Combination of EGFR, HER-2/neu, and HER-3 Is a Stronger Predictor for the Outcome of Oral Squamous Cell Carcinoma Than Any Individual Family Members

Weiya Xia; Yiu-Keung Lau; Hua-Zhong Zhang; Fen-Yuan Xiao; Dennis A. Johnston; Ai-Ru Liu; Lei Li; Ruth L. Katz; Mien-Chie Hung

DOI: Published December 1999

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Fig. 1.
Representative immunohistochemical staining for the expression of four EGFR family members in oral SCC (−, no expression; +, low expression; ++, intermediate expression; +++, high expression).
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Fig. 2.
Representative immunohistochemical staining for the expression of four EGFR family members in normal oral tissues as compared with the carcinoma tissues.
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Fig. 3.
Survival curves for 47 patients expressing EGFR (A), HER-2/neu (B), HER-3 (C), and HER-4 (D) in 47 patients with oral SCC. The log-rank tests of all four EGFR family members, P < 0.0001.
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Fig. 4.
Correlation of coexpression between HER-2/neu and EGFR (A; r = 0.62; P < 0.05), between HER-2/neu and HER-3 (B; r = 0.59; P < 0.05), and between EGFR and HER-3 (C; r = 0.58; P < 0.05) in 111 patients with oral SCC.
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Fig. 5.
Western blot analyses of EGFR and HER-3 expression in seven head and neck SCC cell lines. A, A431 cells, which express a high level of EGFR, were used as a positive control for EGFR protein detection in the cell lines. B, MDA-MB-453 human breast cancer cells, which express a high level of HER-3 expression, were used as a positive control for HER-3 detection in the cell lines.
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Fig. 6.
Heterodimer formation in an oral cancer cell line coexpressing HER-2/neu and HER-3. Coimmunoprecipitation was performed as described in “Materials and Methods.” Tu 138 cells, which coexpress HER-2/neu and HER-3, were used to detect heterodimer formation. Tu 177 cells, which express low or no HER-2/neu and HER-3, were used as a control.

Tables

Figures

Table 1

Immunoreactivity of EGFR family members in 111 oral SCCs

Family member	Score	No. of cases (%)
EGFR	Low or none	70 (63)
	Intermediate	28 (25)
	High	13 (12)
HER-2/neu	Low or none	71 (64)
	Intermediate	22 (20)
	High	18 (16)
HER-3	Low or none	76 (68)
	Intermediate	25 (23)
	High	10 (9)
HER-4	Low or none	56 (50)
	Intermediate	40 (36)
	High	15 (14)

Table 2

Relationship between TNM staging and EGFR families expressing in 111 cases of oral SCCS

TNM	No. of cases (%)	Level of expression^a
				EGFR			C-erb B-2			C-erb B-3			C-erb B-4
				+++/++	+/−	+++/++	+/−	+++/++	+/−	+++/++	+/−
Tumor size
T₁	60 (54.05)	19 (17.11)	41 (36.94)	22 (19.82)	38 (34.23)	18 (16.22)	42 (37.84)	31 (27.93)	29 (26.13)
T_2–3	51 (45.95)	22 (19.82)	29 (26.12)	18 (16.22)	33 (29.73)	27 (15.32)	34 (30.63)	24 (21.62)	27 (24.32)
Ps^b		P >0.21			P >0.88			P >0.87			P >0.63
Nodal stage
N₀	76 (68.47)	18 (18.92)	55 (49.55)	22 (19.83)	54 (48.65)	17 (15.31)	59 (53.15)	33 (29.73)	43 (38.74)
N_1–3	35 (31.53)	20 (18.01)	15 (13.51)	18 (16.22)	17 (15.32)	18 (16.22)	17 (15.32)	22 (11.81)	13 (11.71)
Ps			P <0.003			P <0.022			P <0.002			P >0.06
Metastasis
M₀	96 (86.49)	31 (27.93)	65 (58.56)	29 (26.13)	67 (60.36)	24 (21.62)	72 (64.87)	43 (38.74)	53 (47.75)
M₁	15 (13.51)	10 (9.01)	5 (4.51)	11 (9.91)	4 (3.60)	11 (9.91)	4 (3.60)	12 (10.81)	3 (2.70)
Ps			P <0.001			P <0.001			P <0.001			P <0.001
Total	111 (100)	42 (36.94)	70 (63.06)	40 (36.04)	71 (63.96)	35 (31.53)	76 (68.47)	55 (49.55)	56 (50.45)

^a No. of cases (%).
^b Ps were calculated by the Fisher’s exact test.

Table 3

Characteristics of 47 oral SCCs

Characteristics of the patients^a	No. of patients
Age, yr^b
≥50	27
<50	20
Sex^b
Male	32
Female	15
Primary tumor sites
Tongue	25
Gum	8
Floor of mouth	6
Others	8
Histological grades^b
I	37
II	10
TNM
Tumor size^c
T₁	27
T₂	16
T₃	4
Nodal stage^d
N₀	36
N₁	3
N₂	4
N₃	4
Metastasis^e
M₀	36
M₁	11
Survival months after diagnosis
<12	4
12–36	6
>58	37

^a All patients received surgical treatment.
^b The associations between the expression levels of EGFR family members and age, sex, and histological grade are insignificant (P > 0.05, Fisher’s exact test) except that the association between EGFR expression and age showed P < 0.05.
^c Tumor size: T₁, tumor ≤ 2 cm in greatest dimension; T₂, 2 > cm but ≤4 cm; T₃ tumor > 4 cm.
^d Nodal stages; N₀, no regional lymph node metastasis; N₁, metastasis to a lymph node (<2 cm); N₂, metastasis to one or more lymph nodes (≥2 cm but <5 cm); N₃, metastasis to a lymph node (≥5 cm).
^e Distant metastasis; M₀, no distant metastasis; M₁, distant metastasis.

Table 4

Results of univariate and multivariate analyses using the Cox regression analysis model

	Univariate^a			Multivariate^b
	log likelihood ratio	Partial^cP	Combination of two factors	log likelihood ratio	Partial P	Combination of three factors	log likelihood ratio	Partial P	Combination of all four factors	log likelihood ratio	Partial P
HER-2/neu	−19.20	<0.001	HER-2/neu+HER-3	−13.94	<0.002	HER-2/neu+HER-3+EGFR	−11.99	<0.05	HER-2/neu+HER- 3+EGFR+HER-4	−11.66	>0.25
HER-4	−19.54	<0.001	HER-2/neu+HER-4	−16.84	<0.05	HER-2/neu+HER-3+HER-4	−13.82	>0.5
HER-3	−20.72	<0.001	HER-2/neu+EGFR	−18.35	>0.25
EGFR	−25.75	<0.001

^a Addition of single oncoprotein to Cox regression analyses, which includes histological grade, nodes, and distant metastasis.
^b Multivariate addition of oncoproteins to Cox regression analysis, which includes histological grades, nodes, and distant metastasis.
^c Log likelihood relative to log likelihood of −36.0 for grade, nodal stage, and distant metastasis.