Analyses of tumor microenvironment affecting the survival in patients with ovarian cancer receiving intraperitoneal chemotherapy: Translational research from the phase 3 trial of intraperitoneal therapy for ovarian cancer with carboplatin (TRiPocc).
Authors: Ogasawara Aiko , Matsushita Hirokazu , Tan Tuan Zea , Shintani Daisuke , Ye Jieru , Nagao Shoji , Kobayashi Yukari , Kakimi Kazuhiro , Yamaguchi Rui , Yamamoto Kouji , Fujiwara Keiichi , Huang Ruby Yun-Ju , Tan David Shao Peng , Hasegawa Kosei 
Published: June 2023

5555

Background: The iPocc trial is a randomized, global phase (P) 3 study of intraperitoneal (IP) versus intravenous (IV) carboplatin with dose-dense paclitaxel chemotherapy in epithelial ovarian cancer (EOC) patients that demonstrated an improved progression-free survival (PFS) but not overall survival (OS) in the former. IP chemotherapy induces an antitumor immune response and increases survival in a murine xenograft model. This study aimed to assess whether immunological background affected the clinical outcomes of patients receiving IP chemotherapy. Methods: Fresh frozen tumor samples at the time of primary surgery were obtained from 116 patients who joined the iPocc P3 trial for microarray analysis. Cell-type deconvolution was performed using MCP counter. Single sample Gene Set Enrichment Analysis was performed to evaluate the tumor immune microenvironment. Clinical data were obtained from the iPocc P3 trial. We stratified 116 patients according to the high or low values of each factor determined by the median values. The Kaplan-Meier method and log-rank test were used to analyze PFS and OS. Results: A total of 116 patients were assigned to either the IP (n=59) or IV (n=57) group. The most common histologic type was serous (58.6%), followed by endometrioid (17.2%) and clear cell (12.1%). The patients who received IP therapy had longer OS than those who received IV therapy in the group with a high infiltration of T cells, NK cells, or cytotoxic lymphocytes in the MCP counter (median OS: not reached (NR) vs 75.0 months, P=0.041, NR vs. 75.0 months, P=0.042, NR vs 65.2 months, P=0.031), but not in the group with a low infiltration. Similarly, the IP therapy improved OS in the patients with high expression of immune-related genes such as CD8A, FOXP3 or PDCD1 (median OS; NR vs 65.2 months, P=0.035, NR vs 65.2 months P=0.030, NR vs 53.1 months, P=0.016), but not in the patients with low expression of those genes. In addition, a multifaceted evaluation was conducted because of the limitations of evaluating the interaction between cancer and immunity using a single factor. When the patients were divided into two groups, “Immune Hot” and “Immune Cold” based on the hierarchical clustering analysis with 4 parameters representing “Innate immunity,” “T cells,” “Interferon gamma response” and “Inhibitory molecules,” the IP therapy increased both PFS and OS compared to the IV therapy in the “Immune Hot” group (median PFS; 35.5 vs 23.4 months, P=0.024, median OS; NR vs 75.0 months, P=0.040), but not in the “Immune Cold” group. Conclusions: IP therapy may improve the survivals in EOC patients with a high immunological background. Further studies are warranted to validate this hypothesis and to clarify the impact of IP therapy on the tumor immune microenvironment. Clinical trial information: NCT01506856 / GOTIC-001/ JGOG3019.