Department of Medicine, The Royal Marsden NHS Foundation Trust, London, United Kingdom.
Department of Molecular Diagnostics, Centre for Molecular Pathology, The Royal Marsden NHS Foundation Trust, London, United Kingdom.
Int J Cancer. 2020 Jan 1;146(1):94-102. doi: 10.1002/ijc.32507. Epub 2019 Jul 5.
Little information is available on the clinical significance of cancer-related genes such as KRAS, NRAS, BRAF, PIK3CA and TP53 in nonmetastatic rectal cancer. We investigated mutations of these genes in a large prospective series of locally advanced rectal cancer (LARC) patients who were recruited into two phase II trials. Mutational analyses were performed with diagnostically validated methods including polymerase chain reaction, capillary electrophoresis single-strand conformational analysis, Sanger sequencing and next-generation sequencing. Associations between single or multiple gene mutations and clinicopathological characteristics and treatment outcomes were explored. Of these 269, 210 (78%) patients were assessable. Mutations of KRAS, NRAS, BRAF, PIK3CA and TP53 occurred in 43, 9, 4, 9 and 60% of patients, respectively. Concordance between paired biopsy and resection specimens was 82% for KRAS, 95% for NRAS, 99% for BRAF, 96% for PIK3CA and 63% for TP53. TP53 mutations were associated with extramural venous invasion on baseline MRI (78% vs. 65%, p = 0.04), poor pathological tumour regression (23% vs. 36%, p = 0.05) and a trend toward a worse 5-year progression-free survival (PFS; 60% vs. 74%, HR 1.59, p = 0.06). Patients with tumours harbouring mutation of TP53 and either KRAS or NRAS (32%) had a worse 5-year PFS than those with TP53/KRAS/NRAS wild-type tumours (54% vs. 72%, HR 1.75, p = 0.02). In univariate analysis, BRAF mutation predicted poor 5-year overall survival only among patients treated without cetuximab (20% vs. 73%, HR 3.29, p = 0.03). This is one of the largest biomarker studies in a prospective, largely homogeneous, LARC population. Our findings are hypothesis generating and require validation in independent series.
关于 KRAS、NRAS、BRAF、PIK3CA 和 TP53 等与癌症相关的基因在非转移性直肠癌中的临床意义，目前信息有限。我们对招募入两项 II 期临床试验的局部晚期直肠癌（LARC）患者的大型前瞻性系列研究中这些基因的突变进行了调查。采用包括聚合酶链反应、毛细管电泳单链构象分析、Sanger 测序和下一代测序在内的经过诊断验证的方法进行突变分析。探讨了单个或多个基因突变与临床病理特征和治疗结果之间的关系。在这 269 名患者中，有 210 名（78%）患者可评估。KRAS、NRAS、BRAF、PIK3CA 和 TP53 突变分别发生在 43%、9%、4%、9%和 60%的患者中。KRAS 配对活检和切除标本之间的一致性为 82%，NRAS 为 95%，BRAF 为 99%，PIK3CA 为 96%，TP53 为 63%。TP53 突变与基线 MRI 上的外膜静脉侵犯相关（78% vs. 65%，p = 0.04），与较差的病理肿瘤消退相关（23% vs. 36%，p = 0.05），并且 5 年无进展生存率（PFS；60% vs. 74%，HR 1.59，p = 0.06）呈下降趋势。携带 TP53 突变和 KRAS 或 NRAS 突变的肿瘤患者（32%）的 5 年 PFS 比 TP53/KRAS/NRAS 野生型肿瘤患者（54% vs. 72%，HR 1.75，p = 0.02）更差。在单变量分析中，BRAF 突变仅预测未接受西妥昔单抗治疗的患者的 5 年总生存率较差（20% vs. 73%，HR 3.29，p = 0.03）。这是一项在大型、同质的 LARC 人群中进行的最大规模的生物标志物研究之一。我们的发现是产生假设的结果，需要在独立的系列中进行验证。
