“Targeting” renal cell carcinoma patients with “targeted” agents: Are we there yet?

Table 1 Potential biomarkers evaluated in phase III or pivotal trials of targeted agents in advanced renal cell carcinoma

Targetedagent	Authors	Biomarker		Outcomes
				PFS		OS
				HR (95%CI)	P	HR (95%CI)	P
Sorafenib	Escudier et al[14]; Peña et al[18]	Baseline VEGF	Low-VEGF (25th percentile)	0.92 (0.57-1.49)	0.001	NA	NA
			High-VEGF (25th percentile)	0.42 (0.31-0.56)		NA	NA
			Low-VEGF (75th percentile; ≤ 254 pg/mL)	0.58 (0.43-0.78)	0.02	NA	NA
			High-VEGF (75th percentile; > 254 pg/mL)	0.27 (0.15-0.46)		NA	NA
			Low-VEGF (median value; ≤ 131 pg/mL)	0.64 (0.49-0.83)	0.096	0.89 (0.63-1.27)	0.327
			High-VEGF (median value; > 131 pg/mL)	0.48 (0.38-0.62)		0.81 (0.60-1.09)
	Peña et al[18]	sVEGFR-2	Low-sVEGFR-2 (median value)	0.56 (0.43-0.72)	0.981	0.90 (0.65-1.24)	0.598
			High-sVEGFR-2	0.55 (0.42-0.71)		0.82 (0.60-1.14)
		CAIX	Low-CAIX (median value)	0.52 (0.26-1.03)	0.72	0.98 (0.40-2.42)	0.540
			High-CAIX	0.62 (0.33-1.16)		0.71 (0.35-1.45)
		TIMP-1	Low-TIMP-1 (median value)	0.58 (0.26-1.30)	0.83	0.76 (0.26-2.19)	0.670
			High TIMP-1	0.54 (0.29-0.99)		0.58 (0.29-1.15)
		Ras	Low-Ras (median value)	0.74 (0.37-1.52)	0.27	1.23 (0.50-3.04)	0.180
			High-Ras	0.41 (0.22-0.79)		0.53 (0.25-1.13)
		VHL mutational status	Exon 1 only; WT	0.55 (0.34-0.89)	0.356	0.74 (0.39-1.40)	0.634
			Exon 1 only; mut	0.39 (0.15-1.04)		1.08 (0.32-3.59)
			Exon 2 only; WT	0.45 (0.26-0.77)	0.363	0.56 (0.26-1.22)	0.536
			Exon 2 only; mut	0.89 (0.24-3.34)		0.33 (0.03-3.19)
			Exon 3 only; WT	0.62 (0.38-1.00)	0.985	0.76 (0.40-1.44)	0.991
			Exon 3 only; mut	0.00 (0.00-NA)		0.00 (0.00-NA)
			Exon 1, 2 or 3; WT	0.52 (0.23-1.19)	0.968	1.09 (0.36-3.27)	0.693
			Exon 2, 3 or 3; mut	0.49 (0.22-1.08)		0.88 (0.31-2.48)
Pazopanib	Tran et al[25]	IL-6	Low IL-6	0.55 (0.38-0.81)	0.009	1.41 (0.65-3.05)	0.005
			High IL-6	0.31 (0.21-0.44)		0.42 (0.28-0.63)
		IL-8	Low IL-8	0.41 (0.28-0.60)	0.472	1.49 (0.69-3.22)	0.002
			High IL-8	0.39 (0.27-0.56)		0.42 (0.28-0.63)
		Osteopontin	Low Osteopontin	0.43 (0.29-0.64)	0.343	0.96 (0.50-1.86)	0.033
			High Osteopontin	0.35 (0.24-0.51)		0.41 (0.27-0.62)
		VEGF	Low VEGF	0.47 (0.32-0.69)	0.376	1.2 (0.61-2.39)	0.006
			High VEGF	0.41 (0.28-0.60)		0.41 (0.27-0.62)
		Hepatocyte growth factor	Low HGF	0.40 (0.27-0.58)	0.52	0.68 (0.36-1.27)	0.765
			High HGF	0.46 (0.32-0.67)		0.59 (0.39-0.90)
		TIMP-1	Low TIMP-1	0.38 (0.26-0.55)	0.922	0.64 (0.38-1.10)	0.387
			High TIMP-1	0.40 (0.27-0.59)		0.5 (0.32-0.79)
		E-selectin	Low E-selectin	0.49 (0.33-0.71)	0.219	0.55 (0.34-0.91)	0.872
			High E-selectin	0.36 (0.25-0.52)		0.59 (0.36-0.96)
	Xu et al[27,29]	IL-8	Polymorphism 2767A > T		0.009		0.030
			AA
			AT	1.3 (0.9-1.8)	0.1	NA
			TT	1.8 (1.2-2.7)	0.009	2.2 (1.3-3.6)	0.030
			Polymorphism -251T > A		0.01	NA	NA
			TT
			AT	1.4 (1.0-1.9)	0.08
			AA	1.7 (1.1.-2.5)	0.01
		HIF1A	Polymorphism 1790G > A		0.03	NA	NA
			GG
			AG	1.8 (1.1.-3.1)	0.03
		NR1/2	Polymorphism -25385C > T		0.06	NA
			CC
			CT	1.2 (0.9-1.6)	0.3		NA
			TT	1.5 (1.0-2.2)	0.07		0.020
		VEGFA	Polymorphism-2578A > C		0.7	NA	NA
			AA
			AC	0.8 (0.6-1.2)	0.2
			CC	0.9 (0.6-1.4)	0.7
			Polymorphism -1498C > T		0.7	NA	NA
			CC
			CT	0.8 (0.6-1.2)	0.2
			TT	0.9 (0.6-1.4)	0.7
			Polymorphism -634G > C		0.7	NA	NA
			GG
			CG	0.9 (0.7-1.3)	0.7
			CC	1.0 (0.6-1.7)	0.9
	Xu et al[29]	FGFR2	Polymorphism IVS2 + 906C > T	NA	NA		0.02
			CC
			CT			NA	NA
			TT			1.7 (1.1.-2.8)	0.02
Bevacizumab	Lambrechts et al[47]	VEGFR1	Polymorphisms rs7993418 or rs9554316	1.81 (1.08-3.05)	0.033	0.91 (0.45-1.82)	0.78
			TT
			TC
			CC
			Polymorphism rs9513070	1.68 (1.12-2.52)	0.018	NA	NA
			AA
			AG
			GG
	Escudier et al[46]	Baseline VEGF	Low-VEGF	NA	NA	0.75 (0.51-1.08)	NA
			(median value; < 54 pg/mL)
			High-VEGF	NA	NA	0.92 (0.66-1.28)	NA
			(median value; > 54 pg/mL)
Everolimus	Oudard et al[48]	Baseline VEGF-A	Low-VEGF-A	1.27 (1.03-1.57)	0.028	NA	NA
Temsiroli- mus	Figlin et al[50]	PTEN	Positive	0.66 (0.47-0.93)	NA	NA	NA
			Negative	0.99 (0.58-1.69)
		HIF1α	Positive	0.98 (0.64-1.51)	NA	NA	NA
			Negative	0.72(0.51-1.00)

NA: Not available; PFS: Progression-free survival; OS: Overall survival; HR: Hazard ratio; VEGF: Vascular endothelial growth factor; sVEGFR: Serum vascular endothelial growth factor receptor; CAIX: Carbonic anhydrase IX; TIMP: Tissue inhibitors of metalloproteinases; WT: Wild-type; mut: Mutated; HGF: Hepatocyte growth factor; IL: Interleukin.