Influence of genetic polymorphisms in vascular endothelial-related genes on the clinical outcome of axitinib in patients with metastatic renal cell carcinoma

Figures & data

Table 1. Patients characteristics.

Number of patients 75 (100%)
Gender				IMDC risk classification
	Male	53 (71%)			Favorable	6 (8%)
	Female	22 (29%)			Intermediate	47 (63%)
Age					Poor	22 (29%)
	Median	67		Number of metastatic sites
	Range	25–85			1	22 (29%)
Histology					2	24 (32%)
	Clear cell	71 (95%)			≥3	29 (39%)
	Others	4 (5%)		Site of metastasis and recurrence
Prior nephrectomy					Lung	54 (72%)
	Yes	61 (81%)			Lymph node	39 (52%)
Diagnosis to therapy <1 year					Bone	24 (32%)
	Yes	46 (61%)			Liver	13 (17%)
Number of prior systemic therapy					Contralateral kidney	9 (12%)
	0	35 (47%)			Adrenal	7 (4%)
	1	27 (36%)			Others	20 (27%)
	≥2	13 (17%)		Best response
Detail of prior therapy					CR	3 (4%)
	Cytokines	17 (23%)			PR	27 (36%)
	Sunitinib	15 (20%)			SD	29 (39%)
	Everolimus	13 (17%)			PD	13 (21%)
	Sorafenib	6 (8%)			Unknown	3 (4%)
	Nivolumab	2 (3%)		Reason for axitinib discontinuation
	Temsirolimus	1 (1%)			PD	36 (48%)
Karnofsky PS					AE	21 (28%)
	≥80	48 (64%)			No discontinuation	14 (19%)
	<80	27 (36%)			Others	4 (5%)

PS, performance status; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium; CR, complete remission; PR, partial response; SD, stable disease; PD, progressive disease; AE, adverse event.

Table 2. Association between outcome and pharmacokinetic-associated genetic polymorphisms.

Gene	RS	Position	Genotype	Number of patients	Risk genotype	Time to treatment failure (months)			Progression-free survival (months)			Overall survival (months)
						HR	95% CI	p	HR	95% CI	p	HR	95% CI	p
ACE	rs4362	Ins/Del	Del/Del+Del/Ins	43	Del allele	1.070	0.644–1.777	0.794	1.013	0.575–1.786	0.965	1.322	0.667–2.618	0.424
			Ins/Ins	32
NOS3	rs1799983	G894T	GG+TG	8	G allele	0.673	0.318–1.426	0.301	1.172	0.495–2.775	0.718	1.161	0.407–3.313	0.781
			TT	67
AT1R	rs5186	A1166C	CA	6	C allele	0.871	0.372–2.042	0.751	0.848	0.357–2.016	0.710	1.693	0.404–7.102	0.471
			AA	69

ACE, angiotensin converting enzyme; NOS, nitoric oxide synthase; AT1R, angiotensin II type 1 receptor; RS, reference single nucleotide polymorphism ID number; Del, deletion; ins, insertion; HR, hazard ratio; CI, confidence interval.

Table 3. Distribution of SNP genotypes for the best response.

Gene	RS	Position	Risk genotype	PR+SD vs PD
				In patients with CR, PR, and SD (n = 59)	In patients with PD (n = 13)	OR	95% CI	p
ACE	rs4362	Ins/Del	Del allele	33/59	9/13	0.564	0.156–2.039	0.537
NOS3	rs1799983	G894T	G allele	6/59	2/13	0.623	0.111–3.502	0.629
AT1R	rs5186	A1166C	C allele	5/59	1/13	1.111	0.119–10.398	1.000
Gene	RS	Position	Risk genotype	PR vs SD+PD
				In patients with CR and PR (n = 30)	In patients with PD and SD (n = 42)	OR	95% CI	p
ACE	rs4362	Ins/Del	Del allele	18/30	24/42	1.125	0.434–2.916	1.000
NOS3	rs1799983	G894T	G allele	5/30	3/42	2.600	0.570–11.851	0.265
AT1R	rs5186	A1166C	C allele	4/30	2/42	3.077	0.525–18.023	0.227

SNP, single nucleotide polymorphism; ACE, angiotensin converting enzyme; NOS, nitoric oxide synthase; AT1R, angiotensin II type 1 receptor; RS, reference single nucleotide polymorphism ID number; Del, deletion; ins, insertion; PR, partial response; SD, stable disease; PD, progressive disease; OR, Odd’s ratio; CI, confidence interval.

Table 4. Association between adverse events and vascular endothelial related genetic polymorphisms.

Gene	RS	Position		Risk genotype	Fatigue			Hypertension			Proteinuria
					(≥ G2)			(≥ G2)			(≥ G2)
					OR	95% CI	p	OR	95% CI	p	OR	95% CI	p
ACE	rs4362	Ins/Del	Del/Del+Del/Ins 43 vs Ins/Ins 32	Del allele	0.390	0.147–1.033	0.085	0.421	0.155–1.146	0.097	1.082	0.433–2.705	1.000
NOS3	rs1799983	G894T	GG+TG 8 vs TT 67	G allele	2.045	0.467–8.956	0.437	4.439	0.516–38.190	0.245	9.172	1.068–78.768	0.025
AT1R	rs5186	A1166C	CA 6 vs AA 69	C allele	0.938	0.160–5.494	1.000	1.000	0.170–5.869	1.000	2.313	0.397–13.469	0.419
Gene	RS	Position		Risk genotype	Hand-foot syndrome			Hypothyroidism			Anorexia
					(≥ G2)			(≥ G2)			(≥ G2)
					OR	95% CI	p	OR	95% CI	p	OR	95% CI	p
ACE	rs4362	Ins/Del	Del/Del+Del/Ins 43 vs Ins/Ins 32	Del allele	4.189	1.080–16.242	0.045	1.768	0.670–4.665	0.323	0.893	0.345–2.312	1.000
NOS3	rs1799983	G894T	GG+TG 8 vs TT 67	G allele	1.262	0.229–6.944	0.676	3.907	0.453–33.675	0.256	1.913	0.438–8.360	0.448
AT1R	rs5186	A1166C	CA 6 vs AA 69	C allele	1.964	0.326–11.835	0.062	1.000	0.170–5.869	1.000	4.000	0.682–23.475	0.180
Gene	RS	Position		Risk genotype	Diarrhea			Hoarseness			Renal dysfunction
					(≥ G2)			(≥ G2)			(≥ G2)
					OR	95% CI	p	OR	95% CI	p	OR	95% CI	p
ACE	rs4362	Ins/Del	Del/Del+Del/Ins 43 vs Ins/Ins 32	Del allele	0.990	0.306–3.204	1.000	0.444	0.114–1.730	0.309	4.167	1.548–10.866	0.005
NOS3	rs1799983	G894T	GG+TG 8 vs TT 67	G allele	1.528	0.274–8.513	0.638	2.458	0.422–14.324	0.288	0.896	-	1.000
AT1R	rs5186	A1166C	CA 6 vs AA 69	C allele	2.375	0.389–14.482	0.311	1.333	0.139–12.758	1.000	6.400	0.933–43.916	0.094
Gene	RS	Position		Risk genotype	Discontinuation			At least one AE ≥ G3			Number of AEs ≥ 4
					due to AE
					OR	95% CI	p	OR	95% CI	p	OR	95% CI	p
ACE	rs4362	Ins/Del	Del/Del+Del/Ins 43 vs Ins/Ins 32	Del allele	1.724	0.601–4.943	0.436	0.630	0.32–1.25	0.210	0.742	0.296–1.862	0.641
NOS3	rs1799983	G894T	GG+TG 8 vs TT 67	G allele	2.941	0.662–13.065	0.209	3.422	0.396–29.569	0.422	7.650	1.073–65.690	0.036
AT1R	rs5186	A1166C	CA 6 vs AA 69	C allele	1.316	0.222–7.784	1.000	0.667	-	0.169	5.147	0.571–46.373	0.202

ACE, angiotensin converting enzyme; NOS, nitric oxide synthase; AT1R, angiotensin II receptor type 1; RS, reference single nucleotide polymorphism ID number; Ins, insertion; Del, deletion; G, grade; OR, Odd’s ratio; CI, confidence interval; AE, adverse event.