Combined assessment of EGFR-related molecules to predict outcome of 1st-line cetuximab-containing chemotherapy for metastatic colorectal cancer

Figures & data

Table 1. Previously reported biomarkers and clinical outcome in patients receiving cetuximab.

Author (year)	Number of patients	KRAS status	Setting	Chemo regimen	Results
AREG/EREG
Khambata-Ford et al (2007)	103		Advanced line	Cet alone	AREG and EREG high associated with longer PFS
Jacobs et al (2009)	121	Wild-type	Advanced line	Cet alone or in combination with IRI	AREG and EREG high associated with better outcomes
Kuramochi et al (2012)	65	Wild type	none	none	EREG low associated with better prognosis
Stintzing et al (2012)	99	Wild type	First line	Combined with CAPOX or CAPIRI	AREG and EREG high associated with better outcomes
Pentheroudakis et al (2013)	199		First or advanced line	Cet plus chemo	AREG high associated with better survival time in KRAS wild-type EREG high associated with better outcomes irrespective of KRAS status
EREG
Jonker et al (2014)	385		Advanced line	Cet alone vs. BSC	Cet better in EREG high
Author (year)	Number of patients	EGFR cutoff	Setting	Chemo regimen	RR	PFS	OS	Skin toxicity
EGFR GCN
Moroni et al (2005)	31	≥ 3, < 3	Advanced line	Mono or combined with IRI	✓
Personeni et al (2008)	58	≥ 2.83, < 2.83	Advanced line	Mono or combined with IRI	✓	×	✓
Cappuzzo et al (2008)	85	≥ 2.92, < 2.92	Advanced line	Different regimens	✓	✓	×
Laurent-Puig et al (2009)	116	≥ 2, < 2	Advanced line	Mono or combined with IRI-based	✓	×	✓
Scartozzi et al (2009)	44	≥ 2.6, < 2.6	Advanced line	Combined with IRI-based	✓	×	✓
Tol et al (2010)	155	≥ 3, < 3	First line	Combined with CAPOX		×	×
Stintzing et al (2013)	98	>3.82, ≤ 3.82	First line	Combined with CAPOX or CAPIRI		×	×	×
Author (year)	Number of patients	CA repeat score	Setting	Chemo regimen	RR	PFS	OS	Skin toxicity
EGFR CA-SSR1 polymorphism
Graziano et al (2008)	110	S < 17, L ≥ 17	Advanced line	Combined with IRI-based	✓	✓	✓	✓^†
Lurje et al (2008)	117	S < 20, L ≥ 20	Advanced line	Monotherapy	×	×	×	×
Pander et al (2010)	123	S<20, L ≥ 20	First line	Combined with CAPOX		✓		×
Park et al (2011)	69	S<37, L ≥ 37	First and advanced line	Different regimens		×	×
Dahan et al (2011)	56	S ≤ 35, L > 35	Third line	Mono or combined with IRI	×	×	×	✓^†*
Stintzing et al (2013)	118	S ≤ 16, L>16	First line	Combined with CAPOX or CAPIRI		×	×	×

Cet; cetuximab, IRI; irinotecan, BSC; best supportive care, RR; response rate, PFS; progression-free survival, OS; overall survival

✓;significant, X; not significant ^†; S/S correlates with more ST, * P = 0.058

Table 2. Patients' characteristics (N = 77).

Characteristics	N	%
Gender
Male	44	57
Female	33	43
Age (year)
Median (range)	63 (39–79)
< 65	44	57
≥ 65	33	43
Performance Status
ECOG 0	69	90
ECOG 1	8	10
Diagnosis
Metachronous	18	23
Synchronous	59	77
Number of metastatic sites
1	33	43
≥ 2	44	57
Metastatic Sites
Liver	49	64
Lung	26	34
Para-aortic Lymph node	22	29
Peritoneum	17	22
Primary site of the tumor
Right	11	14
Left	64	83
NA	2	3
Previous adjuvant chemotherapy
Yes	6	8
No	71	92
Type of regimen
modified FOLFOX6	28	36
SOX	49	64

Abbreviations; ECOG, Eastern Cooperative Oncology Group; NA, not assessable.

Figure 1. Probability of progression-free survival by AREG gene expression.

Table 3. Candidate predictors and clinical outcomes.

		Tumor response, RECIST		Early tumor shrinkage		Skin rash until 8 weeks		Progression-free survival		Overall survival
	N	CR, PR	SD, PD	Yes	No	Gr0-1	Gr2-3	Median (95%CI), months	HR (95%CI)	Median (95%CI), months	HR (95%CI)
AREG
≤1.59	13	7 (54%)	6 (46%)	10 (77%)	3 (23%)	7 (64%)	4 (36%)	6.6 (3.0, 13.8)	1	26.5 (5.7, 33.9)	1
>1.59	54	43 (83%)	9 (17%)	43 (83%)	9 (17%)	34 (71%)	14 (29%)	11.6 (9.4, 14.9)	0.52 (0.28, 0.98)	42.8 (27.1, 42.9+)	0.50 (0.22, 1.13)
P*			0.30		0.69		0.72		0.037		0.084
EREG
≤3.21	41	30 (75%)	10 (25%)	30 (75%)	10 (25%)	29 (78%)	8 (22%)	11.0 (8.8, 14.7)	1	33.9 (21.5, 41.1+)	1
>3.21	23	19 (86%)	3 (14%)	20 (91%)	2 (9%)	11 (58%)	8 (42%)	11.2 (7.0, 15.2)	0.90 (0.50, 1.60)	42.8 (27.1, 42.9+)	0.66 (0.29, 1.51)
P^*			0.98		0.18		0.13		0.70		0.29
EGFR GCN
Low	47	33 (75%)	11 (25%)	36 (82%)	8 (18%)	25 (61%)	16 (39%)	9.1 (5.8, 11.7)	1	27.1 (18.3, 42.8)	1
High	30	23 (79%)	6 (21%)	22 (76%)	7 (24%)	20 (77%)	6 (23%)	11.6 (9.2, 15.2)	0.63 (0.38, 1.07)	41.4+ (23.2, 41.4+)	0.52 (0.25, 1.08)
P^*			0.78		0.57		0.20		0.073		0.068
EGFR CA-SSR1
LL	36	24 (73%)	9 (27%)	25 (76%)	8 (24%)	20 (67%)	10 (33%)	11.1 (8.9, 13.6)	1	27.1 (19.0, 42.8)	1
SL	29	23 (79%)	6 (21%)	23 (79%)	6 (21%)	21 (81%)	5 (19%)	9.1 (6.6, 14.5)	0.88 (0.51, 1.52)	42.9+ (20.0, 42.9+)	0.62 (0.30, 1.30)
SS	12	9 (82%)	2 (18%)	10 (91%)	1 (9%)	4 (36%)	7 (64%)	15.2 (3.0, 17.4)	0.75 (0.34, 1.63)	39.8+ (12.6, 39.8+)	0.56 (0.19, 1.64)
P^*			0.75		0.63		0.040		0.74		0.32

* P values were based on Fisher's exact for tumor response, early tumor shrinkage, and skin rash until 8 weeks except for AREG and EREG based on maximal chi-square method for tumor response, log-rank test for PFS and OS in the univariate analysis.

Bold characters; significant, +; Estimates were not reached.

Figure 2. Probability of overall survival by combined assessment with AREG gene expression and EGFR gene copy number (GCN), (A) Kaplan-Meier curves of 3 groups according to AREG gene expression and EGFR GCN, (B) Kaplan-Meier curves of groups with either AREG-high or EGFR GCN-high and both AREG-low and EGFR GCN-low.

Table 4. Association between AREG mRNA levels and EGFR gene copy number and clinical outcomes.

		Tumor response, RECIST		Early tumor shrinkage		Progression-free survival		Overall survival
	N	CR, PR	SD, PD	Yes	No	Median (95%CI), months	HR (95%CI)	Median (95%CI), months	HR (95%CI)
HH	26	20 (80%)	5 (20%)	19 (76%)	6 (24%)	11.8 (9.5, 16.3)	1	41.4+ (27.5, 41.4+)	1
HL	31	25 (83%)	5 (17%)	26 (87%)	4 (13%)	9.7 (6.7, 13.8)	1.63 (0.89, 2.99)	30.5 (18.4, 42.9+)	1.69 (0.71, 4.02)
LL	10	5 (50%)	5 (50%)	8 (80%)	2 (20%)	6.2 (3.0, 15.2)	2.15 (1.00, 4.64)	22.2 (4.4, 33.9)	3.18 (1.15, 8.79)
P*			0.11		0.63		0.082		0.067
HL, LL	41	30 (75%)	10 (25%)	34 (85%)	6 (15%)	9.4 (6.3, 13.6)	1.75 (1.00, 3.08)	30.5 (18.3, 42.9+)	1.98 (0.88, 4.47)
P*			0.77		0.51		0.038		0.086
HH, HL	57	45 (82%)	10 (18%)	45 (82%)	10 (18%)	11.2 (9.2, 14.7)	1	42.8 (27.1, 42.9+)	1
LL	10	5 (50%)	5 (50%)	8 (80%)	2 (20%)	6.2 (3.0, 15.2)	1.69 (0.85, 3.37)	22.2 (4.4, 33.9)	2.34 (0.99, 5.50)
P*			0.043		1.00		0.13		0.042

HH, AREG-high and EGFR high-GCN; HL, either AREG-high or EGFR high-GCN; LL, AREG-low and EGFR low-GCN

* P values were based on Fisher's exact for tumor response and early tumor shrinkage, log-rank test for PFS and OS in the univariate analysis.

Bold characters; significant, +; Estimates were not reached.

Table 5. Prognostic/predictive factors at multivariate analysis.

	Progression-free survival				Overall survival
	HR	95%CI	P-value^*	HR	95%CI	P-value^*
AREG
High vs. Low	0.48	0.25–0.92	0.027	0.40	0.17–0.96	0.040
EREG
High vs. Low	0.71	0.39–1.31	0.28	0.60	0.26–1.42	0.25
EGFR GCN
High vs. Low	0.73	0.41–1.30	0.29	0.49	0.21–1.11	0.087
EGFR CA-SSR1
LL vs. SL, LL	1.10	0.66–1.85	0.71	1.28	0.64–2.57	0.49
LL, SL vs. SS	1.50	0.69–3.26	0.31	1.33	0.45–3.91	0.60
AREG/EGFR GCN
HL, LL vs. HH	1.61	0.87–2.98	0.13	2.06	0.82–5.15	0.12
LL vs. HH, HL	1.77	0.86–3.65	0.12	3.73	1.47–9.46	0.006

* P values were based on Wald test for PFS and OS in the multivariable Cox regression model adjusted for regimen (modified-FOLFOX6 vs SOX), ECOG performance status (0 vs 1), and primary tumor site (right vs left).