Wn oncogenic signaling pathways. Our RPPA analysis was able to recapitulate

Wn oncogenic signaling pathways. Our RPPA analysis was able to recapitulate

Wn oncogenic signaling pathways. Our RPPA Title Loaded From File analysis was able to recapitulate the molecular heterogeneity identified by whole-genomic transcriptional Title Loaded From File Profiling and concordantly identified two prognostically relevant subgroups of ampullary adenocarcinomas. RPPA analysis demonstrated marked activation of both the PI3K-AKT and RAS-RAF-MAPK pathways in our poor prognosis pancreaticobiliary-like ampullary subgroup. Of note, both ampullary adenocarcinoma samples with mutations in PIK3CA in this cohort of patients occurred in the pancreaticobiliary-like subgroup. These findings support the rationale for functional testing of inhibitors against these pathways in biliary-like ampullary carcinomas. In the intestinal-like subgroup a number of intestinal-specific genes were upregulated, which suggests that this subgroup of ampullary carcinomas may arise from the overlying ampullo-duodenal epithelium of the ampulla of Vater. Since prior studies have inconsistently reported the prognostic relevance of CDX-2 expression, CK7+/CK202 expression, and histological subtypes, we examined these markers. [4,5,9?3] We found that CDX-2 expression status represented an imperfect marker in comparison to our gene expression groupings. CK7+/ CK202 expression pattern and histological subtype were the two factors most closely correlated with our ampullary gene expression groupings. In our validation cohort, only histological subtype demonstrated a consistent prognostic impact and was an independent prognostic factor for OS in patients with ampullary adenocarcinoma. These results are consistent with the recently reported ESPAC-3 periampullary randomized study in which the intestinal as opposed to the pancreaticobiliary subtype of ampullary adenocarcinomas demonstrated an improved DFS (45.7 vs. 20.6 m, p = 0.01) but not OS (56 vs. 43.1 m, p = 0.28). [8] At present reporting the histological subtype of ampullary adenocarcinomas is not standard, as was demonstrated by the ESPAC-3 study in which only 45 of all ampullary adenocarcinomas had histological subtype reported. Our data does differ from a prior report that found statistical significance with the use of CDX-2 and CDX-1 staining in 53 resected ampullary carcinoma patients. [13] However, our data is consistent with two subsequent cohorts of 53 and 71 patients that did not identify CDX-2 expression as a prognostic marker [5,12].Gene Profiling of Periampullary CarcinomasRecently, our clinical approach for both metastatic duodenal and biliary adenocarcinomas has improved with the publication of a phase II study evaluating capecitabine and oxaliplatin in small bowel adenocarcinoma and a phase III study evaluating gemcitabine and cisplatin in biliary adenocarcinoma. [31,32] Interestingly, as a testament to the uncertainty of how to approach ampullary adenocarcinomas, both studies included adenocarcinomas of the ampulla of Vater. The recently completed ESPAC-3 study evaluated the role of adjuvant therapy for ampullary adenocarcinomas and found no difference with regard to the use of either gemcitabine or 5-FU in the adjuvant setting. [8] Though our findings do not provide a direct link between the expression profiling or histological subtype of ampullary adenocarcinoma and chemotherapy benefit, we do feel that histological subtype deserves further study as a potential marker to better select patients for adjuvant therapy and possibly as a means to optimally select chemotherapy, 5-FU-based as opposed to gemcitabine-based. Th.Wn oncogenic signaling pathways. Our RPPA analysis was able to recapitulate the molecular heterogeneity identified by whole-genomic transcriptional profiling and concordantly identified two prognostically relevant subgroups of ampullary adenocarcinomas. RPPA analysis demonstrated marked activation of both the PI3K-AKT and RAS-RAF-MAPK pathways in our poor prognosis pancreaticobiliary-like ampullary subgroup. Of note, both ampullary adenocarcinoma samples with mutations in PIK3CA in this cohort of patients occurred in the pancreaticobiliary-like subgroup. These findings support the rationale for functional testing of inhibitors against these pathways in biliary-like ampullary carcinomas. In the intestinal-like subgroup a number of intestinal-specific genes were upregulated, which suggests that this subgroup of ampullary carcinomas may arise from the overlying ampullo-duodenal epithelium of the ampulla of Vater. Since prior studies have inconsistently reported the prognostic relevance of CDX-2 expression, CK7+/CK202 expression, and histological subtypes, we examined these markers. [4,5,9?3] We found that CDX-2 expression status represented an imperfect marker in comparison to our gene expression groupings. CK7+/ CK202 expression pattern and histological subtype were the two factors most closely correlated with our ampullary gene expression groupings. In our validation cohort, only histological subtype demonstrated a consistent prognostic impact and was an independent prognostic factor for OS in patients with ampullary adenocarcinoma. These results are consistent with the recently reported ESPAC-3 periampullary randomized study in which the intestinal as opposed to the pancreaticobiliary subtype of ampullary adenocarcinomas demonstrated an improved DFS (45.7 vs. 20.6 m, p = 0.01) but not OS (56 vs. 43.1 m, p = 0.28). [8] At present reporting the histological subtype of ampullary adenocarcinomas is not standard, as was demonstrated by the ESPAC-3 study in which only 45 of all ampullary adenocarcinomas had histological subtype reported. Our data does differ from a prior report that found statistical significance with the use of CDX-2 and CDX-1 staining in 53 resected ampullary carcinoma patients. [13] However, our data is consistent with two subsequent cohorts of 53 and 71 patients that did not identify CDX-2 expression as a prognostic marker [5,12].Gene Profiling of Periampullary CarcinomasRecently, our clinical approach for both metastatic duodenal and biliary adenocarcinomas has improved with the publication of a phase II study evaluating capecitabine and oxaliplatin in small bowel adenocarcinoma and a phase III study evaluating gemcitabine and cisplatin in biliary adenocarcinoma. [31,32] Interestingly, as a testament to the uncertainty of how to approach ampullary adenocarcinomas, both studies included adenocarcinomas of the ampulla of Vater. The recently completed ESPAC-3 study evaluated the role of adjuvant therapy for ampullary adenocarcinomas and found no difference with regard to the use of either gemcitabine or 5-FU in the adjuvant setting. [8] Though our findings do not provide a direct link between the expression profiling or histological subtype of ampullary adenocarcinoma and chemotherapy benefit, we do feel that histological subtype deserves further study as a potential marker to better select patients for adjuvant therapy and possibly as a means to optimally select chemotherapy, 5-FU-based as opposed to gemcitabine-based. Th.

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