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Impact of CDX2 expression status on the survival of patients after curative resection for colorectal cancer liver metastasis.

ABSTRACT: BACKGROUND:The prognostic biomarker for patients undergoing curative liver metastasectomy for colorectal cancer (CRC) is lacking. The purpose was to investigate the prognostic role of a lack of CDX2 expression, which has been proposed as a potential biomarker for high-risk relapse in early-stage CRC, in patients undergoing curative liver metastasectomy. METHODS:A total of 396 consecutive patients with CRC liver metastasis who underwent potentially curative liver metastasectomy at a single center in Japan between 2005 and 2015 were included. For the immunohistochemical analysis of nuclear CDX2 expression, we adopted the tissue microarray approach using the resected metastatic liver CRCs. Patient subgroups were compared with respect to disease-free survival (DFS) and overall survival (OS) by applying the Kaplan-Meier curve, log-rank tests, and multivariate analyses based on the Cox proportional hazards method. OS is defined as the period from the date of curative liver resection for metastatic CRC until death. DFS is defined as the length of time from curative liver resection to either the first recurrence or death. In patients without recurrence, the latest imaging inspection date was used as the censored date. RESULTS:Thirty-six of the 396 CRCs (9.1%) reduced CDX2 expression. The reduced expression of CDX2 was associated with poor differentiation (P?=?0.02). DFS in days was lower in the patients with CDX2-low CRC than in the patients with CDX2-high CRC (median DFS: 245 days versus 420 days; hazard ratio for disease recurrence: 1.64; 95% confidence interval: 1.08-2.38; P?=?0.02). OS in days was lower in the patients with CDX2-low CRC than in the patients with CDX2-high CRC (median OS: 1024 days versus 3145 days; hazard ratio: 2.41; 95% confidence interval: 1.52-3.85; P?

SUBMITTER: Shigematsu Y

PROVIDER: S-EPMC6192098 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Impact of CDX2 expression status on the survival of patients after curative resection for colorectal cancer liver metastasis.

Shigematsu Yasuyuki Y Inamura Kentaro K Yamamoto Noriko N Mise Yoshihiro Y Saiura Akio A Ishikawa Yuichi Y Takahashi Shunji S Kanda Hiroaki H

BMC cancer 20181016 1

<h4>Background</h4>The prognostic biomarker for patients undergoing curative liver metastasectomy for colorectal cancer (CRC) is lacking. The purpose was to investigate the prognostic role of a lack of CDX2 expression, which has been proposed as a potential biomarker for high-risk relapse in early-stage CRC, in patients undergoing curative liver metastasectomy.<h4>Methods</h4>A total of 396 consecutive patients with CRC liver metastasis who underwent potentially curative liver metastasectomy at ...[more]

PMID: 30326864

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Project description:Chromosomal instability is a well-defined hallmark of tumor aggressiveness and metastatic progression in colorectal cancer. The magnitude of genetic heterogeneity among distinct liver metastases from the same patient at the copy number level, as well as its relationship with chemotherapy exposure and patient outcome, remains unknown. We performed high-resolution DNA copy number analyses of 134 liver metastatic deposits from 45 colorectal cancer patients to assess: (i) intra-patient inter-metastatic genetic heterogeneity using a heterogeneity score based on pair-wise genetic distances among tumor deposits; and (ii) genomic complexity, defined as the proportion of the genome harboring aberrant DNA copy numbers. Results were analyzed in relation to the patients' clinical course; previous chemotherapy exposure and outcome after surgical resection of liver metastases. We observed substantial variation in the level of intra-patient inter-metastatic heterogeneity. Heterogeneity was not associated with the number of metastatic lesions or their genomic complexity. In metachronous disease, heterogeneity was higher in patients previously exposed to chemotherapy. Importantly, intra-patient inter-metastatic heterogeneity was a strong prognostic determinant, stronger than known clinicopathological prognostic parameters. Patients with a low level of heterogeneity (below the median level) had a three-year progression-free and overall survival rate of 23% and 66% respectively, versus 5% and 18% for patients with a high level (hazard ratio0.4, 95% confidence interval 0.2-0.8, P = 0.01; and hazard ratio0.3,95% confidence interval 0.1-0.7, P = 0.007). A low patient-wise level of genomic complexity (below 25%) was also a favorable prognostic factor; however, the prognostic association of intra-patient heterogeneity was independent of genomic complexity in multivariable analyses. In conclusion, intra-patient inter-metastatic genetic heterogeneity is a pronounced feature of metastatic colorectal cancer, and the strong prognostic association reinforces its clinical relevance and places it as a key feature to be explored in future patient cohorts.

Project description:After resection of colorectal cancer liver metastases (CRLM), 2 main histopathological growth patterns can be observed: a desmoplastic and a nondesmoplastic subtype. The desmoplastic subtype has been associated with superior survival. These findings require external validation. An international multicenter retrospective cohort study was conducted in patients treated surgically for CRLM at 3 tertiary hospitals in the United States and the Netherlands. Determination of histopathological growth patterns was performed on hematoxylin and eosin-stained sections of resected CRLM according to international guidelines. Patients displaying a desmoplastic histopathological phenotype (only desmoplastic growth observed) were compared with patients with a nondesmoplastic phenotype (any nondesmoplastic growth observed). Cutoff analyses on the extent of nondesmoplastic growth were performed. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier and multivariable Cox analysis. All statistical tests were 2-sided. In total 780 patients were eligible. A desmoplastic phenotype was observed in 19.1% and was associated with microsatellite instability (14.6% vs 3.6%, P = .01). Desmoplastic patients had superior 5-year OS (73.4%, 95% confidence interval [CI] = 64.1% to 84.0% vs 44.2%, 95% CI = 38.9% to 50.2%, P < .001) and DFS (32.0%, 95% CI = 22.9% to 44.7% vs 14.7%, 95% CI = 11.7% to 18.6%, P < .001) compared with their nondesmoplastic counterparts. A desmoplastic phenotype was associated with an adjusted hazard ratio for death of 0.36 (95% CI = 0.23 to 0.58) and 0.50 (95% CI = 0.37 to 0.66) for cancer recurrence. Prognosis was independent of KRAS and BRAF status. The cutoff analyses found no prognostic relationship between either OS or DFS and the extent of nondesmoplastic growth observed (all P > .1). This external validation study confirms the remarkably good prognosis after surgery for CRLM in patients with a desmoplastic phenotype. The extent of nondesmoplastic growth does not affect prognosis.

Dataset Information

Impact of CDX2 expression status on the survival of patients after curative resection for colorectal cancer liver metastasis.

Publications

Impact of CDX2 expression status on the survival of patients after curative resection for colorectal cancer liver metastasis.

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