The present data reveal novel interactions among T cell infiltration, tumor proliferation index and surgical treatment that are important for prognosis in advanced serous ovarian cancer, and for the first time indicate that biological factors intrinsic to the tumor or to the host response can provide useful information to individualize the surgical management of patients with this disease. Indeed, high frequency of intraepithelial CD8+ T cells and/or low proliferation (Ki67 expression) defined subsets of patients with more indolent tumors in whom the presence of residual tumors larger than one cm did not significantly alter survival. Vice versa, patients with tumors exhibiting unfavorable biologic features such as low frequency of intraepithelial CD8+ T cells and high proliferation had a markedly better prognosis when they had optimal cytoreductive surgery. Significantly, these data also provide evidence that the effects of tumor debulking, CD8+ T cells and tumor proliferation on clinical outcome are independent prognostic factors, but an association exists between increased tumor proliferation and increased frequency of intraepithelial CD8+ T cells.
The benefit of surgical cytoreduction has been established through numerous retrospective studies4-9
and was recently confirmed by analysis of more than 2,250 patients with stage III or IV EOC from four Gynecologic Oncology Group (GOG) phase III trials.2, 3
In fact, these and other smaller studies26
indicate that maximal cytoreduction as close as possible to microscopic residual is associated with the best survival. Our study is in agreement with this line of evidence, as recursive partitioning analysis identified residual tumor of less than one centimeter as the most important predictor of better survival in this cohort of patients.
Although biological factors have been shown to impact the natural course of ovarian cancer, it has remained unclear whether such factors may alter the benefit afforded by surgical cytoreduction. We used Ki67 as a reliable marker of intrinsic tumor aggressiveness and identified CD8 as the best cellular immune response biomarker in this patient cohort. Our study provides the first evidence that intrinsic tumor and host biological factors can influence the benefit of surgical cytoreduction. Although this study did not evaluate prospectively the association of surgical cytoreduction and biological factors with survival, the data still provide provocative evidence to suggest that biological biomarkers can provide useful information for selecting appropriate candidates for aggressive surgical cytoreduction. Based on analysis of four GOG studies,2, 3
Winter et al concluded that ultraradical procedures might be justified to achieve maximal cytoreduction and proposed that a diagnostic surgical procedure should be used first in an attempt to best assess resectability. Patients with disease that is considered optimally resectable could then undergo laparotomy and radical surgical cytoreduction. Our findings provide an additional tool to select patients for aggressive debulking and suggest that every attempt should be made for optimal cytoreduction in patients whose tumors exhibit unfavorable features such as high Ki67 and low CD8 score. Our study should be considered exploratory, as it is based on a relatively small cohort of patients. Although the number of patients in each subgroup are small, these results are strengthened by the fact that all patients in this cohort were treated in a single institution during a period of reasonably standardized surgical approach, and all had serous or poorly differentiated carcinoma. Additional studies are warranted to confirm our findings and test the hypothesis that selection of patients based on CD8 or Ki67 scores may reduce morbidity and maximize efficacy of surgical management. It should be noted that our study did not evaluate patients undergoing upper abdominal ultraradical procedures to achieve microscopic residual, as these were pioneered at a later date in the institution under study.10
Thus, future studies will have to address whether the observed interactions persist following more aggressive debulking procedures.
We identified CD8 as the most robust immune biomarker in this cohort. Although a significant correlation was found between the frequency of CD3+
intraepithelial T cells, intratumoral CD3+
T cells was not a prognostic factor. This is likely due to sample and effect size, as CD3 predicted outcome in other studies.20, 27
There is substantial evidence that T cells infiltrating ovarian cancer recognize and react to tumor antigens ex vivo.28-33
However, it remains unclear to date whether the observed association between intraepithelial T cells and improved clinical outcome can be attributed to the direct function of tumor-infiltrating T cells or merely to an association of T cells with indolent tumors with low proliferation. For example, it could be hypothesized that intraepithelial T cells are more able to accumulate in slowly growing tumors, which are associated with improved survival, while they are outpaced and excluded by aggressive tumors with elevated rates of proliferation, which are associated with poor survival.
The present data identified a positive association between high Ki67 expression and CD8+
T cell infiltrate. Mitotically active ovarian cancers are more likely to exhibit genetic instability34
and we hypothesize that these tumors express a more diverse antigenic repertoire, including neoantigens that elicit a cellular immune response. Similar observations have been made in breast carcinomas with mutations in BRCA1
, a gene involved in maintaining genomic stability,35
which are higher grade but are also characterized by T cell infiltration and improved survival.36, 37
Similarly, colorectal cancers with microsatellite genetic instability are characterized by T cell infiltration and better prognosis in spite of being higher grade.38
Interestingly, a recent study found that ovarian cancers with p53 mutations were more likely to have intraepithelial T cells.39
This data, together with previous epidemiologic evidence,20-23
and molecular and functional studies20, 28-33
suggest that T cells may indeed react to tumor antigens and directly contribute to reduced tumor growth. If this were the case, it is possible that the biomarkers under study could help individualize not only surgery but also medical therapy and guide the selection of chemotherapy combinations that synergize with spontaneous antitumor mechanisms and immune or immunomodulatory therapy.40-42