Fibroblast GFR 2 Overexpression in Rectal Cancer Patients
Fibroblast GFR 2 Overexpression in Rectal Cancer Patients
Aims Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is an increasingly used therapeutic strategy for advanced rectal cancer, but risk stratification and final outcomes remain suboptimal. Recently, the oncogenic role of the fibroblast growth factor/fibroblast growth factor receptor (FGFR) signalling pathway has been recognised; however, its clinical significance in rectal cancer has not been elucidated. In this study, we identify and validate targetable drivers associated with the FGFR signalling pathway in rectal cancer patients treated with CCRT.
Methods Using a published transcriptome of rectal cancers, we found FGFR2 gene significantly predicted response to CCRT. The expression levels of FGFR2, using immunohistochemistry assays, were further evaluated in 172 rectal cancer specimens that had not received any treatment. Expression levels of FGFR2 were statistically correlated with major clinicopathological features and clinical survival in this valid cohort.
Results High expression of FGFR2 was significantly related to advanced pretreatment tumour (p=0.022) and nodal status (p=0.026), post-treatment tumour (p<0.001) and nodal status (p=0.004), and inferior tumour regression grade (p<0.001). In survival analyses, high expression of FGFR2 was significantly associated with shorter local recurrence-free survival (p=0.0001), metastasis-free survival (MeFS; p=0.0003) and disease-specific survival (DSS; p<0.0001). Notably, high expression of FGFR2 was independently predictive of worse outcomes for MeFS (p=0.002, HR=5.387) and DSS (p=0.004, HR=4.997).
Conclusions High expression of FGFR2 is correlated with advanced tumour stage, poor therapeutic response and worse survival in rectal cancer patients receiving neoadjuvant CCRT. These findings indicate that FGFR2 is a prognostic factor for treating rectal cancer.
Rectal cancer, defined as a cancerous lesion of the colon distal to the rectosigmoid junction, is an increasingly prevalent disease in Taiwan. Although ideal treatment recommendations for rectal cancer are still being developed, neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is now considered the standard treatment for locally advanced rectal cancer (LARC). Randomised trials have demonstrated that neoadjuvant CCRT significantly improves local control and reduces toxicity profiles, compared with adjuvant CCRT in LARC. Another advantage of neoadjuvant CCRT is that it may allow some patients to undergo sphincter-preserving surgery. Even though the outcomes using this approach are encouraging, 5-year rates of local and distant recurrence range from 6% to 9% and 33% to 36%, respectively. Furthermore, the incidence of sphincter preservation following CCRT in such patients also varies, ranging from 39% to 94%. To further improve the clinical outcomes for rectal cancer patients treated with CCRT, the development of potential therapeutic targets is highly desirable.
The mammalian fibroblast growth factor (FGF) family comprises 18 ligands which exert their actions through four highly conserved transmembrane tyrosine kinase receptors, including fibroblast growth factor receptor (FGFR) 1, FGFR2, FGFR3 and FGFR4. FGFs and their receptors control a multitude of cellular processes in different contexts, including proliferation, differentiation, survival and motility. As such, this FGF/FGFR system is susceptible to aberration in cancer cells and deregulation of FGFR signalling pathway has been shown to play a critical role in many cancers. For example, FGFR1 mutations and amplifications have been implicated in glioblastoma, prostate, breast and lung cancers, whereas aberrant FGFR2 expression has been observed in endometrial cancer, breast cancer, gastric cancer, lung cancer and melanoma. Furthermore, activating mutations and overexpression of FGFR3 have been reported in bladder cancers and multiple myeloma. Recently, alterations of the FGFR signalling pathway in malignancies have been under the spotlight because of their high incidence rate and therapeutic potential.
Aberrations of the FGFR signalling pathway, including FGFR2, FGFR3 and FGFR4, have been demonstrated in colorectal cancers (CRCs); nevertheless, their clinical impact on therapeutic response and prognosis of rectal cancer patients treated with CCRT have not yet been elucidated. In this study, we analysed the FGFR signalling pathway in one published transcriptome of rectal cancers and identified that upregulated FGFR2 gene was correlated to the response to CCRT. The clinical implications of FGFR2 expression were further validated by studying a well-defined cohort of 172 rectal cancers treated with neoadjuvant CCRT followed by surgery.
Abstract and Introduction
Abstract
Aims Neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is an increasingly used therapeutic strategy for advanced rectal cancer, but risk stratification and final outcomes remain suboptimal. Recently, the oncogenic role of the fibroblast growth factor/fibroblast growth factor receptor (FGFR) signalling pathway has been recognised; however, its clinical significance in rectal cancer has not been elucidated. In this study, we identify and validate targetable drivers associated with the FGFR signalling pathway in rectal cancer patients treated with CCRT.
Methods Using a published transcriptome of rectal cancers, we found FGFR2 gene significantly predicted response to CCRT. The expression levels of FGFR2, using immunohistochemistry assays, were further evaluated in 172 rectal cancer specimens that had not received any treatment. Expression levels of FGFR2 were statistically correlated with major clinicopathological features and clinical survival in this valid cohort.
Results High expression of FGFR2 was significantly related to advanced pretreatment tumour (p=0.022) and nodal status (p=0.026), post-treatment tumour (p<0.001) and nodal status (p=0.004), and inferior tumour regression grade (p<0.001). In survival analyses, high expression of FGFR2 was significantly associated with shorter local recurrence-free survival (p=0.0001), metastasis-free survival (MeFS; p=0.0003) and disease-specific survival (DSS; p<0.0001). Notably, high expression of FGFR2 was independently predictive of worse outcomes for MeFS (p=0.002, HR=5.387) and DSS (p=0.004, HR=4.997).
Conclusions High expression of FGFR2 is correlated with advanced tumour stage, poor therapeutic response and worse survival in rectal cancer patients receiving neoadjuvant CCRT. These findings indicate that FGFR2 is a prognostic factor for treating rectal cancer.
Introduction
Rectal cancer, defined as a cancerous lesion of the colon distal to the rectosigmoid junction, is an increasingly prevalent disease in Taiwan. Although ideal treatment recommendations for rectal cancer are still being developed, neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is now considered the standard treatment for locally advanced rectal cancer (LARC). Randomised trials have demonstrated that neoadjuvant CCRT significantly improves local control and reduces toxicity profiles, compared with adjuvant CCRT in LARC. Another advantage of neoadjuvant CCRT is that it may allow some patients to undergo sphincter-preserving surgery. Even though the outcomes using this approach are encouraging, 5-year rates of local and distant recurrence range from 6% to 9% and 33% to 36%, respectively. Furthermore, the incidence of sphincter preservation following CCRT in such patients also varies, ranging from 39% to 94%. To further improve the clinical outcomes for rectal cancer patients treated with CCRT, the development of potential therapeutic targets is highly desirable.
The mammalian fibroblast growth factor (FGF) family comprises 18 ligands which exert their actions through four highly conserved transmembrane tyrosine kinase receptors, including fibroblast growth factor receptor (FGFR) 1, FGFR2, FGFR3 and FGFR4. FGFs and their receptors control a multitude of cellular processes in different contexts, including proliferation, differentiation, survival and motility. As such, this FGF/FGFR system is susceptible to aberration in cancer cells and deregulation of FGFR signalling pathway has been shown to play a critical role in many cancers. For example, FGFR1 mutations and amplifications have been implicated in glioblastoma, prostate, breast and lung cancers, whereas aberrant FGFR2 expression has been observed in endometrial cancer, breast cancer, gastric cancer, lung cancer and melanoma. Furthermore, activating mutations and overexpression of FGFR3 have been reported in bladder cancers and multiple myeloma. Recently, alterations of the FGFR signalling pathway in malignancies have been under the spotlight because of their high incidence rate and therapeutic potential.
Aberrations of the FGFR signalling pathway, including FGFR2, FGFR3 and FGFR4, have been demonstrated in colorectal cancers (CRCs); nevertheless, their clinical impact on therapeutic response and prognosis of rectal cancer patients treated with CCRT have not yet been elucidated. In this study, we analysed the FGFR signalling pathway in one published transcriptome of rectal cancers and identified that upregulated FGFR2 gene was correlated to the response to CCRT. The clinical implications of FGFR2 expression were further validated by studying a well-defined cohort of 172 rectal cancers treated with neoadjuvant CCRT followed by surgery.
