Surgery for patients with newly diagnosed advanced ovarian cancer: which patient, when and extent?

PURPOSE OF REVIEW: Cytoreduction to no residual disease is the mainstay of primary treatment for advanced epithelial ovarian cancer (AdvEOC). This review addresses recent insights on optimal patient selection, timing, and extent of surgery, intended to optimize cytoreduction in patients with AdvEOC. RECENT FINDINGS: Clinical guidelines recommend primary cytoreductive surgery (PCS) for AdvEOC patients with a high likelihood of achieving complete cytoreduction with acceptable morbidity. In line with this, preoperative prediction markers such as cancer antigen-125, histologic and genomic factors, innovative imaging modalities, and the performance of a diagnostic laparoscopy have been suggested to improve clinical decision-making with regard to optimal timing of cytoreductive surgery. To determine whether these strategies should be incorporated into clinical practice validation in randomized clinical trials is essential. SUMMARY: The past decade has seen a paradigm shift in the number of AvdEOC patients that are being treated with upfront neoadjuvant chemotherapy instead of PCS. However, although neoadjuvant chemotherapy may reduce morbidity at the time of interval cytoreductive surgery, no favorable impact on survival has been demonstrated and it may induce resistance to chemotherapy. Therefore, optimizing patient selection for PCS is crucial. Furthermore, surgical innovations in patients diagnosed with AvdEOC should focus on improving survival outcomes.

Impact of different adjuvant treatment approaches on survival in stage III endometrial cancer: A population-based study.

BACKGROUND: Patients with International Federation of Gynaecology and Obstetrics (FIGO) stage III endometrial cancer (EC) have a substantial risk of adverse outcomes. After surgery, adjuvant therapy is recommended with external beam radiotherapy (EBRT), chemotherapy (CT) or both EBRT and CT. Recent trials suggest that EBRT + CT is superior to EBRT or CT alone but also results in more toxicity. We have compared the outcome of different adjuvant treatments in a population-based cohort to identify subgroups that benefit most from EBRT + CT. METHODS: All patients diagnosed with FIGO stage III EC and treated with surgery in 2005-2016 were identified from the Netherlands Cancer Registry. The primary outcome was overall survival (OS); associations with adjuvant treatment were analysed using Cox regression analysis. RESULTS: Among 1241 eligible patients, EBRT + CT was associated with a better OS than CT (hazard ratio [HR] = 1.84, 95% confidence interval [CI] = 1.34-2.52) and EBRT alone (HR = 1.37, 95% CI = 1.05-1.79). In stage IIIC, there was a significant benefit of EBRT + CT compared with CT or EBRT alone. In stage IIIA-B, there was no difference between EBRT + CT or EBRT alone. In endometrioid EC (EEC) and carcinosarcomas, EBRT + CT was associated with a better OS than CT or EBRT alone. For uterine serous cancers, there was no survival benefit of EBRT + CT over CT. In all analysis by stage and histology, any adjuvant treatment was superior to no adjuvant therapy. CONCLUSIONS: In this population-based study, adjuvant EBRT + CT was associated with improved OS compared with CT or EBRT alone in FIGO stage IIIC EC, EEC and carcinosarcoma. This suggests that application of EBRT + CT in stage III should be further stratified according to these subgroups.

Deep immune profiling of ovarian tumors identifies minimal MHC-I expression after neoadjuvant chemotherapy as negatively associated with T-cell-dependent outcome.

Epithelial Ovarian cancer (EOC) is the most lethal gynecological malignancy and has limited curative therapeutic options. Immunotherapy for EOC is promising, but clinical efficacy remains restricted to a small percentage of patients. Several lines of evidence suggest that the low response rate might be improved by combining immunotherapy with carboplatin and paclitaxel, the standard-of-care chemotherapy for EOC. Here, we assessed the immune contexture of EOC tumors, draining lymph nodes, and peripheral blood mononuclear cells during carboplatin/paclitaxel chemotherapy. We observed that the immune contexture of EOC patients is defined by the tissue of origin, independent of exposure to chemotherapy. Summarized, draining lymph nodes were characterized by a quiescent microenvironment composed of mostly non-proliferating naïve CD4 + T cells. Circulating T cells shared phenotypic features of both lymph nodes and tumor-infiltrating immune cells. Immunologically 'hot' ovarian tumors were characterized by ICOS, GITR, and PD-1 expression on CD4 + and CD8 + cells, independent of chemotherapy. The presence of PD-1 + cells in tumors prior to, but not after, chemotherapy was associated with disease-specific survival (DSS). Accordingly, we observed high MHC-I expression in tumors prior to chemotherapy, but minimal MHC-I expression in tumors after neoadjuvant chemotherapy, even though there were no differences in the number of tumor-infiltrating lymphocytes (TIL) in both groups. We therefore speculate that the TIL influx into the chemotherapy tumor microenvironment may be a consequence of the general inflammatory nature of chemotherapy-experienced tumors. Strategies to upregulate MHC-I during or after neoadjuvant chemotherapy may thus improve treatment outcome in these patients.

A Transcriptionally Distinct CXCL13+CD103+CD8+ T-cell Population Is Associated with B-cell Recruitment and Neoantigen Load in Human Cancer.

The chemokine CXCL13 mediates recruitment of B cells to tumors and is essential for the formation of tertiary lymphoid structures (TLSs). TLSs are thought to support antitumor immunity and are associated with improved prognosis. However, it remains unknown whether TLSs are formed in response to the general inflammatory character of the tumor microenvironment, or rather, are induced by (neo)antigen-specific adaptive immunity. We here report on the finding that the TGFß-dependent CD103+CD8+ tumor-infiltrating T-cell (TIL) subpopulation expressed and produced CXCL13. Accordingly, CD8+ T cells from peripheral blood activated in the presence of TGFß upregulated CD103 and secreted CXCL13. Conversely, inhibition of TGFß receptor signaling abrogated CXCL13 production. CXCL13+CD103+CD8+ TILs correlated with B-cell recruitment, TLSs, and neoantigen burden in six cohorts of human tumors. Altogether, our findings indicated that TGFß plays a noncanonical role in coordinating immune responses against human tumors and suggest a potential role for CXCL13+CD103+CD8+ TILs in mediating B-cell recruitment and TLS formation in human tumors.

Implementation of laparoscopic hysterectomy for endometrial cancer over the past decade.

BACKGROUND: Laparoscopic hysterectomy (LH) for the treatment of early-stage endometrial carcinoma/cancer (EC) has demonstrated to be safe in several randomized controlled trials. Yet, data on implementation of LH in clinical practice are limited. In the present study, implementation of LH for EC was evaluated in a large oncology network in the Netherlands. RESULTS: Retrospectively, a total of 556 EC patients with FIGO stage I-II were registered in the selected years. The proportion of LH gradually increased from 11% in 2006 to 85% in 2015. LH was more often performed in patients with low-grade EC and was not related to the studied patient characteristics. The introduction of TLH was frequently preceded by LAVH. Patients treated in teaching hospitals were more likely to undergo a LH compared to patients in non-teaching hospitals. The conversion rate was 7.7%, and the overall complication rates between LH and AH were comparable, but less postoperative complications in LH. CONCLUSIONS: Implementation of laparoscopic hysterectomy for early-stage EC increased from 11 to 85% in 10 years. Implementation of TLH was often preceded by LAVH and was faster in teaching hospitals.

Immunological profiling of molecularly classified high-risk endometrial cancers identifies POLE-mutant and microsatellite unstable carcinomas as candidates for checkpoint inhibition.

High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutated POLE exonuclease domain-mutant ECs (POLE-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated in POLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in POLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8+ (90% and 69%), PD-1+ (73% and 69%) and PD-L1+ immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8+ cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-rich POLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.

CD103 defines intraepithelial CD8+ PD1+ tumour-infiltrating lymphocytes of prognostic significance in endometrial adenocarcinoma.

INTRODUCTION: Intraepithelial CD8+ tumour-infiltrating T-lymphocytes (TIL) are associated with a prolonged survival in endometrial cancer (EC). By contrast, stromal infiltration of CD8+ TIL does not confer prognostic benefit. A single marker to discriminate these populations would therefore be of interest for rapid assessment of the tumour immune contexture, ex vivo analysis of intraepithelial and stromal T-cells on a functional level and/or adoptive T-cell transfer. Here we determined whether CD103, the αE subunit of the αEß7integrin, can be used to specifically discriminate the epithelial and stromal CD8+ TIL populations in EC. METHODS: CD103+ TIL were quantified in a cohort of 305 EC patients by immunohistochemistry. Localization of CD103+ cells and co-expression of CD103 with CD3, CD8, CD16 and FoxP3 were assessed by immunofluorescence. Further phenotyping of CD103+ cells was performed by flow cytometry on primary endometrial tumour digests. RESULTS: CD8+CD103+ cells were preferentially located in endometrial tumour epithelium, whereas CD8+CD103- cells were located in stroma. CD103+ lymphocytes were predominantly CD3+CD8+ T-cells and expressed PD1. The presence of a high CD103+ cell infiltration was associated with an improved prognosis in patients with endometrial adenocarcinoma (p = 0.035). Moreover, this beneficial effect was particularly evident in high-risk adenocarcinoma patients (p = 0.031). CONCLUSIONS: Because of the restricted expression on intraepithelial CD8+ T-cells, CD103 may be a suitable biomarker for rapid assessment of immune infiltration of epithelial cancers. Furthermore, this intraepithelial tumour-reactive subset might be an interesting T-cell subset for adoptive T-cell transfer and/or target for checkpoint inhibition therapy.

CD103+ intraepithelial T cells in high-grade serous ovarian cancer are phenotypically diverse TCRαß+ CD8αß+ T cells that can be targeted for cancer immunotherapy.

CD103+ tumor-infiltrating lymphocytes (TIL) have been linked to specific epithelial infiltration and a prolonged survival in high-grade serous epithelial ovarian cancer (HGSC). However, whether these cells are induced as part of an ongoing anti-HGSC immune response or represent non-specifically expanded resident or mucosal lymphocytes remains largely unknown. In this study, we first confirmed that CD103+ TIL from HGSC were predominantly localized in the cancer epithelium and were strongly correlated with an improved prognosis. We further demonstrate that CD103+ TIL were almost exclusively CD3+ TCRαß+ CD8αß+ CD4- T cells, but heterogeneously expressed T cell memory and differentiation markers. Activation of peripheral T cells in the presence of HGSC was sufficient to trigger induction of CD103 in over 90% of all CD8+ cells in a T cell receptor (TCR)- and TGFßR1-dependent manner. Finally, CD103+ TIL isolated from primary HGSC showed signs of recent activation and dominantly co-expressed key immunotherapeutic targets PD-1 and CD27. Taken together, our data indicate CD103+ TIL in HGSC are formed as the result of an adaptive anti-tumor immune response that might be reactivated by (dual) checkpoint inhibition.

POLE Proofreading Mutations Elicit an Antitumor Immune Response in Endometrial Cancer.

PURPOSE: Recent studies have shown that 7% to 12% of endometrial cancers are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response, and clinical outcome in cancer, we investigated whether POLE-mutant endometrial cancers showed evidence of increased immunogenicity. EXPERIMENTAL DESIGN: We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA endometrial cancer series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant endometrial cancers. RESULTS: Compared with other endometrial cancers, POLE mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8(+) tumor-infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T-cell gene signature, and strong upregulation of the T-cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF, and granzyme B. This was accompanied by upregulation of T-cell exhaustion markers, consistent with chronic antigen exposure. In silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings. CONCLUSIONS: Ultramutated POLE proofreading-mutant endometrial cancers are characterized by a robust intratumoral T-cell response, which correlates with, and may be caused by an enrichment of antigenic neopeptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers.