Department of Pathology, Austin Health, Heidelberg, VIC, Australia.
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia.
Mod Pathol. 2020 Mar;33(3):483-495. doi: 10.1038/s41379-019-0353-2. Epub 2019 Aug 30.
TP53 mutations drive colorectal cancer development, with missense mutations frequently leading to accumulation of abnormal TP53 protein. TP53 alterations have been associated with poor prognosis and chemotherapy resistance, but data remain controversial. Here, we examined the predictive utility of TP53 overexpression in the context of current adjuvant treatment practice for patients with stage III colorectal cancer. A prospective cohort of 264 stage III patients was tested for association of TP53 expression with 5-year disease-free survival, grouped by adjuvant treatment. Findings were validated in an independent retrospective cohort of 274 stage III patients. Overexpression of TP53 protein (TP53+) was found in 53% and 52% of cases from the prospective and retrospective cohorts, respectively. Among patients receiving adjuvant chemotherapy, TP53+ status was associated with shorter disease-free survival (p ≤ 0.026 for both cohorts), while no difference in outcomes between TP53+ and TP53- cases was observed for patients treated with surgery alone. Considering patients with TP53- tumors, those receiving adjuvant treatment had better outcomes compared with those treated with surgery alone (p ≤ 0.018 for both cohorts), while no treatment benefit was apparent for patients with TP53+ tumors. Combined cohort-stratified analysis adjusted for clinicopathological variables and DNA mismatch repair status confirmed a significant interaction between TP53 expression and adjuvant treatment for disease-free survival (p = 0.030). For the combined cohort, the multivariate hazard ratio for TP53 overexpression among patients receiving adjuvant chemotherapy was 2.03 (95% confidence interval 1.41-2.95, p < 0.001), while the hazard ratio for adjuvant treatment among patients with TP53- tumors was 0.42 (95% confidence interval 0.24-0.71, p = 0.001). Findings were maintained irrespective of tumor location or when restricted to mismatch repair-proficient tumors. Our data suggest that adjuvant chemotherapy benefit in stage III colorectal cancer is restricted to cases with low-level TP53 protein expression. Identifying TP53+ tumors could highlight patients that may benefit from more aggressive treatment or follow-up.
TP53 突变驱动结直肠癌的发展，错义突变常导致异常 TP53 蛋白的积累。TP53 改变与预后不良和化疗耐药有关，但数据仍存在争议。在这里，我们研究了 TP53 过表达在当前 III 期结直肠癌辅助治疗实践中的预测作用。对 264 例 III 期患者进行前瞻性队列研究，检测 TP53 表达与 5 年无病生存率的相关性，按辅助治疗分组。在 274 例 III 期患者的独立回顾性队列中验证了研究结果。前瞻性和回顾性队列中分别有 53%和 52%的病例存在 TP53 蛋白过表达（TP53+）。在接受辅助化疗的患者中，TP53+状态与无病生存率较短相关（两个队列的 p 值均≤0.026），而单独接受手术治疗的患者中，TP53+和 TP53-病例的结局无差异。考虑到 TP53-肿瘤患者，接受辅助治疗的患者与单独接受手术治疗的患者相比，结局更好（两个队列的 p 值均≤0.018），而 TP53+肿瘤患者则无治疗获益。对考虑了临床病理变量和 DNA 错配修复状态的患者进行联合队列分层分析，证实 TP53 表达与无病生存率的辅助治疗之间存在显著交互作用（p=0.030）。对于联合队列，接受辅助化疗的患者中 TP53 过表达的多变量风险比为 2.03（95%置信区间 1.41-2.95，p<0.001），而 TP53-肿瘤患者接受辅助治疗的风险比为 0.42（95%置信区间 0.24-0.71，p=0.001）。无论肿瘤位置如何，或仅限于错配修复有效的肿瘤，结果均保持不变。我们的数据表明，III 期结直肠癌的辅助化疗获益仅限于低水平 TP53 蛋白表达的病例。识别 TP53+肿瘤可以突出可能受益于更积极治疗或随访的患者。
