jgo Journal of Gynecologic Oncology J Gynecol Oncol 2005-0380 2005-0399 Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, Japan Society of Gynecologic Oncology 10.3802/jgo.2017.28.e77 jgo-28-e77 Original Article Prognostic value of programmed death-ligand 1 (PD-L1) expression in ovarian clear cell carcinoma ZhuJun 1 2 WenHao 1 2 BiRui 3 WuYong 3 WuXiaohua 1 2 Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China Department 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 11 2017 04 11 2017 28 6 e77 15062017 23062017 23072017 Copyright © 2017 Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology 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.

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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.

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.

(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.

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.

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.

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.

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

Variables Tumoral PD-L1 expression
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.

Multivariate Cox regression analysis with PFS and OS as endpoint

Factor PFS OS
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;