Dataset Information

Conditional Recurrence-Free Survival after Resection of Colorectal Liver Metastases: Persistent Deleterious Association with RAS and TP53 Co-Mutation.

ABSTRACT: BACKGROUND:Conditional recurrence-free survival (RFS) probability, that is, the probability of remaining recurrence-free after a given interval without recurrence, has not been reported after resection of colorectal liver metastases (CLMs). We aimed to estimate conditional RFS and identify factors affecting conditional RFS. STUDY DESIGN:Patients undergoing initial resection of CLMs during 2000-2016 with mutation data were identified. The RFS and risk factors for recurrence were evaluated at the time of resection for all patients and at 1 year and 2 years after resection for patients who remained recurrence-free. RESULTS:Of 2,118 patients, 485 met the inclusion criteria, of which 225 were recurrence-free at 1 year and 109 were recurrence-free at 2 years. The 5-year RFS rates were 17.3%, 36.8%, and 70.7% for all patients and the 1-year and 2-year recurrence-free groups, respectively, when assessed from the time of initial CLM resection. RAS/TP53 co-mutation was the only factor independently associated with increased risk of recurrence for all groups (all patients, hazard ratio 1.47; 95% CI 1.19 to 1.82; p < 0.001; 1-year recurrence-free, hazard ratio 1.69; 95% CI 1.17 to 2.43; p = 0.005; 2-year recurrence-free, hazard ratio 2.41; 95% CI 1.12 to 5.17; p = 0.024). T category, extrahepatic disease, multiple CLMs, largest CLM diameter, and surgical margin status were risk factors for recurrence in all patients and/or the 1-year recurrence-free group, but not the 2-year recurrence-free group. Median RFS was lower for patients with RAS/TP53 co-mutation than for those with RAS/TP53 wild-type in the 1-year (1.5 vs 2.8 years; p = 0.006) and 2-year recurrence-free groups (3.0 vs 5.9 years; p = 0.024). CONCLUSIONS:Conditional RFS is useful for updating prognosis after a given time interval without recurrence after CLM resection. Importantly, RAS/TP53 co-mutation has a persistent deleterious association with recurrence.

SUBMITTER: Kawaguchi Y

PROVIDER: S-EPMC6703951 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Conditional Recurrence-Free Survival after Resection of Colorectal Liver Metastases: Persistent Deleterious Association with RAS and TP53 Co-Mutation.

Kawaguchi Yoshikuni Y Lillemoe Heather A HA Panettieri Elena E Chun Yun Shin YS Tzeng Ching-Wei D CD Aloia Thomas A TA Kopetz Scott S Vauthey Jean-Nicolas JN

Journal of the American College of Surgeons 20190502 3

<h4>Background</h4>Conditional recurrence-free survival (RFS) probability, that is, the probability of remaining recurrence-free after a given interval without recurrence, has not been reported after resection of colorectal liver metastases (CLMs). We aimed to estimate conditional RFS and identify factors affecting conditional RFS.<h4>Study design</h4>Patients undergoing initial resection of CLMs during 2000-2016 with mutation data were identified. The RFS and risk factors for recurrence were ev ...[more]

PMID: 31054911

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Project description:BackgroundMost current models for predicting survival after resection of colorectal liver metastasis include largest diameter and number of colorectal liver metastases as dichotomous variables, resulting in underestimation of the extent of risk variation and substantial loss of statistical power. The aim of this study was to develop and validate a new prognostic model for patients undergoing liver resection including largest diameter and number of colorectal liver metastases as continuous variables.MethodsA prognostic model was developed using data from patients who underwent liver resection for colorectal liver metastases at MD Anderson Cancer Center and had RAS mutational data. A Cox proportional hazards model analysis was used to develop a model based on largest colorectal liver metastasis diameter and number of metastases as continuous variables. The model results were shown using contour plots, and validated externally in an international multi-institutional cohort.ResultsA total of 810 patients met the inclusion criteria. Largest colorectal liver metastasis diameter (hazard ratio (HR) 1.11, 95 per cent confidence interval 1.06 to 1.16; P < 0.001), number of colorectal liver metastases (HR 1.06, 1.03 to 1.09; P < 0.001), and RAS mutation status (HR 1.76, 1.42 to 2.18; P < 0.001) were significantly associated with overall survival, together with age, primary lymph node metastasis, and prehepatectomy chemotherapy. The model performed well in the external validation cohort, with predicted overall survival values almost lying within 10 per cent of observed values. Wild-type RAS was associated with better overall survival than RAS mutation even when liver resection was performed for larger and/or multiple colorectal liver metastases.ConclusionThe contour prognostic model, based on diameter and number of lesions considered as continuous variables along with RAS mutation, predicts overall survival after resection of colorectal liver metastasis.

Project description:BACKGROUND: Adrenocortical carcinomas (ACCs) are among the most common childhood cancers occurring in infants affected with the Li-Fraumeni and Li- Fraumeni-like (LFS/LFL) syndromes, which are caused by dominant germline mutations in the TP53 gene. In Brazil, a particular mutation, occurring in the tetramerisation domain of the gene, p.R337H, is exceedingly common due to a founder effect and is strongly associated with ACC. In this report, we describe the phenotype and long-term clinical follow-up of a female child diagnosed with ACC and homozygous for the TP53 p.R337H founder mutation. CASE PRESENTATION: At age 11 months, the patient was diagnosed with a virilising anaplastic adrenal cortical tumour, which was completely excised without disturbing the adrenal capsule. Family history was consistent with an LFL tumour pattern, and genotyping identified the TP53 p.R337H mutation in both alleles in genomic DNA from lymphocytes and fibroblasts. Haplotype analysis confirmed the occurrence of the mutation in the same founder haplotype previously described in other Brazilian patients. No other germline or somatic TP53 mutations or rearrangements were identified. At age 9 years, the child was asymptomatic and had no evidence of endocrine derangements. Full body and brain magnetic resonance imaging (MRI) failed to detect any suspicious proliferative lesions, and cardiopulmonary exercise testing results were within the normal reference for the child's age, ruling out a major exercise capacity deficiency. CONCLUSION: This is the first clinical and aerobic functional capacity documentation of a patient who carries two mutant TP53 alleles and no wild-type allele. Our results support the hypothesis that TP53 p.R337H, the most common TP53 mutation ever described in any population, is a conditional mutant. Furthermore, our observations over a long period of clinical follow-up suggest that TP53 p.R337H homozygotes do not have a more severe disease phenotype than do heterozygote carriers of the same mutation. Patients with the homozygous TP53 p.R337H genotype will require careful surveillance for lifetime cancer risk and for effects on metabolic capacity later in life.

Dataset Information

Conditional Recurrence-Free Survival after Resection of Colorectal Liver Metastases: Persistent Deleterious Association with RAS and TP53 Co-Mutation.

Publications

Conditional Recurrence-Free Survival after Resection of Colorectal Liver Metastases: Persistent Deleterious Association with RAS and TP53 Co-Mutation.

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