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The clinical development of antibody drug conjugates (ADCs) in ovarian cancer began in 2008 with farletuzumab, a humanized monoclonal antibody, and vintafolide, an antigen drug conjugate, both targeting alpha folate receptor. Over the years, this novel class of drugs expanded to agents with a more sophisticated design and structure, targeting tissue factor (TF) in cervical cancer or human epidermal growth factor receptor 2 (HER2) in endometrial cancer. Despite the impressive number of patients included in clinical trials investigating different ADCs across gynecological cancers, it was only recently that the Food and Drug Administration (FDA) granted accelerated approvals to the first ADCs in gynecologic cancer. In September 2021, the FDA approved tisotumab vedotin (TV) in recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. This was followed in November 2022, by the approval of mirvetuximab soravtansine (MIRV) for adult patients with folate receptor alpha (FRα) positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens. Currently, the field of ADCs is rapidly expanding and more than 20 ADC formulations are in clinical trials for the treatment of ovarian, cervical and endometrial tumors. This review summarizes key evidence supporting their use and therapeutic indications, including results from late-stage development trials investigating MIRV in ovarian cancer and TV in cervical cancer. We also outline new concepts in the field of ADCs, including promising targets such as NaPi2 and novel drug delivery platforms such as dolaflexin with a scaffold-linker. Finally, we briefly present challenges in the clinical management of ADC toxicities and the emerging role of ADC combination therapies, including chemotherapy, anti-angiogenic and immunotherapeutic agents.

The Cancer Genome Atlas (TCGA) endometrial cancer data expanded our knowledge about the role of different immunotherapeutic approaches based on molecular subtypes. Immune checkpoint inhibitors demonstrated distinct antitumor activities as monotherapy or in combination. In microsatellite unstable (microsatellite instability-high) endometrial cancer, immunotherapy with immune checkpoint inhibitors showed promising single agent activity in recurrent settings. Different strategies are needed to enhance the response or reverse resistance to immune checkpoint inhibitors, or both, in microsatellite instability-high endometrial cancer. On the other hand, single immune checkpoint inhibitors showed underwhelming efficacy in microsatellite stable endometrial cancer but this was significantly improved using a combination approach. Furthermore, studies are also needed to improve response along with ensuring safety and tolerability in microsatellite stable endometrial cancer. This review summarizes the current indications of immunotherapy for the treatment of advanced and recurrent endometrial cancer. We also outline potential future strategies for an immunotherapy based combination approach in endometrial cancer to combat resistance or enhance response to immune checkpoint inhibitors, or both.

The past 5 years have seen several fundamental advances in ovarian cancer, with important new insights towards novel therapeutic opportunities within the DNA repair pathway. With the incorporation of poly (ADP-ribose) polymerase inhibitors (PARPi) into maintenance treatment regimens, the management of short- and long-term adverse events are key clinical priorities. Currently, three different PARPi are clinically beneficial and have been approved for primary and recurrent ovarian cancer: olaparib, niraparib, and rucaparib. The duration of treatment with PARPi in patients with ovarian cancer varies; patients can receive treatment for up to 2 or 3 years in first-line setting, or continue treatment until unacceptable toxicity or progression occurs in recurrent disease. Despite their similar mechanisms of action, these three inhibitors have specific toxicity profiles, which may lead to dose interruptions or discontinuation of treatment. This review summarizes the current indications for PARPi, including their role in recurrent and first-line maintenance treatment for advanced ovarian cancer. We also outline dose modifications leading to treatment disruption and potential changes in quality of life after prolonged treatment. Finally, we highlight the patient groups most likely to benefit from each of the three different PARPi.

Cell surface carbohydrate antigens sialyl Lewis X (sLeX) and Lewis Y (LeY) are paramount glycoconjugates and are abundantly expressed in the receptive endometrium. Furthermore, among the important biological functions of both antigens is their role in leukocytes adhesion and extravasation. Interleukin-1 beta (IL-1β) is involved in the process of human embryo implantation and placenta development. Here, we used an in vitro model to investigate whether sLeX and LeY are playing a role in the embryo implantation process mediated by IL-1β. Our results are showing that the expression of cell surface sLeX was enhanced in endometrial RL95-2 cells after exposure to IL-1β. RT-qPCR detection indicated that the transcript level of glycosyltransferase gene fucosyltransferase 3 (FUT3) was significantly elevated and that of FUT4/7 and ST3 beta-galactoside alpha-2,3-sialyltransferase 3/4 (ST3GAL3/4) were decreased by treatment with IL-1β. Modulatory role of glycosyltransferase FUT3 on sLeX biosynthesis was determined by FUT3 siRNA transfection in RL95-2 cells. Results showed that the expression level of sLeX was suppressed, but no change was observed in regard to LeY. Moreover, IL-1β promoted the HTR-8/SVneo trophoblast spheroids attachment to the RL95-2 endometrial monolayer, which was partially blocked by anti-sLeX antibody and FUT3 knockdown. Gene expression analysis of the RNA-seq transcriptome data from human secretory endometrium demonstrated a significantly higher level of FUT3 in the mid-secretory phase compared to the early secretory phase, which was correlated with the expression of IL1B. In summary, the inflammatory microenvironment at the fetomaternal interface can regulate the glycosylation pattern of endometrial cells at the time of implantation. SLeX can be significantly induced by IL-1β via increasing FUT3 expression, which facilitates the trophoblast adhesion during embryo implantation.

Supplementary Materials and Methods, Supplementary Table S1. List of 9 PRLR gene isoforms in the UCSC Genome Browser based on RNASeqV2 data. Supplementary Table S2. Protein expression profile by RPPA analysis in Ishikawa tumors treated with mannitol or G129R. Supplementary Table S3. Pathological staining results for PRLR using 2 scoring metrics in normal uterine tissue (n=3 patients) and UCEC-EEA (n=3 patients). Supplementary Figure S1 (supporting Figure 1). Expression of PRLR_SF (uc003jjl.3) in UCEC-EEA patients. Supplementary Figure S2 (supporting Figure 1). Expression of PRLR in human uterine cancer cell lines with both PTENmut and PTENWT backgrounds. Supplementary Figure S3 (supporting Figure 2). Representative images from the Ishikawa model showed the different sizes of primary tumors at the uterine horn in different groups. Supplementary Figure S4 (supporting Figure 3). In vitro efficacy of G129R in Ishikawa and Hec1-A cells under hormone-depleted condition. Supplementary Figure S5 (supporting Figure 3). G129R reduced the viabilities of Ishikawa and Hec1A cells in comparison with PRL stimulation at hormone-depleted condition. Supplementary Figure S6 (supporting Figure 5). siRNAs knock down the expression of FOXO3a or EIF-4EBP1 in Ishikawa and Hec1A cells. Supplementary Figure S7 (supporting Figure 4C & 4D, Supplementary Figure S2, and Supplementary Figure S6). Uncropped western blots produced in this study.

Abnormal activity of human prolactin (PRL) and its membrane-associated receptor (PRLR) contributes to the progression of uterine carcinoma. However, the underlying mechanisms are not well understood, and current means of targeting the PRL/PRLR axis in uterine cancer are limited. Our integrated analyses using The Cancer Genome Atlas and Genotype-Tissue Expression (GTEx) databases demonstrated that a short form of PRLR (PRLR_SF) is the isoform predominantly expressed in human uterine cancers; expression of this PRLR_SF was elevated in uterine cancers in comparison with cancer-free uterine tissues. We hypothesized that the overexpression of PRLR_SF in uterine cancer cells contributes, in part, to the oncogenic activity of the PRL/PRLR axis. Next, we employed G129R, an antagonist of human PRL, to block the PRL/PRLR axis in both PTENwt and PTENmut orthotopic mouse models of uterine cancer. In comparison with control groups, treatment with G129R as monotherapy or in combination with paclitaxel resulted in a significant reduction of growth and progression of orthotopic uterine tumors. Results from protein profiling of uterine cancer cells and in vivo tumors revealed a set of new downstream targets for G129R. Our results showed that G129R induced sub-G0 population arrest, decreased nascent protein synthesis, and initiated FOXO3a/EIF-4EBP1–mediated cell death in both PTENwt and PTENmut uterine cancer cells. Collectively, our results show a unique pattern of PRLR_SF expression predominantly in uterine cancer. Moreover, FOXO3a and EIF-4EBP1 are important mediators of cell death following G129R treatment in uterine cancer models.

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Supplementary Table 1. Dataset for the reverse-phase protein array (RPPA) and processed data for Ingenuity Pathway Analysis.

Full report from Ingenuity Pathway Analysis of the RPPA results.

Here, we examined the role of EP-100 [luteinizing hormone-releasing hormone (LHRH) ligand joined to a lytic peptide], improving the efficacy of immune checkpoint blockade. LHRH-R–positive murine ovarian cancer cells (ID8, IG10, IF5, and 2C12) were sensitive to EP-100 and were specifically killed at low micromolar levels through LHRH-R. EP-100 increased PD-L1 levels on murine ovarian cancer cells. In vivo syngeneic mouse models (ID8 and IG10) demonstrated that single-agent EP-100 reduced tumor volume, tumor weight, and ascites volume. The greatest reductions in tumor and ascites volume were observed with the combination of EP-100 with an anti–PD-L1 antibody. Immune profiling analysis showed that the population of CD8+ T cells, natural killer cells, dendritic cells, and macrophages were significantly increased in tumor and ascitic fluid samples treated with anti–PD-L1, EP-100, and the combination. However, monocytic myeloid suppressor cells, B cells, and regulatory T cells were decreased in tumors treated with anti–PD-L1, EP-100, or the combination. In vitro cytokine arrays revealed that EP-100 induced IL1α, IL33, CCL20, VEGF, and Low-density lipoprotein receptor (LDLR) secretion. Of these, we validated increasing IL33 levels following EP-100 treatment in vitro and in vivo; we determined the specific biological role of CD8+ T-cell activation with IL33 gene silencing using siRNA and Cas9-CRISPR approaches. In addition, we found that CD8+ T cells expressed very low level of LHRH-R and were not affected by EP-100. Taken together, EP-100 treatment had a substantial antitumor efficacy, particularly in combination with an anti–PD-L1 antibody. These results warrant further clinical development of this combination.

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Purpose:On the basis of strong preclinical rationale, we sought to confirm recommended phase II dose (RP2D) for olaparib, a PARP inhibitor, combined with the AKT inhibitor capivasertib and assess molecular markers of response and resistance.Patients and Methods:We performed a safety lead-in followed by expansion in endometrial, triple-negative breast, ovarian, fallopian tube, or peritoneal cancer. Olaparib 300 mg orally twice daily and capivasertib orally twice daily on a 4-day on 3-day off schedule was evaluated. Two dose levels (DL) of capivasertib were planned: 400 mg (DL1) and 320 mg (DL-1). Patients underwent biopsies at baseline and 28 days.Results:A total of 38 patients were enrolled. Seven (18%) had germline BRCA1/2 mutations. The first 2 patients on DL1 experienced dose-limiting toxicities (DLT) of diarrhea and vomiting. No DLTs were observed on DL-1 (n = 6); therefore, DL1 was reexplored (n = 6) with no DLTs, confirming DL1 as RP2D. Most common treatment-related grade 3/4 adverse events were anemia (23.7%) and leukopenia (10.5%). Of 32 evaluable subjects, 6 (19%) had partial response (PR); PR rate was 44.4% in endometrial cancer. Seven (22%) additional patients had stable disease greater than 4 months. Tumor analysis demonstrated strong correlations between response and immune activity, cell-cycle alterations, and DNA damage response. Therapy resistance was associated with receptor tyrosine kinase and RAS-MAPK pathway activity, metabolism, and epigenetics.Conclusions:The combination of olaparib and capivasertib is associated to no serious adverse events and demonstrates durable activity in ovarian, endometrial, and breast cancers, with promising responses in endometrial cancer. Importantly, tumor samples acquired pre- and on-therapy can help predict patient benefit.

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OBJECTIVE: To determine the clinical characteristics of patients who attained pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) and to identify specific predictive or prognostic factors associated with pCR. METHODS: Two distinct populations of patients who underwent NACT followed by interval tumor reductive surgery (TRS) were used in this retrospective study. The first contained 472 patients from a single institution. The second contained only pCR patients (67); those identified from population one, plus 44 obtained through collaborative institutions. Cox analysis and log-rank tests were performed to assess associations between clinical characteristics and pCR outcome, recurrence-free survival (RFS), and overall survival (OS). RESULTS: The median RFS and OS in our pCR-only population was 24.2 and 80.8 months, respectively, with a median follow-up time of 32.4 months. In our single institution population, 23 patients attained pCR (4.9%) and had longer RFS compared to non-pCR patients with viable microscopic, optimal, or suboptimal residual disease (24.3 vs. 12.1 vs. 11.6 vs. 9.6 months, p = 0.025, 0.012, 0.008, respectively), and longer OS compared to those with optimal or suboptimal residual disease (54.5 vs. 29.4 vs. 25.7 months, p = 0.027, 0.007, respectively). Patients were more than three-fold likely to attain pCR if their CA125 value was normal at the time of surgery (OR 3.54, 95% CI:1.14 – 11.05, p = 0.029). CONCLUSIONS: Women with pCR after NACT have significantly longer RFS compared to those with residual viable tumor at the time of interval tumor-reductive surgery, and CA125 is plausible biomarker for identifying these extreme responders preoperatively.

Background Preliminary research shows a substantial impact of the COVID-19 pandemic on women’s sexual health, whereby empirical work on sexual well-being of minoritized sexual identities is still rare. Aim The objective of this study was to explore sexual health in heterosexual, lesbian and bisexual cis women during the first wave of COVID-19 pandemic in Germany. Methods An anonymous nationwide online survey was conducted among cis women during the first nationwide lockdown in Germany from April 20th to July 20th, 2020. The questionnaire was distributed via e-mail, online chats and social-media platforms. Outcomes Demographic variables and self-report measures from the Sexual Behavior Questionnaire (SBQ-G) "before the pandemic" and "since the pandemic" were collected. Results A total of 1,368 cis women participants were included: heterosexual women (n = 844), lesbian women (n = 293), bisexual women (n = 231). Results indicate overall decrease in frequency of sexual contacts and masturbation during the COVID-19 pandemic. Regarding differences before and during the pandemic lesbian women showed significant changes in sexual arousal whereas heterosexual women showed significant changes in all dimensions except capability to enjoy sexual intercourse. The data of bisexual women showed significant changes in almost all dimensions except for frequency of sexual intercourse and sexual arousal. Results of the multiple regression analysis revealed that being younger than 36 years-old, and being in a relationship as well as being heterosexual (compared with being lesbian) is positively associated with general satisfaction with sexual life during the pandemic. Clinical Implications The findings suggest that during a pandemic sexual and mental health care for (cis) women should be provided and address the specific needs of sexual minority groups. Strengths & Limitations This is the first study to describe sexual behavior in heterosexual, lesbian and bisexual women during the COVID-19 pandemic in Germany. Limitations, however, include the fact that the data described were obtained at only one time point so there is a possibility of recall bias, and that the results cannot be generalized because of the underrepresentation of women over age 46. Conclusion This study examined the impact of the COVID-19 pandemic and resulting social constraints on the sexual health of particular groups of lesbian and bisexual women, which may improve preparedness for future public health and policy crises.

Purpose The significance of the non-classical G-protein-coupled estrogen receptor (GPER) as positive or negative prognostic factor for ovarian cancer patients remains still controversial. Recent results indicate that an imbalance of both co-factors and co-repressors of nuclear receptors regulates ovarian carcinogenesis by altering the transcriptional activity through chromatin remodeling. The present study aims to investigate whether the expression of the nuclear co-repressor NCOR2 plays a role in GPER signaling which thereby could positively impact overall survival rates of ovarian cancer patients. Methods NCOR2 expression was evaluated by immunohistochemistry in a cohort of 156 epithelial ovarian cancer (EOC) tumor samples and correlated with GPER expression. The correlation and differences in clinical and histopathological variables as well as their effect on prognosis were analyzed by Spearman’s correlation, Kruskal–Wallis test and Kaplan–Meier estimates. Results Histologic subtypes were associated with different NCOR2 expression patterns. More specifically, serous and mucinous EOC demonstrated a higher NCOR2 expression (P = 0.008). In addition, high nuclear NCOR2 expression correlated significantly with high GPER expression (cc = 0.245, P = 0.008). A combined evaluation of both high NCOR2 (IRS > 6) and high GPER (IRS > 8) expression revealed an association of a significantly improved overall survival (median OS 50.9 versus 105.1 months, P = 0.048). Conclusion Our results support the hypothesis that nuclear co-repressors such as NCOR2 may influence the transcription of target genes in EOC such as GPER. Understanding the role of nuclear co-repressors on signaling pathways will allow a better understanding of the factors involved in prognosis and clinical outcome of EOC patients.

Over the past decade, the treatment of patients diagnosed with endometrial cancer (EC) shifted away from the use of chemotherapy to more novel targeted therapy and immunotherapy approaches.The Cancer Genome Atlas data demonstrated different subgroups within ECs, more specifically, it facilitated the identification of predictive biomarkers. In particular, immunotherapies (immuno-oncology (IO)) are active either as monotherapy or in combination with other agents, depending on the biomarker profile of the tumor.In May 2017, pembrolizumab was approved for patients with microsatellite instability high (MSI-H) EC. More recently, this approval was extended for patients harvesting tumors with a high tumor mutational burden status. Furthermore, in July 2021, the combination of pembrolizumab and lenvatinib was approved for patients who do not exhibit MSI-H disease. Given the wealth of targets in EC and different targetable mutations, the challenge will be to choose the proper treatment and the proper sequencing to derive the best outcome in the first-line setting and improve outcomes in subsequent settings. This review summarizes the current indications of immunotherapy for the treatment of advanced and recurrent EC. We outline the role of testing for uterine cancer and its implication in therapy management. Finally, we address new concepts for immunotherapy combinations with other therapies.

Although gynecologic cancers usually affect older women, a significant proportion of patients with rare ovarian tumors are of reproductive age. In a young patient who presents with a pelvic mass, a primary consideration should be the probability of a malignancy. If there is any suspicion of a cancer diagnosis, the patient should be referred to a gynecologic oncologist. Key factors in clinical management include assessment of preoperative studies (physical examination, tumor markers, and imaging) to determine the likelihood of a malignancy, appropriate preoperative counseling (including discussion of fertility preservation), choice of surgical approach (minimally invasive vs open), frozen section examination by a gynecologic pathologist, and intraoperative decision making. Fortunately, the clinical features of several rare ovarian tumors are compatible with fertility preservation. These characteristics include a high proportion of stage I disease and unilateral ovarian involvement for most rare histotypes. Once a final diagnosis of a rare ovarian tumor is determined, further clinical management may include the need for further studies, possible referral to a fertility expert, consideration of further surgery (if the initial surgery was incomplete), and recommendations for postoperative therapy. This article reviews the literature on fertility preservation in the context of the treatment of several rare ovarian tumor subtypes, including malignant germ cell tumors, sex cord-stromal tumors, borderline tumors, low grade serous carcinoma, clear cell carcinoma, mucinous carcinoma, and small cell carcinoma of the hypercalcemic type.

Objective This randomized open-label phase II study evaluated the safety and clinical activity of EP-100 plus weekly paclitaxel in patients with recurrent ovarian cancer expressing positive LHRH receptor. Methods In a limited “run-in” dose escalation phase for EP-100, six patients were treated with ascending dose levels (13 mg/m2, 20 mg/m2, 30 mg/m2). In the randomized phase, patients received weekly paclitaxel (80 mg/m2 intravenously) plus twice weekly EP-100 (30 mg/m2 intravenously; combination arm) or weekly paclitaxel alone (80 mg/m2 intravenously; paclitaxel arm). The primary study endpoint was overall response rate (ORR). Results Forty-four patients were then randomized to either the experimental combination arm (n = 23) or the standard of care paclitaxel monotherapy arm (n = 21). The ORR was 35% (95%CI 16%–57%) for the combination arm and 33% (95% CI 15%–57%) for the paclitaxel arm. An interesting observation from an unplanned analysis was that a subset of patients with target liver lesions showed a greater overall response rate to the combination (69%) compared to paclitaxel alone (16%). The frequency of treatment-related grade 3–4 adverse events was similar between treatment arms: 48% vs 43% for the combination and paclitaxel arms, respectively. Conclusions ORR in the EP-100 combination arm was similar to that in the group treated with paclitaxel alone; however, a subset of patients with liver metastases appeared to benefit from the combination. The addition of EP-100 did not appear to augment the adverse event profile of paclitaxel and was well tolerated.

Purpose of review To highlight relevant strategies to overcome poly(ADP-ribose) polymerase (PARP) inhibitor resistance and present key clinical trials. Recent findings The use of PARP inhibition (PARPi) for frontline maintenance offers substantial clinical benefit in patients with homologous recombination-deficient tumors. However, expanding PARPi from recurrent therapy to frontline maintenance may potentially result in more PARPi resistant tumors earlier in the treatment continuum and data for the use of PARPi after PARPi remain limited. Clinical evidence demonstrates tumors may develop resistance to PARPi through demethylation of the BRCA promoter or BRCA reversion mutations. Multiple clinical trials investigating therapeutic strategies to overcome resistance, such as combinations of PARPi with antiangiogenic drugs, PI3K/AKT/mTOR, or MEK inhibitors have already been reported and more are ongoing. Furthermore, increasing the amount of DNA damage in the tumor using chemotherapy or cell cycle inhibitors such as ATM, ATR/CHK1/WEE1 is also under exploration. Summary There is increasing clinical interest to identify options to enhance PARPi efficacy and overcome adaptive resistance. PARPi represent a class of drugs that have significantly impacted the treatment and maintenance of ovarian cancer; as the use of PARPi increases, better understanding of resistance mechanisms is essential.

Introduction50–70% of epithelial ovarian cancers overexpress epidermal growth factor receptor, and its expression has been correlated with poor prognosis. We conducted a phase Ib/II trial to examine the efficacy, safety, and toxicity of gefitinib, a tyrosine kinase inhibitor, combined with topotecan in women with recurrent ovarian cancer with epidermal growth factor receptor positivity.MethodsPatients with measurable recurrent or persistent cancer after treatment with a platinum containing regimen with positive epidermal growth factor receptor expression, as determined by immunohistochemistry, were eligible for the study. Initial treatment was 250 mg/day gefitinib (oral) and 2.0 mg/m2 topotecan (intravenous) on days 1, 8, and 15, on a 28 day cycle. Dose escalations were planned for topotecan (dose levels 1–3: 2, 3, and 4 mg/m2) until the maximum tolerated dose was reached.Results19 patients received a total of 61 cycles. Median age was 59.8 years (range 42–76 years). Histologic types in treated patients included 74% serous (n=14), 11% mixed (n=2), 11% transitional (n=2), and 5% clear cell (n=1). For phase Ib, three patients were treated at dose level 1, three at dose level 2, and three at dose level 3 for topotecan. The maximum tolerated dose was 4.0 mg/m2 (days 1, 8, and 15) for topotecan and 250 mg (daily) for gefitinib. Therefore, dose level 3 was used for phase II. Among the 19 patients, 63.2% (n=12) had progressive disease, 15.8% (n=3) had stable disease, 10.5% (n=2) had a partial response, and 10.5% (n=2) were not evaluable. The most serious adverse events of any grade attributed to the therapy were anemia (89.4%), neutropenia (68.4%), abdominal pain (84%), constipation (78.9%), and diarrhea (78.9%).ConclusionAlthough the drug combination was relatively well tolerated, this prospective phase Ib/II clinical trial did not show sufficient clinical activity of topotecan combined with gefitinib in patients with epidermal growth factor receptor positive recurrent ovarian, fallopian tube, or peritoneal cancers.

The tyrosine kinase receptor EphB4 is frequently overexpressed in ovarian and other solid tumors and is involved in interactions between tumor cells and the tumor microenvironment, contributing to metastasis. Trans-interaction between EphB4 and its membrane-bound ligand ephrin B2 (EFNB2) mediates bi-directional signaling: forward EFNB2-to-EphB4 signaling suppresses tumor cell proliferation, while reverse EphB4-to-EFNB2 signaling stimulates the invasive and angiogenic properties of endothelial cells. Currently, no small molecule–based, dual-function, EphB4-binding peptides are available. Here, we report our discovery of a bi-directional ephrin agonist peptide, BIDEN-AP which, when selectively internalized via receptor-mediated endocytosis, suppressed invasion and epithelial-mesenchymal transition of ovarian cancer cells. BIDEN-AP also inhibited endothelial migration and tube formation. In vivo, BIDEN-AP and its nanoconjugate CCPM-BIDEN-AP significantly reduced growth of orthotopic ovarian tumors, with CCPM-BIDEN-AP displaying greater antitumor potency than BIDEN-AP. Both BIDEN-AP and CCPM-BIDEN-AP compromised angiogenesis by downregulating epithelial-mesenchymal transition and angiogenic pathways. Thus, we report a novel EphB4-based therapeutic approach against ovarian cancer.

ObjectiveBecause mucinous carcinomas are rare tumors that affect several organ sites and are known to originate from different tissues, leading to frequent misdiagnoses, the objective was to characterize the differences between primary mucinous tumors of the ovary and metastatic mucinous cancer to the ovary by studying the expression pattern of several candidate biomarkers.MethodsTissue samples of mucinous histology were obtained between 1985 and 2015. Individual ovary and colon tissue samples were analyzed, including standard (PAX8, CK20, CK7, CDX2, SATB2, estrogen/progesterone) and new (MUC1, MUC5AC) biomarkers, which were then scored for immunoreactivity semi-quantitatively.ResultsThe study cohort included 98 mucinous tumor samples, including benign mucinous cystadenoma (n=24), mucinous borderline tumors (n=24), mucinous carcinomas (n=40), and metastatic mucinous ovarian carcinomas (n=10). A strong positive correlation was found between PAX8 scoring (p=0.003), CK7 scoring (p=0.0001), and MUC1 scoring (p=0.001) in primary mucinous ovarian cancer. Tumors of increasing invasiveness were analyzed and a significant decrease in the scoring of MUC5AC (p=0.001) was observed, with a stronger expression in adenomas (87%) and borderline tumors (75%), and a lower expression in mucinous cancers (42%). Patients survived significantly longer when their tumors expressed high PAX8 and showed an expansile invasion pattern (p=0.005 and p=0.015, respectively) compared with patients with PAX8-negative tumors and destructive invasion pattern.ConclusionThe study data support the diagnostic value of MUC1 as a new biomarker to differentiate between primary and metastatic mucinous ovarian cancer. In addition, the tumor growth pattern along with the PAX8 immunophenotype might represent potential prognostic biomarkers for primary mucinous ovarian carcinomas.

Major improvements in breast imaging over the last 40 years have led to increased numbers of patients diagnosed with ductal carcinoma in situ (DCIS). Subsequently, after shifting the diagnosis from palpable breast masses to detection of small about 10 mm lesions by mammography, the concept of breast conservative surgery was developed. Therefore, surgical excision and oncoplastic techniques have improved both accuracy of the procedure and subsequent cosmetic result. Approximately 40% of DCIS cases are treated by surgery alone, i.e., local excision, or mastectomy. In addition, radiotherapy and endocrine therapy are recommended for patients after breast conservation. Recently, results from clinical trials investigating the benefit of targeted therapies were reported, however without any meaningful impact on patient outcome. In this review, we summarize our current understanding of the role of conservative surgery in DCIS treatment and present relevant clinical trials in which conservative surgery, radiation, and adjuvant therapies were investigated. We also outline the tumor biology of DCIS in light of recent developments of genetic assays and their potential utility in the clinic.

Unexplained recurrent pregnancy loss (uRPL) is associated with macrophage polarization, which can be modulated by prostaglandin E2 (PGE2). Our previous study demonstrated that PGE2 receptor 3 (EP3) signaling is induced in the first-trimester placentas of uRPL patients compared with its expression in healthy controls. However, whether EP3 plays a role in macrophage polarization at the maternal-fetal interface of uRPL women remains unknown. The positive expression of EP3 in decidual macrophages was confirmed by double immunofluorescence staining in the first-trimester placentas collected from uRPL patients and healthy controls. Antibodies CD68, iNOS, and CD163 were used as immunofluorescence marker for decidual macrophages, M1, and M2 macrophages. To clarify the effects of EP3 on macrophage polarization, THP-1 monocyte cells were applied as M0 macrophages after phorbol 12-myristate 13-acetate (PMA) treatment for in vitro study. The mRNA levels of representative M1 markers (interleukin-1β and interleukin-6) and M2 markers (interleukin-10 and arginase-1) were quantified with qPCR in M0 macrophages being stimulated with sulprostone (an EP3 agonist) or L-798,106 (an EP3 antagonist). We found that EP3 expression was upregulated in the decidual macrophages of first-trimester placentas from uRPL patients compared with healthy controls. Furthermore, EP3 expression was increased in M1 macrophages compared with that in M2 macrophages in first-trimester placentas of uRPL patients. Sulprostone intensified the mRNA levels of IL-6 together with interferon-γ, whereas L-798,106 stimulated the mRNA expression of IL-10 and Arg-1 in a dose-dependent manner.

The platelet-activating factor receptor (PAFR) and its ligand (PAF) are important inflammatory mediators that are overexpressed in ovarian cancer. The receptor is an important player in ovarian cancer development. In this study, we aimed to evaluate the prognostic value of PAFR in epithelial ovarian cancer (EOC) and the potential use of its antagonist, Rupatadine as an experimental treatment. Tissue microarrays of ovarian cancer patients, most markedly those with a non-mucinous subtype, immunohistochemically overexpressed PAFR. Elevated cytoplasmic PAFR expression was found to significantly and independently impair patients’ overall and recurrence-free survival (OS: median 83.48 vs. 155.03 months; p=0.022; RFS: median 164.46 vs. 78.03 months; p=0.015). In vitro, especially the serous ovarian cancer subtypes displayed an elevated PAFR gene and protein expression. siRNA knockdown of PAFR decreased cell proliferation significantly, thus confirming the receptor's protumorigenic effect on ovarian cancer cells. The clinically approved PAFR antagonist Rupatadine effectively inhibited in vitro cell proliferation and migration of ovarian cancer cells. PAFR is a prognostic marker in ovarian cancer patients and its inhibition through Rupatadine may have important therapeutic implications in the therapy of ovarian cancer patients.

Introduction The side effects of systemic cancer therapy and the lack of clinical data on safety and efficacy of COVID-19 vaccination in cancer patients cause uncertainty among the patients about whether to get vaccinated or not. Here, we evaluated attitude towards and effects of COVID-19 vaccination in patients with breast and gynecological cancer undergoing systemic cancer therapy. Methods Since March 15th, 2021, cancer patients who received one of the approved COVID-19 vaccines were routinely interviewed about immediate and late side effects. Clinical parameters such as current therapy, time interval between therapy administration and vaccination, and changes in the therapy schedule due to vaccination were documented. The collected data were analyzed de-identified as a part of routine quality assurance. Results By July 27th, 2021, 218 patients (74.3% breast cancer patients) had received one of two COVID-19 vaccine doses, and 112 patients had received both doses: 77.5% received Conmirnaty (BioNTech/Pfizer), 16.1% Vaxzevria (Astra Zeneca) and 5.9% COVID-19 Vaccine Moderna. The COVID-19 vaccines had an acceptable safety profile with self-limiting local and systemic adverse events, which rarely lasted >48 h post vaccination. Symptoms occurred predominantly after the second dose of the vaccine and less frequently in older patients >55 years. No vaccine-related serious adverse events were reported, and only limited effects of vaccination on the therapy schedule were observed. Conclusions Breast and gynecologic cancer patients tolerate the COVID-19 vaccination while undergoing systemic cancer therapy without any additional side effects beyond those reported in the general population.

Simple Summary The expression of tumor microenvironment-related genes is known to be correlated with ovarian cancer patients’ prognosis. Immunotherapeutic targets are in part located in this complex cluster of cells and soluble factors. In our study, we constructed a prognostic 11-gene signature for advanced serous ovarian cancer from tumor microenvironment-related genes through lasso regression. The established risk score can quantify the prognosis of ovarian cancer patients more accurately and is able to predict the putative biological response of cancer samples to a programmed death ligand 1 blocking immunotherapy. This might empower the role of immunotherapy in ovarian cancer through its usage in future study protocols. Abstract (1) Background: The tumor microenvironment is involved in the growth and proliferation of malignant tumors and in the process of resistance towards systemic and targeted therapies. A correlation between the gene expression profile of the tumor microenvironment and the prognosis of ovarian cancer patients is already known. (2) Methods: Based on data from The Cancer Genome Atlas (379 RNA sequencing samples), we constructed a prognostic 11-gene signature (SNRPA1, CCL19, CXCL11, CDC5L, APCDD1, LPAR2, PI3, PLEKHF1, CCDC80, CPXM1 and CTAG2) for Fédération Internationale de Gynécologie et d’Obstétrique stage III and IV serous ovarian cancer through lasso regression. (3) Results: The established risk score was able to predict the 1-, 3- and 5-year prognoses more accurately than previously known models. (4) Conclusions: We were able to confirm the predictive power of this model when we applied it to cervical and urothelial cancer, supporting its pan-cancer usability. We found that immune checkpoint genes correlate negatively with a higher risk score. Based on this information, we used our risk score to predict the biological response of cancer samples to an anti-programmed death ligand 1 immunotherapy, which could be useful for future clinical studies on immunotherapy in ovarian cancer.