Mirvetuximab soravtansine in folate receptor alpha (FRα)-high platinum-resistant ovarian cancer: final overall survival and post hoc sequence of therapy subgroup results from the SORAYA trial.

OBJECTIVE: The single-arm, phase II SORAYA trial (NCT04296890) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)-high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. METHODS: Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. RESULTS: At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. CONCLUSION: These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.

Harmonization of homologous recombination deficiency testing in ovarian cancer: Results from the MITO16A/MaNGO-OV2 trial.

BACKGROUND: Homologous Recombination Deficiency (HRD) status predicts response to treatment with poly(ADP-ribose) polymerase inhibitors in Ovarian Cancer (OC) patients. The Myriad myChoiceCDx Assay is approved by Food and Drug Agency for the HRD assessment. Here we compared the HRD status obtained by three commercial panels with the results from Myriad reference test. METHODS: The HRD analysis was performed on DNA from formalin-fixed and paraffin-embedded tumor samples of 100 untreated OC patients for which Myriad assay results were available, using TruSight Oncology 500 HRD assay (Illumina), Oncomine Comprehensive Assay Plus (Thermo Fisher Scientific) and SOPHiA DDM HRD solution panel (SOPHiA Genetics). RESULTS: A good overall concordance with the reference method was demonstrated at three different levels: BRCA mutational status (from 94.4 % to 97.7 %), the genomic instability value (from 88.2 % to 95.3 %) and for the HRD status (from 90.4 % to 97.6 %). Moreover, a trend in favour of HRD positive patients for response rate, progression-free survival and overall survival similar to Myriad was observed for all three tests. DISCUSSION: Our data suggest the feasibility of commercial testing for assessing HRD status, with a good concordance with the reference method and association with clinical outcome.

Discordance between GCIG CA-125 progression and RECIST progression in the CALYPSO trial of patients with platinum-sensitive recurrent ovarian cancer.

BACKGROUND: CA-125 alone is widely used to diagnose progressive disease (PD) in platinum-sensitive recurrent ovarian cancer (PSROC) on chemotherapy. However, there are increasing concerns regarding its accuracy. We assessed concordance between progression defined by CA-125 and RECIST using data from the CALYPSO trial. METHODS: We computed concordance rates for PD by CA-125 and RECIST to determine the positive (PPV) and negative predictive values (NPV). RESULTS: Of 769 (79%) evaluable participants, 387 had CA-125 PD, where only 276 had concordant RECIST PD (PPV 71%, 95% CI 67-76%). For 382 without CA-125 PD, 255 had RECIST PD but 127 did not (NPV 33%, 95% CI 29-38). There were significant differences in NPV according to baseline CA-125 (≤100 vs >100: 42% vs 25%, P < 0.001); non-measurable vs measurable disease (51% vs 26%, P < 0.001); and platinum-free-interval (>12 vs 6-12 months: 41% vs 14%, P < 0.001). We observed falling CA-125 levels in 78% of patients with RECIST PD and CA-125 non-PD. CONCLUSION: Approximately 2 in 3 women with PSROC have RECIST PD but not CA-125 PD by GCIG criteria. Monitoring CA-125 levels alone is not reliable for detecting PD. Further research is required to investigate the survival impact of local therapy in radiological detected early asymptomatic PD.

Shallow whole genome sequencing approach to detect Homologous Recombination Deficiency in the PAOLA-1/ENGOT-OV25 phase-III trial.

The bevacizumab (bev)/olaparib (ola) maintenance regimen was approved for BRCA1/2-mutated (BRCAmut) and Homologous Recombination Deficient (HRD) high-grade Advanced Ovarian Cancer (AOC) first line setting, based on a significantly improved progression-free survival (PFS) compared to bev alone in the PAOLA-1/ENGOT-ov25 trial (NCT02477644), where HRD was detected by MyChoice CDx PLUS test. The academic shallowHRDv2 test was developed based on shallow whole-genome sequencing as an alternative to MyChoice. Analytical and clinical validities of shallowHRDv2 as compared to MyChoice on 449 PAOLA-1 tumor samples are presented. The overall agreement between shallowHRDv2 and MyChoice was 94% (369/394). Less non-contributive tests were observed with shallowHRDv2 (15/449; 3%) than with MyChoice (51/449; 11%). Patients with HRD tumors according to shallowHRDv2 (including BRCAmut) showed a significantly prolonged PFS with bev+ola versus bev (median PFS: 65.7 versus 20.3 months, hazard ratio (HR): 0.36 [95% CI: 0.24-0.53]). This benefit was significant also for BRCA1/2 wild-type tumors (40.8 versus 19.5 months, HR: 0.45 [95% CI: 0.26-0.76]). ShallowHRDv2 is a performant, clinically validated, and cost-effective test for HRD detection.

Safety of PARP inhibitors as maintenance therapy in ovarian cancer.

INTRODUCTION: Antiangiogenic agents and poly(ADP-ribose) polymerase inhibitors (PARP-Is) have improved the outcome of patients suffering from ovarian cancer. However, as they are associated with many adverse events (AEs), it is important to be aware of their safety and toxicity profiles. AREAS COVERED: We reviewed PARP-I therapeutical indications, mechanism of action, metabolism, and interactions. We reported on all major and minor AEs that have emerged from clinical trials (SOLO1, PRIMA, PAOLA1, ATHENA, SOLO2, NOVA, ARIEL3, NORA), their follow-ups, meta-analyses, and real-world studies, particularly hematologic toxicities and their management, and secondary malignancies (myelodysplastic syndrome and acute myeloid leukemia). We also addressed gastrointestinal, neurological, respiratory, hepatic, and renal toxicity and the use of PARP-Is in older, pregnant, and lactating patients. No specific research strategy in terms of keywords, inclusive dates and databases was used. EXPERT OPINION: PARP-Is benefits largely outweigh the risks associated with potential AEs. Randomized controlled trials produced strong good, quality data, but they enrolled a selected population and failed to capture rare events. More pharmacovigilance data and real-life studies on a larger and more heterogeneous sample are needed to understand PARP-Is differences and to clarify the incidence of late AEs to balance the risk/benefit ratio.

The role of immunotherapy treatment in non-clear cell renal cell carcinoma: An analysis of the literature.

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group representing 15-30% of renal tumors. They are mostly excluded from immunotherapy trials due to their rarity and worse prognosis. This, alongside nccRCC misdiagnosis/misclassification, lack of immune-biomarker expression rate data, lack of homogeneous data reporting, the retrospective nature of many studies, small sample sizes, and the fact that high-grade evidence only stems from trials mostly addressing the clear cell subtype, result in poorly defined treatments. We thus reviewed available data from several clinical trials, retrospective studies, and meta-analyses on immunotherapy responses and their correlation with histological subtypes and prognostic biomarkers. The papillary and unclassified subtypes are the best candidate for immunotherapy, showing response rates up to ∼35%. Chromophobe cancers, on the other end, have mostly null response rates. Cancers with sarcomatoid features respond very well to immunotherapy, regardless of their histology. Available data for translocation, medullary, collecting duct, and other nccRCCs are inconclusive. Regarding PD-L1, its expression correlates with better responses, but its prognostic value remains to be determined due to small sample sizes hindering direct statistical comparisons. It is necessary to involve a larger number of nccRCC patients and centers in clinical trials and report tumor response rates and PD-(L)1 and other markers' expression rates divided by nccRCC subtypes and not just for the whole cohorts. This will allow us to collect more robust data to best identify patients who can benefit from immunotherapy and ultimately define the standard of treatment. AVAILABILITY OF DATA AND MATERIAL: N/A.

Consensus statements and treatment algorithm to guide clinicians in the selection of maintenance therapy for patients with newly diagnosed, advanced ovarian carcinoma: Results of a Delphi study.

INTRODUCTION: Standard treatment of newly diagnosed, advanced ovarian carcinoma (OC) consists of cytoreductive surgery followed by platinum-based chemotherapy with or without bevacizumab. Maintenance therapy with PARP inhibitors and olaparib-bevacizumab has recently shown to significantly improve progression-free survival in the first-line setting. Some practical aspects of maintenance therapy, however, are still poorly defined. AIM OF THE STUDY: To provide guidance to clinicians in the selection of maintenance therapy for newly diagnosed, advanced ovarian carcinoma. METHODS: A board of six gynecologic oncologists with expertise in the treatment of OC in Italy convened to address issues related to the new options for maintenance treatment. Based on scientific evidences, the board produced practice-oriented statements. Consensus was reached via a modified Delphi study that involved a panel of 22 experts from across Italy. RESULTS: Twenty-seven evidence- and consensus-based statements are presented, covering the following areas of interest: use of biomarkers (BRCA mutations and presence of homologous recombination deficiency); timing and outcomes of surgery; selection of patients eligible for bevacizumab; definition of response to treatment; toxicity and contraindications; evidence of synergy of bevacizumab plus PARP inhibitor. Two treatment algorithms are also included, for selecting maintenance therapy based on timing and outcomes of surgery, response to platinum-based chemotherapy and biomarker status. A score for the assessment of response to chemotherapy is proposed, but its validation is ongoing. CONCLUSIONS: We provide here consensus statements and treatment algorithms to guide clinicians in the selection of appropriate and personalized maintenance therapy in the first-line setting of advanced OC management.

Machine Learning Application Identifies Germline Markers of Hypertension in Patients With Ovarian Cancer Treated With Carboplatin, Taxane, and Bevacizumab.

Pharmacogenomics studies how genes influence a person's response to treatment. When complex phenotypes are influenced by multiple genetic variations with little effect, a single piece of genetic information is often insufficient to explain this variability. The application of machine learning (ML) in pharmacogenomics holds great potential - namely, it can be used to unravel complicated genetic relationships that could explain response to therapy. In this study, ML techniques were used to investigate the relationship between genetic variations affecting more than 60 candidate genes and carboplatin-induced, taxane-induced, and bevacizumab-induced toxicities in 171 patients with ovarian cancer enrolled in the MITO-16A/MaNGO-OV2A trial. Single-nucleotide variation (SNV, formerly SNP) profiles were examined using ML to find and prioritize those associated with drug-induced toxicities, specifically hypertension, hematological toxicity, nonhematological toxicity, and proteinuria. The Boruta algorithm was used in cross-validation to determine the significance of SNVs in predicting toxicities. Important SNVs were then used to train eXtreme gradient boosting models. During cross-validation, the models achieved reliable performance with a Matthews correlation coefficient ranging from 0.375 to 0.410. A total of 43 SNVs critical for predicting toxicity were identified. For each toxicity, key SNVs were used to create a polygenic toxicity risk score that effectively divided individuals into high-risk and low-risk categories. In particular, compared with low-risk individuals, high-risk patients were 28-fold more likely to develop hypertension. The proposed method provided insightful data to improve precision medicine for patients with ovarian cancer, which may be useful for reducing toxicities and improving toxicity management.

Glucocorticoid Receptor and Ovarian Cancer: From Biology to Therapeutic Intervention.

Ovarian cancer (OC) is the leading cause of death from gynecological malignancies worldwide. Fortunately, recent advances in OC biology and the discovery of novel therapeutic targets have led to the development of novel therapeutic agents that may improve the outcome of OC patients. The glucocorticoid receptor (GR) is a ligand-dependent transcriptional factor known for its role in body stress reactions, energy homeostasis and immune regulation. Notably, evidence suggests that GR may play a relevant role in tumor progression and may affect treatment response. In cell culture models, administration of low levels of glucocorticoids (GCs) suppresses OC growth and metastasis. Conversely, high GR expression has been associated with poor prognostic features and long-term outcomes in patients with OC. Moreover, both preclinical and clinical data have shown that GR activation impairs the effectiveness of chemotherapy by inducing the apoptotic pathways and cell differentiation. In this narrative review, we summarize data related to the function and role of GR in OC. To this aim, we reorganized the controversial and fragmented data regarding GR activity in OC and herein describe its potential use as a prognostic and predictive biomarker. Moreover, we explored the interplay between GR and BRCA expression and reviewed the latest therapeutic strategies such as non-selective GR antagonists and selective GR modulators to enhance chemotherapy sensitivity, and to finally provide new treatment options in OC patients.

Biological and clinical impact of membrane EGFR expression in a subgroup of OC patients from the phase IV ovarian cancer MITO-16A/MANGO-OV2A trial.

BACKGROUND: Validated prognostic biomarkers for anti-angiogenic therapy using the anti-VEGF antibody Bevacizumab in ovarian cancer (OC) patients are still an unmet clinical need. The EGFR can contribute to cancer-associated biological mechanisms in OC cells including angiogenesis, but its targeting gave disappointing results with less than 10% of OC patients treated with anti-EGFR compounds showing a positive response, likely due to a non adequate selection and stratification of EGFR-expressing OC patients. METHODS: EGFR membrane expression was evaluated by immunohistochemistry in a cohort of 310 OC patients from the MITO-16A/MANGO-OV2A trial, designed to identify prognostic biomarkers of survival in patients treated with first line standard chemotherapy plus bevacizumab. Statistical analyses assessed the association between EGFR and clinical prognostic factors and survival outcomes. A single sample Gene Set Enrichment-like and Ingenuity Pathway Analyses were applied to the gene expression profile of 195 OC samples from the same cohort. In an OC in vitro model, biological experiments were performed to assess specific EGFR activation. RESULTS: Based on EGFR-membrane expression, three OC subgroups of patients were identified being the subgroup with strong and homogeneous EGFR membrane localization, indicative of possible EGFR out/in signalling activation, an independent negative prognostic factor for overall survival of patients treated with an anti-angiogenic agent. This OC subgroup resulted statistically enriched of tumors of histotypes different than high grade serous lacking angiogenic molecular characteristics. At molecular level, among the EGFR-related molecular traits identified to be activated only in this patients' subgroup the crosstalk between EGFR with other RTKs also emerged. In vitro, we also showed a functional cross-talk between EGFR and AXL RTK; upon AXL silencing, the cells resulted more sensitive to EGFR targeting with erlotinib. CONCLUSIONS: Strong and homogeneous cell membrane localization of EGFR, associated with specific transcriptional traits, can be considered a prognostic biomarker in OC patients and could be useful for a better OC patients' stratification and the identification of alternative therapeutic target/s in a personalized therapeutic approach.

Carboplatin and paclitaxel plus avelumab compared with carboplatin and paclitaxel in advanced or recurrent endometrial cancer (MITO END-3): a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: Adding immunotherapy to first-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. We aimed to compare carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as first-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. METHODS: MITO END-3 is an open-label, randomised, controlled, phase 2 trial conducted at 31 cancer institutes, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III-IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and no previous systemic anticancer therapy as primary treatment for advanced or metastatic disease. Participants were randomly assigned (1:1) using a computerised minimisation procedure stratified by centre, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for six to eight cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those assessing radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed progression-free survival, measured in the intention-to-treat (ITT) population. Patients who received at least one dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80% power and one-tailed α 0·20. This trial is registered with ClinicalTrials.gov (NCT03503786) and EudraCT (2016-004403-31). FINDINGS: From April 9, 2018, to May 13, 2021, 166 women were assessed for eligibility and 39 were excluded. 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n=62) or avelumab plus carboplatin and paclitaxel (n=63) and included in the ITT population. The median follow-up was 23·3 months (IQR 13·2-29·6) and was similar between the two groups. 91 progression-free survival events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median progression-free survival was 9·9 months (95% CI 6·7-12·1) in the standard group and 9·6 months (7·2-17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65-0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3-4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group). Two deaths occurred in the experimental group during treatment (one respiratory failure following severe myositis [possibly related to treatment] and one cardiac arrest [not related to treatment]). INTERPRETATION: Adding avelumab to first-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is warranted. FUNDING: Pfizer.

CA-125 Early Dynamics to Predict Overall Survival in Women with Newly Diagnosed Advanced Ovarian Cancer Based on Meta-Analysis Data.

(1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients' monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy.

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.

Complete and early response to cemiplimab associated to severe immune toxicity in advanced cervical cancer: a case report.

Cervical cancer (CC) is the second most commonly diagnosed cancer and the third leading cause of cancer death among females. The options of treatment for recurrent/advanced CC are limited and patients experiencing recurrence after first line platinum-based chemotherapy have a poor prognosis. In this context, immune checkpoint inhibitors (ICI)s antagonizing PD-1 and programmed death-ligand 1 (PD-L1) have profoundly changed the treatment scenario and outcomes in CC in the first or subsequent lines both as monotherapies or in combination with chemotherapy or other ICIs. Herein, we report the clinical case of a 74-year-old woman with metastatic CC with negative tumor PD-L1 expression who having disease progression after first-line of systemic treatment with platinum, thus undergoing to anti-PD-1 namely cemiplimab. The patient achieved a surprising, fast and complete metabolic response to cemiplimab immediately discontinued after only two cycles due to the onset of rare and severe immune-related adverse events (irAE)s such cardiovascular toxicity and hypertransaminasemia. Despite this, thirteen months later, the patient remains disease-free despite cemiplimab was withdrawn.

Targeting immunometabolism mediated by the IDO1 Pathway: A new mechanism of immune resistance in endometrial cancer.

Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called "kynurenine (Kyn) pathway", which converts the essential amino acid l-tryptophan into the immunosuppressive metabolite l-kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.

AKT Isoforms Interplay in High-Grade Serous Ovarian Cancer Prognosis and Characterization.

High-grade serous ovarian cancer (HGSOC) is among the deadliest gynecological malignancies. The acquired resistance to platinum-based therapies and the intrinsic heterogeneity of the disease contribute to the low survival rate. To improve patients' outcomes, new combinatorial approaches able to target different tumor vulnerabilities and enhance the efficacy of the current therapies are required. AKT inhibitors are promising antineoplastic agents able to act in synergy with PARP inhibitors, but the spectrum of patients who can benefit from this combination is unclear, since the role of the three different isoforms of AKT is still unknown. Here, we study the expression of AKT isoforms on a retrospective cohort of archive tissue by RT-droplet digital PCR (ddPCR) analyzing their association with the clinicopathological features of patients. Based on AKT1/AKT2 and AKT1/AKT3 ratios, we define four AKT classes which were related to patients' survival, tumor morphology and BRCA1 expression. Moreover, our results show that high AKT3 expression levels were frequently associated with tumors having classic features, a low number of mitoses and the presence of psammoma bodies. Overall, our study obtains new insights on AKT isoforms and their associations with the clinicopathological features of HGSOC patients. These evidences could help to better define the subsets of patients who can benefit from AKT and PARP inhibitors therapy in future clinical trials.

The way to precision medicine in gynecologic cancers: The first case report of an exceptional response to alpelisib in a PIK3CA-mutated endometrial cancer.

Endometrial cancer (EC) is the most common gynecologic cancer in Europe and its prevalence is increasing. EC includes a biological and clinical heterogeneous group of tumors, usually classified as type I (endometrioid) or type II (non-endometrioid) based on the histopathological characteristics. In 2013, a new molecular classification was proposed by The Cancer Genome Atlas (TCGA) based on the comprehensive molecular profiling of EC. Several molecular somatic alterations have been described in development and progression of EC. Using these molecular features, EC was reclassified into four subgroups: POLE ultra-mutated, MSI hypermutated, copy-number low, and copy-number high that correlate with the prognosis. To this regard, it is widely reported that EC has more frequent mutations in the phosphatidylinositol 3-kinase (PI3K) pathway signaling than any other tumor. PIK3CA is the main significant mutated gene after PTEN alterations. Overall, over 90% of endometrioid tumors have activating PI3K molecular alterations that suggests its critical role in the EC pathogenesis. Thus, the dysregulation of PI3K pathway represents an attractive target in EC treatment. Herein, we report a radiological and clinically meaningful response to a selective PIK3 inhibitor in a patient with extensively pre-treated advanced endometrioid EC harboring a somatic activating PIK3CA hotspot mutation. These evidences provide the rational for translational strategies of the PI3K inhibition and could support the clinical usefulness of PIK3CA genotyping in advanced EC. To our knowledge, this is the first clinical case of PIK3CA-mutated EC successfully treated with alpelisib.

Evaluation of Angiogenesis-Related Genes as Prognostic Biomarkers of Bevacizumab Treated Ovarian Cancer Patients: Results from the Phase IV MITO16A/ManGO OV-2 Translational Study.

BACKGROUND: Epithelial ovarian cancer (EOC) is a rare, highly lethal disease. In a subset of high grade EOC patients, maintenance therapy with the antiangiogenic drug Bevacizumab (BEV) is a valuable option. To date, no validated predictive or prognostic biomarkers exist for selecting EOC patients that might benefit from BEV treatment. METHODS: Immunohistochemistry and RT-qPCR evaluated the expression of seven angiogenesis-related proteins and of a twelve microRNAs angio-signature in EOC patients, treated in first line with chemotherapy plus BEV (MITO16A/ManGO OV-2 phase IV trial). Centralized statistical analyses assessed the associations between each biomarker, clinical prognostic factors and survival outcomes. RESULTS: High miR-484 expression was associated with longer progression-free and overall survival. Notably, the combined expression of miR-484 and its target VEGFB identified a subset of patients that might mostly benefit from BEV treatment. No other significant correlations were found between the other analyzed biomarkers and patients' survival. The application of a shrinkage procedure to adjust for over-fitting hazard ratio estimates reduced the association significance. CONCLUSIONS: The analysis of angiogenesis related biomarkers in EOC patients homogenously treated with BEV in first line provides novel insight in their prognostic value and suggests that some of them might merit to be tested as predictive markers of drug activity in dedicated randomized trials.

Thromboembolic events and antithrombotic prophylaxis in advanced ovarian cancer patients treated with bevacizumab: secondary analysis of the phase IV MITO-16A/MaNGO-OV2A trial.

INTRODUCTION: The use of routine antithrombotic prophylaxis is not recommended for advanced cancer patients receiving chemotherapy. The effect of bevacizumab-containing therapy on the risk of thromboembolic events remains controversial in ovarian cancer patients. We report on the incidence of thromboembolic events and the prevalence of antithrombotic therapy in patients enrolled in the single arm, phase IV, MITO-16A/MaNGO-OV2A trial. METHODS: In this trial, potential prognostic factors for patients with previously untreated ovarian cancer receiving a combination of platinum-based chemotherapy and bevacizumab were explored and the final analysis has already been reported. In this secondary analysis, the occurrence of thromboembolic events and the use of antithrombotic therapy were described according to the clinical characteristics of the patients. The prognostic role of thromboembolic events for progression-free and overall survival were also evaluated. RESULTS: From October 2012 to November 2014, 398 eligible patients were enrolled. 76 patients (19.1%) were receiving some type of anticoagulant or anti-aggregant treatment at baseline. Overall, 24 thromboembolic events were reported (cumulative incidence of 6.0%). The occurrence of thromboembolic events was not associated with baseline patient characteristics and was not modified by the use of antithrombotic prophylaxis (HR 0.60, 95% CI 0.18 to 2.0). Occurrence of thromboembolic events was not associated with progression-free survival (HR 1.34, 95% CI 0.83 to 2.15) or overall survival (HR 0.78, 95% CI 0.37 to 1.61). CONCLUSIONS: In our study, a 6.0% rate of thromboembolic events was reported during treatment with bevacizumab plus chemotherapy. Thromboembolic events were not associated with the clinical characteristics of the patients or with the use of antithrombotic prophylaxis, nor did they significantly affect the long-term prognosis. TRIAL REGISTRATION NUMBER: NCT01706120.