TP53 Gain-of-Function Status Linked With Outcomes Based on Sidedness in Metastatic CRC

Patients with non–gain-of-function (non-GOF) TP53-mutant right-sided metastatic colorectal cancer (CRC) appeared to have worse survival compared with those diagnosed with left-sided tumors. However, in the left-sided cohort, those with GOF vs non-GOF TP53-mutant tumors had worse survival.

Investigators noted that median overall survival (OS) in those with left-sided tumors and GOF TP53 mutations was worse at 24.6 months vs those with non-GOF TP53 at 33.5 months (P = .01). The difference was observed after adjusting for age, sex, ethnicity, performance status Charlson comorbidity index (CSI), and treatment with chemotherapy (HR, 1.66; 95% CI, 1.20-2.29; P = .002), as well as other clinical features (HR, 1.66; 95% CI, 1.20-2.30; P = .002). Conversely, those with right-sided tumors and GOF TP53 had better median OS at 23.6 months compared with 13.8 months among those with non-GOF TP53 mutations (P = .08). Additionally, the difference was observed after adjusting for age, sex, ethnicity, performance status, and CSI (HR, 0.79; 95% CI, 0.49-1.26), as well as other molecular features (HR, 0.73; 95% CI, 0.47-1.21).

In a study that included 1043 patients with stage IV metastatic disease, next-generation sequencing (NGS) was performed between November 2017 and January 2021. StrataNGS included about 90 common gene mutations such as TP53, KRAS, BRAF, PIK3CA, and microsatellite instability (MSI). The panel was expanded in August 2019 and is presently a pan–solid tumor 429 gene assay. R175H, R248W, R248Q, R249S, R273H, R273L, and R282W were defined as GOF while all other TP53 mutations were classified as non-GOF.

Among the patients included in the study, 308 tumors had wild-type TP53 and 753 had tumors had mutant TP53. The median OS in the overall cohort was 25.1 months. No statistically significant differences in age, sex, performance status, CCI, or receipt of chemotherapy were observed between the GOF and non-GOF populations, although more patients in the GOF group were White and more patients in the non-GOF population were Asian (P = .04). There were also no differences in occurrence of RAS, BRAF, and PIK3CAmutations or MSI-high (MSI-H) status.

Patients with right-sided tumors were older on average with a higher ECOG performance status; higher CCI; more RAS, BRAF, and PIK3CA mutations; and more frequent MSI-H status vs those with left-sided tumors. Those with BRAF or RAS mutations had worse OS than those who with wild-type BRAF (HR, 2.10) or RAS(HR, 1.26).

OS was comparable between patients with mutant vs wild-type TP53, although there was little difference between the GOF and non-GOF cohorts. However, OS appeared to be 30% worse for the GOF group once investigators adjusted for age, sex, ethnicity, performance status, CCI, and receipt of chemotherapy compared with the non-GOF group (HR, 1.30; 95% CI, 1.00-1.68). The difference also remained after further adjusting for molecular features such as RAS, BRAF, and PIK3CA mutations, and MSI-H status (HR, 1.29; 95% CI, 0.99-1.67).

No significant difference in OS was observed between those with wild-type TP53 right-sided and left-sided tumors. However, among those who were TP53-mutant, the median OS in the right-sided group was 17.6 months compared with 30.7 months in the left-sided group (HR, 1.48; 95% CI, 1.14-1.91; P <.001). The significant difference remained after adjusting for age, sex, ethnicity, performance status, CCI, and chemotherapy use (HR, 1.33; 95% CI, 1.02-1.73; P = .03). Moreover, there was no difference in survival between left- and right-sided tumors that with GOF TP53 mutations. However, there was a significant difference in median OS between the right- and left-sided cohorts with non-GOF TP53 mutations, at 13.8 months and 33.5 months, respectively (HR, 1.76; 95% CI, 1.19-2.23; P <.001).

Reference

Pan M, Jiang C, Tse P, et al. TP53 gain-of-function and non–gain-of-function mutations are differentially associated with sidedness-dependent prognosis in metastatic colorectal cancer. J Clin Oncol. 2022;40(2):171-179. doi:10.1200/JCO.21.02014