_:b2009820 . _:b342405928 . _:b2009821 . _:b342405897 . . _:b342405931 . _:b2009814 "Cancers of the biliary tract are the second most common primary hepatobiliary cancer [>>13<<]. There is no satisfactory treatment available for patients with hepatobiliary cancers and chemotherapy has been extremely disappointing." . _:b2009822 . _:b342405942 . _:b342405930 . _:b2009804 "We subjected those samples to PCR-based semi-automated double stranded nucleotide sequencing, per routine of the Eng lab [24,>>25<<]. Exons 18\u201321 (exon-intron junctions and flanking intronic regions) of EGFR were amplified using the primers and conditions described by Lynch et al [3] and those of ERBB2 were amplified using the primers and conditions described by" . _:b342405941 . _:b2009816 . _:b342405940 . _:b342405940 . _:b2009817 . _:b342405943 . _:b2009818 . _:b342405891 . _:b342405942 . _:b2009819 . _:b342405937 . _:b2009821 "A recently published study showed the lack of somatic mutations in EGFR tyrosine kinase domain in 100 hepatocellular carcinomas confirming our findings [>>26<<]. In contrast, we showed that 11% of hepatocellular carcinomas tested have an ERBB2 mutation occurring in the activation domain. None were found in biliary cancer specimens. Given the availability of agents interfering with ERBB2" . _:b342405936 . _:b2009805 "Exons 18\u201321 (exon-intron junctions and flanking intronic regions) of EGFR were amplified using the primers and conditions described by Lynch et al [>>3<<] and those of ERBB2 were amplified using the primers and conditions described by Stephens et al [6]." . _:b342405901 . _:b342405939 . _:b2009813 . _:b342405938 . . . _:b342405949 . _:b342405948 . . _:b342405948 . . _:b342405950 . . _:b342405945 . _:b342405912 . _:b342405935 . _:b342405944 . _:b342405900 . _:b2009811 . . _:b342405947 . . _:b342405946 . . _:b342405893 . _:b2009802 _:b2009804 . _:b2009807 _:b2009816 . _:b2009807 _:b2009817 . _:b2009802 _:b2009805 . _:b2009802 _:b2009806 . _:b2009807 _:b2009818 . _:b2009807 _:b2009819 . _:b342405917 . . _:b2009802 _:b2009803 . _:b2009807 _:b2009808 . _:b2009807 _:b2009809 . . _:b2009807 _:b2009810 . . _:b2009807 _:b2009811 . _:b2009807 _:b2009812 . _:b2009807 _:b2009813 . _:b342405929 . _:b2009807 _:b2009814 . _:b2009807 _:b2009815 . _:b2009807 "background" . _:b342405934 . . . . _:b342405920 . _:b342405889 . . . _:b342405931 . _:b342405906 . . . . _:b342405893 "3"^^ . . _:b342405892 "3"^^ . _:b2009820 _:b2009821 . _:b2009820 _:b2009822 . _:b342405916 . _:b342405917 . _:b342405918 . _:b342405895 "3"^^ . _:b342405919 . . . _:b342405912 . "10.1186%2F1471-2407-6-278" . _:b342405913 . _:b342405914 . _:b342405894 "3"^^ . _:b2009807 . _:b342405915 . _:b342405908 . _:b342405909 . _:b342405910 . _:b2009802 . . _:b342405895 . _:b342405911 . _:b342405889 "4"^^ . _:b342405904 . _:b342405905 . . _:b342405905 . _:b342405906 . . _:b342405907 . _:b342405888 "4"^^ . _:b342405900 . _:b342405901 . . _:b342405936 . _:b342405902 . _:b342405891 "3"^^ . _:b2009810 . _:b342405903 . _:b2009820 . _:b342405896 . _:b342405897 . _:b342405898 . _:b342405890 "3"^^ . _:b342405899 . _:b342405892 . _:b342405893 . _:b342405901 "2"^^ . _:b342405894 . . _:b342405895 . _:b342405888 . _:b2009804 . _:b342405889 . _:b342405900 "2"^^ . _:b2009816 . _:b342405890 . _:b342405891 . _:b342405948 . . _:b342405949 . _:b342405903 "2"^^ . _:b342405950 . _:b342405944 . _:b342405945 . _:b342405902 "2"^^ . _:b342405946 . _:b342405947 . _:b342405940 . _:b342405941 . _:b342405897 "2"^^ . _:b342405942 . _:b342405943 . . _:b342405936 . _:b342405937 . _:b342405896 "2"^^ . _:b342405938 . _:b342405939 . _:b342405932 . _:b342405904 . . _:b342405933 . _:b342405899 "2"^^ . _:b342405934 . _:b342405898 . _:b342405918 . _:b342405935 . _:b342405928 . _:b342405929 . _:b342405898 "2"^^ . _:b342405930 . . _:b342405931 . . _:b342405924 . _:b342405925 . _:b2009803 . _:b342405909 "2"^^ . _:b342405926 . _:b342405927 . _:b342405920 . _:b342405921 . _:b342405908 "2"^^ . _:b342405922 . _:b342405923 . _:b342405911 "2"^^ . _:b2009811 "In addition to NSCLC, mutations in the ERBB2 kinase domain were described in gastric, colorectal, and breast cancers [>>10<<,11]. In our study, we sought to determine if similar respective gain-of-function EGFR and ERBB2 mutations were present in hepatoma and biliary cancers to determine the potential for ERBB -targeted therapy." . . _:b342405910 "2"^^ . . . _:b342405905 "2"^^ . . _:b2009816 "Studies indicate that EGFR is expressed in up to 85% and 80% of hepatoma and biliary cancers, respectively [14], and EGF might be required for the growth of those cells [>>15<<,16]. ERBB2 is also expressed in a significant number of hepatoma and biliary cancers acting as an independent prognostic factor and a major contributor to carcinogenesis [17-21]. Recently, a multi-center phase 2 study looked at the" . _:b342405904 "2"^^ . _:b2009812 . _:b342405907 "2"^^ . _:b342405932 . . _:b2009818 . _:b342405906 "2"^^ . . _:b342405917 "2"^^ . _:b342405939 . _:b342405916 "2"^^ . _:b342405927 . _:b342405950 . _:b342405919 "2"^^ . . _:b342405918 "2"^^ . _:b342405911 . _:b2009822 . _:b342405913 "2"^^ . _:b342405899 . _:b342405912 "2"^^ . _:b2009810 "reported the presence of ERBB2 mutations located in the kinase domain (exons 19 and 20) in non-small cell lung carcinomas (NSCLC) that could potentially result in the activation of the tyrosine kinase activity of the receptor protein [>>6<<-9]. In addition to NSCLC, mutations in the ERBB2 kinase domain were described in gastric, colorectal, and breast cancers [10,11]." . _:b342405915 "2"^^ . _:b2009802 "methods" . . _:b2009817 "Studies indicate that EGFR is expressed in up to 85% and 80% of hepatoma and biliary cancers, respectively [14], and EGF might be required for the growth of those cells [15,>>16<<]. ERBB2 is also expressed in a significant number of hepatoma and biliary cancers acting as an independent prognostic factor and a major contributor to carcinogenesis [17-21]. Recently, a multi-center phase 2 study looked at the efficacy" . _:b2009815 . _:b342405914 "2"^^ . . _:b342405925 "2"^^ . _:b2009806 "(exon-intron junctions and flanking intronic regions) of EGFR were amplified using the primers and conditions described by Lynch et al [3] and those of ERBB2 were amplified using the primers and conditions described by Stephens et al [>>6<<]. Double stranded sequencing was performed with the ABI-3700. Mutations or variants were confirmed in both directions as well as confirmed by a second independent PCR reaction." . _:b2009818 . _:b342405924 "2"^^ . . _:b342405927 "2"^^ . . _:b342405896 . _:b342405926 "2"^^ . _:b342405921 "2"^^ . . . _:b342405920 "2"^^ . _:b342405923 "2"^^ . . _:b342405922 "2"^^ . _:b342405933 "2"^^ . . _:b342405932 "2"^^ . . . _:b342405935 "2"^^ . . . _:b342405934 "2"^^ . . _:b342405929 "2"^^ . _:b2009818 . _:b342405928 "2"^^ . . . _:b2009819 . _:b342405931 "2"^^ . _:b342405923 . _:b342405930 "2"^^ . . _:b342405941 "2"^^ . _:b342405940 "2"^^ . _:b342405910 . _:b342405943 "2"^^ . _:b342405942 "2"^^ . _:b2009809 . . _:b342405937 "2"^^ . _:b342405908 . _:b342405933 . _:b342405936 "2"^^ . _:b342405939 "2"^^ . _:b2009819 "Recently, a multi-center phase 2 study looked at the efficacy and tolerability of erlotinib in advanced hepatoma and biliary cancers with encouraging results [22,>>23<<]. In hepatoma, the reported PFS at 6 months of 32% with disease control (PR + SD) of 59% for a median duration of 4 months. The median overall survival (OS) was 13 months. In biliary cancers, the reported PFS at 6 months was 25% with" . _:b2009808 . _:b342405943 . _:b342405894 . _:b342405938 "2"^^ . . _:b342405949 "2"^^ . _:b342405948 "2"^^ . _:b342405915 . . _:b2009814 . _:b342405947 . _:b342405950 "2"^^ . _:b342405938 . _:b342405945 "2"^^ . _:b2009810 . _:b342405890 . _:b342405944 "2"^^ . _:b342405947 "2"^^ . _:b2009808 "These receptors form either homo- or heterodimeric complexes which provides amplification and diversification [>>1<<]. Heterodimerization of the ERBB2 and EGFR is associated with a more robust signaling than homodimerization [2]. Several studies showed that gain-of-function somatic mutations affecting the catalytic domain (specifically the ATP binding" . . _:b342405946 "2"^^ . . _:b342405893 . . _:b2009803 "We subjected those samples to PCR-based semi-automated double stranded nucleotide sequencing, per routine of the Eng lab [>>24<<,25]. Exons 18\u201321 (exon-intron junctions and flanking intronic regions) of EGFR were amplified using the primers and conditions described by Lynch et al [3] and those of ERBB2 were amplified using the primers and conditions described by" . _:b342405892 . . . _:b342405895 . _:b342405894 . _:b342405926 . _:b2009812 "In addition to NSCLC, mutations in the ERBB2 kinase domain were described in gastric, colorectal, and breast cancers [10,>>11<<]. In our study, we sought to determine if similar respective gain-of-function EGFR and ERBB2 mutations were present in hepatoma and biliary cancers to determine the potential for ERBB -targeted therapy." . _:b342405889 . . _:b342405888 . _:b342405891 . _:b2009809 "the catalytic domain (specifically the ATP binding site, exons 18\u201321) of EGFR in non-small cell lung carcinomas were strongly associated with response to gefitinib and erlotinib, both related EGFR-tyrosine kinase inhibitors (TKI) [>>3<<-5]. More recently, a number of studies reported the presence of ERBB2 mutations located in the kinase domain (exons 19 and 20) in non-small cell lung carcinomas (NSCLC) that could potentially result in the activation of the tyrosine" . _:b342405890 . _:b342405902 . _:b2009818 "ERBB2 is also expressed in a significant number of hepatoma and biliary cancers acting as an independent prognostic factor and a major contributor to carcinogenesis [>>17<<-21]. Recently, a multi-center phase 2 study looked at the efficacy and tolerability of erlotinib in advanced hepatoma and biliary cancers with encouraging results [22,23]. In hepatoma, the reported PFS at 6 months of 32% with disease" . _:b342405913 . _:b342405901 . . _:b342405946 . _:b342405900 . _:b2009821 . _:b342405909 . _:b342405903 . . _:b342405902 . _:b342405897 . _:b342405924 . _:b342405896 . _:b2009809 . _:b342405921 . _:b342405925 . _:b342405899 . _:b2009805 . _:b342405892 . _:b342405898 . _:b342405945 . _:b342405941 . _:b342405909 . _:b342405888 . _:b342405908 . . _:b2009818 . _:b342405911 . _:b2009813 "Hepatoma is the most common malignant tumor of the liver with a clear rising incidence in the number of cases in the United States, and is largely attributed to the increase in hepatitis C related liver disease [>>12<<]. Cancers of the biliary tract are the second most common primary hepatobiliary cancer [13]." . . "PMC0" . . _:b342405910 . . _:b342405905 . . _:b2009817 . _:b342405904 . _:b342405907 . _:b2009806 . _:b342405906 . _:b342405917 . . _:b342405916 . . _:b342405919 . _:b342405907 . . _:b342405918 . _:b2009820 "discussions and conclusion" . _:b342405919 . _:b342405937 . . _:b342405913 . _:b2009804 . _:b342405912 . . _:b2009805 . _:b342405915 . _:b2009806 . _:b2009822 "not linked to kinase mutations of EGFR, one single response case was actually linked to a mutation in exon 20 of ERBB2 establishing the potential predictive value of such mutations on responses to agents that target ERBB2 and/or EGFR [>>28<<]. In conclusion, our findings suggest that mutations in the tyrosine kinase domain of ERBB2 in hepatoma may underlie responsiveness to agents that target ERBB2 and/or EGFR." . _:b342405914 . . _:b2009807 . _:b342405925 . . _:b342405924 . . _:b342405927 . _:b2009802 . _:b2009815 "Studies indicate that EGFR is expressed in up to 85% and 80% of hepatoma and biliary cancers, respectively [>>14<<], and EGF might be required for the growth of those cells [15,16]." . _:b342405926 . _:b2009803 . _:b342405914 . _:b342405949 . . _:b342405921 . _:b2009812 . _:b342405920 . _:b2009810 . _:b2009809 . _:b2009813 . _:b342405903 . . _:b342405923 . _:b2009814 . . _:b342405922 . . _:b2009815 . _:b342405928 . _:b342405933 . _:b342405916 . _:b2009808 . . _:b342405922 . _:b342405932 . _:b342405944 . _:b2009809 . _:b342405935 . . . _:b2009810 . _:b342405930 . _:b342405934 . _:b2009811 . . _:b342405929 .