Serous Carcinoma Research Articles

Unusual Pattern of Spread of High-Grade Serous Fallopian Tubal Carcinoma in a Woman with BRCA1 Gene Mutation

A 40-year-old woman presented with chronic watery vaginal discharge for one-month and right pelvic pain radiating to the right flank for 2 weeks. Physical and pelvic examination revealed a right pelvic mass. Computerized tomography and magnetic resonance of whole abdomen revealed a 6-cm of heterogeneous mass at the right adnexa and a larger mass of 8-cm with internal cystic portions compressing on the inferior vena cava. Her serum cancer antigen (CA) 125 elevated to 540 U/ml. Surgical intervention revealed a right fallopian tube mass with an intact serosal surface, several enlarged pelvic and para-aortic nodes, and a bulky precaval node. No gross peritoneal nor other organ invasion was found. Complete surgical staging was performed by gynecologic oncologists and a surgeon, resulting in optimal surgery. Pathology revealed high-grade serous carcinoma of the right fallopian tube with metastasis to all resected nodes and a positive peritoneal cytology. Subsequent blood testing showed BReast CAncer (BRCA) 1 gene mutation. Adjuvant therapy with paclitaxel/carboplatin/bevacizumab was given for six cycles. Maintenance therapy with bevacizumab/olaparib, and periodic surveillance for other cancers, including breast magnetic resonance imaging were planned. This case presented an unusual pattern fallopian tubal cancer spread to a large precaval lymph node which was bulkier than the primary tumor. A thorough pre-operative evaluation and a surgical team specialized in cancer surgery are crucial for successful surgical management. Appropriate adjuvant treatment and follow-up for a woman with BRCA mutation were also to be emphasized.

MYC is Sufficient to Generate Mid-Life High-Grade Serous Ovarian and Uterine Serous Carcinomas in a p53-R270H Mouse Model.

Mouse models using transgenes which generate spontaneous cancers are essential tools to examine the etiology of human diseases. Here, the first Myc-driven spontaneous model is described as a valid HGSOC model. Surprisingly, aspects of uterine serous carcinoma were also observed in this model.

Role of Fyn expression in predicting the sensitivity to platinum‑based chemotherapy in patients with ovarian serous carcinoma.

Ovarian serous carcinoma is a gynecological malignancy associated with a high mortality rate, which is commonly diagnosed in the first instance at a late stage and has a propensity to develop resistance to platinum-based chemotherapy. Identifying reliable biomarkers for platinum sensitivity is critical for improving patient outcomes. The present retrospective study included 64 patients with high-grade serous ovarian carcinoma (Federation of Gynecology and Obstetrics stages III or IV). Patients were classified as platinum-sensitive (no relapse within 6 months of the last platinum administration) or platinum-resistant (relapse within 6 months). Immunohistochemical analysis was performed to evaluate Fyn expression in tumor tissues, and Fyn knockdown experiments were performed using the OVSAHO ovarian cancer cell line to assess carboplatin sensitivity. Fyn expression was significantly higher in platinum-resistant patients compared with in platinum-sensitive patients (P<0.01). A weighted Fyn expression score was developed and a cutoff score of 6 was determined to predict platinum sensitivity with a specificity of 65.5% and a sensitivity of 62.9%. Patients with low Fyn expression (score ≤6) exhibited higher platinum sensitivity and longer overall survival (P<0.05). Multivariate analysis identified Fyn expression and postoperative residual tumor size as independent predictors of platinum sensitivity (P=0.033 and P=0.023, respectively). In vitro, Fyn knockdown significantly increased carboplatin sensitivity in ovarian cancer cells (P<0.05). Fyn, a member of the Src family of kinases, serves a crucial role in various cellular functions and has been implicated in chemotherapy resistance. The results demonstrated a notable association between Fyn expression and platinum sensitivity in ovarian serous carcinoma. The findings suggested that Fyn may serve as a predictive biomarker for response to platinum-based chemotherapy, offering the potential for more personalized treatment strategies. To the best of our knowledge, the present study is the first to establish an association between Fyn expression and platinum sensitivity in advanced ovarian serous carcinoma. Prospective studies with larger, multi-center cohorts and comprehensive biomarker analyses are recommended to validate and extend these results, ultimately improving therapeutic strategies and patient prognosis.

Germline genetic testing reveals pathogenic variants in uterine serous carcinoma patients

An increase in the risk of developing uterine serous carcinoma (USC) has been observed among BRCA1 and BRCA2 germline pathogenic variant carriers in the published literature. However, routine germline genetic testing is not currently incorporated into USC management guidelines. The primary objective of this study is to define the incidence of germline pathogenic variants identified through genetic counseling referrals for USC patients at our institution. A retrospective cohort study was performed of patients diagnosed with USC at a single institution over a seven-year interval. A total of 91 patients with uterine serous carcinoma were identified. Almost half of the patients were referred to genetic counseling, and just over half of referred patients (24/43, 56%) ultimately underwent germline genetic testing. Pathogenic variants were noted in 12.5% (3/24) of the patients who were tested. Pathogenic mutations were found in BRCA1, BRCA2, and MSH6. Variants of unknown significance (VUS) were seen in 16.6% (4/24) of patients. Based on our findings, we recommend integration of germline testing into the standard management of patients with USC.

Use of menopausal hormone therapy before and after diagnosis and ovarian cancer survival-A prospective cohort study in Australia.

Menopausal hormone therapy (MHT) use before ovarian cancer diagnosis has been associated with improved survival but whether the association varies by type and duration of use is inconclusive; data on MHT use after treatment, particularly the effect on health-related quality of life (HRQOL), are scarce. We investigated survival in women with ovarian cancer according to MHT use before and after diagnosis, and post-treatment MHT use and its association with HRQOL in a prospective nationwide cohort in Australia. We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) and propensity scores to reduce confounding by indication. Among 690 women who were peri-/postmenopausal at diagnosis, pre-diagnosis MHT use was associated with a significant 26% improvement in ovarian cancer-specific survival; with a slightly stronger association for high-grade serous carcinoma (HGSC, HR = 0.69, 95%CI 0.54-0.87). The associations did not differ by recency or duration of use. Among women with HGSC who were pre-/perimenopausal or aged ≤55 years at diagnosis (n = 259), MHT use after treatment was not associated with a difference in survival (HR = 1.04, 95%CI 0.48-2.22). Compared to non-users, women who started MHT after treatment reported poorer overall HRQOL before starting MHT and this difference was still seen 1-3 months after starting MHT. In conclusion, pre-diagnosis MHT use was associated with improved survival, particularly in HGSC. Among women ≤55 years, use of MHT following treatment was not associated with poorer survival for HGSC. Further large-scale studies are needed to understand menopause-specific HRQOL issues in ovarian cancer.

Unusual Scenario: Ipsilateral Pelvic Lymph Node Metastasis in High- Grade Serous Ovarian Carcinoma without Peritoneal Extension - A Case Report

Introduction:: Ovarian cancers are the third most common gynecological cancers worldwide with serous carcinomas being the most common subtype with 90% of them as high-grade carcinomas. Case Presentation:: In the present case report a 60 years postmenopausal, nulliparous woman presented with complaints of bleeding per vaginum for 1-2 months with a left-sided solid-cystic ovarian mass of size 4x5 cm and ipsilateral enlarged external iliac and obturator lymph nodes which were diagnosed on histopathological examination as high-grade serous ovarian carcinoma (HGSOCs) with ipsilateral pelvic lymph node metastasis in presence of intact ovarian capsule and no metastatic deposits over the uterus, contralateral ovary and fallopian tubes, omentum, or any other gross peritoneal deposits. There was coexisting non-atypical endometrial hyperplasia. The patient was managed successfully with staging laparotomy with modified radical hysterectomy, and bilateral pelvic lymphadenectomy followed by six cycles of adjuvant chemotherapy with Paclitaxel and Carboplatin injections. Conclusion:: Patients with HGSOCs can have varied presentations with unusual involvement of lymph nodes in the absence of peritoneal spread. Hence, the clinician must be aware of these unusual presentations for the successful management of such cases.

1957P Integrative proteomic profiling in high-grade serous ovarian carcinoma: Unraveling biomarkers and therapeutic targets

1957P Integrative proteomic profiling in high-grade serous ovarian carcinoma: Unraveling biomarkers and therapeutic targets

Comparative Analysis of Gene Expression Profiles in Ovarian Clear Cell Carcinoma and High-Grade Serous Ovarian Cancer.

To evaluate disparities in gene expression profiles between Ovarian Clear Cell Carcinoma (OCCC) and High-Grade Serous Ovarian Carcinoma (HGSOC). A descriptive study. Place and Duration of the Study: The Second People's Hospital of Jingdezhen, Jiangxi, China, between 31st December 2017 and December 2023. Basic and clinical diagnostic information, along with genetic test reports, were compiled from all patients within the included groups. Differential gene expression between the two cohorts was scrutinised to elucidate its clinical significance. Comparative analysis revealed nine differentially expressed genes in OCCC relative to HGSOC, with six exhibiting significant disparities (p <0.05). These genes are implicated in pivotal cellular processes including the cell cycle, apoptosis, DNA damage repair, and the PI3K pathway. Notably, aberrant expression patterns, such as overexpression of MET and downregulation of PTEN and SMARCA4, correlated with adverse prognosis and survival outcomes in selected patients. Distinctive gene expression profiles between OCCC and HGSOC underscore disparate tumorigenic mechanisms, thereby laying a foundation for the tailored therapeutic interventions. Further elucidation of the identified differentially expressed genes is warranted to delineate their role in OCCC pathogenesis and prognostic significance. Ovarian clear cell carcinoma, High-grade serous ovarian cancer, Gene expression profiles, Homologous recombination repair.

5 Twenty-Year Retrospective Review of Adjuvant Treatment of Stage I-II Serous Endometrial Carcinoma at a Single Canadian Institution

5 Twenty-Year Retrospective Review of Adjuvant Treatment of Stage I-II Serous Endometrial Carcinoma at a Single Canadian Institution

Improving Specificity for Ovarian Cancer Screening Using a Novel Extracellular Vesicle–Based Blood Test: Performance in a Training and Verification Cohort

The low incidence of ovarian cancer (OC) dictates that any screening strategy needs to be both highly sensitive and highly specific. This study explored the utility of detecting multiple colocalized proteins or glycosylation epitopes on single tumor-associated extracellular vesicles (EVs) from blood. The novel OC Test employs immunoaffinity capture of tumor-associated EVs followed by proximity-ligation qPCR to detect combinations of up to three biomarkers to maximize specificity and measures multiple combinations to maximize sensitivity. A high-grade serous carcinoma (HGSC) case-control training set of EDTA plasma samples from 397 women was used to lock down the test design, the data interpretation algorithm, and the cut-off between cancer and non-cancer. Performance was verified and compared to CA125 in an independent blinded case-control set of serum samples from 390 women (132 controls, 66 HGSC, 83 non-HGSC OC, 109 benign). In the verification study, the OC Test showed a specificity of 97.0% (128/132; 95% CI: 92.4%-99.6%), a HGSC sensitivity of 97.0% (64/66; 95% CI: 87.8%-99.2%), and an AUC of 0.97 (95% CI 0.93-0.99) and also detected 73.5% (61/83; 95% CI: 62.7%-82.6%) of the non-HGSC OC cases. This test exhibited fewer false positives in subjects with benign ovarian tumors, non-ovarian cancers, and inflammatory conditions when compared to CA125. The combined sensitivity and specificity of this new test suggests it may have potential in OC screening.

752P Clinical and molecular predictors of outcome in patients with tubo-ovarian high-grade serous carcinoma and exceptional survival

752P Clinical and molecular predictors of outcome in patients with tubo-ovarian high-grade serous carcinoma and exceptional survival

P53 Abnormal (Copy Number High) Endometrioid Endometrial Carcinoma Has a Prognosis Indistinguishable From Serous Carcinoma.

Among the 4 molecular subgroups of endometrial carcinoma, the p53 abnormal (copy number high) subgroup has the worst prognosis; however, the histologic characteristics of this subgroup are not well established. Also, it is not well established whether low-grade tumors can belong to the p53 abnormal molecular subgroup and if so, what is the prognostic significance of the p53-mutated molecular subgroup in low-grade tumors. In the current study, we included 146 p53-mutated endometrial carcinomas and performed molecular subgrouping either based on a combination of immunohistochemical studies for p53 and MMR protein expression and POLE mutation testing (81 cases) or based on array-based and sequencing-based technologies (65 cases). We excluded cases that belonged to the POLE mutant or MSI molecular subgroups and only studied p53 abnormal (molecular subgroup) endometrial carcinomas (125 cases). In 71 cases, the molecular subgroup was determined by a combination of immunohistochemical studies and POLE mutation testing, and in 54 cases by array-based and sequencing-based methods. We reviewed 1 to 2 representative digital slides from each case and recorded the morphologic characteristics as well as clinical, treatment, and survival follow-up data. Overall, 47 cases were classified as endometrioid carcinoma, 55 serous carcinoma, and 23 other histotypes. Eight cases were FIGO 1, 21 were FIGO 2, and 91 were FIGO 3. A significant proportion of the cases (24.2%) were histologically classified as low-grade (FIGO 1 or 2) endometrioid carcinoma. There was no morphologic characteristic that showed prognostic implication. There was no significant difference in survival among different histotypes (P=0.60). There was no significant difference in survival among low-grade endometrioid (FIGO 1 or 2) versus high-grade (FIGO 3) tumors (P=0.98). Early-stage (stage I), low-grade tumors showed no significant survival advantage over early-stage, high-grade tumors (P=0.16) and this was more evident in FIGO 2 tumors. Although not statistically significant, the FIGO 2 tumors showed a trend toward worse survival than FIGO 3 tumors. Among the cases with available treatment data, more patients with early-stage high-grade tumors received adjuvant treatment, compared to patients with early-stage low-grade tumors, possibly explaining this trend (P=0.03). In conclusion, the findings of our study suggest that low-grade p53 abnormal endometrioid endometrial carcinomas (especially FIGO 2 tumors) have an aggressive course, with a prognosis similar to high-grade tumors. Furthermore, our study suggests that patients who had early-stage low-grade p53 abnormal disease might have been undertreated because of the "low-grade" histotype.

Molecular classification of ovarian high-grade serous/endometrioid carcinomas through multi-omics analysis: JGOG3025-TR2 study.

Considerable interobserver variability exists in diagnosis of ovarian high-grade endometrioid carcinoma (HGEC) and high-grade serous carcinoma (HGSC) due to histopathological similarities. While homologous recombination deficiency (HRD) correlates with drug sensitivity in HGSC, the molecular features of HGEC are unclear. Fresh-frozen samples from 15 ovarian HGECs and 274 ovarian HGSCs in the JGOG-TR2 cohort were submitted to targeted DNA sequencing, RNA sequencing, DNA methylation array, and SNP array. We additionally analyzed 555 ovarian HGSCs from TCGA-OV and 287 endometrial high-grade carcinomas from TCGA-UCEC. Unsupervised clustering using copy number signatures identified four distinct tumor groups (C1, C2, C3 and C4). C1 (n = 41) showed CCNE1 amplification and poor survival. C2 (n = 160) and C3 (n = 59) showed high BRCA1/2 alteration frequency with low and moderate ploidy, respectively. C4 (n = 22) was characterized by favorable outcome, higher HGEC proportion, no BRCA1/2 alteration or CCNE1 amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, and WT1 gene expression. Notably, C4 exhibited a normal endometrium-like DNA methylation profile, thus, defined as "HGEC-type" tumors, which were also identified in TCGA-OV and TCGA-UCEC. Ovarian "HGEC-type" tumors present a non-HRD status, favorable prognosis, and endometrial differentiation, possibly constituting a subset of clinically diagnosed HGSCs.

Sulindac exhibits anti-proliferative and anti-invasive effects in uterine serous carcinoma cells

PurposeUterine serous carcinoma (USC) is a highly aggressive and frequently recurring subtype of endometrial cancer with limited treatment options for advanced or recurrent stages. Sulindac, a classic non-steroidal anti-inflammatory drug, has demonstrated anti-tumor activity in several pre-clinical tumor models. This study aims to evaluate the effect of sulindac on cell proliferation and invasion in USC cells.MethodsHuman USC cell lines ARK-1 and SPEC2 were treated with different concentrations of sulindac. Cell proliferation was assessed using MTT and colony formation assays. ELISA assays measured cellular stress, cleaved caspase 3 activity, antioxidant ability, and adhesion. Cell cycle arrest was evaluated by Cellometer. The invasive capability was detected by wound healing assay. Western blotting was used to analyze the changes in protein expression induced by sulindac.ResultsExposure to sulindac decreased cellular viability in a dose-dependent manner in ARK-1 and SPEC2 cells. Sulindac effectively inhibited cell cycle progression, increased cellular stress, caused apoptosis, and reduced cell adhesion and invasion in USC cells. Additionally, sulindac decreased the expression of COX-2 and blocked phosphorylation of NF-κB induced by TNF-α.ConclusionSulindac is a potential therapeutic agent for USC that deserves further exploration in pre-clinical studies and potentially future clinical trials.

Spectrum of Surgico-Pathological Factors and Lymph Node Metastasis among Epithelial Ovarian Cancers: Experience of a Single Tertiary Care Institution from India

Introduction Epithelial ovarian cancer (EOC) is one of the leading causes of mortality among women worldwide. The present study aimed to estimate the frequency of various histopathological types, clinical and surgico-pathological factors, and spectrum of lymph node (LN) metastasis in early and advanced EOC. Material and Methods Women with EOCs who underwent cytoreductive surgery (CRS) between January 2019 and May 2022 were included. The distribution of Clinico-demographic parameters, histological type, stage, and LN metastasis were analyzed. Results A total of 101 women with EOCs underwent CRS, out of which 5 (4.95%) with coexistent endometrial cancer were excluded (N = 96). Fifty women (52%) underwent primary CRS and 46 (48%) women underwent interval CRS. The mean age of the women was 48.42 ± 11.6 years. Initial serum cancer antigen 125 (CA 125) level was elevated (&gt;35 U/mL) in 88 (91.67%) women and normal in 8 (8.33%) women. Complete cytoreduction was achieved in 75 (78.12%) cases. High-grade serous carcinoma was the most common histology (66/96, 68.75%), followed by mucinous carcinoma (15/96, 15.63%), endometrioid carcinoma (6/96, 6.25%), low-grade serous carcinoma (4/96, 4.17%), and carcinosarcoma (2/96, 2.08%). The majority of women, 69 (71.88%), were in stages III and IV at presentation. Most serous carcinomas were diagnosed at stage III (71.22%) or IV (13.64%). In contrast, the majority of endometrioid, mucinous, and clear cell carcinomas were diagnosed at stages I and II. Seventy-five women (78.13%) with EOC underwent pelvic and/or para-aortic lymphadenectomy, out of which 23 (30.67%) were histologically positive. Three out of 23 patients (13%) with early-stage disease showed positive LNs. Conclusion Serous carcinoma ovary is the most common histological subtype, presenting mostly in the advanced stage. A significant number of affected women were younger at presentation and diagnosis was made a decade earlier than the western population. A systematic pelvic and para-aortic lymphadenectomy in apparently early-stage (pelvic confined) ovarian cancer could detect additional LNs in 13% of women, especially in high-grade tumors and serous histology, suggesting the role of systematic lymphadenectomy for accurate staging in apparently early-stage ovarian cancer.

MRI Evaluation and Characterization of Ovarian Lesions Based on Ovarian-Adnexal Reporting and Data System MRI.

Background Managing ovarian lesions requires differentiating between benign and malignant cases. The development of a multiparametric MRI approach combining anatomical and functional criteria has led to the creation of the Ovarian-Adnexal Reporting and Data System (O-RADS) MRI scoring system, which enhances diagnostic accuracy. Objectives To study ovarian lesions and their characteristics, along with their risk stratification based on MRI O-RADS. Methods A prospective study used the O-RADS MRI criteria to categorize ovarian lesions. Clinical findings and MRI results were compared with histopathological outcomes to assess diagnostic accuracy. Results We identifiedabdominal pain as the most prevalent clinical finding among our cases (64, 91.43%), followed by a lump in the abdomen (33, 47.5%), dysmenorrhea (33, 47.5%), bleeding per vaginal (15, 21.43%), and weight loss (11, 15.71%). A total of 80 ovarian lesions were examined and characterized on the basis of the O-RADSMRI risk stratification system.Among the 80 ovarian lesions, 54 were histopathologically confirmed ovarian lesions (39 (72.22%) were benign, and 15 (27.77%) were malignant). The most common benign lesions were ovarian serous cystadenoma (28.20%) and ovarian mucinous cystadenoma (20.51%), while the most common malignant lesions were serous carcinoma (33.33%) and mucinous carcinoma (20%). Using the O-RADS MRI scoring system, we categorized six lesions (7.5%) as O-RADS 1 (all benign), 34 lesions (42.50%) as O-RADS 2 (32 benign and 2 malignant), 24 lesions (30%) as O-RADS 3 (23 benign and 1 malignant), seven lesions (8.75%) as O-RADS 4 (four benign and three malignant), and nine lesions (11.25%) as O-RADS 5 (all malignant). Our findings revealed significant differences in the size of lesions, the presence of thick septa, high T2-weighted signal intensity within solid tissue, and patterns of solid component enhancement and wall irregularity between malignant and benign lesions. The MRI cut-off score of ≥4 for malignancy demonstrated a sensitivity of 94.59%, a specificity of 97.5%, an accuracy of 97.62%, a positive predictive value of 94.5%, and a negative predictive value of 97.5%. The positive likelihood ratio was 32.7, while the negative likelihood ratio was 0.025. These results affirm the high diagnostic accuracy of the O-RADS MRI scoring system in distinguishing benign from malignant ovarian lesions. Conclusion The O-RADS MRI score is a highly accurate tool for differentiating between benign and malignant ovarian lesions. Its application can significantly enhance the management and treatment outcomes for patients with adnexal masses. The study confirms the scoring system's high sensitivity, specificity, and overall diagnostic accuracy.

PpIX-enabled fluorescence-based detection and photodynamic priming of platinum-resistant ovarian cancer cells under fluid shear stress.

Over 75% percent of ovarian cancer patients are diagnosed with advanced-stage disease characterized by unresectable intraperitoneal dissemination and the presence of ascites, or excessive fluid build-up within the abdomen. Conventional treatments include cytoreductive surgery followed by multi-line platinum and taxane chemotherapy regimens. Despite an initial response to treatment, over 75% of patients with advanced-stage ovarian cancer will relapse and succumb to platinum-resistant disease. Recent evidence suggests that fluid shear stress (FSS), which results from the movement of fluid such as ascites, induces epithelial-to-mesenchymal transition and confers resistance to carboplatin in ovarian cancer cells. This study demonstrates, for the first time, that FSS-induced platinum resistance correlates with increased cellular protoporphyrin IX (PpIX), the penultimate downstream product of heme biosynthesis, the production of which can be enhanced using the clinically approved pro-drug aminolevulinic acid (ALA). These data suggest that, with further investigation, PpIX could serve as a fluorescence-based biomarker of FSS-induced platinum resistance. Additionally, this study investigates the efficacy of PpIX-enabled photodynamic therapy (PDT) and the secretion of extracellular vesicles under static and FSS conditions in Caov-3 and NIH:OVCAR-3 cells, two representative cell lines for high-grade serous ovarian carcinoma (HGSOC), the most lethal form of the disease. FSS induces resistance to ALA-PpIX-mediated PDT, along with a significant increase in the number of EVs. Finally, the ability of PpIX-mediated photodynamic priming (PDP) to enhance carboplatin efficacy under FSS conditions is quantified. These preliminary findings in monolayer cultures necessitate additional studies to determine the feasibility of PpIX as a fluorescence-based indicator, and mediator of PDP, to target chemoresistance in the context of FSS.

PTEN Loss Shapes Macrophage Dynamics in High-Grade Serous Ovarian Carcinoma.

High-grade serous ovarian carcinoma (HGSC) remains a disease with poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations, such as PTEN loss, are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesized that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a targeting opportunity. Single-cell RNA sequencing identified populations of resident macrophages specific to Pten-null omental tumors in murine models, which were confirmed by flow cytometry. These macrophages were derived from peritoneal fluid macrophages and exhibited a unique gene expression program, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). Targeting resident peritoneal macrophages prevented the appearance of HMOX1hi macrophages and reduced tumor growth. In addition, direct inhibition of HMOX1 extended survival in vivo. RNA sequencing identified IL33 in Pten-null tumor cells as a likely candidate driver, leading to the appearance of HMOX1hi macrophages. Human HGSC tumors also contained HMOX1hi macrophages with a corresponding gene expression program. Moreover, the presence of these macrophages was correlated with activated tumoral PI3K/mTOR signaling and poor overall survival in patients with HGSC. In contrast, tumors with low numbers of HMOX1hi macrophages were marked by increased adaptive immune response gene expression. These data suggest targeting HMOX1hi macrophages as a potential therapeutic strategy for treating poor prognosis HGSC. Significance: Macrophages with elevated HMOX1 expression are enriched in PTEN-deficient high-grade serous ovarian carcinoma, promote tumor growth, and represent a potential therapeutic target.

Immunohistochemical Evaluation of Schlafen 11 (SLFN11) Expression in Cancer in the Search of Biomarker-Informed Treatment Targets: A Study of 127 Entities Represented by 6658 Tumors.

Schlafen 11 (SLFN11), a DNA/RNA helicase, acts as a regulator of cellular response to replicative stress and irreversibly triggers replication block and cell death. Several preclinical in vitro studies and clinical trials established that SLFN11 expression predicts outcomes in patients with advanced cancer treated with DNA-damaging chemotherapeutics and more recently with poly(ADP-ribose) polymerase inhibitors. SLFN11 expression status remains unknown in many cancer types, especially in mesenchymal tumors. This study evaluated a cohort of well characterized 3808 epithelial and 2850 mesenchymal and neuroectodermal tumors for SLFN11 expression using immunohistochemistry. Nuclear SLFN11 expression was rare in some of the most common carcinomas, for example, hepatocellular (1%), prostatic (2%), colorectal (5%), or breast (16%) cancers. In contrast, other epithelial tumors including mesotheliomas (92%), clear cell renal cell carcinomas (79%), small cell lung cancers (76%), squamous cell carcinomas of the tonsil (89%) and larynx (71%), or ovarian serous carcinomas (69%) were mostly SLFN11-positive. Compared with epithelial malignancies, SLFN11 expression was overall higher in neuroectodermal and mesenchymal tumors. Most positive entities included desmoplastic small round cell tumor (100%), Ewing sarcoma (92%), undifferentiated sarcoma (92%), solitary fibrous tumor (91%), dedifferentiated liposarcoma (89%), synovial sarcoma (86%), and malignant peripheral nerve sheath tumor (85%). Also, this study identifies tumors with potentially worse response to DNA-damaging drugs including antibody drug conjugates due to the absence of SLFN11 expression. Such entities may benefit from alternative treatments or strategies to overcome SLFN11 deficiency-related drug resistance. Our approach and results should serve as a foundation for future biomarker-associated clinical trials.

Molecular Analysis of High-Grade Serous Ovarian Carcinoma Exhibiting Low-Grade Serous Carcinoma and Serous Borderline Tumor.

Ovarian cancer is classified as type 1 or 2, representing low- and high-grade serous carcinoma (LGSC and HGSC), respectively. LGSC arises from serous borderline tumor (SBT) in a stepwise manner, while HGSC develops from serous tubal intraepithelial carcinoma (STIC). Rarely, HGSC develops from SBT and LGSC. Herein, we describe the case of a patient with HGSC who presented with SBT and LGSC, and in whom we analyzed the molecular mechanisms of carcinogenesis. We performed primary debulking surgery, resulting in a suboptimal simple total hysterectomy and bilateral salpingo-oophorectomy due to strong adhesions. The diagnosis was stage IIIC HGSC, pT3bcN0cM0, but the tumor contained SBT and LGSC lesions. After surgery, TC (Paclitaxel + Carbopratin) + bevacizumab therapy was administered as adjuvant chemotherapy followed by bevacizumab as maintenance therapy. The tumor was chemo-resistant and caused ileus, and bevacizumab therapy was conducted only twice. Next-Generation Sequencing revealed KRAS (p.G12V) and NF2 (p.W184*) mutations in all lesions. Interestingly, the TP53 mutation was not detected in every lesion, and immunohistochemistry showed those lesions with wild-type p53. MDM2 was amplified in the HGSC lesions. DNA methylation analysis did not show differentially methylated regions. This case suggests that SBT and LGSC may transform into HGSC via p53 dysfunction due to MDM2 amplification.