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Lung cancer
Phase II Study of Pemetrexed as a Salvage Chemotherapy for Thymidylate Synthase–Low Squamous Cell Lung Cancer
Mihong Choi, Heung Tae Kim, Ji-Youn Han, Geon Kook Lee, Soo-Hyun Lee, Kun Young Lim, Jungnam Joo, Hye Jin Won, Jin Soo Lee, Youngjoo Lee
Cancer Res Treat. 2021;53(1):87-92.   Published online August 13, 2020
DOI: https://doi.org/10.4143/crt.2020.741
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Squamous cell carcinomas (SqCC) of the lung often express high levels of thymidylate synthase (TS), which is associated with primary resistance to pemetrexed. We explored the efficacy of pemetrexed in a selected population of patients with lung SqCC with low TS expression.
Materials and Methods
In this single-arm phase II trial, we enrolled 32 previously-treated patients with advanced lung SqCC exhibiting low immunohistochemical staining for TS (i.e., in 10% or less of tumor cells). The primary endpoint was 12-week progression-free survival (PFS) rate.
Results
Of 32 patients, eight patients (25%) had an Eastern Cooperative Oncology Group performance status of 2, and seven patients (22%) had previously received three or more lines of chemotherapy. The disease control rate from pemetrexed treatment was 30%, and no objective response was observed. The 12-week PFS rate was 24.5% (95% confidence interval [CI], 13.0 to 46.1). Median PFS was 1.3 months (95% CI, 1.3 to 2.7), and median overall survival was 11.8 months (95% CI, 8.1 to not applicable). Most of adverse events were grade 1 or 2.
Conclusion
Pemetrexed demonstrated modest activity as a salvage chemotherapy in patients with advanced lung SqCC with low TS expression, although its toxicity was generally manageable.

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  • Bioengineered miR-7-5p modulates non–small cell lung cancer cell metabolism to improve therapy
    Gavin M. Traber, Mei-Juan Tu, Su Guan, Neelu Batra, Ai-Ming Yu
    Molecular Pharmacology.2025; 107(1): 100006.     CrossRef
  • 7,033 View
  • 129 Download
  • 1 Crossref
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Immunohistochemistry Biomarkers Predict Survival in Stage II/III Gastric Cancer Patients: From a Prospective Clinical Trial
Min Hwan Kim, Xianglan Zhang, Minkyu Jung, Inkyung Jung, Hyung Soon Park, Seung-Hoon Beom, Hyo Song Kim, Sun Young Rha, Hyunki Kim, Yoon Young Choi, Taeil Son, Hyoung-Il Kim, Jae-Ho Cheong, Woo Jin Hyung, Sung Hoon Noh, Hyun Cheol Chung
Cancer Res Treat. 2019;51(2):819-831.   Published online September 27, 2018
DOI: https://doi.org/10.4143/crt.2018.331
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Identification of biomarkers to predict recurrence risk is essential to improve adjuvant treatment strategies in stage II/III gastric cancer patients. This study evaluated biomarkers for predicting survival after surgical resection.
Materials and Methods
This post-hoc analysis evaluated patients from the CLASSIC trial who underwent D2 gastrectomy with or without adjuvant chemotherapy (capecitabine plus oxaliplatin) at the Yonsei Cancer Center. Tumor expressions of thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), and programmed death-ligand 1 (PD-L1) were evaluated by immunohistochemical (IHC) staining to determine their predictive values.
Results
Among 139 patients, IHC analysis revealed high tumor expression of TS (n=22, 15.8%), ERCC1 (n=23, 16.5%), and PD-L1 (n=42, 30.2%) in the subset of patients. Among all patients, high TS expression tended to predict poor disease-free survival (DFS; hazard ratio [HR], 1.80; p=0.053), whereas PD-L1 positivity was associated with favorable DFS (HR, 0.33; p=0.001) and overall survival (OS; HR, 0.38; p=0.009) in multivariate Cox analysis. In the subgroup analysis, poor DFS was independently predicted by high TS expression (HR, 2.51; p=0.022) in the adjuvant chemotherapy subgroup (n=66). High PD-L1 expression was associated with favorable DFS (HR, 0.25; p=0.011) and OS (HR, 0.22; p=0.015) only in the surgery-alone subgroup (n=73). The prognostic impact of high ERCC1 expression was not significant in the multivariate Cox analysis.
Conclusion
This study shows that high TS expression is a predictive factor for worse outcomes on capecitabine plus oxaliplatin adjuvant chemotherapy, whereas PD-L1 expression is a favorable prognostic factor in locally advanced gastric cancer patients.

Citations

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  • Utility of TMPRSS4 as a Prognostic Biomarker and Potential Therapeutic Target in Patients with Gastric Cancer
    Hirofumi Tazawa, Takahisa Suzuki, Akihisa Saito, Akira Ishikawa, Toshiaki Komo, Haruki Sada, Norimitsu Shimada, Naoto Hadano, Takashi Onoe, Takeshi Sudo, Yosuke Shimizu, Kazuya Kuraoka, Hirotaka Tashiro
    Journal of Gastrointestinal Surgery.2022; 26(2): 305.     CrossRef
  • Scoring systems for PD-L1 expression and their prognostic impact in patients with resectable gastric cancer
    Marina Alessandra Pereira, Marcus Fernando Kodama Pertille Ramos, André Roncon Dias, Renan Ribeiro, Leonardo Cardili, Bruno Zilberstein, Ivan Cecconello, Ulysses Ribeiro, Evandro Sobroza de Mello, Tiago Biachi de Castria
    Virchows Archiv.2021; 478(6): 1039.     CrossRef
  • Epstein–Barr Virus Positive Gastric Cancer: A Distinct Subtype Candidate for Immunotherapy
    Marina Alessandra Pereira, Daniel Amadeus Molon Batista, Marcus Fernando Kodama Pertille Ramos, Leonardo Cardili, Renan Ribeiro e Ribeiro, Andre Roncon Dias, Bruno Zilberstein, Ulysses Ribeiro Jr, Ivan Cecconello, Venâncio Avancini Ferreira Alves, Evandro
    Journal of Surgical Research.2021; 261: 130.     CrossRef
  • Cytotoxic T‐lymphocyte‐associated protein 4 in gastric cancer: Prognosis and association with PD‐L1 expression
    Marina Alessandra Pereira, Tiago Biachi de Castria, Marcus Fernando Kodama Pertille Ramos, André Roncon Dias, Leonardo Cardili, Rafael Dyer Rodrigues de Moraes, Bruno Zilberstein, Sergio Carlos Nahas, Ulysses Ribeiro, Evandro Sobroza de Mello
    Journal of Surgical Oncology.2021; 124(7): 1040.     CrossRef
  • Remnant gastric cancer: a neglected group with high potential for immunotherapy
    Marcus Fernando Kodama Pertille Ramos, Marina Alessandra Pereira, Tiago Biachi de Castria, Renan Ribeiro e Ribeiro, Leonardo Cardili, Evandro Sobroza de Mello, Bruno Zilberstein, Ulysses Ribeiro-Júnior, Ivan Cecconello
    Journal of Cancer Research and Clinical Oncology.2020; 146(12): 3373.     CrossRef
  • Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma
    Jose J. G. Marin, Laura Perez-Silva, Rocio I. R. Macias, Maitane Asensio, Ana Peleteiro-Vigil, Anabel Sanchez-Martin, Candela Cives-Losada, Paula Sanchon-Sanchez, Beatriz Sanchez De Blas, Elisa Herraez, Oscar Briz, Elisa Lozano
    Cancers.2020; 12(8): 2116.     CrossRef
  • Clinical Significance of CLDN18.2 Expression in Metastatic Diffuse-Type Gastric Cancer
    Seo Ree Kim, Kabsoo Shin, Jae Myung Park, Han Hong Lee, Kyo Yong Song, Sung Hak Lee, Bohyun Kim, Sang-Yeob Kim, Junyoung Seo, Jeong-Oh Kim, Sang-Young Roh, In-Ho Kim
    Journal of Gastric Cancer.2020; 20(4): 408.     CrossRef
  • Prognostic and Predictive Factors for the Curative Treatment of Esophageal and Gastric Cancer in Randomized Controlled Trials: A Systematic Review and Meta-Analysis
    van den Ende, ter Veer, Mali, van Berge Henegouwen, Hulshof, van Oijen, van Laarhoven
    Cancers.2019; 11(4): 530.     CrossRef
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Thymidylate Synthase, Thymidine Phosphorylase, VEGF and p53 Protein Expression in Primary Colorectal Cancer for Predicting Response to 5-fluorouracil-based Chemotherapy
Myung-Ju Ahn, Jung-Hye Choi, Ho-Suk Oh, Young-Yeul Lee, In-Soon Kim, Il-Young Choi, Kang-Hong Lee, Kang-Won Song, Chan-Kum Park
Cancer Res Treat. 2005;37(4):216-222.   Published online August 31, 2005
DOI: https://doi.org/10.4143/crt.2005.37.4.216
AbstractAbstract PDFPubReaderePub
Purpose

In the treatment of advanced metastatic colorectal cancer, several new agents, such as irinotecan and oxaliplatin, have been developed, which have improved both disease free and overall survivals. Among these agents, 5-fluorouracil (5-FU) still remains one of the most active agents, and the selection of patients who can benefit from 5-FU-based chemotherapy is still important, as those unlikely to benefit could be spared the harmful side effects. The expression levels of thymidylate synthase (TS), thymidine phosphorylase (TP) and p53 have been known to be associated with the clinical response to 5-FU-based therapy as well as the prognosis, and that of vascular endothelial growth factor (VEGF) is associated with poor survival.

Materials and Methods

The relationship between the expressions of TS, TP, VEGF and p53 in primary tumors, using immunohistochemistry, and the response of 45 metastatic colorectal cancer patients (M:F=25:20, median age 59 yrs) to 5-FU-based chemotherapy were evaluated.

Results

Thirty-seven patients were treated with 5-FU/LV/irinotecan (FOLFIRI) and 8 with 5-FU/LV/oxaplatin (FOLFOX). The overall response rate was 28.9% (13/45). When immunohistochemically analyzed with monoclonal antibodies against TS, TP, VEGF and p53, 55.6% of the patients (25/45) were positive for TS, 48.9% (22/45) for TP, 82.2% (37/45) for VEGF, and 80% (36/45) for p53. There was a significant difference in the intensity of TS expression between the clinical responders and non-responders (p=0.036). In terms of the staining pattern of TS expression, diffuse staining was correlated with a poor response (p=0.012) and poor survival (p=0.045). However, there was no correlation between the expressions of TP, VEGF or P53 and the response to chemotherapy.

Conclusion

These results suggest that the expression of TS in primary colorectal cancer might be an important prognostic factor for chemotherapy response and survival, and might be a useful therapeutic marker for the response of chemotherapy.

Citations

Citations to this article as recorded by  
  • Epigenetic Approaches to Overcome Fluoropyrimidines Resistance in Solid Tumors
    Laura Grumetti, Rita Lombardi, Federica Iannelli, Biagio Pucci, Antonio Avallone, Elena Di Gennaro, Alfredo Budillon
    Cancers.2022; 14(3): 695.     CrossRef
  • Immunoexpression of TS, p53, COX2, EGFR, MSH6 and MLH1 biomarkers and its correlation with degree of differentiation, tumor staging and prognostic factors in colorectal adenocarcinoma: a retrospective longitudinal study
    Wilson Roberto Batista, Gianni Santos, Flávia Maria Ribeiro Vital, Delcio Matos
    Sao Paulo Medical Journal.2019; 137(1): 33.     CrossRef
  • Thymidine phosphorylase expression and prognosis in colorectal cancer treated with 5‑fluorouracil‑based chemotherapy: A meta‑analysis
    Jia Che, Lun Pan, Xiangling Yang, Zhiting Liu, Lanlan Huang, Chuangyu Wen, Aihua Lin, Huanliang Liu
    Molecular and Clinical Oncology.2017;[Epub]     CrossRef
  • Does anti-p53 antibody status predict for clinical outcomes in metastatic colorectal cancer patients treated with fluoropyrimidine, oxaliplatin, plus bevacizumab as first-line chemotherapy?
    Hiroki Osumi, Eiji Shinozaki, Mitsukuni Suenaga, Yosuke Kumekawa, Mariko Ogura, Masato Ozaka, Satoshi Matsusaka, Keisho Chin, Noriko Yamamoto, Nobuyuki Mizunuma
    BMC Cancer.2015;[Epub]     CrossRef
  • Comparison of thymidine phosphorylase expression and prognostic factors in gallbladder and bile duct cancer
    Hye Sung Won, Myung Ah Lee, Eun-Seon Chung, Dong-Goo Kim, Young Kyoung You, Tae Ho Hong, In-Seok Lee
    BMC Cancer.2010;[Epub]     CrossRef
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  • 36 Download
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Drug Resistance to 5 - Fluorouracil and Overexpression of Thymidylate Synthase mRNA in Human Gastrointestinal Malignancies
Tae You Kim, Baek Yeol Ryoo, Yung Hyuck Im, Yoon Koo Kang, Sang Jae Lee, Yung Jue Bang, Noe Kyeong Kim
J Korean Cancer Assoc. 2000;32(1):44-52.
AbstractAbstract PDF
PURPOSE
The cytotoxicity by 5-fluorouracil (5-FU) is mediated by inhibition of thymi- dylate synthase (TS), which is a rate-limiting enzyme for DNA synthesis. To test whether the resistance to 5-FU would be associated with cellular TS activity, we analyzed TS gene expression from human gastrointestinal cancer cell lines.
MATERIALS AND METHODS
We established the experimental conditions for quantitating TS mRNA expression by competitive RT-PCR using mimic DNA. Based on this method, we compared TS mRNA expression between 5-FU resistant cell line and parent cell line and investigated the expression of TS mRNA following 5-FU administration in 6 human gas- trointestinal cancer cell lines.
RESULTS
Competitive RT-PCR using mimic DNA seemed to be more effective than Northern blot analysis for quantitation of TS gene expression. The quantity of TS mRNA and IC50 value of 5-FU in 5-FU resistant H630 was found to be 2.5 and 10 times higher than in parent cell line, respectively. And also, we observed linear relationship between TS mRNA level and IC50 value of 5-FU (r 0.76) in 6 gastrointestinal cancer cell lines.
CONCLUSION
These results suggest that overexpression of TS mRNA may play a role in the development of 5-FU resistance in human gastrointestinal malignancies
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