399
Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel 2235-1795/14/0034-0399$39.50/0 www.karger.com/lic
Editorial
Biomarkers and Personalized Sorafenib Therapy Prof. M. Kudo
Editor Liver Cancer
Compared with other types of cancer, hepatocellular carcinoma (HCC) is highly heterogeneous because of the intrinsic diversity in its pathogenesis, molecular heterogeneity, its multicentric occurrence, and its etiology, among others. Until now, locoregional therapies such as resection, ablation, and transarterial chemoembolization (TACE) have been performed extensively to treat HCC because the application of systemic chemotherapy using cytotoxic anticancer drugs is limited by the presence of pancytopenia and hepatic dysfunction caused by the cirrhosis that usually accompanies HCC. Since its approval in 2007 as a systemic chemotherapeutic agent that improves the survival of patients with unresectable advanced HCC, sorafenib has been widely used as a novel treatment option in patients with advanced HCCs with extrahepatic spread and/or vascular invasion. Need for Personalized Sorafenib Therapy Sorafenib is the only anticancer drug with proven prognostic efficacy in HCC [1, 2]; however, it should be administered with care because of various adverse effects, including hand– foot skin reaction, hypertension, diarrhea, and liver dysfunction. Moreover, because cases of ineffective and incomplete response to sorafenib have been reported, and because the drug is extremely expensive, the development of prognostic factors and biomarkers for predicting adverse events are eagerly awaited. The ability to predict treatment outcome and adverse events would make it possible to avoid administering sorafenib to patients who would not benefit from it and to exclude patients likely to develop serious side effects. This would not only increase safety but also markedly improve the medico-economic situation. Consequently, studies are currently underway to develop biomarkers for predicting treatment outcome and adverse events, and some biomarkers for novel molecularly targeted drugs have already been identified in the early phase of clinical trials and subsequently evaluated in phase III trials.
400
Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel www.karger.com/lic
Signals Triggering Proliferation of Hepatocellular Carcinoma Mutations of specific genes that play an important role in cancer proliferation (oncogene addiction), such as the BRAF V600E mutation in malignant melanoma [3] and the ALK fusion gene mutation in lung cancer [4], are perfect targets for molecularly targeted drugs. However, with regard to HCC, no study has reported a specific gene mutation that causes oncogene addiction, despite various proliferation-related signal transduction pathways being activated, such as those of MAP kinase [5], PI3K/Akt/mTOR [6], c-MET [7], IGF [8], Wntbeta-catenin [9, 10], hedgehog [11], vascular endothelial growth factor (VEGF) receptor, and platelet-derived growth factor (PDGF) receptor [12]. It is therefore difficult to use gene mutations as biomarkers in HCC. The multikinase inhibitor sorafenib suppresses the proliferation of vascular endothelial cells and pericytes by inhibiting the activity of tyrosine kinase in the cytosolic domain of the VEGF and PDGF receptors. It also suppresses the proliferation of tumor cells by inhibiting the activity of Raf serine/threonine kinase in the MAP kinase cascade responsible for such proliferation. Sorafenib, therefore, exerts a multifaceted anticancer effect by inhibiting various kinases and appears to work well in HCC. In other words, the difficulty in identifying a specific biomarker in sorafenib therapy for HCC may be caused by the presence of multiple molecular targets. Despite previous reports of potential biomarkers, no definitive biomarker for sorafenib has been reported (Table 1 [13–24]). FGF3/4 Gene Amplification The SHARP [1] and Asia Pacific [2] trials revealed extremely low response rates in patients treated with sorafenib: the overall response was as low as a few percent, with almost no tumor response. In general, a drug’s inhibitory action on tumor proliferation improves patient survival. In Japan, there has been a stream of super responders (i.e., complete responders and partial responders) to sorafenib since its approval in 2009, suggesting a common, yet unknown response factor in Japanese people [25]. In fact, when we gathered biopsy specimens from sorafenib super responders across Japan and performed genome analysis, the results revealed a high expression level of FGF3/4, lung metastasis, and poorly differentiated HCC as common factors [24], suggesting that each of these factors could serve as biomarkers. Although high expression of FGF3/4 may be a good marker because of its affinity for various molecular targets, it is difficult to use high levels of FGF3/4 expression as a general purpose marker because the FGF3/4 mutation has been observed in only a few percent of all HCC patients. c-Jun N-Terminal Kinase In addition, c-Jun N-terminal kinase (JNK), which acts as an intracellular signaling protein, is highly upregulated in patients with no response to sorafenib. Because JNK activation is closely related to CD133 expression, CD133 and JNK expression may serve as a biomarker for no tumor response to sorafenib [23].
401
Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel www.karger.com/lic
Table 1. Potential biomarkers for predicting treatment outcome and adverse events of sorafenib treatment in HCC Biomarker
Author
Year
Reference
Dermal toxicity
Vincenzi B
2010
13
Symtoms and signs
Hypertension
Estfan B
2013
14
Lung metastasis
Yau T
2009
21
AFP decrease after 6 weeks (>20%)
Yau T
2011
15
Serum markers
AFP decrease in the early phase (comparing AFP after 2 and 4 weeks)
DCP increase after 2 weeks
NX-DCP and DCP
Serum VEGF decrease after 8 weeks
Kuzuya T
2011
16
Ueshima K
2011
17
Miyahara K
Tsuchiya K
2013
2014
18
19
Angiopoietin-2, G-CSF, HGF, leptin
Miyahara K
2011
20
pERK
Zhang Z
2009
22
Genes and proteins JNK activity
FGF3/FGF4 amplification
Hagiwara S
Arao T
2012
2013
23
24
AFP = alpha-fetoprotein; DCP = des-γ-carboxyprothrombin; G-CSF = granulocyte colony-stimulating factor; HGF = hepatocyte growth factor; pERK = phosphorylated extracellular-signal-regulated kinases.
Cytokine Biomarkers Miyahara et al. measured changes in the levels of several serum angiogenesis markers before and after sorafenib treatment and showed that the number of HCC patients with progressive disease was high among HCC patients with high levels of serum angiogenesis markers before the treatment [20]. In addition, Tsuchiya et al. reported that chronological changes in serum VEGF levels can serve as a useful prognostic indicator [19]. As shown in these studies, changes in the levels of serum markers during drug therapy can be used to predict treatment outcome to a certain extent. Although the aim is to use biomarkers to predict treatment outcome and adverse events before drug treatment, this is difficult to do at present. We await the results of genome-wide association studies currently underway. Another way to predict adverse events is to monitor laboratory test values and hemodynamics throughout drug therapy.
402
Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel www.karger.com/lic
Proteins Induced by Vitamin K Absence Proteins induced by vitamin K absence (PIVKA)-II are markers for HCC. In hepatic cells, γ-glutamyl carboxylase and vitamin K are coenzymes responsible for the carboxylation of ten glutamic acid residues in the Gla domain located at the N-terminus of the prothrombin precursor, thereby converting the precursor to prothrombin, which possesses coagulation activity and is secreted into the bloodstream. However, when vitamin K is deficient, prothrombin is released into the circulation without complete carboxylation. PIVKA-II proteins are the non-functional precursors that accumulate in the circulation. Because sorafenib administration rapidly increases PIVKA-II levels in many cases, we retrospectively investigated the relationship between tumor progression and increases in PIVKA-II levels. The results showed that time to progression (TTP) was significantly prolonged in patients whose PIVKA-II level had been upregulated two-fold 2 weeks after sorafenib administration [17]. We believe that prolonged TTP is a reflection of ischemia in HCC caused by the anti-angiogenic effect of sorafenib. Such ischemia alters the actin molecules making up the cytoskeleton of HCC cells, thereby impairing the endocytosis of vitamin K. This subsequently leads to vitamin K deficiency and an increase in PIVKA-II levels, and means that PIVKA-II has potential as a surrogate marker for cellular ischemia as well as a monitoring marker for the anti-angiogenic effect of sorafenib. Comparison of Images Taken Before and after Treatment Because tumors develop ischemic conditions when sorafenib exerts its anti-angiogenic effect, the monitoring of hemodynamics by computed tomography or magnetic resonance imaging may provide useful evaluation criteria on whether to continue drug administration. Our investigation showed that survival was significantly prolonged in HCC patients with necrosis or decreased blood flow, even if only partial, compared with that in HCC patients with no change in blood flow [26]. In conclusion, it is not currently possible to predict treatment outcome or the likelihood of adverse effects of sorafenib treatment before administering the drug. Despite the discovery of genes that are potential biomarkers, such as FGF3/4, these genes have not been put to practical use: current clinical practice consists of starting sorafenib administration and monitoring patients individually to determine the treatment effects. In particular, we need to monitor the radiological response and response of tumor markers (AFP and PIVKA-II) carefully during the initial phase of drug administration (approximately 4 weeks.) At the time of evaluating the treatment effect (after 8 weeks), it may be considered to discontinue administration in patients who have not responded to sorafenib since the likely result will be progressive disease. However, in the real world clinical practice in those patients with slow growing HCCs (long stable diseases), administration of sorafenib even beyond progressive diseases should be continued since there is no second line targeted agents available at the present and maybe sorafenib is beneficial for prolonging survival of such patient population.
403
Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel www.karger.com/lic
References 1 Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, SHARP Investigators Study Group: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390. 2 Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25–34. 3 Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, BRIM-3 Study Group: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507– 2516. 4 Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561–566. 5 Schmidt CM, McKillop IH, Cahill PA, Sitzmann JV: Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun 1997;236:54–58. 6 Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M: mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004;10:8421–8425. 7 Boix L, Rosa JL, Ventura F, Castells A, Bruix J, Rodés J, Bartrons R: c-met mRNA overexpression in human hepatocellular carcinoma. Hepatology 1994;19:88–91. 8 Scharf JG, Braulke T: The role of the IGF axis in hepatocarcinogenesis. Horm Metab Res 2003;35:685–693. 9 de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C: Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 1998;95:8847–8851. 10 Klaus A, Birchmeier W: Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008;8:387–398. 11 Patil MA, Zhang J, Ho C, Cheung ST, Fan ST, Chen X: Hedgehog signaling in human hepatocellular carcinoma. Cancer Biol Ther 2006;5:111–117. 12 Poon RT, Ng IO, Lau C, Zhu LX, Yu WC, Lo CM, Fan ST, Wong J: Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a prospective study. Ann Surg 2001;233:227–235. 13 Vincenzi B, Santini D, Russo A, Addeo R, Giuliani F, Montella L, Rizzo S, Venditti O, Frezza AM, Caraglia M, Colucci G, Del Prete S, Tonini G: Early skin toxicity as a predictive factor for tumor control in hepatocellular carcinoma patients treated with sorafenib. Oncologist 2010;15:85–92. 14 Estfan B, Byrne M, Kim R: Sorafenib in advanced hepatocellular carcinoma: hypertension as a potential surrogate marker for efficacy. Am J Clin Oncol 2013;36:319–324. 15 Yau T, Yao TJ, Chan P, Wong H, Pang R, Fan ST, Poon RT: The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib. Oncologist 2011;16:1270–1279. 16 Kuzuya T, Asahina Y, Tsuchiya K, Tanaka K, Suzuki Y, Hoshioka T, Tamaki S, Kato T, Yasui Y, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Izumi N: Early decrease in α-fetoprotein, but not des-γ-carboxy prothrombin, predicts sorafenib efficacy in patients with advanced hepatocellular carcinoma. Oncology 2011;81:251–258. 17 Ueshima K, Kudo M, Takita M, Nagai T, Tatsumi C, Ueda T, Kitai S, Ishikawa E, Yada N, Inoue T, Hagiwara S, Minami Y, Chung H, Sakurai T: Des-γ-carboxyprothrombin may be a promising biomarker to determine the therapeutic efficacy of sorafenib for hepatocellular carcinoma. Dig Dis 2011;29:321–325. 18 Miyahara K, Nouso K, Morimoto Y, Tomoda T, Kobayashi S, Takeuchi Y, Hagihara H, Kuwaki K, Ohnishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Yamamoto K, Okayama Liver Cancer Group: Evaluation of the effect of sorafenib using serum NX-des-γ-carboxyprothrombin in patients with hepatocellular carcinoma. Hepatol Res 2013;43:1064–1070. 19 Tsuchiya K, Asahina Y, Matsuda S, Muraoka M, Nakata T, Suzuki Y, Tamaki N, Yasui Y, Suzuki S, Hosokawa T, Nishimura T, Ueda K, Kuzuya T, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Izumi N: Changes in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma. Cancer 2014;120:229–237. 20 Miyahara K, Nouso K, Tomoda T, Kobayashi S, Hagihara H, Kuwaki K, Toshimori J, Onishi H, Ikeda F, Miyake Y, Nakamura S, Shiraha H, Takaki A, Yamamoto K: Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2011;26:1604– 1611. 21 Yau T, Chan P, Ng KK, Chok SH, Cheung TT, Fan ST, Poon RT: Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response. Cancer 2009;115:428–436. 22 Zhang Z, Zhou X, Shen H, Wang D, Wang Y: Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: evidence from an in vitro study. BMC Med 2009;7:41-52.
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Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel www.karger.com/lic
23 Hagiwara S, Kudo M, Nagai T, Inoue T, Ueshima K, Nishida N, Watanabe T, Sakurai T: Activation of JNK and high expression level of CD133 predict a poor response to sorafenib in hepatocellular carcinoma. Br J Cancer 2012;106:1997–2003. 24 Arao T, Ueshima K, Matsumoto K, Nagai T, Kimura H, Hagiwara S, Sakurai T, Haji S, Kanazawa A, Hidaka H, Iso Y, Kubota K, Shimada M, Utsunomiya T, Hirooka M, Hiasa Y, Toyoki Y, Hakamada K, Yasui K, Kumada T, Toyoda H, Sato S, Hisai H, Kuzuya T, Tsuchiya K, Izumi N, Arii S, Nishio K, Kudo M: FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma. Hepatology 2013;57:1407–1415. 25 Kudo M, Ueshima K: Positioning of a molecular-targeted agent, sorafenib, in the treatment algorithm for hepatocellular carcinoma and implication of many complete remission cases in Japan. Oncology 2010;78(Suppl 1):154–166. 26 Arizumi T, Ueshima K, Takeda H, Osaki Y, Takita M, Inoue T, Kitai S, Yada N, Hagiwara S, Minami Y, Sakurai T, Nishida N, Kudo M: Comparison of systems for assessment of post-therapeutic response to sorafenib for hepatocellular carcinoma. J Gastroenterol 2014; epub ahead of print.
Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel 2235-1795/14/0034-0399$39.50/0 www.karger.com/lic
Editorial
Biomarkers and Personalized Sorafenib Therapy Prof. M. Kudo
Editor Liver Cancer
Compared with other types of cancer, hepatocellular carcinoma (HCC) is highly heterogeneous because of the intrinsic diversity in its pathogenesis, molecular heterogeneity, its multicentric occurrence, and its etiology, among others. Until now, locoregional therapies such as resection, ablation, and transarterial chemoembolization (TACE) have been performed extensively to treat HCC because the application of systemic chemotherapy using cytotoxic anticancer drugs is limited by the presence of pancytopenia and hepatic dysfunction caused by the cirrhosis that usually accompanies HCC. Since its approval in 2007 as a systemic chemotherapeutic agent that improves the survival of patients with unresectable advanced HCC, sorafenib has been widely used as a novel treatment option in patients with advanced HCCs with extrahepatic spread and/or vascular invasion. Need for Personalized Sorafenib Therapy Sorafenib is the only anticancer drug with proven prognostic efficacy in HCC [1, 2]; however, it should be administered with care because of various adverse effects, including hand– foot skin reaction, hypertension, diarrhea, and liver dysfunction. Moreover, because cases of ineffective and incomplete response to sorafenib have been reported, and because the drug is extremely expensive, the development of prognostic factors and biomarkers for predicting adverse events are eagerly awaited. The ability to predict treatment outcome and adverse events would make it possible to avoid administering sorafenib to patients who would not benefit from it and to exclude patients likely to develop serious side effects. This would not only increase safety but also markedly improve the medico-economic situation. Consequently, studies are currently underway to develop biomarkers for predicting treatment outcome and adverse events, and some biomarkers for novel molecularly targeted drugs have already been identified in the early phase of clinical trials and subsequently evaluated in phase III trials.
400
Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel www.karger.com/lic
Signals Triggering Proliferation of Hepatocellular Carcinoma Mutations of specific genes that play an important role in cancer proliferation (oncogene addiction), such as the BRAF V600E mutation in malignant melanoma [3] and the ALK fusion gene mutation in lung cancer [4], are perfect targets for molecularly targeted drugs. However, with regard to HCC, no study has reported a specific gene mutation that causes oncogene addiction, despite various proliferation-related signal transduction pathways being activated, such as those of MAP kinase [5], PI3K/Akt/mTOR [6], c-MET [7], IGF [8], Wntbeta-catenin [9, 10], hedgehog [11], vascular endothelial growth factor (VEGF) receptor, and platelet-derived growth factor (PDGF) receptor [12]. It is therefore difficult to use gene mutations as biomarkers in HCC. The multikinase inhibitor sorafenib suppresses the proliferation of vascular endothelial cells and pericytes by inhibiting the activity of tyrosine kinase in the cytosolic domain of the VEGF and PDGF receptors. It also suppresses the proliferation of tumor cells by inhibiting the activity of Raf serine/threonine kinase in the MAP kinase cascade responsible for such proliferation. Sorafenib, therefore, exerts a multifaceted anticancer effect by inhibiting various kinases and appears to work well in HCC. In other words, the difficulty in identifying a specific biomarker in sorafenib therapy for HCC may be caused by the presence of multiple molecular targets. Despite previous reports of potential biomarkers, no definitive biomarker for sorafenib has been reported (Table 1 [13–24]). FGF3/4 Gene Amplification The SHARP [1] and Asia Pacific [2] trials revealed extremely low response rates in patients treated with sorafenib: the overall response was as low as a few percent, with almost no tumor response. In general, a drug’s inhibitory action on tumor proliferation improves patient survival. In Japan, there has been a stream of super responders (i.e., complete responders and partial responders) to sorafenib since its approval in 2009, suggesting a common, yet unknown response factor in Japanese people [25]. In fact, when we gathered biopsy specimens from sorafenib super responders across Japan and performed genome analysis, the results revealed a high expression level of FGF3/4, lung metastasis, and poorly differentiated HCC as common factors [24], suggesting that each of these factors could serve as biomarkers. Although high expression of FGF3/4 may be a good marker because of its affinity for various molecular targets, it is difficult to use high levels of FGF3/4 expression as a general purpose marker because the FGF3/4 mutation has been observed in only a few percent of all HCC patients. c-Jun N-Terminal Kinase In addition, c-Jun N-terminal kinase (JNK), which acts as an intracellular signaling protein, is highly upregulated in patients with no response to sorafenib. Because JNK activation is closely related to CD133 expression, CD133 and JNK expression may serve as a biomarker for no tumor response to sorafenib [23].
401
Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel www.karger.com/lic
Table 1. Potential biomarkers for predicting treatment outcome and adverse events of sorafenib treatment in HCC Biomarker
Author
Year
Reference
Dermal toxicity
Vincenzi B
2010
13
Symtoms and signs
Hypertension
Estfan B
2013
14
Lung metastasis
Yau T
2009
21
AFP decrease after 6 weeks (>20%)
Yau T
2011
15
Serum markers
AFP decrease in the early phase (comparing AFP after 2 and 4 weeks)
DCP increase after 2 weeks
NX-DCP and DCP
Serum VEGF decrease after 8 weeks
Kuzuya T
2011
16
Ueshima K
2011
17
Miyahara K
Tsuchiya K
2013
2014
18
19
Angiopoietin-2, G-CSF, HGF, leptin
Miyahara K
2011
20
pERK
Zhang Z
2009
22
Genes and proteins JNK activity
FGF3/FGF4 amplification
Hagiwara S
Arao T
2012
2013
23
24
AFP = alpha-fetoprotein; DCP = des-γ-carboxyprothrombin; G-CSF = granulocyte colony-stimulating factor; HGF = hepatocyte growth factor; pERK = phosphorylated extracellular-signal-regulated kinases.
Cytokine Biomarkers Miyahara et al. measured changes in the levels of several serum angiogenesis markers before and after sorafenib treatment and showed that the number of HCC patients with progressive disease was high among HCC patients with high levels of serum angiogenesis markers before the treatment [20]. In addition, Tsuchiya et al. reported that chronological changes in serum VEGF levels can serve as a useful prognostic indicator [19]. As shown in these studies, changes in the levels of serum markers during drug therapy can be used to predict treatment outcome to a certain extent. Although the aim is to use biomarkers to predict treatment outcome and adverse events before drug treatment, this is difficult to do at present. We await the results of genome-wide association studies currently underway. Another way to predict adverse events is to monitor laboratory test values and hemodynamics throughout drug therapy.
402
Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel www.karger.com/lic
Proteins Induced by Vitamin K Absence Proteins induced by vitamin K absence (PIVKA)-II are markers for HCC. In hepatic cells, γ-glutamyl carboxylase and vitamin K are coenzymes responsible for the carboxylation of ten glutamic acid residues in the Gla domain located at the N-terminus of the prothrombin precursor, thereby converting the precursor to prothrombin, which possesses coagulation activity and is secreted into the bloodstream. However, when vitamin K is deficient, prothrombin is released into the circulation without complete carboxylation. PIVKA-II proteins are the non-functional precursors that accumulate in the circulation. Because sorafenib administration rapidly increases PIVKA-II levels in many cases, we retrospectively investigated the relationship between tumor progression and increases in PIVKA-II levels. The results showed that time to progression (TTP) was significantly prolonged in patients whose PIVKA-II level had been upregulated two-fold 2 weeks after sorafenib administration [17]. We believe that prolonged TTP is a reflection of ischemia in HCC caused by the anti-angiogenic effect of sorafenib. Such ischemia alters the actin molecules making up the cytoskeleton of HCC cells, thereby impairing the endocytosis of vitamin K. This subsequently leads to vitamin K deficiency and an increase in PIVKA-II levels, and means that PIVKA-II has potential as a surrogate marker for cellular ischemia as well as a monitoring marker for the anti-angiogenic effect of sorafenib. Comparison of Images Taken Before and after Treatment Because tumors develop ischemic conditions when sorafenib exerts its anti-angiogenic effect, the monitoring of hemodynamics by computed tomography or magnetic resonance imaging may provide useful evaluation criteria on whether to continue drug administration. Our investigation showed that survival was significantly prolonged in HCC patients with necrosis or decreased blood flow, even if only partial, compared with that in HCC patients with no change in blood flow [26]. In conclusion, it is not currently possible to predict treatment outcome or the likelihood of adverse effects of sorafenib treatment before administering the drug. Despite the discovery of genes that are potential biomarkers, such as FGF3/4, these genes have not been put to practical use: current clinical practice consists of starting sorafenib administration and monitoring patients individually to determine the treatment effects. In particular, we need to monitor the radiological response and response of tumor markers (AFP and PIVKA-II) carefully during the initial phase of drug administration (approximately 4 weeks.) At the time of evaluating the treatment effect (after 8 weeks), it may be considered to discontinue administration in patients who have not responded to sorafenib since the likely result will be progressive disease. However, in the real world clinical practice in those patients with slow growing HCCs (long stable diseases), administration of sorafenib even beyond progressive diseases should be continued since there is no second line targeted agents available at the present and maybe sorafenib is beneficial for prolonging survival of such patient population.
403
Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel www.karger.com/lic
References 1 Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, SHARP Investigators Study Group: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378–390. 2 Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z: Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25–34. 3 Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O’Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, BRIM-3 Study Group: Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507– 2516. 4 Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H: Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 2007;448:561–566. 5 Schmidt CM, McKillop IH, Cahill PA, Sitzmann JV: Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun 1997;236:54–58. 6 Sahin F, Kannangai R, Adegbola O, Wang J, Su G, Torbenson M: mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004;10:8421–8425. 7 Boix L, Rosa JL, Ventura F, Castells A, Bruix J, Rodés J, Bartrons R: c-met mRNA overexpression in human hepatocellular carcinoma. Hepatology 1994;19:88–91. 8 Scharf JG, Braulke T: The role of the IGF axis in hepatocarcinogenesis. Horm Metab Res 2003;35:685–693. 9 de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, Fabre M, Chelly J, Beldjord C, Kahn A, Perret C: Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 1998;95:8847–8851. 10 Klaus A, Birchmeier W: Wnt signalling and its impact on development and cancer. Nat Rev Cancer 2008;8:387–398. 11 Patil MA, Zhang J, Ho C, Cheung ST, Fan ST, Chen X: Hedgehog signaling in human hepatocellular carcinoma. 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Liver Cancer 2014;3:399–404 DOI: 10.1159/000343870 Published online: August 8, 2014
© 2014 S. Karger AG, Basel www.karger.com/lic
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