title: Intratumoral lymphocyte density in serous ovarian carcinoma is superior to ERCC1 expression for predicting response to platinum-based therapy.
abstract: Intratumoral immune cells and ERCC1 expression are likely to play a role in the response of ovarian carcinoma to chemotherapy, but their impact on therapy outcome is still unclear. Therefore, 41 cases of optimally resected high grade serous ovarian carcinomas were examined retrospectively for stromal and intraepithelial lymphocyte populations and ERCC1 status in relation to response to platinum-based therapy. Based on RECIST criteria, 27 patients were classified as responsive and 14 as therapy resistant, respectively. Using immunohistochemistry for CD3, CD8, CD4, TIA1, MUM1 and FOX P3 on representative tumor sections, we quantitatively evaluated the intratumoral density of lymphocyte subpopulations. In addition, ERCC1 protein and mRNA expression were determined by immunohistochemistry using the Steffensen score and quantitative RT-PCR, respectively. Furthermore, ERCC1 SNP's C8092A and codon 118 were analysed. Response to chemotherapy was significantly associated with higher numbers of stromal CD3+ (mean 21.33 lymphocytes/HPF versus 8.21 lymphocytes/HPF, p = 0.002) and CD8+ lymphocytes (mean 9.22 lymphocytes/HPF versus 4.57 lymphocytes/HPF, p = 0.013). Counts of intraepithelial CD3+ and CD8+ lymphocytes, stromal and intraepithelial FOXP3+ and TIA1+ cells, CD4+ lymphocytes, and MUM1+ plasma cells did not reach statistical significance. Neither ERCC1 protein expression (p = 0.232) nor SNPs codon 118 and C8092A of the ERCC1 gene (p = 0.269 and p = 0.543) showed an association with therapy response. The same was true for ERCC1 mRNA levels (p = 0.896), probably due to intratumoral lymphocyte contamination. In conclusion, the density of CD3+ and CD8+ T-cells in tumor stroma proved to be a significant predictor for response to platinum-based therapy, whereas examination of ERCC1 failed to identify therapy-responsive patients.
authors.affiliation: Department of Pathology, Krankenhaus Barmherzige Schwestern Linz, Seilerstätte 4, 4020, Linz, Austria. hans-christian.boesmueller@bhs.at
authors.forename: Hans
authors.initials: H
authors.lastname: Bösmüller
authors.forename: Sophie
authors.initials: S
authors.lastname: Haitchi-Petnehazy
authors.forename: Gerald
authors.initials: G
authors.lastname: Webersinke
authors.forename: Renate
authors.initials: R
authors.lastname: Marschon
authors.forename: Franz
authors.initials: F
authors.lastname: Roithmeier
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stummvoll
authors.forename: Tanja
authors.initials: T
authors.lastname: Fehm
authors.forename: Margit
authors.initials: M
authors.lastname: Klier-Richter
authors.forename: Irina
authors.initials: I
authors.lastname: Bonzheim
authors.forename: Annette
authors.initials: A
authors.lastname: Staebler
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000276:immunology*; D004720:Endonucleases / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D017671:Platinum Compounds / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000032:analysis; D012189:Retrospective Studies; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D017671:Platinum Compounds; D012333:RNA, Messenger; C071447:ERCC1 protein, human; D004720:Endonucleases