Oncology Pharmacy Unit, Complejo Hospitalario Universitario of Santiago, Santiago de Compostela, Spain.
Int J Radiat Oncol Biol Phys. 2012 Jan 1;82(1):138-44. doi: 10.1016/j.ijrobp.2010.09.053. Epub 2010 Dec 16.
5-Fluorouracil-based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients. We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series.
A total of 93 Stage II-III rectal cancer patients were genotyped using peripheral blood samples. The genes analyzed were X-ray cross-complementing group 1 (XRCC1), ERCC1, MTHFR, EGFR, DPYD, and TYMS. The patients were treated with 225 mg/m(2)/d continuous infusion of 5-fluorouracil concomitantly with radiotherapy (50.4 Gy) followed by total mesorectal excision. The outcomes were measured by tumor regression grade (TRG) as a major response (TRG 1 and TRG 2) or as a poor response (TRG3, TRG4, and TRG5).
The major histopathologic response rate was 47.3%. XRCC1 G/G carriers had a greater probability of response than G/A carriers (odds ratio, 4.18; 95% confidence interval, 1.62-10.74, p = .003) Patients with polymorphisms associated with high expression of thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) showed a greater pathologic response rate compared with carriers of low expression (odds ratio, 2.65; 95% confidence interval, 1.10-6.39, p = .02) No significant differences were seen in the response according to EGFR, ERCC1, MTHFR_C677 and MTHFR_A1298 expression.
XRCC1 G/G and thymidylate synthase (2R/3G, 3C/3G, and 3G/3G) are independent factors of a major response. Germline thymidylate synthase and XRCC1 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5-fluorouracil.
在全直肠系膜切除术前进行 5-氟尿嘧啶为基础的放化疗是目前治疗 II 期和 III 期直肠癌患者的标准治疗方法。我们使用已知的预测性药物遗传学生物标志物来确定我们系列中术前放化疗的反应者。
共对 93 例 II-III 期直肠癌患者进行了外周血样本的基因分型。分析的基因包括 X 射线修复交叉互补组 1（XRCC1）、ERCC1、MTHFR、EGFR、DPYD 和 TYMS。患者接受 225mg/m2/d 5-氟尿嘧啶连续输注，同时进行放疗（50.4Gy），然后进行全直肠系膜切除术。通过肿瘤消退分级（TRG）作为主要反应（TRG1 和 TRG2）或作为不良反应（TRG3、TRG4 和 TRG5）来测量结果。
主要组织病理学反应率为 47.3%。XRCC1 G/G 携带者比 G/A 携带者更有可能有反应（比值比，4.18；95%置信区间，1.62-10.74，p=0.003）。与低表达（比值比，2.65；95%置信区间，1.10-6.39，p=0.02）相比，胸苷酸合成酶高表达的多态性（2R/3G、3C/3G 和 3G/3G）患者的病理反应率更高。未观察到 EGFR、ERCC1、MTHFR_C677 和 MTHFR_A1298 表达的反应差异。
XRCC1 G/G 和胸苷酸合成酶（2R/3G、3C/3G 和 3G/3G）是主要反应的独立因素。种系胸苷酸合成酶和 XRCC1 多态性可能作为预测新辅助 5-氟尿嘧啶化疗直肠癌肿瘤反应的有用标志物。
