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Background Knowing the homologous recombination deficiency (HRD) status in advanced epithelial ovarian cancer (EOC) is vital for patient management. HRD is determined by BRCA1/BRCA2 pathogenic variants or genomic instability. However, tumor DNA analysis is inconclusive in 15–19% of cases. Peritoneal fluid, available in > 95% of advanced EOC cases, could serve as an alternative source of cell-free tumor DNA (cftDNA) for HRD testing. Limited data show the feasibility of cancer panel gene testing on ascites cfDNA but no study, to date, has investigated HRD testing. Methods We collected ascites/peritoneal washings from 53 EOC patients (19 from retrospective cohort and 34 from prospective cohort) and performed a Cancer Gene Panel (CGP) using NGS for TP53/HR genes and shallow Whole Genome Sequencing (sWGS) for genomic instability on cfDNA. Results cfDNA was detectable in 49 out of 53 patients (92.5%), including those with limited peritoneal fluid. Median cfDNA was 3700 ng/ml, with a turnaround time of 21 days. TP53 pathogenic variants were detected in 86% (42/49) of patients, all with HGSOC. BRCA1 and BRCA2 pathogenic variants were found in 14% (7/49) and 10% (5/49) of cases, respectively. Peritoneal cftDNA showed high sensitivity (97%), specificity (83%), and concordance (95%) with tumor-based TP53 variant detection. NGS CGP on cftDNA identified BRCA2 pathogenic variants in one case where tumor-based testing failed. sWGS on cftDNA provided informative results even when tumor-based genomic instability testing failed. Conclusion Profiling cftDNA from peritoneal fluid is feasible, providing a significant amount of tumor DNA. This fast and reliable approach enables HRD testing, including BRCA1/2 mutations and genomic instability assessment. HRD testing on cfDNA from peritoneal fluid should be offered to all primary laparoscopy patients.

In situ mantle cell neoplasia (ISMCN) is a rare entity of disputed clinical significance. We report an additional case, unusual by its presentation in the large intestine and its multifocal involvement of several nodal and extranodal sites. The diagnosis was made in a 46-year-old male patient from a surgical specimen resected for cecal adenocarcinoma. Gross examination showed multiple small polypoid lesions surrounding the ileocecal valve, corresponding to lymphoid aggregates with hyperplastic follicles. Numerous cyclin D1/SOX11+ lymphoid cells, harboring the t(11;14)(q13;q32) translocation, were present in the inner layers of mantle zones. The same lesions were found in the ileum, the appendix, and the regional lymph nodes. The final diagnosis was multifocal ISMCN of the ileocecal region, with both nodal and extra-nodal involvement. A simple surveillance was decided. Our observation expands the clinical spectrum of the disease and underlines the necessity to closely examine even normal-appearing reactive lymphoid tissues.

Next-generation sequencing (NGS) assays based on plasma cell-free DNA (cfDNA) are increasingly used for clinical trials inclusion. Their optimized limit of detection applied to a large number of genes leads to the identification of mutations not confirmed in tissue. It becomes essential to describe the characteristics and consequences of these liquid biopsy-only mutations . In the STING protocol (Gustave Roussy, NCT04932525), 542 patients with advanced solid cancer had cfDNA-based and tissue-based NGS analysis (performed by FoundationOne® Liquid CDx and FoundationOne CDx™, respectively). Mutations identified in the liquid biopsy but not in the paired tissue were considered as liquid biopsy-only mutations irrespective of their variant allelic frequency (VAF). Out of 542 patients, 281 (51.8%) harbored at least one liquid biopsy-only mutation . These patients were significantly older, and more heavily pretreated. Liquid biopsy-only mutations occurring in TP53 , and in DDR genes ( ATM , CHEK2, ATR, BRCA2, and BRCA1) accounted for 90.8% of all the mutations. The median VAF of these mutations was generally low (0.37% and 0.40% for TP53 and DDR genes respectively). The variant type repartition depended on the gene. Liquid biopsy-only mutations affected hotspot in TP53 codon 273, 125, 195, 176, 237 or 280 and ATM codon 2891 and 3008. In a subset of 37 patients, 75.0%, 53.5% and 83.3% of the liquid biopsy-only mutations occurring respectively in ATM , TP53, and CHEK2 were confirmed in the matching whole blood sample. Although liquid biopsy-only mutations makes the interpretation of liquid biopsy results more complex, they have distinct characteristics making them more easily identifiable.

FDA-approved next-generation sequencing assays based on cell-free DNA offers new opportunities in a molecular-tumor-board context thanks to the noninvasiveness of liquid biopsy, the diversity of analyzed parameters and the short turnaround time. It gives the opportunity to study the heterogeneity of the tumor, to elucidate complex resistance mechanisms and to adapt treatment strategies. However, lowering the limit of detection and increasing the panels’ size raise new questions in terms of detection of incidental germline alterations, occult malignancies and clonal hematopoiesis of indeterminate potential mutations. In this review, after a technological discussion and description of the common problematics encountered, we establish recommendations in properly using these FDA-approved tests in a molecular-tumor-board context.

Key Clinical Message This is the first case of a promyelocytic sarcoma diagnosed on pleural effusion and exposed the difficulty of demonstrating a leukemic phase in patients with bone diseases, such as Gorham's disease. It also showed that promyelocytic sarcoma can be treated by ATRA/ATO‐based therapy with an efficient and tolerated response. Myeloid sarcoma (MS) is a rare extramedullary tumoral infiltration of immature myeloid cells and can occur in different sites of the body, without leukemic infiltration. A 38‐year‐old woman patient presented at emergency with a pleural effusion, bicytopenias, and Gorham's disease, a very rare bone disorder. In the following days, she worsened with a chylothorax and pancytopenias. Pleural puncture cytologically revealed promyelocytes with Auer rods. Cytogenetic and molecular analyses subsequently confirmed the presence of the t(15:17) translocation. However, no circulating phase of these atypical promyelocytes was found. Similarly, no other origin was identified. We conclude that the patient had a MS of unknown etiology in the form of a pleural effusion with pathological promyelocytes. The patient was treated with a combination of oral all‐trans retinoic acid (ATRA) and arsenic trioxide (ATO) with a cytological and molecular remission persisting 3 months after diagnosis. We report here the first case of a promyelocytic MS of pleural origin without concomitant evidence of acute promyelocytic leukemia. We also show the efficacy of ATRA/ATO treatment in this etiology. Pleural effusion showed atypical promyelocytes with Auer bodies. This finding was confirmed by FISH with the identification of the t(15:17) translocation.

Abstract The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are chronic malignancies associated with high-risk complications and suboptimal responses to JAK inhibitors such as ruxolitinib. A better understanding of cellular changes induced by ruxolitinib is required to develop new combinatory therapies to improve treatment efficacy. Here, we demonstrate that ruxolitinib induced autophagy in JAK2 V617F cell lines and primary MPN patient cells through the activation of protein phosphatase 2A (PP2A). Inhibition of autophagy or PP2A activity along with ruxolitinib treatment reduced proliferation and increased the death of JAK2 V617F cells. Accordingly, proliferation and clonogenic potential of JAK2 V617F -driven primary MPN patient cells, but not of normal hematopoietic cells, were markedly impaired by ruxolitinib treatment with autophagy or PP2A inhibitor. Finally, preventing ruxolitinib-induced autophagy with a novel potent autophagy inhibitor Lys05 improved leukemia burden reduction and significantly prolonged the mice’s overall survival compared with ruxolitinib alone. This study demonstrates that PP2A-dependent autophagy mediated by JAK2 activity inhibition contributes to resistance to ruxolitinib. Altogether, our data support that targeting autophagy or its identified regulator PP2A could enhance sensitivity to ruxolitinib of JAK2 V617F MPN cells and improve MPN patient care. Not available.

Breast cancer is the most common malignancy in woman, and its associated mortality is still rising worldwide. Among all the different subtypes of breast cancer, invasive lobular carcinoma (ILC) is the second most frequent. Several histological variants of ILC currently exist such as solid, alveolar, pleomorphic, tubulo-lobular, and mixed types. Recently, a new variant of ILC with a papillary growth pattern has been described. Here, we make a review of the literature and report the sixth case of a woman suffering from this very uncommon variant. Of note, she had a concomitant axillary lymph node metastasis, a manifestation not yet described so far. Molecular analysis showed CDH1 and PIK3CA mutations, along with similar quantitative chromosomal alterations in both primary and metastasis. Because ILC and papillary carcinoma are managed differently, our aim here is to raise awareness among the pathologists to avoid misdiagnosis of this unusual variant and subsequent inappropriate treatment.

Differential diagnosis between constitutional mismatch repair deficiency (CMMRD) and neurofibromatosis type 1 (NF1) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated phenotype, supporting the diagnosis of CMMRD. Germline analyses identified two variants (one pathogenic variant and one classified as variant(s) of unknown significance) in the PMS2 gene and subsequent functional assays on blood lymphocytes confirmed the diagnosis of CMMRD. The large plexiform neurofibroma of the thigh and the freckling were however more compatible with NF1. Indeed, a NF1 PV (variant allele frequencies of 20%, 3% and 9% and in blood, skin and saliva samples, respectively) was identified confirming a mosaicism for NF1. Retrospective analysis of a French cohort identified NF1 mosaicism in blood DNA in 2 out of 22 patients with CMMRD, underlining the existence of early postzygotic PV of NF1 gene in patients with CMMRD whose tumours have been frequently reported to exhibit somatic NF1 mutations. It highlights the potential role of this pathway in the pathogenesis of CMMRD-associated gliomas and argues in favour of testing MEK inhibitors in this context.

Introduction/BackgroundPlatinum sensitivity and homologous recombinaison deficiency (HRD) are predictive biomarkers for PARP inhibitors (PARPi) benefit in HGOC patients. The only validated assays to assess HRD are BRCA-mutation (BRCAmut) analysis and genomic instability scores (GIS) designed to detect genomic ‘scars’ in tumor DNA. However, these tests require large samples and yield non-contributive (NA) in 15% of cases. Bevacizumab and PARPi are approved as maintenance therapy regardless HRD status and the optimal maintenance strategy in case of non-contributive HRD test is a major unmet medical need. We aim to report the clinical characteristics and behavior under chemotherapy of NA HGOC pts.MethodologyThis is a retrospective analysis of all pts tested for GIS by myChoice HRD Plus assay (Myriad Genetic Laboratories). Pts included presented HGOC with advanced FIGO III/IV diseases and treated according to guidelines. GIS was performed on baseline pretreatment samples, preferably. Platinum-free interval (PFI) was calculated from the date of last platinum-based chemotherapy to the date of relapse.Results210 patients were recruited: 100 were classified HRD negative (HRD-, score <42), 81 HRD positive (HRD+, score ≥42) and 29 NA (14%). HRD+ cohort was significantly enriched with BRCAmut pts (21/81 = 27%) compared to HRD- and NA. In the NA cohort, median age was 64 years, 86% had an high-grade serous tumor and 10% presented germinal BRCAmut. With a median follow-up of 39 months, median PFI in the overall population was 19.8 months (95%CI 16.7–24.4). In the HRD+, HRD- and NA cohorts (excluding BRCAmut), median PFI were 34.0 (95%CI 16.7–64.4), 14.6 (95%CI 12.0–20.9) and 37.3 months (95%CI 21.0-NA) respectively (P=0.004).ConclusionOur results suggest that patients with NA GIS results behave like HRD+ tumors harboring high platinum-sensitivity and therefore may benefit from PARPi maintenance. The reason for non-contributivity in the first place is unknown and may explain these observations.