Immune landscape and TAM density in endometrial cancer: implications for immune checkpoint inhibitors efficacy.

Background: Immune checkpoint inhibitors (ICIs) have shown efficacy in endometrial cancer (EC); however, their efficacy varies according to mismatch repair (MMR) status. Notably, even among patients with MMR-deficient (MMRd) or microsatellite instability-high (MSI-H) tumors, approximately one-third exhibit primary resistance to ICI monotherapy.

Objectives: We aimed to characterize dissimilarities in the tumor immune microenvironment of ICI-treated MMRd/MSI-H versus MMR-proficient (MMRp)/microsatellite stable (MSS) EC, and to identify mechanisms of resistance.

HERV-derived epitopes represent new targets for T-cell-based immunotherapies in ovarian cancer.

Background: Ovarian cancer represents the most lethal gynecological cancer with poor response to checkpoint inhibitors. Human endogenous retroviruses (HERVs) are aberrantly expressed by tumor cells and may represent a source of shared T-cell epitopes for cancer immunotherapy regardless of the tumor mutational burden.

Methods: A transcriptomic analysis based on RNA sequencing was developed to quantify the expression of HERV-K sequences containing the selected epitopes.

[Optimal tissue quantity for molecular ancillary studies in multicenter clinical trials in gynecological oncology: Experience of the GINECO pathologists' group].

The national investigators group for ovarian and breast cancer studies (GINECO) is an academic clinical research group specialized in gynecological oncology. Within the translational research group, the pathologists have several roles, including qualifying samples from patients included in clinical trials (tumor surface and cellularity). Since 2015, several clinical trials have required the qualification of tissue material, leading to a substantial database gathering tumor surface and cellularity associated with the concentration and quantity of DNA/RNA extracted.

NUTM1/NUTM2B-Rearranged Intra-abdominal Sarcomas: A Distinct Entity From Sarcomas With ESR1 Overexpression as a Therapeutic Target.

Emerging evidence reports that NUTM1 rearrangements also occur in noncarcinomas, including skin tumors, leukemias, and high-grade sarcomas. Recently, a distinct subset of NUTM1-rearranged sarcomas was identified intra-abdominally, mainly of colonic origin, differing molecularly, based on limited methylation analysis. This study aimed to further explore 5 patients with NUTM1/NUTM2-rearranged intra-abdominal sarcomas at clinical, histologic, immunohistochemical, and transcriptomic levels.

Unraveling the Tumor Microenvironment and PD-L1 Expression across Tissue Types in High-Grade Serous Ovarian Cancer in the NeoPembrOV/GINECO Phase II Randomized Trial.

Purpose: To describe PD-L1 expression across tissue types and its associated tumor microenvironment and to investigate how it affects its predictive value for response to pembrolizumab in treatment-naïve patients with ovarian cancer included in the NeoPembrOV phase II trial (NCT03275506).

Experimental Design: PD-L1 expression was assessed for 85 patients (56 on metastasis and 29 on tubo-ovary) using tumor proportion score (TPS) and immune cell (IC) score, considering positivity if ≥1% and high expression if ≥5%. RNA sequencing and multiplex immunofluorescence were conducted.

Broad versus limited gene panels to guide treatment in patients with advanced solid tumors: a randomized controlled trial.

Large genomic programs have contributed to improving drug development in cancer. To assess the potential benefit of using larger gene panels to guide molecular-based treatments, we conducted a multicenter randomized trial in patients with advanced and/or metastatic solid cancer. Molecular alterations were determined using either a panel of 324 cancer-related genes (Foundation OneCDX (F1CDX)) or a limited panel of 87 single-nucleotide/indel genes and genome-wide copy number variations (CTL) and reviewed by a molecular tumor board to identify molecular-based recommended therapies (MBRTs).

The MEF2D::NCOA2 Fusion Defines a Distinct Emerging Vulvovaginal Myxoid Epithelioid Tumor With Smooth Muscle Differentiation.

Myocyte-specific enhancer factor 2D gene and nuclear receptor coactivator 2 gene fusion (MEF2D::NCOA2) was recently reported in 2 vulvovaginal myxoid epithelioid smooth muscle tumors. We aimed to perform an integrated approach combining clinical, morphologic, immunohistochemical, and molecular profiling analyses, including targeted RNA sequencing, targeted gene expression analysis profiling with clustering, DNA mutational analysis, and array comparative genomic hybridization in a series of 3 MEF2D::NCOA2 fusion-associated vulvovaginal tumors, to better describe this entity. The median age at diagnosis was 45 years.

Mucinous ovarian carcinoma: Impact of ovarian stimulation, hormonal contraception, and hormone replacement therapy.

Unlike high-grade serous carcinoma (HGSC), which mainly affects postmenopausal women, mucinous ovarian carcinoma (MOC) affects younger patients, with a median age at diagnosis of 53 years, and is rare among premenopausal women. After they receive anticancer treatment, these women encounter specific issues involving fertility preservation (FP) and/or pregnancy, which potentially require assisted reproductive technology (ART) as well as the prescription of hormonal contraception (HC) or hormone replacement therapy (HRT). We reviewed the available literature in PubMed/Medline concerning the risks of the development of ovarian cancer (OC), including MOC, associated with ART, HC and HRT, and literature on the impact of ovarian stimulation in the context of FP and/or ART, HC and HRT in women previously treated for OC, including MOC.

Breast Cancer Specificities of Patients With Anti-Ri Paraneoplastic Neurologic Syndromes.

Background And Objectives: Breast cancers (BCs) of patients with paraneoplastic neurologic syndromes and anti-Yo antibodies (Yo-PNS) overexpress human epidermal growth factor receptor 2 (HER2) and display genetic alterations and overexpression of the Yo-onconeural antigens. They are infiltrated by an unusual proportion of B cells. We investigated whether these features were also observed in patients with PNS and anti-Ri antibodies (Ri-PNS).

Can Morphology and Immune Infiltration Predict the Homologous Recombination Deficiency Status in Newly Diagnosed High-Grade Serous Ovarian Carcinoma?: Lessons From the PAOLA-1/ENGOT-ov25 Trial, a GINECO Study.

Context.—: A correlation between the morphology of ovarian high-grade serous carcinomas (HGSOCs) and BRCA mutations has been previously reported.

Objective.

Primary Vulvar and Vaginal Adenocarcinomas of Intestinal Type Are Closer To Colorectal Adenocarcinomas Than To Carcinomas of Müllerian Origin.

Primary vulvar and vaginal adenocarcinomas of intestinal type (VVAIts) are very rare tumors, displaying morphologic and immunohistochemical overlap with colorectal adenocarcinomas. However, their immunoprofile and genomics are poorly studied, and their origin is still debated. Here, we studied a series of 8 VVAIts (4 vulvar and 4 vaginal) using a large panel of immunohistochemistry and DNA and RNA sequencing with clustering analyses.

Targeting ERK-MYD88 interaction leads to ERK dysregulation and immunogenic cancer cell death.

The quest for targeted therapies is critical in the battle against cancer. The RAS/MAP kinase pathway is frequently implicated in neoplasia, with ERK playing a crucial role as the most distal kinase in the RAS signaling cascade. Our previous research demonstrated that the interaction between ERK and MYD88, an adaptor protein in innate immunity, is crucial for RAS-dependent transformation and cancer cell survival.

Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.

PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8PD-1 T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.

Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial.

This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional.

Olaparib Addition to Maintenance Bevacizumab Therapy in Ovarian Carcinoma With BRCA-Like Genomic Aberrations.

Importance: Testing for homologous recombination deficiency is required for the optimal treatment of high-grade epithelial ovarian cancer. The search for accurate biomarkers is ongoing.

Objective: To investigate whether progression-free survival (PFS) and overall survival (OS) of patients with high-grade epithelial ovarian cancer treated with maintenance olaparib or placebo differed between patients with a tumor BRCA-like genomic profile and patients without a tumor BRCA-like profile.

BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges.

genes are part of homologous recombination (HR) DNA repair pathways in charge of error-free double-strand break (DSB) repair. Loss-of-function mutations of genes have been associated for a long time with breast and ovarian cancer hereditary syndrome. Recently, polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) have revolutionized the therapeutic landscape of -mutated tumors, especially of high-grade serous ovarian cancer (HGSC), taking advantage of HR deficiency through the synthetic lethality concept.

The CSF-1R inhibitor pexidartinib affects FLT3-dependent DC differentiation and may antagonize durvalumab effect in patients with advanced cancers.

Tumor-associated macrophages (TAMs) are a critical determinant of resistance to PD-1/PD-L1 blockade. This phase 1 study (MEDIPLEX, NCT02777710) investigated the safety and efficacy of pexidartinib, a CSF-1R-directed tyrosine kinase inhibitor (TKI), and durvalumab (anti-PD-L1) in patients with advanced colorectal and pancreatic carcinoma with the aim to enhance responses to PD-L1 blockade by eliminating CSF-1-dependent suppressive TAM. Forty-seven patients were enrolled.

[A curious biphasic breast lesion].

Adenomyoepithelioma represents 0.5% of breast tumors in postmenauposal women. Prognosis is good when the tumor is benign.

p4EBP1 staining predicts outcome in ER-positive endocrine-resistant metastatic breast cancer patients treated with everolimus and exemestane.

Background: To identify patients most likely to respond to everolimus, a mammalian target of rapamycin (mTOR) inhibitor, a prospective biomarker study was conducted in hormone receptor-positive endocrine-resistant metastatic breast cancer patients treated with exemestane-everolimus therapy.

Methods: Metastatic tumor biopsies were processed for immunohistochemical staining (p4EBP1, PTEN, pAKT, LKB1, and pS6K). ESR1, PIK3CA and AKT1 gene mutations were detected by NGS.

Pan-TRK immunohistochemistry in gynaecological mesenchymal tumours: diagnostic implications and pitfalls.

Aims: NTRK-rearranged sarcomas of the female genital tract mainly occur in the uterus (more commonly cervix than corpus) and are characterized by a "fibrosarcoma-like" morphology and NTRK gene rearrangements. These neoplasms may exhibit histological overlap with other entities and can present diagnostic difficulties without molecular confirmation. Pan-TRK immunohistochemistry was developed to identify tumours harbouring NTRK rearrangements.

MDR1-EXPRESSING CD4 T CELLS WITH TH1.17 FEATURES RESIST TO NEOADJUVANT CHEMOTHERAPY AND ARE ASSOCIATED WITH BREAST CANCER CLINICAL RESPONSE.

Background: Multidrug resistance-1 (MDR1) transporter limits the intracellular accumulation of chemotherapies (paclitaxel, anthracyclines) used in breast cancer (BC) treatment. In addition to tumor cells, MDR1 is expressed on immune cell subsets in which it confers chemoresistance. Among human T cells, MDR1 is expressed by most CD8 T cells, and a subset of CD4 T helper (Th) cells.

An Early Neoplasia Index (ENI10), Based on Molecular Identity of CD10 Cells and Associated Stemness Biomarkers, is a Predictor of Patient Outcome in Many Cancers.

Unlabelled: An accurate estimate of patient survival at diagnosis is critical to plan efficient therapeutic options. A simple and multiapplication tool is needed to move forward the precision medicine era. Taking advantage of the broad and high CD10 expression in stem and cancers cells, we evaluated the molecular identity of aggressive cancer cells.