High-grade Serous Ovarian Carcinoma Research Articles

Molecular Subgroups of HRD Positive Ovarian Cancer and Their Prognostic Significance

Homologous recombination repair deficiency (HRD) is involved in the development of high-grade serous ovarian carcinoma (HGSOC) and its elevated sensitivity to platinum-based chemotherapy. To investigate the heterogeneity of the HRD-positive HGSOC we evaluated the HRD status, including BRCA mutations, genomic scar score, and methylation status of BRCA1/2 genes in 352 HGSOC specimens. We then divided the HRD-positive cohort into three molecular subgroups, the BRCA mutation cohort (BRCA+), BRCA1 methylation cohort (Meth+), and the rest of the HRD+ cohort (HRD+BRCA-Meth-), and evaluated their first-line chemotherapy response, benefit from olaparib, and progression-free survival (PFS). HRD-positive status was detected in 65% (228/352) of samples. The first group, BRCA+, accounted for 45% (102/228) of HRD positive cases and showed the best outcome in platinum therapy (ORR 96%), the highest olaparib benefit (p = 0.006) and the highest median PFS (46 months). The frequency of the second cohort, Meth+, among HRD-positive patients was 23% (52/228). Patients with Meth+ HGSOC showed a significantly poorer outcome, with a median PFS of 19 months, a significantly lower ORR to platinum therapy (84%) and a modest, but not significant, benefit from olaparib maintenance. The third HRD+BRCA-Meth- group accounted for 32% (74/228) of HRD-positive patients and showed an ORR to platinum therapy similar to that of the BRCA+ group (90%), a higher, but not statistically significant, benefit from olaparib and a median PFS of 23 months. In conclusion, Meth+ subgroup had poor outcomes in terms of chemotherapy response, olaparib benefit, and PFS compared to the other HRD+ subgroups, requiring a more thorough follow-up.

Morphologic Characteristics Seen in High-grade Serous Ovarian Carcinoma Metastases in Postneoadjuvant Chemotherapy Resections.

The morphologic features of metastatic high-grade serous ovarian carcinoma (HGSOC) after neoadjuvant chemotherapy have not been described. We conducted a 1-year retrospective, single-institution review of pretreatment biopsy and posttreatment metastases in cases of HGSOC treated with neoadjuvant chemotherapy. Two gynecologic pathologists and 1 pathology resident reviewed 11 cases looking for 6 morphologic features. We correlated these features with patient information on HRD abnormalities (HRD score, germline, and/or somatic BRCA mutations). When compared with the pretreatment biopsies of metastases taken at the time of diagnosis, the postneoadjuvant, treated metastases had unique morphologic findings, such as cytoplasmic vacuolization, cellular enlargement with eosinophilic cytoplasm, macro-nucleoli, cellular discohesion, and micropapillary architecture with abundant psammoma bodies. Metastases were also morphologically different from the primary site in the postneoadjuvant resection specimens.

Characterizing the genomic landscape through the lens of FOLR1 status in low and high grade serous ovarian carcinoma

ObjectiveTargeted therapy in folate receptor alpha (FOLR1)-positive high grade serous ovarian carcinoma (HGSOC) is now a mainstay for platinum-resistant disease. However, the rate of FOLR1-positivity in low grade serous ovarian carcinoma (LGSOC) is not well documented. Less common than HGSOC, LGSOC tends to respond poorly to traditional platinum-based chemotherapeutic regimens, particularly in recurrence. Thus, there is an urgent need to identify molecular targets that may assist in identifying more efficacious treatments for LGSOC. In this work, we assessed the genomic and transcriptomic landscapes in FOLR1-positive/negative LGSOC compared to its high-grade counterpart. MethodsUsing a large precision oncology database, next-generation sequencing and immunohistochemistry was performed on a cohort of 281 LGSOC and 5086 HGSOC. Associated MAPK activation was calculated based on NGS results and patient survival analysis was completed stratified by molecular alteration. ResultsCompared with LGSOC (24.6 %), HGSOC tumors have significantly higher prevalence of FOLR1+ status (43.5 %) and significantly higher PD-L1+ status. Conversely, LGSOC had higher prevalence of KRAS and NRAS mutations, with a near exclusivity for BRAF mutation compared to HGSOC. FOLR1- LGSOC and HGSOC had similar prevalences of T cell-inflamed tumors, though FOLR1+ LGSOC had a significantly lower prevalence of T-Cell inflamed tumors than FOLR1+ HGSOC. MAPK activation, quantified via MAPK activation score (MPAS), was significantly higher in low-grade tumors compared to HGSOC, yet no difference between FOLR1+ vs FOLR1- LGSOC was observed. ConclusionsThough less than in high-grade disease, a notable portion of low-grade tumors were FOLR1+, suggesting FOLR1 expression in LGSOC could be a viable target for this rare histology, particularly in the recurrent setting.

Predictive impact of clinical factors on chemosensitivity in advanced high-grade serous ovarian carcinoma according to chemotherapy response score

The use of neoadjuvant chemotherapy (NAC) as a first-line therapy for advanced high-grade serous ovarian carcinoma (HGSOC) has increased. However, several studies have reported NAC-induced platinum resistance. This study aimed to evaluate the predictive impact of clinical factors on chemotherapy response score (CRS) and to select patients who would respond well to NAC. This multicenter retrospective (study included patients treated between January 2016 and December 2021). International Federation of Gynecology and Obstetrics stage IIIC and IV HGSOC patients were eligible. Institutionally strict complete resectability criteria were used in the present study. Pathological slides were scored according to the CRS criteria. Among 172 patients with HGSOC, 87 (50.6%) had stage IIIC disease and 85 (49.4%) had stage IV disease. And 35 (20.4%) had CRS1, 103 patients were CRS2 (59.9%), and 34 patients were CRS3 (19.7%). Compared with CRS1, simultaneous metastases to distant lymph nodes and solid organs confirmed by imaging were associated with a 75% reduction in CRS2 (odds ratio = 0.25; 95% confidence interval: 0.09–0.70; P = .008). And breast cancer susceptibility gene 1/2 mutation was positively (odds ratio = 8.41; 95% confidence interval: 2.25–31.52; P = .002) associated with CRS3 compared to CRS1. Patients with CRS3 had significantly longer progression-free survival (PFS), with median PFS of 9.8, 14.8, and 27.0 months for CRS of 1, 2, and 3, respectively (P < .001). Overall survival was also prolonged in patients with CRS3 (P < .001). Germline breast cancer susceptibility gene 1/2 mutation was a predictor of CRS3 and a good prognostic factor for the survival rate. Simultaneous metastasis to distant lymph nodes and solid organs is a predictor of CRS1. CRS inversely correlated with PFS and overall survival.

Evaluation of the recently established Dutch nationwide Archipelago of Ovarian Cancer Research biobank

Fundamental and translational research in ovarian cancer aims to enhance understanding of disease mechanisms and improve treatment and survival outcomes. To support this, we established the Dutch multicenter, interdisciplinary Archipelago of Ovarian Cancer Research (AOCR) infrastructure, which includes a nationwide biobank. In this study, we share our experiences in establishing the infrastructure, offer guidance for similar initiatives, and evaluate the AOCR patient cohort. Key challenges included obtaining Data Protection Impact Assessment (DPIA) clearance, drafting the consortium agreement, and securing ethical approval from all hospitals. Over three years, 1093 patients were enrolled across 17 hospitals, resulting in the collection of 1339 tissue samples and 2280 blood samples. Of the 523 patients with currently available clinical and pathological data, 74 % (n = 387) had primary ovarian cancer. Among these patients, 73.4 % was diagnosed with high-grade serous ovarian carcinoma, and 80.9 % presented with advanced-stage disease. Surgery was performed on 93 % of patients with primary ovarian cancer, and chemotherapy was administered to 90.4 % of these patients. In conclusion, the AOCR biobank has established a robust foundation for future fundamental and translational ovarian cancer research. This manuscript provides valuable insights and guidance for developing future research infrastructures and biobanks, and contains detailed information about the AOCR patient cohort to date.

Repurposing colforsin daropate to treat MYC-driven high-grade serous ovarian carcinomas.

High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers for women, with a low survival rate, no early detection biomarkers, a high rate of recurrence, and few therapeutic options. Forskolin, an activator of cyclic AMP signaling, has several anticancer activities, including against HGSOC, but has limited use in vivo. Its water-soluble derivative, colforsin daropate, has the same mechanism of action as forskolin and is used to treat acute heart failure. Here, we investigated the potential of colforsin daropate as a treatment for HGSOC. We found that colforsin daropate induced cell cycle arrest and apoptosis in cultured HGSOC cells and spheroids but had negligible cytotoxicity in immortalized, nontumorigenic fallopian tube secretory cells and ovarian surface epithelial cells. Colforsin daropate also prevented HGSOC cells from invading ovarian surface epithelial cell layers in culture. In vivo, colforsin daropate reduced tumor growth, synergized with cisplatin (a standard chemotherapy in ovarian cancer care), and improved host survival in subcutaneous and intraperitoneal xenograft models. These antitumor effects of colforsin daropate were mediated in part by its reduction in the abundance and transcriptional activity of the oncoprotein c-MYC, which is often increased in HGSOC. Our findings demonstrate that colforsin daropate may be a promising therapeutic that could be combined with conventional therapies to treat HGSOC.

Abstract C052: Induction of senescence by paclitaxel in high-grade serous ovarian carcinoma (HGSOC) cells renders the cells resistant to paclitaxel but sensitizes them to BCL-xL targeting agents

Abstract High-grade serous ovarian carcinoma (HGSOC) is a very aggressive form of ovarian cancer, contributing to most ovarian cancer deaths. Paclitaxel is one of the major components of the first line treatment for HGSOC, but the development of chemoresistance to paclitaxel leads to the frequent relapse of the disease and poor prognosis in HGSOC patients. However, the mechanism underlying the chemoresistance has not been well established nor have the strategies to overcome the resistance been developed, which was investigated in the present study using three representative HGSOC cell lines (i.e. Kuramochi, OVCAR4, and OVCAR3 cells) in vitro. The results from our study show that induction of senescence contributes to paclitaxel-induced chemoresistance in HGSOC cells. More importantly, we found that senescent HGSOC cells induced by paclitaxel became highly dependent on BCL-xL for survival and thus were very sensitive to BCL-xL targeting agents, particularly to DT2216 (a BCL-xL specific proteolysis targeting chimera or PROTAC) and 753b (a BCL-xL and BCL-2 dual PROTAC). Because these PROTACs are more potent against senescent HGSOC cells but less toxic to platelets than ABT263 (a BCL-xL and BCL-2 dual inhibitor), they have the potential to be developed as new senolytics to overcome HGSOC chemoresistance to paclitaxel without causing the on-target and dose-limiting thrombocytopenia associated with ABT263 treatment. Citation Format: Yang Yang. Induction of senescence by paclitaxel in high-grade serous ovarian carcinoma (HGSOC) cells renders the cells resistant to paclitaxel but sensitizes them to BCL-xL targeting agents [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C052.

Microtubule poleward flux as a target for modifying chromosome segregation errors

Cancer cells often display errors in chromosome segregation, some of which result from improper chromosome alignment at the spindle midplane. Chromosome alignment is facilitated by different rates of microtubule poleward flux between sister kinetochore fibers. However, the role of the poleward flux in supporting mitotic fidelity remains unknown. Here, we introduce the hypothesis that the finely tuned poleward flux safeguards against lagging chromosomes and micronuclei at mitotic exit by promoting chromosome alignment in metaphase. We used human untransformed RPE-1 cells depleted of KIF18A/kinesin-8 as a system with reduced mitotic fidelity, which we rescued by three mechanistically independent treatments, comprising low-dose taxol or codepletion of the spindle proteins HAUS8 or NuMA. The rescue of mitotic errors was due to shortening of the excessively long overlaps of antiparallel microtubules, serving as a platform for motor proteins that drive the flux, which in turn slowed down the overly fast flux and improved chromosome alignment. In contrast to the prevailing view, the rescue was not accompanied by reduction of overall microtubule growth rates. Instead, speckle microscopy revealed that the improved chromosome alignment in the rescue treatments was associated with slower growth and flux of kinetochore microtubules. In a similar manner, a low-dose taxol treatment rescued mitotic errors in a high-grade serous ovarian carcinoma cell line OVKATE. Collectively, our results highlight the potential of targeting microtubule poleward flux to modify chromosome instability and provide insight into the mechanism through which low doses of taxol rescue certain mitotic errors in cancer cells.

PATH-51. CENTRAL NERVOUS SYSTEM METASTASES ARE GENOMICALLY DIVERGENT FROM THEIR RESPECTIVE EXTRACRANIAL SITES

Abstract INTRODUCTION Next-generation sequencing (NGS) has become standard of care in establishing the diagnosis and guiding treatment of cancers. Our understanding of genomic evolution of brain metastases (BM) and leptomeningeal disease (LMD) from solid tumor malignancies remains limited. Here we present updated data from our pilot study. METHODS We prospectively collected clinical data and NGS of seventeen patients undergoing craniotomy for symptomatic BM from solid tumor malignancies or cerebrospinal fluid (CSF) sampling for LMD. Matched systemic and CNS analyses were performed using a research-based NGS assay. When extracranial disease tissue was unavailable, liquid NGS served as a surrogate. RESULTS CNS metastases were present at initial diagnosis in 10/17 and 11/17 patients had not received systemic therapy prior to CNS tissue sampling. The predominant cancer type was NSCLC (n=11), followed by breast cancer (n=3), ovarian high grade serous carcinoma (n=1), GEJ adenocarcinoma (n=1), and basosquamous carcinoma of skin (n=1). The mean tumor mutational burden in extracranial samples was 3.65 (SD 3.34; SEM 0.97), in contrast to CNS samples 21.63 (SD 26.47; SEM 7.64). Concordant mutations in matched sampling had an increase in CNS variant allele frequency (VAF) (27.8% vs 17.3%; arithmetic difference = 10.5, p=0.054) and CNS gene copy number alterations (CNA) (2.4 copies vs 0.8 copies; arithmetic difference = 1.6, p=0.171). Known driver alterations in EGFR, KRAS and PIK3CA were retained. LMD was present in 4/17 patients, with two present at enrollment and two developing during the study. CONCLUSIONS Matched sequencing reveals CNS metastases to harbor a significantly higher TMB, retention of primary driver alterations with a trend towards higher VAF and CNA of concordant mutations. While limited by small sample size, these data indicate genetic evolution in CNS metastases regardless of prior treatment status.

A novel ITGB8 transcript variant sustains ovarian cancer cell survival through genomic instability and altered ploidy on a mutant p53 background

BackgroundTranscript variants and protein isoforms are central to unique tissue functions and maintenance of homeostasis, in addition to being associated with aberrant states such as cancer, where their crosstalk with the mutated tumor suppressor p53 may contribute to genomic instability and chromosomal rearrangements. We previously identified several novel splice variants in ovarian cancer RNA-sequencing datasets; herein, we aimed to elucidate the biological effects of the Integrin Subunit Beta 8 variant (termed pITGB8-205).MethodsResolution of the full-length sequence of pITGB8-205 through rapid amplification of cDNA ends (RACE-PCR). Cell cycle analysis and karyotype studies were performed to further explore genomic instability. RNA-seq and proteomics analyses were used to identify the differential expression of the genes.ResultsThis full-length study revealed a unique 5’ sequence in pITGB8-205 that differed from the reported ITGB8-205 sequence, suggesting differential regulation of this novel transcript. Under a p53 mutant background, overexpression of pITGB8-205 triggered genetic instability reminiscent of oncogene-induced replicative stress with extensive abnormal mitoses and chromosomal and nuclear aberrations indicative of chromosomal instability, leading to near whole-genome duplication that imposes energy stress on cellular resources. Micronuclei and aneuploidy are striking features of pITGB8-205-overexpressing p53-mutant cells but are not enhanced in p53 wild-type (WT) cells. RNA-seq and proteomics analyses further suggested that p53 inactivation in ovarian cancer provides a permissive intracellular molecular niche for pITGB8-205 to mediate its effects on genomic instability. This observation is pivotal considering that most high-grade serous ovarian carcinoma (HGSC) tumors express mutant p53. The resulting aneuploid clones with enhanced self-renewal and survival capabilities disrupt clonal dominance under stress yet maintain a balance between replicative stress and prosurvival advantages.ConclusionpITGB8-205-overexpressing clones sustain ovarian tumor cell survival, achieve homeostasis and are formidable opponents of therapy.

Dual Targeting of CX3CR1 and PARP in Models of High-Grade Serous Ovarian Carcinoma.

Clinical use of poly(ADP-ribose) polymerase inhibitors (PARPis) against metastatic high-grade serous ovarian carcinoma (HGSOC) is limited to cases with deficient a homologous recombination (HR). Our objective was to determine whether the impairment of the fractalkine receptor (CX3CR1) could sensitize HR-proficient cases to PARPis. The efficacy of a dual drug combination, including AZD8797, an inhibitor of CX3CR1, and several PARPis was examined using cell lines and xenograft models. The effectiveness of PARPis and AZD8797 drug combinations ranged from additive to strongly synergistic. Olaparib was synergistic with AZD8797 in OVCAR-4, Caov-3, and OHSAHO. Niraparib and AZD8797 produced synergy in OVCAR-4 and ES2. Rucaparib and AZD8797 were strongly synergistic in Caov-3 and OVSAHO. Veliparib was strongly synergistic with AZD8797 in OVCAR-4 and Caov-3. Notably, a combination of veliparib and AZD8797 produced a strong synergistic effect in a xenograft model. While the exact mechanisms determining the nature of the PARPis and AZD8797 interaction remain to be uncovered, our data indicate that, in a subset of models, selected PARPis strongly synergize with the inhibition of CX3CR1, suggesting a potential therapeutic opportunity.

Time-Trend Analysis and Risk Factors for Niraparib-Induced Nausea and Vomiting in Ovarian Cancer: A Prospective Study.

Nausea and vomiting are major non-hematological adverse events associated with niraparib maintenance therapy. This study aimed to investigate the time-trend patterns of niraparib-induced nausea and vomiting (NINV) and the associated risk factors in patients with ovarian cancer. In this prospective study, we enrolled patients with stage III-IV epithelial ovarian cancer who received niraparib as frontline maintenance therapy. The clinicopathological characteristics and time-trend patterns of patients with NINV were collected through in-person surveys and electronic medical records from the National Cancer Center. Of 53 patients, 50 (94.3%) were diagnosed with high-grade serous ovarian carcinoma. BRCA mutations and homologous recombination deficiency (HRD) were identified in 23 (43.4%) and 32 (60.4%) patients, respectively. Thirty-one patients (58.5%) had NINV. Time-trend analyses revealed that the first peak intensity of NINV was reached at 3 h post-dose, and the second peak intensity was reached at 11 h post-dose. NINV significantly decreased from week 1 to weeks 8 and 12. In multivariate analyses of risk factors for NINV, HRD-positive tumors (p<0.001) and prior experience of chemotherapy-induced nausea and vomiting (p=0.004) were associated with the occurrence of NINV. Pre-emptive treatment with antiemetics are required to manage early-phase NINV during niraparib maintenance therapy in patients with risk factors. Additional larger studies are needed to confirm these findings and to develop optimal preventive strategies for NINV.

Intraoperative imaging of residual ovarian cancer after neoadjuvant chemotherapy using indocyanine green

ObjectivesInterval debulking surgery has similar outcomes and less morbidity compared with primary debulking in advanced ovarian cancer. However, there is controversy regarding the selection of chemotherapy-resistant clones. Complete resection is...

Spatial RNA sequencing supports programmed death ligand 2 (PD-L2) as a potential immunotherapy target in high-grade serous ovarian carcinoma

Spatial RNA sequencing supports programmed death ligand 2 (PD-L2) as a potential immunotherapy target in high-grade serous ovarian carcinoma

Deep quantitative proteomics identifies elevated MUC16 in low- compared to high-grade serous ovarian carcinoma

Deep quantitative proteomics identifies elevated MUC16 in low- compared to high-grade serous ovarian carcinoma

Changes in HRD status during treatment for ovarian high-grade serous carcinoma

Changes in HRD status during treatment for ovarian high-grade serous carcinoma

Tumor-intrinsic chemosensitivity assessed by KELIM and prognosis by BRCA status in patients with advanced ovarian carcinomas.

Treatment of high-grade serous ovarian carcinomas relies on surgery and chemotherapy, potentially followed by bevacizumab and/or poly (ADP-ribose) polymerase inhibitors (PARPi). The modeled CA-125 ELIMination rate constant K (KELIM) is a pragmatic indicator of tumor primary chemosensitivity. Although it is well established that BRCA mutations are associated with platinum sensitivity, the relationship between BRCA status and KELIM score has yet to be elucidated. This study aimed to evaluate the interactions between BRCA and KELIM, and their respective prognostic values. We retrospectively collected data from 743 patients with high-grade serous ovarian carcinomas included in a French nationwide registry (NCT03275298) treated with neoadjuvant platinum-based chemotherapy followed by surgery. We analyzed the interactions between BRCA and KELIM, and their impacts on progression-free survival and overall survival. BRCA-mutated (BRCAm) patients had higher standardized KELIM than BRCA-wild type (BRCAwt) tumors (median 1.16 vs 1.06, respectively; p=0.001). The prognostic value of the KELIM score was independent of BRCA in multivariate analyses. KELIM score and BRCA could be combined to define three prognostic groups: (1) an unfavorable prognostic group with both BRCAwt and unfavorable KELIM (median progression-free survival 12.0 months); (2) an intermediate prognostic group with either BRCAm and unfavorable KELIM, or BRCAwt and favorable KELIM (median progression-free survival of 16.0 and 18.8 months, respectively; HR 0.64 compared with the unfavorable group, p<0.001); and (3) a favorable prognostic group with both BRCAm and favorable KELIM (median progression-free survival 28.8 months; HR 0.37 compared with the unfavorable group, p<0.001). The KELIM score provides complementary prognostic information with respect to BRCA, and discriminates different prognoses within BRCAm or BRCAwt patients. Patients with both BRCAwt/unfavorable KELIM have a poor prognosis, underscoring the urgent need for novel therapeutic strategies.

Multimodal Optical Imaging of Ex Vivo Fallopian Tubes to Distinguish Early and Occult Tubo-Ovarian Cancers.

Background: There are currently no effective screening measures to detect early or occult tubo-ovarian cancers, resulting in late-stage detection and high mortality. This work explores whether an optical imaging catheter can detect early-stage tubo-ovarian cancers or precursor lesions where they originate in the fallopian tubes. Methods: This device collects co-registered optical coherence tomography (OCT) and autofluorescence imaging (AFI). OCT provides three-dimensional assessment of underlying tissue structures; autofluorescence imaging provides functional contrast of endogenous fluorophores. Ex vivo fallopian tubes (n = 28; n = 7 cancer patients) are imaged; we present methods for the calculation of and analyze eleven imaging biomarkers related to fluorescence, optical attenuation, and OCT texture for their potential to detect tubo-ovarian cancers and other lesions of interest. Results: We visualize folded plicae, vessel-like structures, tissue layering, hemosiderin deposits, and regions of fibrotic change. High-grade serous ovarian carcinoma appears as reduced autofluorescence paired with homogenous OCT and reduced mean optical attenuation. Specimens containing cancerous lesions demonstrate a significant increase in median autofluorescence intensity and decrease in Shannon entropy compared to specimens with no lesion. Non-cancerous specimens demonstrate an increase in optical attenuation in the fimbriae when compared to the isthmus or the ampulla. Conclusions: We conclude that this approach shows promise and merits further investigation of its diagnostic potential.

A Comprehensive Review of TRPS1 as a Diagnostic Immunohistochemical Marker for Primary Breast Carcinoma: Latest Insights and Diagnostic Pitfalls.

Immunohistochemical expression of TRPS1 (trichorhinophalangeal syndrome type 1) protein is usually used by pathologists to confirm breast origin for triple-negative breast cancers (TNBC) or metastatic carcinomas of unknown primary. However, recent studies have reported TRPS1 expression in a variety of non-breast lesions. This review aims to provide a comprehensive evaluation of TRPS1 expression across various tumor types, highlighting both its diagnostic utility and potential pitfalls that may arise in clinical practice. A thorough search of the PubMed database on TRPS1 immunoexpression in tumor pathology was conducted. While the gene itself has been known for several decades, most studies regarding its use in immunohistochemistry emerged in the late 2010s. Particular emphasis was placed on case reports and cohort studies that examined the implications of TRPS1 expression in non-breast tissues, as well as variations in the results between commercially available TRPS1 clones, which may influence the staining intensity and specificity. TRPS1 demonstrated a strong diagnostic utility in identifying primary breast lesions, particularly in TNBC cases. However, its expression in a growing number of non-breast cancers, such as lung adenocarcinoma, prostate adenocarcinoma, urothelial carcinoma, ovarian high-grade serous carcinoma, and endometrial adenocarcinoma, as well as up to 96% of synovial sarcomas with SS18-SSX fusion, emphasizes the need for caution when interpreting TRPS1 positivity and suggests a multi-marker approach in order to increase the diagnostic accuracy. While TRPS1 remains a highly sensible immunohistochemical marker for confirming breast primary lesions, pathologists should be aware of its low specificity and incorporate complementary diagnostic methods in order to ensure accurate clinical management. Further research should focus on elucidating the molecular pathways regulating TRPS1 expression in various tumor types, which may better define its clinical utility.

Assessing the impact of deep-learning assistance on the histopathological diagnosis of serous tubal intraepithelial carcinoma (STIC) in fallopian tubes.

In recent years, it has become clear that artificial intelligence (AI) models can achieve high accuracy in specific pathology-related tasks. An example is our deep-learning model, designed to automatically detect serous tubal intraepithelial carcinoma (STIC), the precursor lesion to high-grade serous ovarian carcinoma, found in the fallopian tube. However, the standalone performance of a model is insufficient to determine its value in the diagnostic setting. To evaluate the impact of the use of this model on pathologists' performance, we set up a fully crossed multireader, multicase study, in which 26 participants, from 11 countries, reviewed 100 digitalized H&E-stained slides of fallopian tubes (30 cases/70 controls) with and without AI assistance, with a washout period between the sessions. We evaluated the effect of the deep-learning model on accuracy, slide review time and (subjectively perceived) diagnostic certainty, using mixed-models analysis. With AI assistance, we found a significant increase in accuracy (p < 0.01) whereby the average sensitivity increased from 82% to 93%. Further, there was a significant 44 s (32%) reduction in slide review time (p < 0.01). The level of certainty that the participants felt versus their own assessment also significantly increased, by 0.24 on a 10-point scale (p < 0.01). In conclusion, we found that, in a diverse group of pathologists and pathology residents, AI support resulted in a significant improvement in the accuracy of STIC diagnosis and was coupled with a substantial reduction in slide review time. This model has the potential to provide meaningful support to pathologists in the diagnosis of STIC, ultimately streamlining and optimizing the overall diagnostic process.