Functional impact of somatic mutations in early-onset (EO) versus average onset (AO) microsatellite stable (MSS) stage III colorectal cancer (CRC).
Authors: Harrold Emily , Solter Mark , Walch Henry S. , Chatila Walid Khaled , Keane Fergus , Lumish Melissa Amy , Yaeger Rona , Weiss Jill A. , Palmaira Randze Lerie , Krishnan Asha , Diaz Luis A. , Stadler Zsofia Kinga , Cercek Andrea 
Published: June 2022

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Background: Analysis of the IDEA database demonstrates significantly worse disease-free survival in high-risk stage III EO CRC vs AO CRC, regardless of adjuvant therapy intensity or duration. Critically this analysis omits somatic mutational data and germline status. Enrichment of TP53 in EO metastatic CRC (mCRC) is well described and functionality of individual TP53 mutations has been proposed as a potential mechanism of chemotherapy resistance. The prognostic and functional impact of somatic mutations merits analysis in the EO high-risk Stage III cohort. Methods: The Memorial Sloan Kettering MSKCC IMPACT database was queried for MSS Stage III AO CRC (≥50 yrs) and EO CRC ( < 50 yrs) patients(pts); clinico-pathological characteristics, systemic therapies received, and survival outcomes were reviewed. MSI, POLE mutated or hereditary syndrome associated tumors were excluded. We further classified TP53 mutations as GOF (gain of function) versus non GOF/ LOF (loss of function) (Pan M, JCO. 2022, Muller PA, Cancer cell. 2014). Results: 272 pts were included in the analysis (EO = 184, AO = 88). 50% of the EO and 62.5 % of the AO cohorts were male. Tumors were predominantly adenocarcinoma (EO 89% vs AO 91%), moderately differentiated (EO 78% vs AO 74%) and left sided (EO 77% vs AO 48.8%). 87% of the EO and 63.6 % of the AO cohort were TP53mut (p value 0.0003); TP53mut was enriched in the EO cohort regardless of sidedness but there was no significant difference in TP53 mutations between EO high vs low risk. Classifying by 7 putative GOF mutations (R175H, R248Q/W, R249S, R273H/L and R282W) 28.7% of the EO cohort harbored a GOF mutation vs 19.6% of the AO cohort. There was no statistically significant survival difference between pts with TP53mut tumors vs TP53 wild type (TP53wt) in the entire cohort (AO+EO) (p 0.041) or EO or AO cohorts (p 0.049). There was no significant difference in survival outcomes across all cohorts of TP53mut groups, both high and low risk, both GOF and non GOF, treated with 3 vs 6 months of chemotherapy (p 0.67). The EO TP53wt group was enriched relative to the EO TP53mut group for KRAS (60% vs 32%), BRAF (11% vs 4%), and PI3K driver alterations (PIK3CA, 20% vs 13%) and PTEN: (8% vs 3%) In the multivariate survival analysis of EO Stage III CRC BRAFmut status is highly statistically significant (p < 0.001). Conclusions: EO Stage III CRC is enriched for TP53 mutations regardless of sidedness and GOF mutations are identified in a higher proportion of EO CRC than AO CRC. We found no statistically significant difference in survival by TP53mut status across the entire MSS Stage III CRC cohort. There was no interaction between TP53mut status, duration of chemotherapy and overall survival. The functional impact of additional molecular features is being explored and the novel prognostic significance of BRAF demonstrated in this EO Stage III cohort requires further validation.