Predictive biomarkers of sorafenib efficacy in advanced hepatocellular carcinoma: Are we getting there?

Table 1 Studies on predictive and prognostic markers for advanced hepatocellular carcinoma - serum or plasma markers

	Authors	Treatment	Findings supportive of
			Predictive markers	Prognostic markers	Others
VEGF-A	Llovet et al[11]	Sorafenib vs placebo	No predictive values	Low VEGF-A → longer OS	-
	Shao et al[12]	Sorafenib plus UFT	No predictive values	Low VEGF-A → longer OS	-
	Miyahara et al[13]	Sorafenib	High VEGF → PD	No prognostic values	Not associated with PFS
IL-6 & 8	Shao et al[12]	Sorafenib plus UFT	-	High IL-6 and IL-8 → shorter OS	High IL-6 and IL-8 → shorter PFS
Ang-2	Llovet et al[11]	Sorafenib vs placebo	No predictive values	High Ang-2 → shorter OS	-
	Miyahara et al[13]	Sorafenib	High Ang-2 → PD	No associations	High Ang-2 → shorter PFS
IGF-1	Shao et al[20]	Sorafenib plus UFT or bevacizumab plus capecitabine	High IGF-1 → better DCR	High IGF-1 → longer OS	High IGF-1 → longer PFS
TGF-β1	Lin et al[23]	Sorafenib with or without UFT	-	High TGF-β1 → shorter OS	High TGF-β1 → shorter PFS
HGF	Llovet et al[11]	Sorafenib vs placebo	Low HGF → better efficacy1	-	-
	Miyahara et al[13]	Sorafenib	High HGF → PD	No associations	High HGF → shorter PFS
G-CSF	Miyahara et al[13]	Sorafenib	High G-CSF → PD	No associations	High G-CSF → shorter PFS
AFP response	Shao et al[31]	Sorafenib or thalidomide with tegafur/uracilBevacizumab with capecitabine	AFP response → longer DCR	AFP response → longer OS	AFP response → longer PFS
	Personeni et al[32], Yau et al[33], and Kuzuya et al[34]	Sorafenib	AFP response → longer DCR	AFP response → longer OS	AFP response → longer PFS
	Nakazawa et al[35]	Sorafenib	AFP elevation → PD	AFP elevation → shorter OS	AFP elevation → shorter PFS
Circulating endothelial cells or progenitors	Shao et al[46]	Sorafenib plus UFT	Increase in post-treatment total CEC or viable CEC → PD1	High CEP → shorter OS	High CEP → shorter PFS
Neutrophil-to-lymphocyte ratio	Zheng et al[52]	Sorafenib	High ratio → shorter TTP	High ratio → shorter OS	-
ERK activity changes	Caraglia et al[55]	Sorafenib + octreotide	Post-treatment increase → PD	-	-
Soluble c-Kit	Llovet et al[11]	Sorafenib vs placebo	High c-Kit → better efficacy1	-	-
Leptin	Miyahara et al[13]	Sorafenib	High leptin → PD	No associations	High leptin → shorter PFS
LDH	Faloppi et al[56]	Sorafenib	-	LDH decrease → longer OS	LDH decrease → longer PFS

¹Borderline significant. AFP: Alpha-fetoprotein; CEC: Circulating endothelial cells; CEP: Circulating endothelial progenitors; DCP: Des-γ-carboxy prothrombin; DCR: Disease control rate; G-CSF: Granulocyte-colony stimulating factor; HGF: Hepatocyte growth factor; IGF: Insulin-like growth factor; IL: Interleukin; LDH: Lactate dehydrogenase; ORR: Objective response rates; OS: Overall survival; PD: Progressive disease; PFS: Progression-free survival; TTP: Time to progression; UFT: Tegafur/uracil; VEGF: Vascular endothelial growth factor.

Table 2 Studies on predictive and prognostic markers for advanced hepatocellular carcinoma -- tissue biomarkers, clinical parameters, and others

Markers	Authors	Treatment	Findings supportive of
			Predictive markers	Prognostic markers	Others
Tissue biomarkers
p-ERK expression	Abou-Alfa et al[57]	Sorafenib	High p-ERK → longer TTP	-	-
	Ozenne et al[58]	Sorafenib	No predictive values	-	-
	Chen et al[59]	Sorafenib	High p-ERK → longer TTP	-	-
p-c-Jun expression	Hagiwara et al[61]	Sorafenib	High p-c-Jun expression → poor response, shorter TTP	p-c-Jun expression → shorter OS	-
Clinical parameter
DCE-MRI	Hsu et al[63]	Sorafenib plus UFT	High baseline Ktrans or decreased Ktrans after treatment→ higher DCR	Vascular response1→ longer OS	Vascular response1→ longer PFS
Positron emission tomography	Lee et al[68]	Sorafenib	-	Low SUV → longer OS	Low SUV → longer PFS
Hypertension	Estfan et al[71]	Sorafenib	Hypertension → longer TTP (?)2	Hypertension → longer OS	-
	Otsuka et al[72]	Sorafenib	No predictive values	No prognostic values	-
Skin toxicity	Otsuka et al[72]	Sorafenib	No predictive values	Skin toxicities → longer OS	-
	Lee et al[73]	Sorafenib	-	≥ grade 2 skin toxicities → longer OS	≥ grade 2 skin toxicities → longer PFS
	Vincenzi et al[74]	Sorafenib	Early4≥ grade 1 skin toxicities → longer DCR and TTP	Early ≥ grade 1 skin toxicities → longer OS3	-
Hepatitis etiology	Shao et al[78]	Sorafenib vs other treatments	Synthesized hazard ratio for overall mortality: 0.65 in patients with HCV etiology and 0.87 in patients with non-HCV etiology
Novel approaches
FGF3/FGF4 amplification	Arao et al[79]	Sorafenib	FGF3/FGF4 amplification → higher tumor response	-	-
VEGFA amplification	Horwitz et al[85]	Sorafenib	-	VEGFA amplification → longer OS	-
p-Mapk14, p-Atf2 expression	Rudalska et al[86]	Sorafenib	-	High p-Mapk14 or p-Atf2 expression → shorter OS	-

¹Defined as ≥ 40% decreased in K^trans after treatment;

²Statistical values of the comparison not reported;

³Borderline statistical significance;

⁴Within the first month of treatment. DCE-MRI: Dynamic contrast-enhanced magnetic resonance imaging; DCR: Disease control rate; OS: Overall survival; p-: Phospho-; PBMC: Peripheral blood mononuclear cells; PFS: Progression-free survival; TTP: Time to progression; UFT: Tegafur/uracil.