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Tumor-infiltrating Lymphocytes Expression in Stage IIIc/IV of High-grade Serous Ovarian Cancer: Variation with Neoadjuvant Chemotherapy and Prognostic Value

K Rojas*1, G Prado-Vazquez2, C Barcena3, L Trilla-Fuertes2, A Gamez-Pozo 2,4, A Zapater-Moros4, M Ferrer-Gomez 4, L Lema1, R Garcia-Martin3, A Maroto3, J L Rodriguez3, C Mendiola1, J A Fresno Vara4, L Paz-Ares1

1Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain
2Biomedica Molecular Medicine SL, Madrid, Spain
3Department of Pathology, Hospital 12 de Octubre, Madrid, Spain
4Molecular Oncology & Pathology Lab, Institute of Medical and Molecular Genetics-INGEMM, Hospital Universitario La Paz, Madrid, Spain

Corresponding author: Dr. Katerin Rojas Laimito, Department of Medical Oncology, Hospital 12 de Octubre, Av. Cordoba, s/n, 28041 Madrid, Spain

Received: January 23, 2019
Published: March 14, 2019

ABSTRACT

Background: Ovarian cancer is a malignancy with a complex immune suppressive microenvironment mediated by the recruitment or induction of cluster differentiation factor 4+ (CD4+) regulatory T cells. The purpose of this study was to assess the effect of neoadjuvant chemotherapy (NACT) on immune activation in stage IIIc/IV of High-Grade Serous Ovarian Carcinoma (HGSC), and its relationship to treatment response.

Patients and Methods: We retrospectively identified 33 patients diagnosed with HGSC and treated with neoadjuvant platinum-paclitaxel from 2005-2014. Pre- and post-neoadjuvant treatment tissue samples were submitted to immunohistochemical analyses with anti-CD3, CD4 and CD8 antibodies for the identification of tumor-infiltrating lymphocytes (TILs). The staining results were analyzed and were blindly evaluated with respect to clinical features. Pathological response classification to NACT was made according to Steffen Bohm.

Results: The mean age of patients was 63.44 years (46.53-84.14). Germline BRCA1/2-mutation status was negative in 58.82% of patients (10/17); BRCA1/2-mutation was positive in 11.76 %( 2/17); and a variant of uncertain significance was found in 29.41 %( 5/17). The majority of patients (78.8%) were stage IIIc. The area under the ROC curve of post-surgery TILs for complete pathological response was: CD4 (epithelial): [0.73(0.5; 0.97), p: 0.084]; CD4 (stromal): [0.74(0.51; 0.97), p: 0.077] and CD8 (epithelial): [0.81(0.63; 1.0), p: 0.02]. The expression of epithelial CD4 TILs in pre-surgery samples (≤ 0.5[OR: 0.7(0.01; 0.86), p: 0.038]) and epithelial CD8 TILs in post-surgery samples (≤ 5.4[OR: 0.1(0.01; 1.19, p: 0.06]) proved to be a marker of good prognosis for pathological response. Survival analysis demonstrated that the expression of epithelial CD3 ≤ 4, 3 in pre-surgery samples is a marker of poor prognosis.

Conclusion: The high number of tumor-infiltrating lymphocytes in post-surgery samples was significantly associated with higher rates of complete pathological response and better prognosis. It is convenient to carry out further and multicentric studies to validate these results.

Keywords: tumor-infiltrating lymphocytes, ovarian cancer, neo-adjuvant chemotherapy.

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