Table 1.

Summary of molecular biomarker status for predicting response in RCC (4, 10–21)

BiomarkerAssociated outcomesComments
Circulating biomarkers
VEGF and VEGF-related proteins
Elevated baseline VEGFElevated pretreatment VEGF (>median) associated with trend to prolonged PFS with sorafenib compared with placebo (5.5 vs. 2.7 mo with placebo; HR, 0.48, 95% CI, 0.38–0.62) than low pretreatment VEGF (≤median; 5.5 vs. 3.3 mo with placebo; HR, 0.64; 95% CI, 0.49–0.83; P for interaction between VEGF and treatment arm = 0.096; n = 712; ref. 10)VEGF levels correlate inversely with PFS and OS in RCC but higher baseline VEGF levels may be associated with better clinical outcome with sorafenib therapy
Low baseline VEGFR-3Increased PFS (21.7 vs. 10.9 mo; HR, 2.40; P = 0.01) and OS (NR vs. 23.3 mo; HR, 1.68; P = 0.07) in sunitinib recipients with low baseline sVEGFR-3 (n = 33; ref. 11)Low baseline sVEGFR-3 and VEGF-C levels may predict improved outcome following sunitinib treatment
Low baseline VEGFR-3 and VEGF-CLonger PFS in patients with sunitinib in bevacizumab-refractory mRCC with VEGFR-3 <median versus >median (36.7 vs. 19.4 wks; HR, 0.4457; P = 0.0060) and VEGF-C <median versus >median (46.1 vs. 21.9 wks; HR, 0.3662; P = 0.0006), and significantly lower baseline VEGFR-3 and VEGF-C in patients with PR compared with those with SD or PD (n = 59; ref. 4)
VEGF, sVEGFR-2, and sVEGFR-3Larger changes over first 28 days of treatment in VEGF (P = 0.0001), sVEGFR-2 (P = 0.0003), and sVEGFR-3 (P = 0.042) levels in sunitinib recipients with objective response versus those with SD or PD (n = 63; ref. 12)Sunitinib inhibition of VEGF signaling via receptor blockade results in modulation of plasma levels of circulating VEGF proteins. The association of degree of modulation with clinical outcome is unclear
On-treatment reduction in sVEGFR-2 levels did not correlate with PFS in sunitinib-treated patients (n = 26; ref. 13)
On-treatment increase in VEGF was greater in patients with PD than in those with clinical benefit during sunitinib therapy (n = 39; ref. 14)
CAFs
Elevated baseline IL-6Increased PFS with pazopanib versus placebo (HR, 0.32 in the high IL-6 group and 0.57 in the low IL-6 group; P value for interaction = 0.009; n = 344; ref. 15)Only IL-6 was predictive of PFS benefit of the CAFs evaluated; IL-6 was both a prognostic marker and a predictive marker for pazopanib therapy
LDH
Elevated serum LDHIncreased OS in temsirolimus versus IFN-α recipients in patients with an elevated baseline LDH (>ULN; 6.9 vs. 4.2 mo; P < 0.002; n = 404; ref. 16)LDH is a known prognostic marker in RCC. Baseline serum LDH is a potential predictive biomarker for OS in patients with poor-risk RCC treated with temsirolimus
Tissue-based biomarkers
VHL pathway
VHL mutationNo association with clinical outcome to VEGF-targeting agents (n = 123; ref. 17)
VHL and c-myc combinationElevated c-myc activity and enhanced proliferation found (in vivo) in pVHL-deficient tumors expressing HIF-2α (n = 160; ref. 18)pVHL status, HIF-α, and c-myc expression may have value as predictive biomarkers of response to targeted therapy in RCC
Increased PFS in sunitinib recipients with c-myc negative versus c-myc–positive primary tumors (median PFS, 11.4 vs. 5.4 mo; P = 0.0062; n = 58; ref. 19)
mTOR pathway
Elevated phospho-S6 expressionIncreased ORR (P = 0.02) in patients treated with temsirolimus. No patient (n = 20) without high expression of phospho-S6 experienced an ORR (20)This was a very small study that has not been replicated
Elevated pAKT expressionWith every percentage increase in pAKT, decreases in PFS (HR, 1.04; P = 0.0411) and OS (HR, 1.15; P = 0.0173) were observed in sorafenib (±IFN-α) recipients (n = 40; ref. 21)pAKT expression is a potential prognostic factor which may affect survival through angiogenic pathways

Abbreviations: NR, not reached; PD, progressive disease; PR, partial response; pVHL, von Hippel Lindau protein; s, soluble; SD, stable disease.