Jensen Garrett L, Pourfarrokh Niloufar, Volz Marcus, Morales Linden L, Walker Kimberly, Hammonds Kendall P, El-Ghamry Moataz, Wong Lucas, Hodjat Parsa, Castro Eduardo, Rao Arundhati, Jhavar Sameer G
Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USA.
Departments of Pathology, Baylor Scott & White Health, 2401 S. 31 St., Temple, TX 76508, USA.
Clin Transl Radiat Oncol. 2023 Jul 24;42:100667. doi: 10.1016/j.ctro.2023.100667. eCollection 2023 Sep.
With the growing interest in total neoadjuvant treatment for locally advanced rectal adenocarcinoma (LARC) there is an urgent unmet need to identify predictive markers of response to long-course neoadjuvant concurrent chemoradiotherapy (LCRT). O6-Methylguanine (O6-MG)-DNA-methyltransferase (MGMT) gene methylation has been associated in some malignancies with response to concurrent chemoradiotherapy. We attempted to find if pathologic response to LCRT was associated with MGMT promoter hypermethylation (MGMTh).
Patients were identified with LARC, available pre-treatment biopsy specimens, and at least 1 year of follow-up who received LCRT followed by surgical resection within 6 months. Biopsies were tested for MGMTh using a Qiagen pyrosequencing kit (Catalog number 970061). The primary outcome of LCRT responsiveness was based on tumor regression grade (TRG), with grades of 0-1 considered to have excellent response and grades of 2-3 considered to be non-responders. Secondary outcomes included overall survival (OS) and recurrence free survival (RFS).
Of 96 patients who met inclusion criteria, 76 had samples which produced reliable assay results. MGMTh corresponded with higher grade and age of the biopsy specimen. The percentage of responders to LCRT was higher amongst the MGMTh patients than the MGMTn patients (60.0% vs 27.5%, p value = 0.0061). MGMTh was not significantly associated with improved OS (2-year OS of 96.0% vs 98.0%, p = 0.8102) but there was a trend for improved RFS (2-year RFS of 87.6% vs 74.2%, p = 0.0903).
Significantly greater tumor regression following LCRT was seen in MGMTh LARC. Methylation status may help identify good candidates for close observation without surgery following LCRT.
随着对局部晚期直肠腺癌（LARC）全新辅助治疗的兴趣日益增加，迫切需要确定长程新辅助同步放化疗（LCRT）反应的预测标志物。O6-甲基鸟嘌呤（O6-MG）-DNA甲基转移酶（MGMT）基因甲基化在一些恶性肿瘤中与同步放化疗反应相关。我们试图探究LCRT的病理反应是否与MGMT启动子高甲基化（MGMTh）相关。
纳入LARC患者，有可用的治疗前活检标本，且接受LCRT后6个月内进行手术切除并至少随访1年。使用Qiagen焦磷酸测序试剂盒（产品编号970061）检测活检标本的MGMTh。LCRT反应性的主要结局基于肿瘤退缩分级（TRG），0-1级被认为反应良好，2-3级被认为无反应。次要结局包括总生存期（OS）和无复发生存期（RFS）。
96例符合纳入标准的患者中，76例有产生可靠检测结果的样本。MGMTh与活检标本的更高分级和年龄相关。MGMTh患者中LCRT反应者的百分比高于MGMTn患者（60.0%对27.5%，p值 = 0.0061）。MGMTh与OS改善无显著相关性（2年OS为96.0%对98.0%，p = 0.8102），但RFS有改善趋势（2年RFS为87.6%对74.2%，p = 0.0903）。
MGMTh的LARC患者在LCRT后肿瘤退缩明显更大。甲基化状态可能有助于识别LCRT后无需手术而密切观察的合适候选者。
