Nuclear maspin expression as a predictive marker for fluorouracil treatment response in colon cancer

Figures & data

Table I. Patient characteristics and maspin expression for patients included in the analyses.

Covariate	Colorectal			Colon			Rectum
	Surgery alone n = 190	Adjuvant (5-FU/LEV) n = 190	Total n = 380	Surgery alone n = 132	Adjuvant (5-FU/LEV) n = 137	Total n = 269	Surgery alone n = 58	Adjuvant (5-FU/LEV) n = 53	Total n = 111
Age at inclusion
Mean (SD)	62 (9)	60 (10)	61 (9)	63 (9)	61 (10)	62 (9)	62 (9)	59 (10)	60 (10)
Gender
Male	98 (52%)	99 (52%)	197 (52%)	63 (48%)	64 (47%)	127 (47%)	35 (60%)	35 (66%)	70 (63%)
Female	92 (48%)	91 (48%)	183 (48%)	69 (52%)	73 (53%)	142 (53%)	23 (40%)	18 (34%)	41 (37%)
Stage (TNM)
Stage II	115 (61%)	110 (58%)	225 (59%)	83 (63%)	86 (63%)	169 (63%)	32 (55%)	24 (45%)	56 (50%)
Stage III	75 (39%)	80 (42%)	155 (41%)	49 (37%)	51 (37%)	100 (37%)	26 (45%)	29 (55%)	55 (50%)
Differentiation^a
High/moderate	158 (83%)	155 (82%)	313 (82%)	103 (78%)	109 (80%)	212 (79%)	55 (95%)	46 (87%)	101 (91%)
Low	30 (16%)	30 (16%)	60 (16%)	27 (21%)	24 (18%)	51 (19%)	3 (5%)	6 (11%)	9 (8%)
Ki67^b
< 40%	78 (38%)	89 (43%)	167 (39%)	58 (44%)	62 (45%)	62 (45%)	18 (31%)	26 (49%)	44 (40%)
≥ 40%	92 (45%)	78 (38%)	170 (40%)	57 (43%)	56 (41%)	56 (41%)	32 (55%)	21 (40%)	53 (48%)
Histological type^c
Adenocarcinoma	170 (90%)	170 (90%)	340 (90%)	114 (86%)	120 (88%)	234 (87%)	56 (96%)	50 (94%)	106 (96%)
Mucinous carcinoma	11 (6%)	14 (7%)	25 (7%)	10 (8%)	13 (10%)	23 (9%)	1 (2%)	1 (2%)	2 (2%)
Signet ring cell carcinoma	4 (2%)	1 (0.5%)	5 (1%)	3 (2%)	1 (1%)	4 (2%)	1 (2%)	0	1 (1%)
Localization
Proximal	69 (36%)	77 (40%)	146 (39%)	69 (52%)	77 (56%)	146 (54%)
Distal	63 (33%)	60 (32%)	123 (32%)	63 (48%)	60 (44%)	123 (46%)
Rectum	58 (31%)	53 (28%)	111 (29%)
Maspin expression (0–300)
Mean (SD)	118 (57)	130 (60)	124 (58)	121 (55)	136 (62)	128 (59)	112 (60)	114 (52)	113 (56)
Low	70 (37%)	65 (34%)	135 (36%)	47 (36%)	43 (31%)	90 (33%)	23 (40%)	22 (42%)	45 (40%)
Medium or High	120 (63%)	125 (66%)	245 (64%)	85 (64%)	94 (69%)	179 (67%)	35 (60%)	31 (58%)	66 (60%)

^aData regarding differentiation were missing from 7 patients; ^bdata regarding Ki67-score were missing from 88 patients; ^cdata regarding histological type were missing from 10 patients.

Figure 1. Immunohistochemistry for maspin. (A) Normal colon. (B) Colon tumor, negatively stained. (C) Colon tumor, strong nuclear staining. (D) Colon tumor, strong nuclear and intermediate cytoplasmic staining.

Table II. Nuclear maspin expression score according to patient and tumor characteristics.

	Colorectal tumors			Colon tumors			Rectal tumors
	N^a	Mean (SD)	p^b	N^a	Mean (SD)	p^b	N^a	Mean (SD)	p^b
Sex
Male	197	122 (56)	0.470	127	127 (56)	0.698	70	112 (55)	0.922
Female	183	126 (61)		142	130 (62)		41	113 (57)
Age
≤ 65	221	124 (58)	0.954	150	130 (59)	0.744	71	112 (54)	0.755
> 65	159	124 (59)		119	127 (59)		40	115 (60)
Randomization group
Adjuvant therapy	190	130 (60)	0.055	137	136 (62)	0.039	53	114 (52)	0.846
Surgery alone	190	118 (57)		132	121 (55)		58	112 (60)
Stage
Stage II	225	121 (63)	0.207	169	127 (64)	0.519	56	103 (57)	0.057
Stage III	155	128 (51)		100	132 (50)		55	123 (53)
Differentiation
High/moderate	313	123 (58)	0.608	212	130 (58)	0.608	101	110 (56)	0.097
Low	60	127 (59)		51	125 (61)		9	142 (50)
Ki67
< 40%	164	126 (57)	0.849	120	127 (60)	0.264	44	126 (49)	0.052
≥ 40%	166	125 (63)		113	135 (60)		53	103 (62)
Localization
Proximal colon				146	127 (62)	0.627
Distal colon				123	130 (56)
Colon	269	128 (59)	0.017
Rectum	111	113 (56)

^aNumber of patients; ^bStudent’s t-test.

Figure 2. Survival of colon cancer patients (stage II+ III) according to nuclear maspin expression and treatment. Survival is presented as DFS (A and B) and CSS (C and D) for low (A and C) versus high (B and D) expression of maspin. CSS, cancer-specific survival; DFS, disease-free survival.

Table III. Univariate Cox regression analysis for cancer-specific survival.

	Colorectal		Colon		Rectum
Covariate	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
Sex (male vs. female)	1.12 (0.78–1.60)	0.544	0.99 (0.63–1.55)	0.957	1.28 (0.68–2.42)	0.451
Age (continuous)	0.99 (0.98–1.01)	0.510	1.01 (0.98–1.03)	0.562	0.97 (0.94–0.99)	0.042
Stage (III vs. II)	4.75 (3.20–7.03)	<0.001	4.30 (2.69–6.88)	<0.001	5.72 (2.74–12.0)	<0.001
Tumor differentiation (low vs. medium/high)	1.62 (1.04–2.52)	0.032	1.74 (1.04–2.89)	0.034	1.65 (0.65–4.18)	0.295
Ki67 [low (< 40%) vs. high (≥ 40%)]	1.89 (1.28–2.80)	0.001	2.25 (1.37–3.70)	0.001	1.36 (0.70–2.65)	0.360
Tumor localization (rectum vs. colon)^a	1.34 (0.94–1.99)	0.099
Tumor localization (distal vs. proximal colon)^a			1.18 (0.76–1.85)	0.462
Randomization group^b	1.07 (0.75–1.53)	0.714	0.98 (0.62–1.53)	0.913	1.31 (0.72–2.39)	0.376
Maspin expression pr 50
Total	1.13 (0.97–1.31)	0.130	1.14 (0.94–1.38)	0.187	1.17 (0.90–1.52)	0.254
In patients receiving adjuvant chemotherapy	1.33 (1.08–1.64)	0.008	1.48 (1.13–1.94)	0.004	1.21 (0.82–1.78)	0.339
In patients treated with surgery only	0.92 (0.73–1.15)	0.460	0.82 (0.62–1.10)	0.185	1.12 (0.77–1.62)	0.551

^aVariable not included in multivariate analyses; ^badjuvant chemotherapy versus surgery only.

Figure 3. Survival of colon cancer patients stage III according to nuclear maspin expression and treatment. Survival is presented as DFS (A and B) and CSS (C and D) for low (A and C) versus high (B and D) expression of maspin. CSS, cancer-specific survival; DFS, disease-free survival.

Table IV. Multivariate Cox regression analysis for cancer-specific survival.

	Colorectal		Colon		Rectum
Covariate	HR (95% CI)	P	HR (95% CI)	P	HR (95% CI)	P
Sex (male vs. female)	1.14 (0.77–1.69)	0.506	0.98 (0.60–1.60)	0.944	1.62 (0.81–3.27)	0.176
Age (continuous)	0.99 (0.97–1.01)	0.370	1.00 (0.97–1.03)	0.978	0.97 (0.93–1.00)	0.055
Stage (III vs. II)	5.00 (3.24–7.73)	< 0.001	4.56 (2.73–7.63)	< 0.001	6.84 (2.85–16.4)	< 0.001
Tumor differentiation (low vs. medium/high)	1.52 (0.93–2.50)	0.098	1.50 (0.84–2.66)	0.169	2.12 (0.66–6.83)	0.209
Ki67 [low (< 40%) vs. high (≥ 40%)]	1.77 (1.19–2.64)	0.005	2.21 (1.32–3.68)	0.002	1.16 (0.57–2.37)	0.677
Interaction Randomization group by maspin expression		0.101		0.045		0.571
Randomization group^a
for maspin expression score 60	0.59 (0.30–1.15)	0.122	0.49 (0.21–1.15)	0.101	0.95 (0.31–2.92)	0.935
for maspin expression score 130	0.90 (0.60–1.36)	0.632	0.94 (0.56–1.59)	0.827	0.74 (0.35–1.56)	0.431
for maspin expression score 180	1.23 (0.72–2.11)	0.448	1.51 (0.77–2.96)	0.232	0.62 (0.23–1.66)	0.343
Maspin expression pr 50
In patients receiving adjuvant chemotherapy	1.31 (1.01–1.69)	0.039	1.43 (1.06–1.94)	0.021	0.99 (0.62–1.57)	0.949
In patients treated with surgery only	0.96 (0.74–1.25)	0.762	0.89 (0.63–1.26)	0.523	1.18 (0.78–1.79)	0.442
Total^b	1.13 (0.94–1.36)	0.188	1.17 (0.93–1.48)	0.169	1.09 (0.80–1.49)	0.592
Randomization group^a,b	1.09 (0.73–1.62)	0.682	1.02 (0.62–1.66)	0.944	1.34 (0.63–2.82)	0.445

All information is based on a model including the Randomization group by maspin interaction, unless otherwise stated.

^aAdjuvant chemotherapy versus surgery only; ^bwithout Randomization group by maspin interaction in model.