p19^INK4d mRNA and protein expression as new prognostic factors in ovarian cancer patients

Figures & data

Figure 1. p19^INK4d protein expression in two different ovarian carcinomas (400× , hematoxylin counterstain): (A) low p19^INK4d expression, (B) high p19^INK4d expression.

Table 1. p19^INK4d and TP53 expression in ovarian carcinomas

	All patients n = 446	TP-treated group n = 199	PC/PAC-treated group n = 246
p19^INK4d expression:
Low (overall score ≤ 3)	158 (35%)	71 (36%)	87 (35%)
High (overall score ≥ 4)	288 (65%)	128 (64%)	160 (65%)
TP53 expression:
TP53-positive carcinomas (≥ 10%)	263 (59%)	118 (59%)	145 (59%)
TP53-negative carcinomas (< 10%)	182 (41%)	81 (41%)	101 (41%)

Table 2. Associations of p19^INK4d expression with clinical endpoints in ovarian cancer* (univariate Cox proportional hazards and logistic regression models)

	All patients		TP53^− group
	OR/HR [95% CI]	P value	OR/HR [95% CI]	P value
Platinum-treated group
Complete remission
p19^INK4d expression
Low (overall score ≤ 3)	1.0		-
High (overall score ≥ 4)	0.53 [0.31, 0.91]	0.022	-
Overall survival
p19^INK4d expression
Low (overall score ≤ 3)	-		1.0
High (overall score ≥ 4)	-		1.59 [1.02, 2.46]	0.035**
Taxane–platinum-treated group
Overall survival
p19^INK4d expression
Low (overall score ≤ 3)	-		1.0
High (overall score ≥ 4)	-		2.03 [1.15, 3.58]	0.015**

* There were no associations with p19^INK4d in the TP53⁺ group. **Kaplan–Meier curve

Figure 2. Prognostic significance of p19^INK4d (CDKN2D) expression. Patients treated with cisplatin/cyclophosphamide (A) and taxane–platinum (B) regimens with high p19^INK4d expression had a significantly worse overall survival than patients with low p19^INK4d expression (Kaplan–Meier curve). CDKN2D gene expression at the mRNA level correlated with enhanced risk of death in taxane–platinum-treated group (C).

Table 3. Associations of p19^INK4d expression and clinico-pathological factors with overall survival in ovarian cancer patients* (multivariate Cox proportional hazards models)

	TP53^− group
	HR [95% CI]	P value
Platinum-treated group
p19^INK4d expression
Low (overall score ≤ 3)	1.0
High (overall score ≥ 4)	1.61 [1.00, 2.58]	0.049
Residual tumor size
0	1.0
≤ 2 cm	-
> 2 cm	1.63 [1.03, 2.58]	0.034
FIGO stage
IIB, IIC	0.12 [0.02, 0.53]	0.005
IIIA, IIIB	-
IIIC	1.0
IV	-
Taxane–platinum-treated group
p19^INK4d expression
Low (overall score ≤ 3)	1.0
High (overall score ≥ 4)	2.00 [1.13, 3.54]	0.016

* There were no associations with p19^INK4d expression in the entire group and TP53⁺ subgroup.

Table 4. Associations of CDKN2D mRNA expression and clinico-pathological factors with overall survival in taxane-platinum-treated group* (uni- and multivariate Cox proportional hazards model)

	TP53^− group
	HR [95% CI]	P value
Univariate analysis
CDKN2D mRNA expression	2.94 [1.33, 6.49]	0.008
Multivariate analysis
CDKN2D mRNA expression	4.24 [1.80, 9.98]	0.001
Histological grade
G2	1.0
G3	-
G4	6.11 [2.00, 18.70]	0.001

* There were no associations with CDKN2D mRNA expression in the entire group and TP53⁺ group.

Table 5. Patients’ characteristics

	All patients n = 445	TP-treated group n = 199	PC/PAC-treated group n = 246
Age (years)
Range	20–78	20–78	24–77
Mean	54.3	54.9	53.9
FIGO stage
IIB, IIC	27 (6%)	10 (5%)	17 (7%)
IIIA, IIIB	84 (19%)	28 (14%)	56 (23%)
IIIC	284 (64%)	141 (71%)	143 (58%)
IV	50 (11%)	20 (10%)	30 (12%)
Residual tumor size
0	89 (20%)	37 (18%)	52 (21%)
≤ 2 cm	144 (32%)	80 (40%)	64 (26%)
> 2 cm	212 (48%)	82 (42%)	130 (53%)
Histological type
Serous	342 (77%)	148 (74%)	194 (79%)
Endometrioid	22 (5%)	8 (4%)	14 (6%)
Clear cell	15 (3%)	4 (2%)	11 (4%)
Undifferentiated	34 (8%)	21 (11%)	13 (5%)
Other types	32 (7%)	18 (9%)	14 (6%)
Histological grade
G 2	56 (13%)	26 (12%)	30 (12%)
G 3	268 (60%)	114 (58%)	154 (63%)
G 4	121 (27%)	59 (30%)	62 (25%)
Response to chemotherapy
Complete remission	265 (59%)	131 (65%)	134 (55%)
Partial remission/no change	113 (26%)	62 (32%)	51 (20%)
Progression	67 (15%)	6 (3%)	61 (25%)
Platinum-sensitive	133 (30%)	68 (34%)	65 (26%)
Platinum-resistant	225 (51%)	87 (45%)	138 (56%)
Number of patients at risk (OS)
1 y	398 (89%)	188 (94%)	210 (85%)
2 y	284 (56%)	148 (74%)	136 (55%)
3 y	187 (42%)	98 (49%)	89 (36%)
4 y	124 (28%)	61 (31%)	63 (26%)
5 y	87 (20%)	42 (21%)	45 (18%)
Number of patients at risk (DFS)
1 y	150 (57%)	76 (58%)	74 (55%)
2 y	87 (33%)	44 (34%)	43 (32%)
3 y	65 (25%)	32 (24%)	33 (25%)
4 y	49 (19%)	23 (18%)	26 (19%)
5 y	32 (12%)	14 (11%)	18 (13%)
Follow-up time
Range (month)	4.4–198.3	4.8–103.4	4.4–198.3
Mean	30	35.5	27.5
Outcome
NED	46 (10%)	28 (14%)	18 (7%)
AWD	47 (10%)	36 (18%)	11 (4%)
DOD	342 (77%)	130 (65%)	212 (87%)
DOC	10 (3%)	5 (3%)	5 (2%)

PC, cyclophosphamide and cisplatin; PAC, PC plus doxorubicin; TP, taxane–platinum therapy; NED, no evidence of disease; AWD, alive with disease; DOD, died of disease; DOC, died of other causes; OS, overall survival; DFS, disease free survival.