FcγRIIA and IIIA polymorphisms predict clinical outcome of trastuzumab-treated metastatic gastric cancer

Figures & data

Table 1 Patient characteristics by genotypes in metastatic gastric cancer

Features	FcγRIIA				FcγRIIIA				FcγRIIA and IIIA
	H/H (%), n=56	R/R (%), n=14	H/R (%), n=40	P-value	V/V (%), n=19	F/F (%), n=40	V/F (%), n=51	P-value	H/H or V/V, n=61	Others, n=49	P-value
Her-2 status				0.52				0.38			0.37
Positive	19 (45.2)	7 (16.7)	16 (38.1)		5 (11.9)	18 (42.9)	19 (45.2)		21 (50.0)	21 (50.0)
Negative	37 (54.4)	7 (10.3)	24 (35.3)		14 (20.6)	22 (32.4)	32 (47.1)		40 (58.8)	28 (41.2)
Age (years, median 52)				0.52				0.97			0.38
<52	23 (45.1)	7 (13.7)	21 (41.2)		9 (17.6)	19 (37.3)	23 (45.1)		26 (51.0)	25 (49.0)
≥52	33 (55.9)	7 (11.9)	19 (32.2)		10 (16.9)	21 (35.6)	28 (47.5)		35 (59.3)	24 (40.7)
Gender				0.08				0.08			0.56
Male	33 (50.0)	5 (7.6)	28 (42.4)		7 (10.6)	26 (39.4)	33 (50.0)		35 (53.0)	31 (47.0)
Female	23 (52.3)	9 (20.5)	12 (27.3)		12 (27.3)	14 (31.8)	18 (40.9)		26 (59.1)	18 (40.9)
ECOG score				0.25				0.08
0	42 (48.3)	10 (11.5)	35 (40.2)		15 (17.2)	36 (41.4)	36 (41.4)		47 (54.0)	40 (46.0)	0.56
1	14 (60.9)	4 (17.4)	5 (21.7)		4 (17.4)	4 (17.4)	15 (65.2)		14 (60.9)	9 (39.1)
Gastrectomy				0.47				0.27			0.99
Yes	43 (51.8)	12 (14.5)	28 (33.7)		12 (14.5)	33 (39.8)	38 (45.8)		46 (55.4)	37 (44.6)
No	13 (48.1)	2 (7.4)	12 (44.4)		7 (25.9)	7 (25.9)	13 (48.1)		15 (55.6)	12 (44.4)
Location of tumor				0.87				0.36			0.81
Proximal	14 (60.9)	3 (13.0)	6 (26.1)		3 (13.0)	9 (39.1)	11 (47.8)		14 (60.9)	9 (39.1)
Middle	16 (50.0)	4 (12.5)	12 (37.5)		8 (25.0)	10 (31.3)	14 (43.8)		18 (56.3)	14 (43.8)
Distal	23 (46.9)	7 (14.3)	19 (38.8)		6 (12.2)	21 (42.9)	22 (44.9)		25 (51.0)	24 (49.0)
Others	3 (50.0)	0 (0.0)	3 (50.0)		2 (33.3)	0 (0.0)	4 (66.7)		4 (66.7)	2 (33.3)
Degree of differentiation				0.53				0.16			0.50
Well-differentiated adenocarcinoma	1 (33.3)	0 (0.0)	2 (66.71)		0 (0.0)	3 (100.0)	0 (0.0)		1 (33.3)	2 (66.7)
Moderately differentiated adenocarcinoma	13 (65.0)	2 (10.0)	5 (25.0)		2 (10.0)	7 (35.0)	11 (55.0)		13 (65.0)	7 (35.0)
Poorly differentiated/signet ring cell carcinoma/mucinous adenocarcinoma	42 (48.3)	12 (13.8)	33 (37.9)		17 (19.5)	30 (34.5)	51 (46.0)		47 (54.0)	40 (46.0)
Lauren classification				0.48				0.81			0.83
Intestinal type	10 (62.5)	0 (0.0)	6 (37.5)		2 (12.5)	6 (37.5)	8 (50.0)		10 (62.5)	6 (37.5)
Diffuse type	34 (50.0)	9 (13.2)	25 (36.8)		14 (20.6)	23 (33.8)	31 (45.6)		37 (54.4)	31 (45.6)
Mixed type	12 (46.2)	5 (19.2)	9 (34.6)		3 (11.5)	11 (42.3)	12 (46.2)		14 (53.8)	12 (46.2)
Smoke				0.53				0.69			0.98
Present or previous	20 (52.6)	3 (7.9)	15 (39.5)		5 (13.2)	15 (39.5)	18 (47.4)		21 (55.3)	17 (44.7)
Never	36 (50.0)	11 (15.3)	25 (34.7)		14 (19.4)	25 (34.7)	33 (45.8)		40 (55.6)	32 (44.4)
Drink				0.69				0.51			0.94
Present or previous	15 (48.4)	3 (9.7)	13 (41.9)		4 (12.9)	10 (32.3)	17 (54.8)		17 (54.8)	14 (45.2)
Never	41 (51.9)	11 (13.9)	27 (34.2)		15 (19.0)	30 (38.0)	34 (43.0)		44 (55.7)	35 (44.3)
Metastasis				0.95				0.86			0.38
Single	26 (51.0)	7 (13.7)	18 (35.3)		8 (15.7)	18 (35.3)	25 (49.0)		26 (51.0)	25 (49.0)
Multiple	30 (50.8)	7 (11.9)	22 (37.3)		11 (18.6)	22 (37.3)	26 (44.1)		35 (59.3)	24 (40.7)

Abbreviation: ECOG, Eastern Cooperative Oncology Group.

Table 2 FcγR polymorphisms and tumor responses in metastatic GC

	Set A (n=42)									Set B (n= 68)
	No (%)	Response								No (%)	Response
		CR no (%)	PR no (%)	SD no (%)	PD no (%)	ORR no (%)	DCR no (%)	P-value for ORR	P-value for DCR		CR no (%)	PR no (%)	SD no (%)	PD no (%)	ORR no (%)	DCR no (%)	P-value for ORR	P-value for DCR
FcγRIIA
H/H	19 (45.2)	1 (5.3)	11 (57.9)	6 (31.6)	1 (5.3)	12 (63.2)	18 (94.7)			37 (54.4)	0 (0.0)	14 (37.8)	13 (35.1)	10 (27.0)	14 (37.8)	27 (73.0)
H/R	16 (38.1)	0 (0.0)	8 (50.0)	2 (12.5)	6 (37.5)	8 (50.0)	10 (62.5)			24 (35.3)	0 (0.0)	6 (25.0)	13 (54.2)	5 (20.8)	6 (25.0)	19 (79.1)
R/R	7 (16.7)	0 (0.0)	5 (71.0)	2 (28.6)	0 (0.0)	5 (71.0)	7 (100.0)			7 (10.3)	0 (0.0)	2 (28.6)	1 (14.3)	4 (57.1)	2 (28.6)	3 (42.9)
H/R or R/R	23 (54.8)	0 (0.0)	13 (56.5)	4 (17.4)	6 (26.1)	13 (56.5)	17 (73.9)			31 (45.6)	0 (0.0)	8 (25.8)	14 (45.2)	9 (29.0)	8 (25.8)	22 (71.0)
H/H vs H/R vs R/R								0.58	0.02								0.57	0.18
H/H vs H/R or R/R								0.66	0.07								0.29	0.85
FcγRIIIA
V/V	5 (11.9)	0 (0.0)	4 (80.0)	1 (20.0)	0 (0.0)	4 (80.0)	5 (100.0)			14 (20.6)	0 (0.0)	7 (50.0)	1 (7.1)	6 (42.9)	7 (50.0)	8 (57.0)
V/F	19 (45.2)	1 (5.3)	10 (52.6)	3 (15.8)	5 (26.3)	11 (57.9)	14 (73.7)			32 (47.1)	0 (0.0)	9 (28.1)	15 (46.9)	8 (25.0)	9 (28.1)	24 (75.0)
F/F	18 (42.9)	0 (0.0)	10 (55.6)	6 (33.3)	2 (11.1)	10 (55.6)	16 (88.9)			22 (32.4)	0 (0.0)	6 (27.3)	11 (50.0)	5 (22.7)	6 (27.3)	17 (77.3)
V/F or F/F	37 (88.1)	0 (0.0)	21 (56.8)	9 (24.3)	7 (18.9)	21 (56.8)	30 (81.0)			54 (79.4)	0 (0.0)	15 (27.8)	26 (48.1)	13 (24.1)	15 (27.8)	41 (75.9)
V/V vs V/F vs F/F								0.61	0.27								0.29	0.38
V/V vs V/F or F/F								0.32	0.29								0.11	0.16
FcγRIIA and IIIA								0.35	0.04								0.28	0.65
H/H or V/V	21 (50.0)	1 (61.9)	13 (66.7)	6 (28.6)	1 (4.8)	14 (66.7)	20 (95.2)			40 (58.8)	0 (0.0)	15 (37.5)	13 (32.50)	12 (30.0)	15 (37.5)	28 (70.0)
Others	21 (50.0)	0 (0.0)	11 (52.4)	4 (19.0)	6 (28.6)	11 (52.4)	15 (71.4)			28 (41.2)	0 (0.0)	7 (25.0)	14 (50.0)	7 (25.0)	7 (25.0)	21 (75.0)

Notes: Set A: patients with Her-2–positive GC who received trastuzumab combined with chemotherapy as the first-line treatment. Set B: patients with Her-2–negative GC who received chemotherapy only as the first-line treatment.

Abbreviations: CR, complete response; DCR, disease control rate; FcγR, Fc γ receptor; GC, gastric cancer; ORR, objective response rate; PD, progressed disease; PR, partial response; SD, stable disease.

Figure 1 Progression-free survival for patients with metastatic gastric cancer receiving chemotherapy and trastuzumab (A, P=0.02) or chemotherapy only (B, P=0.83) as the first-line treatment, according to FcγRIIA polymorphisms (H/R or R/R vs H/H).

Abbreviation: FcγR, Fc γ receptor.

Figure 2 Progression-free survival for patients with metastatic gastric cancer receiving chemotherapy and trastuzumab (A, P=0.12) or chemotherapy only (B, P=0.96) as the first-line treatment, according to FcγRIIIA polymorphisms (F/V or F/F vs V/V).

Abbreviation: FcγR, Fc γ receptor.

Figure 3 Progression-free survival for patients with metastatic gastric cancer receiving chemotherapy and trastuzumab (A, P=0.004) or chemotherapy only (B, P=0.62) as the first-line treatment, according to FcγRIIA and IIIA polymorphisms (others vs H/H or V/V).

Abbreviation: FcγR, Fc γ receptor.

Table 3 The prognostic value of FcγRIIA and FcγRIIIA polymorphisms for PFS in patients with metastatic GC: univariate and multivariate analyses

	Set A (n=42)					Set B (n=68)
	Median PFS (months)	Univariate		Multivariate		Median PFS (months)	Univariate		Multivariate
		Hazard ratio (95% CI)	P-value	Adjusted hazard ratio (95% CI)	P-value		Hazard ratio (95% CI)	P-value	Adjusted hazard ratio (95% CI)	P-value
General	7.23					5.27
FcγRIIA polymorphism			0.02		0.001			0.83		0.78
H/R or R/R	4.93	1 (reference)		1 (reference)		5.67	1 (reference)		1 (reference)
H/H	11.7	0.36 (0.16–0.82)		0.18 (0.07–0.48)		4.60	1.06 (0.61–1.86)		0.91 (0.50–1.69)
FcγRIIIA polymorphism			0.12		0.09			0.96		0.94
F/V or F/F	6.87	1 (reference)		1 (reference)		6.07	1 (reference)		1 (reference)
V/V		0.20 (0.03–1.49)		0.15 (0.02–1.31)		2.93	1.02 (0.50–2.06)		0.97 (0.45–2.09)
FcγRIIA and IIIA	−		0.004		<0.001			0.62		0.94
Others	4.33	1 (reference)		1 (reference)		5.67	1 (reference)		1 (reference)
H/H or V/V	15.93	0.29 (0.13–0.67)		0.17 (0.07–0.45)		4.60	1.15 (0.66–2.03)		1.03 (0.56–1.90)

Notes: Set A: patients with Her-2-positive GC who received trastuzumab combined with chemotherapy as the first-line treatment. Set B: patients with Her-2–negative GC who received chemotherapy only as the first-line treatment. Multivariate analysis for the prognostic value of FcγRIIA and FcγRIIIA polymorphisms was adjusted by age (<02/≥52 years), gender (male/female), ECOG score (0/1), degree of differentiation (well-differentiated adenocarcinoma/moderately differentiated adenocarcinoma/poorly differentiated/signet ring cell carcinoma/mucinous adenocarcinoma), and Lauren classification (intestinal type/diffuse type/mixed type).

Abbreviations: ECOG, Eastern Cooperative Oncology Group; FcγR, Fc γ receptor; GC, gastric cancer; ORR, objective response ratio; PFS, progression-free survival.

Figure S1 The CONSORT diagram.

Table S1 Patient characteristics by treatment settings

Characteristics	Set A, no (%)	Set B, no (%)
Her-2 status
Positive	42 (100.0)	0
Negative	0	68 (100.0)
Age (years)
Median (range)	56 (25–72)	51 (22–73)
Gender
Male	32 (76.2)	34 (50.0)
Female	10 (23.8)	34 (50.0)
Gastrectomy
Yes	33 (78.6)	50 (73.5)
No	9 (21.4)	18 (26.5)
Location of tumor
Proximal	12 (28.6)	11 (16.2)
Middle	15 (35.7)	17 (25.0)
Distal	14 (33.3)	35 (51.5)
Others	1 (2.4)	5 (7.4)
Degree of differentiation
Well-differentiated adenocarcinoma	2 (4.8)	1 (1.5)
Moderate differentiated adenocarcinoma	13 (31.0)	7 (10.3)
Poorly differentiated/signet ring cell carcinoma/mucinous adenocarcinoma	27 (64.3)	60 (88.2)
Lauren classification
Intestinal type	14 (33.3)	2 (2.9)
Diffuse type	23 (54.8)	45 (66.2)
Mixed type	5 (11.9)	21 (30.9)

Notes: Setting A: patients with Her-2-positive GC who received trastuzumab combined with chemotherapy as the first-line treatment. Setting B: patients with Her-2-negative GC who received chemotherapy only as the first-line treatment.

Abbreviation: GC, gastric cancer.