Prognostic value of programmed death-ligand 1 (PD-L1) expression in ovarian clear cell carcinoma

Jun Zhu; Hao Wen; Rui Bi; Yong Wu; Xiaohua Wu

doi:10.3802/jgo.2017.28.e77

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Zhu, Wen, Bi, Wu, and Wu: Prognostic value of programmed death-ligand 1 (PD-L1) expression in ovarian clear cell carcinoma

Original Article

J Gynecol Oncol 2017;28(6):e77.

Published online: 4 November 2017

DOI: https://doi.org/10.3802/jgo.2017.28.e77

Prognostic value of programmed death-ligand 1 (PD-L1) expression in ovarian clear cell carcinoma

Jun Zhu^1,², Hao Wen^1,², Rui Bi³, Yong Wu³, Xiaohua Wu^1,^2,

¹Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China

²Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

³Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China

Correspondence to Xiaohua Wu Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, 270 Dong An Road, Shanghai 200032, China. E-mail: docwuxh@yahoo.com

Received 15 June 2017 Revised 23 June 2017 Accepted 23 July 2017

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Objective

Programmed death-ligand 1 (PD-L1) was expressed in various tumors and antibodies targeting its receptor programmed cell death-1 (PD-1) are emerging cancer therapeutics. This study was designed to evaluate the expression of PD-L1 and its correlation with clinicopathologic features and clinical outcomes in ovarian clear cell carcinoma (OCCC).

Methods

The PD-L1 expression was measured by tissue-microarray-based immunohistochemistry from 122 eligible patients diagnosed with OCCC. The associations of clinicopathologic features with progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method and multivariate analysis was further performed by Cox regression model.

Results

Overall, high PD-L1 expression (PD-L1 ^high) was observed in 44.7% (55/123) of OCCC patients, and was strongly associated with advanced stages (p=0.020), positive ascitic fluid (p=0.016), platinum-resistant (PR) disease (p=0.045), and recurrence (p=0.038). Moreover, patients with PD-L1 ^high were associated with poorer OS (hazard ratio [HR]=2.877; p=0.001) and PFS (HR=1.843; p=0.021) than those with low PD-L1 expression (PD-L1 ^low). In subgroup analysis, PD-L1 ^high patients experienced a poorer PFS (HR=1.926; p=0.044) and OS (HR=2.492; p=0.021) than PD-L1 ^low cases among advanced stages (III–IV), but this difference was not observed in stage I–II patients. Meanwhile, PD-L1 ^high was associated with poorer prognosis than PD-L1 ^low in PR patients (OS, HR=2.253; p=0.037; PFS, HR=1.448; p=0.233). Multivariate analysis revealed that PD-L1 ^high and advanced stages (III–IV) were adverse independent prognosticators for both PFS (HR _PD-L1=2.0; p _PD-L1=0.038; HR _stage=10.2; p _stage<0.001) and OS (HR _PD-L1=3.0; p _PD-L1=0.011; HR _stage=14.3; p _stage<0.001).

Conclusion

PD-L1 ^high might serve as a risk factor for PFS and OS in patients with OCCC. It is possible that immunotherapy targeting PD-L1 pathway could be used in OCCC.

Keywords: Ovarian Neoplasms, Adenocarcinoma, Clear Cell, Antigens, CD274, Prognosis

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Fig. 1.

The overview of staining intensities of the tissue array is shown (3+. 2+, 1+, and 0+), with an example each (A-D) for a membranous and/or for a cytoplasmic staining pattern.

Fig. 2.

Immunohistochemical staining for PD-L1 in OCCC tumor tissues. The staining intensities are shown (0+, 1+, 2+, 3+), with an example each (A-D) for a membranous and/or a cytoplasmic staining pattern. The placenta tissue (E) is used as a positive control for PD-L1 expression. The total number of each staining intensity are shown in (F). OCCC, ovarian clear cell carcinoma; PD-L1, programmed death-ligand 1.

Fig. 3.

(A, B) PFS and OS curves in patients with OCCC. (C) Patients with PD-L1 ^high (blue dotted line) showed significantly worse PFS compared with those with low expression (yellow solid line). (D) Patients with PD-L1 ^low (yellow solid line) presented a better survival outcome than those with PD-L1 ^high (blue dotted line). OCCC, ovarian clear cell carcinoma; OS, overall survival; PD-L1, programmed death-ligand 1; PD-L1 ^high, high PD-L1 expression; PD-L1 ^low, low PD-L1 expression; PFS, progression-free survival.

Fig. 4.

PFS and OS curves stratified by FIGO stage between high and low PD-L1 expression (yellow solid lines, PD-L1 ^low; blue dotted lines, PD-L1 ^high, respectively). (A) OS curves between high and PD-L1 ^low in FIGO stage I/II cases. (B) PFS curves between high and PD-L1 ^low in FIGO stage I/II cases. (C) OS curves between high and PD-L1 ^low in stage III/IV cases. (D) PFS curves between high and PD-L1 ^low in stage III/IV cases. Patients with PD-L1 ^high revealed a worse OS and PFS compared with those with PD-L1 ^low in stage III/IV cases, with significant differences observed. FIGO, International Federation of Gynecology and Obstetrics; OCCC, ovarian clear cell carcinoma; OS, overall survival; PD-L1, programmed death-ligand 1; PD-L1 ^high, high PD-L1 expression; PD-L1 ^low, low PD-L1 expression; PFS, progression-free survival.

Fig. 5.

PFS and OS curves stratified by the sensitivity to chemotherapy between high and low PD-L1 expression (yellow solid lines, PD-L1 ^low; blue dotted lines, PD-L1 ^high, respectively). (A) OS curves between high and PD-L1 ^low in PS cases. (B) PFS curves between high and PD-L1 ^low in PS cases. (C) OS curves between high and PD-L1 ^low in PR cases. (D) PFS curves between high and PD-L1 ^low in PR cases. Patients with PD-L1 ^high revealed a worse OS and PFS compared with those with PD-L1 ^low in PR cases, with significant differences observed. OS, overall survival; PD-L1, programmed death-ligand 1; PD-L1 ^high, high PD-L1 expression; PD-L1 ^low, low PD-L1 expression; PFS, progression-free survival; PR, platinum-resistant; PS, platinum-sensitive.

Table 1.

Univariate analysis of factors associated with PFS and OS

Factors	No.	Recurrent (%)	p-value	Death (%)	p-value
Age at diagnosis (yr)			0.368		0.848
≤55	76	32 (42.1)		24 (31.6)
>55	46	23 (50.0)		15 (32.6)
Family history of malignancy			0.843		0.702
Yes	30	13 (45.7)		9 (30.0)
None	92	42 (43.3)		30 (32.6)
Menopause			0.753		0.395
Postmenopausal	75	33 (44.0)		23 (30.7)
Premenopausal	47	22 (46.8)		16 (34.0)
BMI			0.880		0.888
≤25	61	27 (44.3)		18 (29.5)
>25	61	28 (45.9)		21 (34.4)
Pretreatment CA125 level (U/mL)			0.002		0.023
<244	55	18 (32.7)		13 (23.6)
≥244	52	30 (57.7)		19 (36.5)
Ascites			0.133		0.077
Negative	68	27 (39.7)		18 (26.5)
Positive	49	25 (51.0)		18 (36.7)
Tumor site			0.001		<0.001
Unilateral	99	39 (39.4)		26 (26.3)
Bilateral	23	16 (69.6)		13 (56.5)
Tumor volume (cm)			0.139		0.038
<10	49	26 (53.1)		21 (42.9)
≥10	73	29 (39.7)		18 (24.7)
Tumor stage			<0.001		<0.001
I	57	10 (17.5)		5 (7.9)
II	19	8 (42.1)		6 (30.0)
III	36	28 (77.8)		25 (58.1)
IV	10	9 (90.0)		8 (80.0)
Residual disease (cm)			<0.001		<0.001
R₀	98	36 (36.7)		23 (23.5)
≤1	18	13 (72.2)		10 (55.6)
>1	6	6 (100.0)		6 (100.0)
Sensitivity to chemotherapy			<0.001		<0.001
Sensitive	81	14 (17.3)		7 (8.6)
Insensitive	40	40 (100)		31 (77.5)
PD-L1 expression			0.021		0.001
Low	68	25 (36.8)		13 (19.1)
High	54	30 (55.6)		26 (48.1)

BMI, body mass index; OS, overall survival; PD-L1, programmed death-ligand 1; PFS, progression-free survival; R₀, no visible residual disease.

Table 2.

Correlations between the expression of PD-L1 and clinicopathological characteristics in OCCCs

Variables	Tumoral PD-L1 expression
Variables	Low expression	High expression	p-value
Age (yr)			0.260
≤55	39 (57.4)	37 (68.5)
>55	29 (42.6)	17 (31.5)
Stage			0.020
Early (I–II)	48 (70.6)	27 (50.0)
Advanced (III–IV)	20 (29.4)	27 (50.0)
BMI			0.068
≤25	29 (42.6)	32 (59.3)
>25	39 (57.4)	22 (40.7)
Menopause status			0.264
Premenopausal	23 (33.8)	24 (44.4)
Postmenopausal	45 (66.2)	30 (55.6)
Pretreatment CA125 (U/mL)			0.699
<244	32 (53.3)	23 (48.9)
≥244	28 (46.7)	24 (51.1)
Ascitic fluid			0.016
Negative	45 (68.2)	23 (45.1)
Positive	21 (31.8)	28 (54.9)
Tumor site			0.245
Unilateral	58 (85.3)	41 (75.9)
Bilateral	10 (14.7)	13 (24.1)
Tumor volume (cm)			0.854
<10	28 (41.2)	21 (38.9)
≥10	40 (58.8)	33 (61.1)
Sensitivity to chemotherapy			0.045
Sensitive	50 (74.6)	31 (57.4)
Insensitive	17 (25.4)	23 (42.6)
Recurrence status			0.038
Relapse	25 (36.8)	30 (55.6)
No relapse	43 (63.2)	24 (44.4)

BMI, body mass index; OCCC, ovarian clear cell carcinoma; PD-L1, programmed death-ligand 1.

Table 3.

Multivariate Cox regression analysis with PFS and OS as endpoint

Factor	PFS			OS
Factor	HR	95% CI	p-value	HR	95% CI	p-value
Pretreatment serum CA125 level (< 244 U/mL vs. ≥ 244 U/mL)	0.922	0.457–1.860	0.820	0.578	0.259–1.292	0.182
Ascitic fluid (positive vs. negative)	1.110	0.883–3.566	0.107	1.111	0.511–2.414	0.790
FIGO stage (advanced vs. early)	10.165	4.513–22.894	<0.001	14.323	4.744–43.240	<0.001
PD-L1 expression (high vs. low)	1.970	1.039–3.737	0.038	3.032	1.285–7.153	0.011
Tumor volume (<10 cm vs. ≥10 cm)	0.928	0.069–1.248	0.621	0.752	0.513–1.102	0.144
Residual disease (>1 cm vs. R₀, ≤1 cm)	1.063	0.566–1.999	0.849	1.767	0.824–3.787	0.143

CI, confidence interval; FIGO, International Federation of Gynecology and Obstetrics; HR, hazard ratio; OS, overall survival; PD-L1, programmed death-ligand 1;

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