The Impact of Neoadjuvant Chemotherapy on Ovarian Cancer Tumor Microenvironment: A Systematic Review of the Literature.

Immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has shown limited efficacy in treating ovarian cancer (OC), possibly due to diverse T cell infiltration patterns in the tumor microenvironment. This review explores how neoadjuvant chemotherapy (NACT) impacts the immune landscape of OC, focusing on tumor-infiltrating lymphocytes (TILs), PD-1/PD-L1 expression, and their clinical implications. A comprehensive literature search across four databases yielded nine relevant studies. These studies evaluated stromal (sTILs) and intra-epithelial (ieTILs) TILs before and after NACT. sTIL responses varied, impacting prognostic outcomes, and ieTILs increased in some patients without clear survival associations. PD-L1 expression after NACT correlated with improved overall survival (OS), and increases in granzyme B+ and PD-1 correlated with longer progression-free survival (PFS). Remarkably, reduced FoxP3+ TILs post-NACT correlated with better prognosis. NACT often increases sTIL/ieTIL and CD8+ subpopulations, but their correlation with improved PFS and OS varies. Upregulation of co-inhibitory molecules, notably PD-L1, suggests an immunosuppressive response to chemotherapy. Ongoing trials exploring neoadjuvant ICIs and chemotherapy offer promise for advancing OC treatment. Standardized measurements assessing TIL density, location, and heterogeneity are crucial for addressing genetic complexity and immunological heterogeneity in OC.

Effect of bevacizumab in advanced low grade serous ovarian cancer: Data from the MITO 22 trial.

OBJECTIVE: The aim of the present analysis was to explore the efficacy of Bevacizumab (Bev) on survival outcome in advanced low grade serous ovarian cancer (LGSOC) both in first line and in recurrent setting. METHODS: In retrospective observational multicenter study, we described the outcome of LGSOC patients enrolled in the MITO 22 study and treated with chemotherapy (CT) with or without Bev. Patients receiving Bev in first-line or in recurrence were considered and compared with patients receiving CT alone (stage III and IV in first line; platinum based-CT in second line). Descriptive and survival analyses were performed for each group. RESULTS: Out of 128 patients included in MITO 22, 46 LGSOC patients receiving Bev in first line setting or at the time of first recurrence were identified. In first line, 30 patients received Bev + CT and 65 CT alone and the median PFS were 47.86 months (95% CI: 31.48 - NR) and 22.63 months (95% CI 15-39.24) (p-value 0.0392), respectively. In the recurrent setting, 16 patients who received Bev + CT were compared to 33 women treated with platinum-based CT alone. Median PFS were 37.1 months (95% CI: 13.42-40.56) and 11.22 months (95% CI: 8.26-15.63) (p-value 0.013), respectively. CONCLUSIONS: Our study suggests that Bev might be effective in LGSOC both at diagnosis and at the time of relapse. These data warrants further studies.

Clinical characteristics and molecular aspects of low-grade serous ovarian and peritoneal cancer: a multicenter, observational, retrospective analysis of MITO Group (MITO 22).

BACKGROUND: Low-grade serous ovarian and peritoneal cancer (LGSC) is a rare disease and few data on the clinical and genomic landscape have been published. METHODS: A retrospective analysis of patients diagnosed with LGSC between 1996 and 2019 was conducted in MITO centers. Objective Response Rate (ORR) to treatments, progression-free survival (PFS) and overall survival (OS) were assessed. Additionally, the tumor molecular profile of 56 patients was evaluated using the Next Generation Sequencing (NGS) FoundationOne CDX (Foundation Medicine®). RESULTS: A total of 128 patients with complete clinical data and pathologically confirmed diagnosis of LGSC were identified. ORR to first and subsequent therapies were 23.7% and 33.7%, respectively. PFS was 43.9 months (95% CI:32.4-53.1) and OS was 105.4 months (95% CI: 82.7-not reached). The most common gene alterations were: KRAS (n = 12, 21%), CDKN2A/B (n = 11, 20%), NRAS (n = 8, 14%), FANCA (n = 8, 14%), NF1 (n = 7, 13%) and BRAF (n = 6, 11%). Unexpectedly, pathogenetic BRCA1 (n = 2, 4%), BRCA2 (n = 1, 2%) and PALB2 (n = 1, 2%) mutations were found. CONCLUSIONS: MITO 22 suggests that LGSC is an heterogenous disease for both its clinical behavior in response to standard therapies and its molecular alterations. Future prospective studies should test treatments according to biological and molecular tumor's characteristics. CLINICAL TRIAL REGISTRATION: This study is registered under NCT02408536 on ClinicalTrials.gov .

Immunotherapy for Cervical Cancer: Are We Ready for Prime Time?

The prognosis of invasive cervical cancer (CC) remains poor, with a treatment approach that has remained the same for several decades. Lately, a better understanding of the interactions between the disease and the host immune system has allowed researchers to focus on the employment of immune therapy in various clinical settings. The most advanced strategy is immune checkpoint inhibitors (ICIs) with numerous phase II and III trials recently concluded with very encouraging results, assessing single agent therapy, combinations with chemotherapy and radiotherapy. Apart from ICIs, several other compounds have gained the spotlight. Tumor Infiltrating Lymphocytes (TILs) due to their highly selective tumoricidal effect and manageable adverse effect profile have received the FDA's Breakthrough Therapy designation in 2019. The antibody drug conjugate (ADC) Tisotumab-Vedotin has shown activity in metastatic CC relapsed after at least one line of chemotherapy, with a phase III trial currently actively enrolling patients. Moreover, the deeper understanding of the ever-changing immune landscape of CC carcinogenesis has resulted in the development of active therapeutic vaccines. This review highlights the different immunotherapeutic strategies being explored reflects on what role immunotherapy might have in therapeutic algorithms of CC and addresses the role of predictive biomarkers.

Differences in PARP Inhibitors for the Treatment of Ovarian Cancer: Mechanisms of Action, Pharmacology, Safety, and Efficacy.

Poly(ADP-ribose) polymerases (PARP) are proteins responsible for DNA damage detection and signal transduction. PARP inhibitors (PARPi) are able to interact with the binding site for PARP cofactor (NAD+) and trapping PARP on the DNA. In this way, they inhibit single-strand DNA damage repair. These drugs have been approved in recent years for the treatment of ovarian cancer. Although they share some similarities, from the point of view of the chemical structure and pharmacodynamic, pharmacokinetic properties, these drugs also have some substantial differences. These differences may underlie the different safety profiles and activity of PARPi.

Immuno-Metabolism and Microenvironment in Cancer: Key Players for Immunotherapy.

Immune checkpoint inhibitors (ICIs) have changed therapeutic algorithms in several malignancies, although intrinsic and secondary resistance is still an issue. In this context, the dysregulation of immuno-metabolism plays a leading role both in the tumor microenvironment (TME) and at the host level. In this review, we summarize the most important immune-metabolic factors and how they could be exploited therapeutically. At the cellular level, an increased concentration of extracellular adenosine as well as the depletion of tryptophan and uncontrolled activation of the PI3K/AKT pathway induces an immune-tolerant TME, reducing the response to ICIs. Moreover, aberrant angiogenesis induces a hypoxic environment by recruiting VEGF, Treg cells and immune-suppressive tumor associated macrophages (TAMs). On the other hand, factors such as gender and body mass index seem to affect the response to ICIs, while the microbiome composition (and its alterations) modulates both the response and the development of immune-related adverse events. Exploiting these complex mechanisms is the next goal in immunotherapy. The most successful strategy to date has been the combination of antiangiogenic drugs and ICIs, which prolonged the survival of patients with non-small-cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC), while results from tryptophan pathway inhibition studies are inconclusive. New exciting strategies include targeting the adenosine pathway, TAMs and the microbiota with fecal microbiome transplantation.

Veliparib: a new therapeutic option in ovarian cancer?

The role of poly ADP ribose polymerase inhibitors in ovarian cancer is rapidly evolving. Three different poly ADP ribose polymerase inhibitors (olaparib, niraparib and rucaparib) have been already approved as maintenance after response to platinum-based chemotherapy; two of them (olaparib and rucaparib) also as single agents. Veliparib, a novel PARPI, showed promising results in preclinical and early clinical settings. The aim of this review is to discuss veliparib's mechanisms of action, to provide a clinical update on its safety and activity in ovarian cancer, and to highlight future perspectives for its optimal use. Veliparib favorable toxicity profile encourages its use either as monotherapy or in combination. Its peculiar neuroprotective and radio-sensitizing effect warrant further investigation.

Role of Cyclin-Dependent Kinase Inhibitors in Endometrial Cancer.

Endometrial Cancer (EC) is an important cause of death in women worldwide. Despite early diagnosis and optimal treatment of localized disease, relapsed patients have few therapeutic options because after first line therapy, currently no standard of care exists. On the basis of endocrine positivity of most endometrioid ECs, Endocrine Therapy (ET) is a reasonable and widely accepted option. Better knowledge of molecular mechanisms involved in cancer highlighted the deregulated activity of Cyclin-Dependent Kinases (CDKs) in the cell cycle as a hallmark of carcinogenesis supporting the development of a new class of drugs: CDK inhibitors (CDKis). The aim of this review is to give an overview on CDKis preclinical, early clinical activity and future development in EC. Use of CDKis has a strong preclinical rationale but we have poor clinical data. Similar to breast cancer, most ongoing trials are investigating synergistic associations between CDKis and ET. These trials will probably help in defining the best clinical setting of CDKis in ECs, which are the best partner drugs, and how to manage CDKis toxicities with a focus on potential biomarkers of response.

Real-life efficacy and safety of cemiplimab in advanced cervical cancer from a nominal use program in Italy: The MITO 44 study.

BACKGROUND: cemiplimab is an immunoglobulin G4 monoclonal antibody targeting the programmed cell death-1 receptor. A nominal use program is available in Italy in advanced cervical cancer (CC) patients treated with platinum based chemotherapy based on the results of EMPOWER-Cervical 1/GOG-3016/ENGOTcx9 trial. This real-world, retrospective cohort, multicenter study aimed at describing clinical outcomes of patients with advanced CC treated with cemiplimab in Italy. METHODS: The primary objective of the study was to assess the feasibility and the replicability of the initial results in a real world setting of cemiplimab nominal use. The primary endpoint of our analysis was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS) and safety data. RESULTS: From March 2022 to December 2023, 135 patients were treated in 12 Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) Centers. Forty-two percent of patients had one or more comorbidities, hypertension being the most common (23.4%). Median PFS was 4.0 months (range 3.0-6.0) and median OS was 12.0 months (12.0- NR) with no differences according to PD-L1 status. Complete response (CR) or no evidence of disease (NED) were observed in 8.6%; partial response (PR) in 21.1%, stable disease (SD) in 14.8% and progression was recorded in 44.5% of patients. Most common drug related adverse events (AEs) were anemia (39.1%) and fatigue (27.8%). Immune related AEs occurred in 18.0%. CONCLUSIONS: This study confirms the feasibility and the replicability of the cemiplimab nominal use in advanced CC, in a real-world practice in Italy.

Prescribing pattern of anticoagulants in patients with cancer associated thrombosis: Results of a survey among MITO group and AIOM society.

INTRODUCTION: Low molecular weight heparin (LMWH) has been the backbone of the treatment of cancer associated thrombosis (CAT). Direct-acting oral anticoagulants (DOACs) have shown efficacy and safety not inferior to LMWH and guidelines included DOACs as an option for CAT treatment. Nevertheless, DOACs are still poorly prescribed in patients with cancer. The aim of this survey was to better understand prescription patterns of anticoagulants, in particular of DOACs, especially in gynecological cancers (GCs). METHODS: Our survey was made up of 21 questions, the last four questions addressed to medical doctors (MDs) involved in GCs. An invitation to complete the survey was sent by e-mail to 691 MITO (Multicentre Italian Trials in Ovarian cancer and gynaecologic malignancies) and 2093 AIOM (Associazione Italiana di Oncologia Medica) members. RESULTS: Overall, 113 MDs completed the questionnaire, 69 involved in GCs. Most respondents (46, 41%) were aged 30-40 years old, worked in public hospitals (59, 52.2%), were medical oncologists (86, 76.1%). LMWH was the preferred choice for the treatment of CAT (104, 92%). However, 89 respondents (78.8%) prescribed or asked to prescribe a DOAC for CAT. The major concern about DOACs was the difficulty in verifying the therapeutic effect and the absence of antidotes in case of bleeding (37.9%). In patients with GCs, DOACs were used with niraparib, olaparib, rucaparib and immune checkpoint inhibitors (ICIs) in less than 10 patients by 23%, 20%, 9% and 10.2% of respondents, respectively. CONCLUSION: The responders are aware of the Direct-acting oral anticoagulants option and would like to use them.

Management of metastatic endometrial cancer: physicians' choices beyond the first line after approval of checkpoint inhibitors.

Introduction: Endometrial cancer (EC) represents 3.4% of all newly diagnosed cancer cases and is responsible for 2.1% of all cancer-related deaths. Approximately 10%-15% of women with EC are diagnosed with advanced-stage disease, resulting in a reported 5-year survival rate of only 17% for those with distant metastases. A better understanding of its molecular features has ushered in a new era of immunotherapy for the treatment of EC, allowing for alternative therapeutic approaches, even in cases of advanced disease. Methods: We administered a multi-choice online survey for Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) members. The questionnaire was available for 2 months, starting in October 2022. Our objective was to evaluate the current attitude of incorporating molecular characterization of EC into routine clinical practice, appraise the implementation of newly available therapies, and compare the outcomes with the previous survey conducted in April-May 2021 to ascertain the actual changes that have transpired during this recent time period. Results: The availability of molecular classification in Italian centers has changed in 1 year. Seventy-five percent of centers performed the molecular classification compared with 55.6% of the previous survey. Although this percentage has increased, only 18% performed all the tests. Significant changes have occurred in the administration of new treatments in EC patients in MITO centers. In 2022, 82.1% of the centers administrated dostarlimab in recurrent or advanced MMR-deficient (dMMR) EC experiencing disease progression after platinum-based chemotherapy regimens, compared to only 24.4% in 2021. In 2022, 85.7% of the centers already administrated the pembrolizumab plus lenvatinib combination as a second-line therapy for MMR-proficient (pMMR) patients with advanced or recurrent EC who had progressed from first-line platinum-based therapy. Conclusion: Both the therapeutic and diagnostic scenarios have changed over the last couple of years in MITO centers, with an increased prescription of immune checkpoint inhibitors and use of the molecular classification.

Analysis of the adequacy of control arms in oncology randomised clinical trials published between 2017 and 2021: a meta-research study.

INTRODUCTION: Randomised controlled trials (RCTs) are usually considered the highest level of evidence for clinical practice. Patients assigned to control arm in RCTs should always receive the best available treatments to protect participants while also allowing for proper interpretation and applicability of study results. Here we analysed RCTs published in oncology between 2017 and 2021 to describe the frequency of suboptimal control arms. METHODS: We identified phase III studies testing active treatments in patients with solid tumours among 11 major oncology journals. Each control arm was analysed, and the standard of care was determined according to international guidelines and scientific evidence at accrual beginning and until accrual completion. We identified studies with suboptimal control arm from the beginning (type 1) and studies with an initially optimal control arm which became outdated during the accrual period (type 2). RESULTS: This analysis included 387 studies. Forty-three (11.1%) control arms were judged as suboptimal: 24 (6.2%) type 1 and 19 (4.9%) type 2. These rates were higher in industry-sponsored compared to academic trials: 9.3% versus 1.9% for type 1 (p = 0.003); 7.9% versus 0.6% for type 2 (p = 0.001). Rates of suboptimal control arms were higher in studies with positive results: 8.1% versus 4.0% for type 1 (p = 0.09); 7.6% versus 1.7% for type 2 (p = 0.007). CONCLUSIONS: Many trials have suboptimal control arms, even in journals with high-impact factors, leading to suboptimal treatment of control patients and biased evaluation of trial results.

MITO39: Efficacy and Tolerability of Pegylated Liposomal Doxorubicin (PLD)-Trabectedin in the Treatment of Relapsed Ovarian Cancer after Maintenance Therapy with PARP Inhibitors-A Multicenter Italian Trial in Ovarian Cancer Observational Case-Control Study.

OBJECTIVE: While PLD-Trabectedin is an approved treatment for relapsed platinum-sensitive ovarian cancer, its efficacy and tolerability has so far not been tested extensively in patients who progress after poly ADP-ribose polymerase inhibitor (PARPi) treatment. METHODOLOGY: This multicenter, retrospective analysis had the objective of comparing patients receiving PLD-Trabectedin after being treated with PARP-I (cases) with PARPi-naïve patients. Descriptive and survival analyses were performed for each group. RESULTS: Data from 166 patients were collected, composed of 109 cases and 57 controls. In total, 135 patients were included in our analyses, composing 46 controls and 89 cases. The median PFS was 11 months (95% IC 10-12) in the control group vs. 8 months (95% IC 6-9) in the case group (p value 0.0017). The clinical benefit rate was evaluated, with an HR for progression of 2.55 (1.28-5.06) for the case group (p value 0.008), persisting when adjusted for BRCA and line with treatment. We compared hematological toxicity, gastro-intestinal toxicity, hand-foot syndrome (HFS), fatigue, and liver toxicity, and no statistically significant disparity was noted, except for HFS with a p value of 0.006. The distribution of G3 and G4 toxicities was also equally represented. CONCLUSION: The MITO39 study showed a statistically significant difference in terms of PFS, suggesting that previous exposure to PARPi might inhibit the efficacy of PLD-Trabectedin. Regarding tolerability, no remarkable disparity was noted; PLD-Trabectedin was confirmed to be a well-tolerated scheme in both groups. To our knowledge, these are the first data regarding this topic, which we deem to be of great relevance in the current landscape.

Corrigendum: Management of metastatic endometrial cancer: physicians' choices beyond the first line after approval of checkpoint inhibitors.

[This corrects the article DOI: 10.3389/fonc.2023.1247291.].

Ki67 as a Predictor of Response to PARP Inhibitors in Platinum Sensitive BRCA Wild Type Ovarian Cancer: The MITO 37 Retrospective Study.

BACKGROUND: There is compelling need for novel biomarkers to predict response to PARP inhibitors (PARPi) in BRCA wild-type (WT) ovarian cancer (OC). METHODS: MITO 37 is a multicenter retrospective study aiming at correlating Ki67 expression at diagnosis with a clinical outcome following platinum treatment and PARPi maintenance. Clinical data were collected from high grade serous or endometroid BRCAWT OC treated with niraparib or rucaparib maintenance between 2010-2021 in 15 centers. Ki67 expression was assessed locally by certified pathologists on formalin-fixed paraffin embedded (FFPE) tissues. Median Ki67 was used as a cut-off. RESULTS: A total of 136 patients were eligible and included in the analysis. Median Ki67 was 45.7% (range 1.0-99.9). The best response to platinum according to median Ki67 was 26.5% vs. 39.7% complete response (CR), 69.1% vs. 58.8% partial response (PR), 4.4% vs. 1.5% stable disease (SD). The best response to PARPi according to median Ki67 was 19.1% vs. 36.8% CR, 26.5% vs. 26.5% PR, 26.5 vs. 25% SD, 27.9% vs. 16.2% progressive disease (PD). No statistically significant differences in progression free survival (PFS) and overall survival (OS) were identified between low and high Ki67. PFS and OS are in line with registration trials. CONCLUSIONS: Ki67 at diagnosis did not discriminate responders to PARPi.

Retrospective Analysis of the Correlation of MSI-h/dMMR Status and Response to Therapy for Endometrial Cancer: RAME Study, a Multicenter Experience.

BACKGROUND: There is poor evidence regarding sensitivity to chemotherapy in endometrial cancer (EC) based on microsatellite instability (MSI)/mismatch repair (MMR) status. METHODOLOGY: The RAME study is a retrospective analysis aiming to assess response to chemotherapy in MSI-high (h)/deficient (d) MMR and MSI-low (l)/proficient (p) MMR EC patients. Primary endpoints were recurrence-free survival (RFS) for patients with localized disease and progression-free survival (PFS) and overall survival (OS) in patients with advanced/recurrent disease. RESULTS: A total of 312 patients treated between 2010 and 2022 in four high-volume Multicenter Italian Trial in Ovarian cancer and gynecological malignancies (MITO) centers were selected. In total, 239 patients had endometrioid EC (76.6%), 151 had FIGO stage I at diagnosis (48.9%) and 71 were MSI-h/dMMR (22.8%). Median age was 65 (range 31-91) years. Among patients with localized disease, median RFS was 100.0 months (95% CI 59.4-140.7) for MSI-l/pMMR and 120.9 months (60.0-181.8) for MSI-h/dMMR (p = 0.39). Seventy-seven patients received first-line chemotherapy for advanced/recurrent disease. Patients with MSI-h/dMMR ECs had a significantly worse OS (p = 0.039). In patients receiving platinum-based chemotherapy, no statistically significant differences in PFS (p = 0.21) or OS (p = 0.057) were detected, although PFS and OS were numerically longer in the MSI-l/pMMR population. CONCLUSIONS: Patients with metastatic MSI-h/dMMR EC receiving first-line chemotherapy had a significantly worse OS.

MEK inhibitor as single agent in low grade serous ovarian and peritoneal cancer: a systematic review and meta-analysis.

BACKGROUND: Low grade serous carcinoma of the ovary and peritoneum (LGSC) is characterized by low response rates to chemotherapy and by MAPK pathway alterations. Phase II/III clinical trials tested different MEK inhibitors (MEKis) in this complex malignancy, with heterogenous results. Purpose of this systematic review and meta-analysis is to define activity and efficacy of these agents and explore differences in clinical outcomes related to RAS/RAF mutational status. METHODS: In March 2022, we searched Pubmed, Web of Science, Scopus, and the major conference proceedings (ASCO, ESMO) for randomized and non-randomized clinical trials evaluating MEKi as single agent in recurrent LGSC. The screening was performed independently by two reviewers. Objective response rate (ORR) and progression-free survival (PFS) data were extracted, and RevMan 5.3 software was used for statistical analysis. RESULTS: A total of 4 clinical trials involving 648 patients were included. In the intention-to-treat population, use of a MEK inhibitor was not associated with a significant improvement in PFS, with a pooled Hazard Ratio equal to 0.75 (95 % CI: 0.30 - 1.86, P = 0.54). Heterogeneity was significant (I2 = 92 %; P = 0.0004). In the overall study population, the pooled odds ratio of ORR for MEKis compared to control treatment was 2.61 (95 % CI: 0.65 - 10.54, P = 0.18). Specifically, ORR was 20.12 % in patients treated with MEKis compared to 9.09 % in women receiving standard treatment. Heterogeneity was significant (I2 = 85 %; P = 0.009). CONCLUSIONS: Although no statistically significant improvement in PFS was demonstrated, the available data show clear signals of activity, at least for some MEKis.

Management of Metastatic Endometrial Cancer: Physicians' Choices Beyond the First Line. A MITO Survey.

Background: Endometrial cancer (EC) therapeutic and diagnostic approaches have been changed by the development of a new prognostic molecular classification, the introduction of dostarlimab in microsatellite instability (MSI) high pre-treated advanced EC patients with further expected innovation deriving from lenvatinib plus pembrolizumab regardless MSI status. How this is and will be translated and embedded in the clinical setting in Italy is not known; this is why we developed Multicentre Italian Trials in Ovarian cancer and gynaecologic malignancies (MITO) survey on the current practice and expected future changes in EC. Methods: We designed a self-administered, multiple-choice online questionnaire available only for MITO members for one month, starting in April 2021. Results: 75.6% of the respondents were oncologists with a specific focus on gynaecologic malignancies and 73.3% of the respondents declared the availability of clinical trials in second line treatment for advanced EC. The therapeutic algorithm in second line was heterogeneous, being the most frequent choice administering anthracyclines followed by endocrine therapy or enrolling in clinical trials. While more than half of the clinicians declared that they performed the molecular classification, only six/45 respondents (13.3%) ran all the tests needed for it. On the other hand, 80% of them declared regular assessment of MSI status with IHC as recommended. The therapeutic approach in MSI high advanced EC patients has changed since dostarlimab approval. Indeed the most frequent choice in second line has been chemotherapy (53.3%) before its availability, while dostarlimab has been preferred in more than three-fourths of the cases (75.6%) after its approval. As for MSS patients, 77.8% of clinicians would choose lenvatinib plus pembrolizumab for them in second line once approved. Conclusions: Despite the selected sample of respondents from Italian MITO centres showing good knowledge of diagnostic and therapeutic innovations in EC, these are not fully implemented in everyday clinics, except for MSI status assessment.

Biological Role of Tumor/Stromal CXCR4-CXCL12-CXCR7 in MITO16A/MaNGO-OV2 Advanced Ovarian Cancer Patients.

This study investigated the prognostic role of the CXCR4-CXCL12-CXCR7 axis in advanced epithelial ovarian cancer (EOC) patients receiving first-line treatment within the MITO16A/MaNGO-OV2 phase-IV trial. CXCR4-CXCL12-CXCR7 expression was evaluated in the epithelial and stromal component of 308 EOC IHC-stained tumor samples. The statistical analysis focused on biomarkers' expression, their association with other variables and prognostic value. Zero-inflated tests, shrinkage, bootstrap procedures, and multivariable models were applied. The majority of EOC (75.0%) expressed CXCR4 and CXCR7, 56.5% expressed the entire CXCR4-CXCL12-CXCR7 axis, while only 4.6% were negative for CXCL12 and its cognate receptors, in regard to the epithelial component. Stromal CXCL12 and CXCR7, expressed in 11.2% and 65.5%, respectively, were associated with the FIGO stage. High CXCL12 in epithelial cancer cells was associated with shorter progression-free and overall survival. However, after adjusting for overfitting due to best cut-off multiplicity testing, the significance was lost. This is a wide-ranging, prospective study in which CXCR4-CXCL12-CXCR7 were systematically evaluated in epithelial and stromal components, in selected stage III-IV EOC. Although CXCL12 was not prognostic, epithelial expression identified high-risk FIGO stage III patients for PFS. These data suggest that it might be worth studying the CXCL12 axis as a therapeutic target to improve treatment efficacy in EOC patients.

The Role of PARP Inhibitors in the Ovarian Cancer Microenvironment: Moving Forward From Synthetic Lethality.

PARP inhibitors (PARPi) have shown promising clinical results and have revolutionized the landscape of ovarian cancer management in the last few years. While the core mechanism of action of these drugs has been largely analyzed, the interaction between PARP inhibitors and the microenvironment has been scarcely researched so far. Recent data shows a variety of mechanism through which PARPi might influence the tumor microenvironment and especially the immune system response, that might even partly be the reason behind PARPi efficacy. One of many pathways that are affected is the cGAS-cGAMP-STING; the upregulation of STING (stimulator of interferon genes), produces more Interferon ϒ and pro inflammatory cytokines, thus increasing intratumoral CD4+ and CD8+ T cells. Upregulation of immune checkpoints such as PD1-PDL1 has also been observed. Another interesting mechanism of interaction between PARPi and microenvironment is the ability of PARPi to kill hypoxic cells, as these cells show an intrinsic reduction in the expression and function of the proteins involved in HR. This process has been defined "contextual synthetic lethality". Despite ovarian cancer having always been considered a poor responder to immune therapy, data is now shedding a new light on the matter. First, OC is much more heterogenous than previously thought, therefore it is fundamental to select predictive biomarkers for target therapies. While single agent therapies have not yielded significant results on the long term, influencing the immune system and the tumor microenvironment via the concomitant use of PARPi and other target therapies might be a more successful approach.