The predictive value of KRAS, NRAS, BRAF, PIK3CA and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis

Figures & data

Table I. Summary of study characteristics.

Study	N	Median age (range)	Sex (% men/women)	Line of treatment (% in 1st/2nd/ 3rd/≥ 4th)	Treatment protocols
Douillard et al. 2013	325	62 (27–85)	59/41	84/16^b	pmab + FOLFOX4
Peeters et al. 2013	138	61 (27–89)	62/38	65^c/35^d	pmab
Soeda et al. 2013	31	57 (31–80)	58/42	0/25/58/42	cmab; cmab + iri
Tural et al. 2013	41	58 (35–75)	56/44	0/100/0/0	cmab + iri-based chemotherapy
Bokemeyer et al. 2012	398	61 (24–79)	61/39	100/0/0/0	cmab + FOLFIRI/FOLFOX4
Modest et al. 2011	96	61–67 (32–75)	72/28	74/26^b	cmab + CAPIRI/CAPOX
Sood et al. 2012	32	59 (34–93)	29/71	2/30/43/25	cmab; pmab; cmab/pmab + iri/chemotherapy
Ulivi et al. 2012	53	61 (34–79)	58/42	0/22/42/36	cmab; cmab + iri/FOLFIRI/FOLFOX4
Gao et al. 2011	48	57 (24–81)	64/36	46/24/31/0	cmab + iri/oxa/5-FU-based chemotherapy
Inno et al. 2011	48	58 (28–80)	59/40	29/26/36/10	cmab + FOLFOX4/UFOX/FOLFIRI/iri
Molinari et al. 2011	54	NR	59/41	3/17/65/16	cmab; pmab; cmab + iri/oxa-based chemotherapy
Park et al. 2011	50	59 (29–78)^a	63/37	6/94^b	cmab; cmab + iri/oxa/5-FU-based chemotherapy
Saridaki et al. 2011	75	66 (23–83)	61/39	0/59/41/0	cmab + iri/oxa-based chemotherapy
Wong et al. 2011	19	57 (33–77)	53/47	NR	cmab + XELOX + beva
Garcia-Albeniz et al. 2010	74	63 (38–84)	63/37	0/0/100/0	cmab + iri
De Roock et al. 2010	370	61 (22–86)	58/42	0/13/50/37	cmab + iri/oxa-based chemotherapy
Tol et al. 2010	162	62^a	58/42	84/16/0/0	cmab + XELOX + beva
Laurent-Puig et al. 2009	116	NR	NR	1/8/45/47	cmab; cmab + iri; cmab + FOLFIRI
Loupakis et al. 2009a	53	62 (38–78)	59/41	18/49/33	cmab + iri
Loupakis et al. 2009b	87	61 (42–77)	55/45	0/100^b	cmab + iri
Perrone et al. 2009	29	57 (36–78)	63/38	0/0/53/47	cmab + Iri
Santore-Bianchi et al. 2009	96	64 (26–85)	65/35	10/14/49/27	pmab; cmab; cmab + iri-based chemotherapy

^amean; ^b2nd line or greater; ^c1st and 2nd line together; ^d3rd line or greater. beva, bevacizumab; cmab, cetuximab; iri, irinotecan; N, number of KRAS exon 2 wild type EGFR-treated tumors; NR, not reported; oxa, oxalipatin; pmab, panitumubab.

Table II. Summary of mutation data and outcome measures.

Study	KRAS analysis codons (exon)	Other genes analyzed (exon)	Compliance (%)	Clinical end point	Abs. mut. freq. (%)	Mut. freq. in KRAS WT (%)
Douillard et al, 2013	12, 13	KRAS (3,4)	97	OS	NR	10
		NRAS (2,3,4)	99	OS	NR	6
		BRAF (15)	97	OS	NR	8
Peeters et al. 2013	12, 13, 61	NRAS (2,3)	98	ORR	6	7
		BRAF (15)	83	ORR, PFS	8	9
		PIK3CA (1,2,9,10,20)	88	ORR	10	7
		PTEN (all exons)	94	ORR	6	7
Soeda et al. 2013	12, 13	KRAS (3)	–	ORR	28	3
		BRAF (15)	–	ORR	5	6
		PIK3CA (9, 20)	–	ORR	5	6
Tural et al. 2013	12, 13	BRAF (15)	–	ORR, PFS	NR	16
		PTEN (immunostaining)	–	ORR, PFS	NR	58
Bokemeyer et al. 2012	12, 13	BRAF (15)	96	ORR	NR	8
Modest et al. 2011	12, 13	BRAF (15)	–	ORR	12	17
Sood et al. 2012	12, 13, 61	PTEN (immunostaining)	–	PFS, OS	NR	NR
Ulivi et al. 2012	(exon 2)	BRAF (15)	–	PFS, OS	18	21
Gao et al. 2011	12, 13	BRAF (15)	–	ORR	8	10
Inno et al. 2011	12, 13, 61	BRAF (15)	96	ORR	NR	4
Molinari et al. 2011	12, 13	KRAS (3)	97	ORR	4	5
		BRAF (15)	95	ORR	7	10
		PIK3CA (9, 20)	98	ORR	7	4
		PTEN (immunostaining)	81	ORR	29	18
Park et al. 2011	12, 13	BRAF (15)	–	ORR	8	16
Saridaki et al. 2011	(exon 2)	BRAF (15)	–	PFS, OS	10	11
		PIK3CA (9, 20)	–	PFS, OS	20	11
		PTEN (immunostaining)	95	PFS, OS	20	19
Wong et al. 2011	12, 13	PIK3CA (9, 20)	–	ORR	10	11
Garcia-Albeniz et al. 2010	12.13	BRAF (15)	74	PFS, OS	8	12
De Roock et al. 2010	12, 13, 61, 146	KRAS (3,4)	97	ORR	4	6
		NRAS (2,3)	85	ORR, PFS, OS	4	8
		BRAF (15)	99	ORR, PFS, OS	5	8
		PIK3CA (9, 20)	96	ORR, PFS, OS	15	6
Tol et al. 2010	12, 13	BRAF (15)	94	PFS	NR	21
Laurent-Puig et al. 2009	12, 13	PTEN (immunostaining)	94	ORR	19	20
Loupakis et al. 2009a	12, 13	PTEN (immunostaining)	89		42	37
Loupakis et al. 2009b	12, 13	KRAS (3,4)	87	ORR, PFS, OS	NR	11
		BRAF (15)	–	ORR, PFS, OS	NR	15
Santore-Bianchi et al. 2009	(exon 2)	PTEN (immunostaining)	–	ORR, PFS, OS	31	29
Perrone et al. 2009	12, 13	BRAF (11,15)	97	ORR	10	9
		PIK3CA (9, 20)	97	ORR	13	9
		PTEN (5–9)	97	ORR	10	9

Abs. mut. Freq, absolute mutation frequency; Mut. freq in KRAS WT, mutation frequency in KRAS wild-type; NR, not reported; ORR, objective response rate; OS, overall survival; PFS, progression free survival.

Figure 1. The association between KRAS mutations in exons 3 and 4 with the a) ORR, b) PFS and c) OS in patients with KRAS exon 2 wild-type mCRC treated with anti-EGFR monoclonal antibodies. control, wild-type; events, response; experimental, mutant type; HR, hazard ratio; OR, odds ratio, seTE, standard error of HR; TE, Ln(HR).

Figure 2. The association of NRAS mutations with the a) ORR, b) PFS and c) OS of patients with KRAS wild-type mCRC treated with anti-EGFR monoclonal antibodies. control, wild-type; events, response; experimental, mutant type; HR, hazard ratio; OR, odds ratio, seTE, standard error of HR; TE, Ln(HR).

Figure 3. The associations of BRAF mutations with the a) ORR, b) PFS and c) OS of patients with KRAS wild-type mCRC treated with anti-EGFR monoclonal antibodies. control, wild-type; events, response; experimental, mutant type; HR, hazard ratio; OR, odds ratio, seTE, standard error of HR; TE, Ln(HR).

Figure 4. The associations of PIK3CA mutations with the a) ORR, b) PFS and c) OS of patients with KRAS wild-type mCRC treated with anti-EGFR monoclonal antibodies. control, wild-type; events, response; experimental, mutant type; HR, hazard ratio; OR, odds ratio, seTE, standard error of HR; TE, Ln(HR).

Figure 5. The associations of PTEN alterations with the a) ORR, b) PFS and c) OS of patients with KRAS wild-type mCRC treated with anti-EGFR monoclonal antibodies. control, wild-type; events, response; experimental, mutant type; HR, hazard ratio; OR, odds ratio, seTE, standard error of HR; TE, Ln(HR).

Table III. Response rates in metastatic colorectal cancer to anti-EGFR treatment.

	Response rates related to gene alterations
Study	KRAS	BRAF KRAS	PIK3CA BRAF KRAS	PTEN PIK3CA BRAF KRAS
Soeda et al. 2013	34%		41%
Modest et al. 2011		75%
Ulivi et al. 2012			37%
Gao et al. 2011	35%	37%
Molinari et al. 2011	35%	42%	45%	55%
Wong et al. 2011	37%	38%
De Roock et al. 2010	36%	38%
Loupakis et al. 2009b		58%
Sartore-Bianchi et al. 2009				51%
Perrone et al. 2009	45%	40%	44%	47%

Figure 6. The EGFR-related pathways with genes of interest highlighted in gray. The mean mutation frequencies in KRAS exon 2 wild-type primary tumors from the 22 studies included are shown (*refers to mutations found in exons 3 and 4).