Hypertension and hand-foot skin reactions related to VEGFR2 genotype and improved clinical outcome following bevacizumab and sorafenib.
BACKGROUND
Hypertension (HT) and hand-foot skin reactions (HFSR) may be related to the activity of bevacizumab and sorafenib. We hypothesized that these toxicities would correspond to favorable outcome in these drugs, that HT and HFSR would coincide, and that VEGFR2 genotypic variation would be related to toxicity and clinical outcomes.


METHODS
Toxicities (> or = grade 2 HT or HFSR), progression-free survival (PFS), and overall survival (OS) following treatment initiation were evaluated. Toxicity incidence and VEGFR2 H472Q and V297I status were compared to clinical outcomes.


RESULTS
Individuals experiencing HT had longer PFS following bevacizumab therapy than those without this toxicity in trials utilizing bevacizumab in patients with prostate cancer (31.5 vs 14.9 months, n = 60, P = 0.0009), and bevacizumab and sorafenib in patients with solid tumors (11.9 vs. 3.7 months, n = 27, P = 0.052). HT was also linked to a > 5-fold OS benefit after sorafenib and bevacizumab cotherapy (5.7 versus 29.0 months, P = 0.0068). HFSR was a marker for prolonged PFS during sorafenib therapy (6.1 versus 3.7 months respectively, n = 113, P = 0.0003). HT was a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib (OR(95%CI) = 3.2(1.5-6.8), P = 0.0024). Carriers of variant alleles at VEGFR2 H472Q experienced greater risk of developing HT (OR(95%CI) = 2.3(1.2 - 4.6), n = 170, P = 0.0154) and HFSR (OR(95%CI) = 2.7(1.3 - 5.6), n = 170, P = 0.0136).


CONCLUSIONS
This study suggests that HT and HFSR may be markers for favorable clinical outcome, HT development may be a marker for HFSR, and VEGFR2 alleles may be related to the development of toxicities during therapy with bevacizumab and/or sorafenib.
Jain
Lokesh
L
Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Sissung
Tristan M
TM
Danesi
Romano
R
Kohn
Elise C
EC
Dahut
William L
WL
Kummar
Shivaani
S
Venzon
David
D
Liewehr
David
D
English
Bevin C
BC
Baum
Caitlin E
CE
Yarchoan
Robert
R
Giaccone
Giuseppe
G
Venitz
Jürgen
J
Price
Douglas K
DK
Figg
William D
WD
D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000008:administration & dosage; D000068258:Bevacizumab; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D005533:Foot Dermatoses / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D005838:Genotype; D006229:Hand Dermatoses / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008297:Male; D009369:Neoplasms / Q000150:complications* / Q000628:therapy; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage; D000077157:Sorafenib; D015996:Survival Rate; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001557:Benzenesulfonates; D004273:DNA, Neoplasm; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2