Please use this identifier to cite or link to this item: http://ahro.austin.org.au/austinjspui/handle/1/21661
Title: Overexpression of TP53 protein is associated with the lack of adjuvant chemotherapy benefit in patients with stage III colorectal cancer.
Authors: Williams, David S;Mouradov, Dmitri;Browne, Clare;Palmieri, Michelle;Elliott, Meg J;Nightingale, Rebecca;Fang, Catherine G;Li, Rita;Mariadason, John M;Faragher, Ian;Jones, Ian T;Churilov, Leonid;Tebbutt, Niall C;Gibbs, Peter;Sieber, Oliver M
Affiliation: Department of Surgery, Western Health, Footscray, VIC, Australia
Department of Surgery, The University of Melbourne, Parkville, VIC, Australia
Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
Department of Surgery, Royal Melbourne Hospital, Parkville, VIC, Australia
Department of Pathology, Austin Health, Heidelberg, Victoria, Australia
Olivia Newton-John Cancer Research Institute, Heidelberg, Victoria, Australia
Department of Pathology, The University of Melbourne, Parkville, VIC, Australia
Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
School of Cancer Medicine, La Trobe University, Bundoora, VIC, Australia
Department of Medical Oncology, Austin Health, Heidelberg, Victoria, Australia
Department of Medical Oncology, Royal Melbourne Hospital, Parkville, VIC, Australia
Department of Medical Oncology, Western Health, Footscray, VIC, Australia
Issue Date: 30-Aug-2019
EDate: 2019-08-30
Citation: Modern pathology 2019; online first: 30 August
Abstract: 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 (pinteraction = 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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/21661
DOI: 10.1038/s41379-019-0353-2
ORCID: 0000-0001-5677-4951
0000-0001-9480-0786
0000-0001-9123-7684
0000-0002-9807-6606
PubMed URL: 31471586
Type: Journal Article
Appears in Collections:Journal articles

Files in This Item:
There are no files associated with this item.


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.