Smad4 Status and 5-FU-Based Treatment in Colorectal Cancer
Aims To determine whether expression of Smad4, a tumour suppressor found to be absent in 10% of colorectal cancer (CRC), is associated with outcomes in patients with CRC.
Methods Tumour samples from 241 consecutive patients with CRC who underwent upfront colon resection between 2005 and 2009 were obtained. Triplicate tissue cores from resected primary colon tumours and matched normal controls were used to construct the tissue microarrays (TMAs). We examined the expression of Smad4 using immunohistochemistry. Clinicopathological records were obtained for all patients. TMAs were reviewed by two pathologists and scored as either 'positive' or 'negative' for nuclear staining. In total, 21 of 241 tumours (8.6%) were Smad4 negative.
Results Loss of Smad4 expression correlated with significantly worse overall survival (OS) (p=0.011) and disease-free survival (DFS) (p=0.024). Patients with loss of Smad4 expression had a median OS of 31 months compared with 89 months positive Smad4 expression. Loss of Smad4 remained significant on multivariate analysis for OS (p=0.0097). In patients with node-positive disease, loss of Smad4 predicts for worse DFS (p=0.012). In patients with metastatic and recurrent disease, Smad4 loss predicts for worse OS (p=0.012). Of the patients that received capecitabine over the course of their treatment, those with Smad4 loss (n=13) had significantly worse DFS (p=0.003) and OS (p=0.0007).
Conclusions Loss of Smad4 expression is associated with worse DFS and OS in multiple subsets of patients with CRC. Further studies are required to validate our findings and ascertain the role of Smad4 status in the management of this disease.
Colorectal carcinoma (CRC) is the third most common type of cancer in the USA and the third leading cause of cancer death. The molecular pathogenesis of CRC involves a stepwise progression of genetic changes known as the adenoma–carcinoma transition. Mutations in the APC/β-catenin pathway, as well as those in KRAS and BRAF, represent early and intermediate genetic alterations in the adenoma–carcinoma transition, respectively. KRAS mutations are found in ~40% of CRCs, and BRAF mutations are found in ~8%. Alterations in the transforming growth factor β (TGF-β) signalling pathway are thought to be a late event in the adenoma-to-carcinoma transition in CRC and are found in ~40–50% of tumours.
The TGF-β signalling pathway helps govern developmental programmes, morphogenesis, cellular proliferation and tumorigenesis. Smad4, a tumour suppressor located on chromosome 18q21, is a key effector of the TGF-β signalling pathway and is found to be mutated in ~10% of CRCs. Smad4 has previously been shown to be a negative prognostic marker in patients with CRC and is more frequently mutated in invasive carcinomas with distant metastases as well as in metastatic foci.
Outcomes in CRC are most closely related to disease stage at diagnosis. Surgical resection is the mainstay of treatment for patients with localised CRC, and current clinical guidelines indicate that adjuvant therapy in the setting of stage II node-negative disease has variable benefits. However, in patients with stage III CRC, defined by the presence of lymph node metastases, adjuvant therapy with 5-fluorouracil (FU)-based regimens is warranted. According to the 1973–2005 Surveillance, Epidemiology, and End Results database, 5-year survival rates for patients with stage IIIA-C disease are 73.1%, 46.3% and 28.0%, respectively. Identification of molecular biomarkers that may be used to stratify patients most likely to benefit from chemotherapy is an important clinical need.
The objective of this study was to use tissue microarray (TMA) technology to determine whether expression levels of Smad4 are associated with outcomes in patients with CRC and whether Smad4 status could serve as a useful biomarker in predicting failure of response to 5-FU-based chemotherapy.
Abstract and Introduction
Abstract
Aims To determine whether expression of Smad4, a tumour suppressor found to be absent in 10% of colorectal cancer (CRC), is associated with outcomes in patients with CRC.
Methods Tumour samples from 241 consecutive patients with CRC who underwent upfront colon resection between 2005 and 2009 were obtained. Triplicate tissue cores from resected primary colon tumours and matched normal controls were used to construct the tissue microarrays (TMAs). We examined the expression of Smad4 using immunohistochemistry. Clinicopathological records were obtained for all patients. TMAs were reviewed by two pathologists and scored as either 'positive' or 'negative' for nuclear staining. In total, 21 of 241 tumours (8.6%) were Smad4 negative.
Results Loss of Smad4 expression correlated with significantly worse overall survival (OS) (p=0.011) and disease-free survival (DFS) (p=0.024). Patients with loss of Smad4 expression had a median OS of 31 months compared with 89 months positive Smad4 expression. Loss of Smad4 remained significant on multivariate analysis for OS (p=0.0097). In patients with node-positive disease, loss of Smad4 predicts for worse DFS (p=0.012). In patients with metastatic and recurrent disease, Smad4 loss predicts for worse OS (p=0.012). Of the patients that received capecitabine over the course of their treatment, those with Smad4 loss (n=13) had significantly worse DFS (p=0.003) and OS (p=0.0007).
Conclusions Loss of Smad4 expression is associated with worse DFS and OS in multiple subsets of patients with CRC. Further studies are required to validate our findings and ascertain the role of Smad4 status in the management of this disease.
Introduction
Colorectal carcinoma (CRC) is the third most common type of cancer in the USA and the third leading cause of cancer death. The molecular pathogenesis of CRC involves a stepwise progression of genetic changes known as the adenoma–carcinoma transition. Mutations in the APC/β-catenin pathway, as well as those in KRAS and BRAF, represent early and intermediate genetic alterations in the adenoma–carcinoma transition, respectively. KRAS mutations are found in ~40% of CRCs, and BRAF mutations are found in ~8%. Alterations in the transforming growth factor β (TGF-β) signalling pathway are thought to be a late event in the adenoma-to-carcinoma transition in CRC and are found in ~40–50% of tumours.
The TGF-β signalling pathway helps govern developmental programmes, morphogenesis, cellular proliferation and tumorigenesis. Smad4, a tumour suppressor located on chromosome 18q21, is a key effector of the TGF-β signalling pathway and is found to be mutated in ~10% of CRCs. Smad4 has previously been shown to be a negative prognostic marker in patients with CRC and is more frequently mutated in invasive carcinomas with distant metastases as well as in metastatic foci.
Outcomes in CRC are most closely related to disease stage at diagnosis. Surgical resection is the mainstay of treatment for patients with localised CRC, and current clinical guidelines indicate that adjuvant therapy in the setting of stage II node-negative disease has variable benefits. However, in patients with stage III CRC, defined by the presence of lymph node metastases, adjuvant therapy with 5-fluorouracil (FU)-based regimens is warranted. According to the 1973–2005 Surveillance, Epidemiology, and End Results database, 5-year survival rates for patients with stage IIIA-C disease are 73.1%, 46.3% and 28.0%, respectively. Identification of molecular biomarkers that may be used to stratify patients most likely to benefit from chemotherapy is an important clinical need.
The objective of this study was to use tissue microarray (TMA) technology to determine whether expression levels of Smad4 are associated with outcomes in patients with CRC and whether Smad4 status could serve as a useful biomarker in predicting failure of response to 5-FU-based chemotherapy.
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