor for pemetrexed treatment for advanced breast cancer patients. The present results suggested that TYMS expression levels predicts therapeutic sensitivity of pemetrexed chemotherapy in advanced breast cancer, indicating that it may be a useful biomarker to choose chemotherapy regimens.

Deregulation of folate pathway gene expression correlates with poor prognosis in acute leukemia

“…We also found that patients with AL with relapse showed increased mRNA expression levels of TS. Our results are in line with previous reports showing a significant aggressive phenotype and poor prognosis (47–49). These data indicate that TS is involved in disease progression and relapse in cancer, which occur because TS is a target enzyme of MTXPG and is overexpressed in AL and in patients with relapse.…”

“…TS is a folate-dependent enzyme that plays a central role in deoxythymidine monophosphate synthesis, which is critical for the synthesis and repair of DNA by serving as the main intracellular source of dUTM (46,47). Our results show increased levels of TS mRNA in patients with AL, similar to findings observed in breast cancer (47) and pancreatic cancer (20). We also found that patients with AL with relapse showed increased mRNA expression levels of TS.…”

Individualized chemotherapy guided by the expression of ERCC1, RRM1, TUBB3, TYMS and TOP2A genes versus classic chemotherapy in the treatment of breast cancer: A comparative effectiveness study

“…TUBB3 is thought to be a marker of taxane resistance, and high expression levels of TUBB3 are reported to correlate with low response rates in patients treated with taxane-containing regimens (8,9). The expression level of TYMS, which is a central enzyme in the folate metabolic pathway and a major target for cytotoxic antifolate chemotherapeutic agents, such as 5-fluorouracil and capecitabine, is negatively associated with the efficacy of antimetabolic drugs (10,11). TOP2A is an essential nuclear enzyme that changes DNA topology and is the primary molecular target of various cytotoxic agents, including anthracyclines.…”

Associations between polymorphisms at microRNA-binding sites in TYMS and breast cancer risk among Chinese women

“…[19] Additionally, TYMS polymorphisms may predict the chemosensitivity to 5-fluorouracil, doxorubicin, cyclophosphamide, pemetrexed and so on. [20,21,9] TYMS SNPs influence cancer susceptibility and chemosensitivity via effects on TYMS expression [22] and its effects differ with respect to race. [23,11] However, inconsistent results have been obtained regarding the association between the miRNA binding sites of TYMS SNPs and breast cancer and data from Asian populations are lacking.…”

“…[5] As a proliferation marker, TYMS expression may be related to pathological complete response (pCR) rates in triple-negative breast cancer (TNBC). [7] Furthermore, TYMS is used to predict chemosensitivity [6,9] and trastuzumab resistance [10].…”