Pre-therapy mRNA expression of TNF is associated with regimen-related gastrointestinal toxicity in patients with esophageal cancer: a pilot study
- 197 Downloads
Esophageal cancer has a high mortality rate, and its multimodality treatment is often associated with significant rates of severe toxicity. Effort is needed to uncover ways to maximize effectiveness of therapy through identification of predictive markers of response and toxicity. As such, the aim of this study was to identify genes predictive of chemoradiotherapy-induced gastrointestinal toxicity using an immune pathway-targeted approach.
Adults with esophageal cancer treated with chemotherapy consisting of 5-fluorouracil and cisplatin and 45–50 Gy radiation were recruited to the study. Pre-therapy-collected whole blood was analyzed for relative expression of immune genes using real-time polymerase chain reaction (RT-PCR). Gene expression was compared between patients who experienced severe regimen-related gastrointestinal toxicity vs. those experiencing mild to moderate toxicity.
Blood from 31 patients were analyzed by RT-PCR. Out of 84 immune genes investigated, TNF was significantly elevated (2.05-fold, p = 0.025) in the toxic group (n = 12) compared to the non-toxic group (n = 19). Nausea and vomiting was the most commonly documented severe toxicity. No associations between toxicity and response, age, sex, histology, or treatment were evident.
This study supports evidence of TNF as a predictive biomarker in regimen-related gastrointestinal toxicity. Confirming these findings in a larger cohort is warranted.
KeywordsToxicity Chemoradiation Esophageal cancer Mucositis RT-PCR
We acknowledge the assistance provided by Bronwen Jones and Jeff Bull in patient identification, Associate Professor Peter Devitt and DrNimitSinghal for patient recruitment, Mr Tim Bright for tumor response classification, and Mark Van der Hoek for RNA bioanalysis.
Conflict of interest
The authors have no conflict of interest associated with publication of this manuscript.
- 10.Cortez MA, Scrideli CA, Yunes JA, Valera ET, Toledo SR, Pavoni-Ferreira PC, Lee ML, Petrilli AS, Brandalise SR, Tone LG (2009) Mrna expression profile of multidrug resistance genes in childhood acute lymphoblastic leukemia. Low expression levels associated with a higher risk of toxic death. Pediatr Blood Cancer 53:996–1004CrossRefPubMedGoogle Scholar
- 11.Hummerich J, Werle-Schneider G, Popanda O, Celebi O, Chang-Claude J, Kropp S, Mayer C, Debus J, Bartsch H, Schmezer P (2006) Constitutive mrna expression of DNA repair-related genes as a biomarker for clinical radio-resistance: a pilot study in prostate cancer patients receiving radiotherapy. Int J Radiat Biol 82:593–604CrossRefPubMedGoogle Scholar
- 14.Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M (2008) German FUTSG: Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the german 5-fu toxicity study group. J Clin Oncol 26:2131–2138CrossRefPubMedGoogle Scholar
- 15.Zhang L, Yang M, Bi N, Ji W, Wu C, Tan W, Zhao L, Yu D, Lin D, Wang L (2010) Association of tgf-beta1 and xpd polymorphisms with severe acute radiation-induced esophageal toxicity in locally advanced lung cancer patients treated with radiotherapy. Radiother Oncol 97:19–25CrossRefPubMedGoogle Scholar
- 21.Meirovitz A, Kuten M, Billan S, Abdah-Bortnyak R, Sharon A, Peretz T, Sela M, Schaffer M, Barak V (2010) Cytokines levels, severity of acute mucositis and the need of peg tube installation during chemo-radiation for head and neck cancer—a prospective pilot study. Radiat Oncol 5:16PubMedCentralCrossRefPubMedGoogle Scholar
- 22.Morales-Rojas T, Viera N, Moron-Medina A, Alvarez CJ, Alvarez A (2012) Proinflammatory cytokines during the initial phase of oral mucositis in patients with acute lymphoblastic leukaemia. Int J Paediatr Dent Br Paedodontic Soc Int Assoc Dent Child 22:191–196Google Scholar
- 24.Hildebrandt MA, Komaki R, Liao Z, Gu J, Chang JY, Ye Y, Lu C, Stewart DJ, Minna JD, Roth JA, Lippman SM, Cox JD, Hong WK, Spitz MR, Wu X (2010) Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer. PLoS One 5:e12402PubMedCentralCrossRefPubMedGoogle Scholar
- 28.Keefe DM, Elting LS, Nguyen HT, Grunberg SM, Aprile G, Bonaventura A, Selva-Nayagam S, Barsevick A, Koczwara B, Sonis ST (2014) Risk and outcomes of chemotherapy-induced diarrhea (CID) among patients with colorectal cancer receiving multi-cycle chemotherapy. Cancer Chemother Pharmacol 74:675–680CrossRefPubMedGoogle Scholar
- 30.Meluch AA, Greco FA, Gray JR, Thomas M, Sutton VM, Davis JL, Kalman LA, Shaffer DW, Yost K, Rinaldi DA, Hainsworth JD (2003) Preoperative therapy with concurrent paclitaxel/carboplatin/infusional 5-fu and radiation therapy in locoregional esophageal cancer: final results of a minnie pearl cancer research network phase ii trial. Cancer J 9:251–260CrossRefPubMedGoogle Scholar
- 31.Brucher BL, Stein HJ, Zimmermann F, Werner M, Sarbia M, Busch R, Dittler HJ, Molls M, Fink U, Siewert JR (2004) Responders benefit from neoadjuvant radiochemotherapy in esophageal squamous cell carcinoma: results of a prospective phase-ii trial. Eur J Surg Oncol 30:963–971CrossRefPubMedGoogle Scholar
- 33.Adelstein DJ, Rice TW, Rybicki LA, Saxton JP, Videtic GM, Murthy SC, Mason DP, Rodriguez CP, Ives DI (2009) Mature results from a phase ii trial of postoperative concurrent chemoradiotherapy for poor prognosis cancer of the esophagus and gastroesophageal junction. J Thorac Oncol 4:1264–1269CrossRefPubMedGoogle Scholar
- 36.Ishida K, Ando N, Yamamoto S, Ide H, Shinoda M (2004) Phase ii study of cisplatin and 5-fluorouracil with concurrent radiotherapy in advanced squamous cell carcinoma of the esophagus: a japan esophageal oncology group (jeog)/japan clinical oncology group trial (jcog9516). Jpn J Clin Oncol 34:615–619CrossRefPubMedGoogle Scholar
- 37.Kato H, Sato A, Fukuda H, Kagami Y, Udagawa H, Togo A, Ando N, Tanaka O, Shinoda M, Yamana H, Ishikura S (2009) A phase ii trial of chemoradiotherapy for stage i esophageal squamous cell carcinoma: Japan clinical oncology group study (jcog9708). Jpn J Clin Oncol 39:638–643CrossRefPubMedGoogle Scholar
- 38.Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, Bekele BN, Raber-Durlacher J, Donnelly JP, Rubenstein EB (2004) Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100:1995–2025CrossRefPubMedGoogle Scholar
- 40.Schwab M, Zanger UM, Marx C, Schaeffeler E, Klein K, Dippon J, Kerb R, Blievernicht J, Fischer J, Hofmann U, Bokemeyer C, Eichelbaum M (2008) Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the german 5-fu toxicity study group. J Clin Oncol 26:2131–2138CrossRefPubMedGoogle Scholar
- 43.Maher SG, Gillham CM, Duggan SP, Smyth PC, Miller N, Muldoon C, O'Byrne KJ, Sheils OM, Hollywood D, Reynolds JV (2009) Gene expression analysis of diagnostic biopsies predicts pathological response to neoadjuvant chemoradiotherapy of esophageal cancer. Ann Surg 250:729–737CrossRefPubMedGoogle Scholar
- 44.Motoori M, Takemasa I, Yamasaki M, Komori T, Takeno A, Miyata H, Takiguchi S, Fujiwara Y, Yasuda T, Yano M, Matsuura N, Matsubara K, Monden M, Mori M, Doki Y (2010) Prediction of the response to chemotherapy in advanced esophageal cancer by gene expression profiling of biopsy samples. Int J Oncol 37:1113–1120PubMedGoogle Scholar
- 45.van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hosper GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ et al (2012) Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 366:2074–2084CrossRefPubMedGoogle Scholar