E-Cadherin Mutational Landscape and Outcomes in Breast Invasive Lobular Carcinoma.

Invasive lobular carcinomas (ILC) are characterized by the loss of E-cadherin expression and CDH1 gene inactivation. Diagnostic reproducibility for this tumor type is currently suboptimal and could be improved by a better understanding of its histomolecular and clinical heterogeneity. We have analyzed the relationship between the presence, type, or position of CDH1 mutations, E-cadherin expression, and clinicopathological features (including outcome) in a retrospective series of 251 primary ILC with a long follow-up (median: 9.5 years). The mutational status of E-cadherin gene (CDH1) was determined by RNA sequencing from frozen tumor samples. E-cadherin immunohistochemistry (IHC) was performed with antibodies directed against the intracellular domain (clone 4A2C7) and the extracellular domain (clone NCH38). IHC expression of p120 and ß-catenin was also assessed in E-cadherin diffusely positive cases. Three major patterns of E-cadherin membrane expression were identified by IHC, with good agreement between the 2 clones (overall concordance: 83.8%, Kappa 0.67): null/focal expression (≤10%) (72.8% of cases for 4A2C7 and 83.8% for NCH38), heterogeneous expression (11%-89%) (19.2% of cases for 4A2C7 and 6.9% for NCH38), and diffuse expression (≥90%) (8% of cases for 4A2C7 and 9.3% for NCH38). E-cadherin membranous expression, when present, was abnormal (incomplete labeling and/or reduced intensity). ILC with diffuse E-cadherin expression showed abnormal ß-catenin or p120-catenin staining in 21% of cases. Interestingly, these cases with diffusely expressed E-cadherin had a CDH1 mutation rate as high as the E-cadherin null/focal cases (∼70%) but were enriched in nontruncating mutations. Regarding CDH1 mutation location, intracytoplasmic domain mutations correlated with a divergent E-cadherin IHC phenotype between the 2 antibodies (4A2C7 ≤ 10%/NCH38 ≥ 10%). Clinico-pathological correlation analyses found that stromal amount (inversely correlated with tumor cellularity) and tumor-infiltrating lymphocytes were less abundant in ILC with E-cadherin null/focal cases. In addition, CDH1 truncating mutations were associated with radiohistologic size discordance and were identified in multivariate survival analysis as an independent poor prognosis factor in terms of metastasis risk and breast cancer-related mortality. Overall, our study highlights the importance of the precise mutational status of CDH1 in the clinical, radiological, histologic, and phenotypic expression of lobular carcinomas. These findings should be taken into account in future attempts to improve diagnostic criteria or methods for ILC, as well as for clinicobiological studies dedicated to this tumor type.

External validation of Standardized KELIM and platinum-resistant recurrence scores in patients with advanced epithelial ovarian cancer.

BACKGROUND: Neoadjuvant chemotherapy followed by interval debulking surgery is currently a common treatment option for advanced epithelial ovarian cancer (EOC). The Standardized CA-125 ELIMination rate constant K (Std KELIM) and the Platinum Resistant Recurrence (PtRR) Score have been proposed as markers of tumor chemosensitivity. The aim of our study was to validate these tools for predicting platinum sensitivity in a real-world population of patients with advanced EOC treated with neoadjuvant chemotherapy. EXPERIMENTAL DESIGN: All patients with advanced EOC treated with neoadjuvant chemotherapy at the Institut Curie between 2000 and 2015 were included. The Std KELIM was calculated with the CA-125 concentrations during the first 100 days of chemotherapy. The predictive value of Std KELIM and PtRR scores for the risk of subsequent PtRR was assessed using receiver operating characteristic (ROC) curve analysis, logistic regression and calibration curve. Kaplan-Meier survival analysis was performed for the treatment-free interval from platinum (TFIp) therapy and overall survival (OS). RESULTS: Std KELIM data were available for 149 patients. The AUC was 0.67 for PtRR. A low Std KELIM was significantly associated with PtRR (OR = 0.19 (95% CI [0.06, 0.53], p = 0.002)) according to the univariate analysis. The calibration curve of the PtRR showed a slight but significant underestimation (p = 0.02) of the probability of platinum resistance. Favorable Std KELIM (≥ 1) alone and combined with the completeness of surgery were associated with significantly better survival in terms of TFIp and OS. CONCLUSIONS: Std KELIM is an early prognostic marker of chemosensitivity in a real-life setting complementary to surgical status. It could help the clinician in the early management of patients by identifying those with a worse prognosis.

Evaluating the satisfaction and utility of social networks in medical practice and continuing medical education.

BACKGROUND: Digital health has surged during the Covid health crisis, and the use of social media, already prevalent in medicine, has significantly increased. There are Social Networks groups dedicated to physicians with an educational purpose. These groups also facilitate peer discussions on medical questions and the sharing of training materials. OBJECTIVES: The aim of our study was to assess the value of these new tools and their contribution to medical education. METHODS: An anonymous questionnaire was conducted among members of a Social Networks community group for physicians. The survey received responses from 1451 participants. RESULTS: The majority of participants believed they had enriched their medical knowledge and accessed documents they would not have accessed without the group. Subgroup analysis showed that the contribution of this tool is more pronounced for general practitioners and doctors practicing in limited healthcare access. CONCLUSION: It is essential to develop digital tools that enhance physician training, and social networks represent a valuable educational tool.

Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway.

Although cancer-associated fibroblast (CAF) heterogeneity is well-established, the impact of chemotherapy on CAF populations remains poorly understood. Here we address this question in high-grade serous ovarian cancer (HGSOC), in which we previously identified 4 CAF populations. While the global content in stroma increases in HGSOC after chemotherapy, the proportion of FAP+ CAF (also called CAF-S1) decreases. Still, maintenance of high residual CAF-S1 content after chemotherapy is associated with reduced CD8+ T lymphocyte density and poor patient prognosis, emphasizing the importance of CAF-S1 reduction upon treatment. Single cell analysis, spatial transcriptomics and immunohistochemistry reveal that the content in the ECM-producing ANTXR1+ CAF-S1 cluster (ECM-myCAF) is the most affected by chemotherapy. Moreover, functional assays demonstrate that ECM-myCAF isolated from HGSOC reduce CD8+ T-cell cytotoxicity through a Yes Associated Protein 1 (YAP1)-dependent mechanism. Thus, efficient inhibition after treatment of YAP1-signaling pathway in the ECM-myCAF cluster could enhance CD8+ T-cell cytotoxicity. Altogether, these data pave the way for therapy targeting YAP1 in ECM-myCAF in HGSOC.