Wnt, glucocorticoid and cellular prion protein cooperate to drive a mesenchymal phenotype with poor prognosis in colon cancer.

BACKGROUND: The mesenchymal subtype of colorectal cancer (CRC), associated with poor prognosis, is characterized by abundant expression of the cellular prion protein PrPC, which represents a candidate therapeutic target. How PrPC is induced in CRC remains elusive. This study aims to elucidate the signaling pathways governing PrPC expression and to shed light on the gene regulatory networks linked to PrPC. METHODS: We performed in silico analyses on diverse datasets of in vitro, ex vivo and in vivo models of mouse CRC and patient cohorts. We mined ChIPseq studies and performed promoter analysis. CRC cell lines were manipulated through genetic and pharmacological approaches. We created mice combining conditional inactivation of Apc in intestinal epithelial cells and overexpression of the human prion protein gene PRNP. Bio-informatic analyses were carried out in two randomized control trials totalizing over 3000 CRC patients. RESULTS: In silico analyses combined with cell-based assays identified the Wnt-ß-catenin and glucocorticoid pathways as upstream regulators of PRNP expression, with subtle differences between mouse and human. We uncover multiple feedback loops between PrPC and these two pathways, which translate into an aggravation of CRC pathogenesis in mouse. In stage III CRC patients, the signature defined by PRNP-CTNNB1-NR3C1, encoding PrPC, ß-catenin and the glucocorticoid receptor respectively, is overrepresented in the poor-prognosis, mesenchymal subtype and associates with reduced time to recurrence. CONCLUSIONS: An unleashed PrPC-dependent vicious circle is pathognomonic of poor prognosis, mesenchymal CRC. Patients from this aggressive subtype of CRC may benefit from therapies targeting the PRNP-CTNNB1-NR3C1 axis.

TROP2, androgen receptor, and PD-L1 status in histological subtypes of high-grade metaplastic breast carcinomas.

AIMS: High-grade metaplastic breast carcinoma (HG-MBC) is a rare subtype of invasive breast carcinoma, mostly triple-negative. Metaplastic carcinomas are less responsive to neoadjuvant chemotherapy and are associated with a worse outcome than invasive carcinomas of no special type. METHODS: Clinicopathological characteristics and immunophenotype were retrospectively assessed in a series of 65 patients diagnosed with HG-MBC between 2005 and 2017 at the Curie Institute (antibody panel: oestrogen receptor [ER], progesterone receptor [PR], androgen receptor [AR], human epidermal growth factor receptor 2 [HER2], programmed death ligand-1 [PD-L1], and trophoblast cell surface antigen 2 [TROP2]). RESULTS: The median age at diagnosis was 59.5 years. Six (9%) patients had metastatic disease at diagnosis. Among the nonmetastatic patients receiving neoadjuvant therapy, 26% (5/19) achieved pathological complete response. Most tumours were pT1/pT2 (77%) and 12% were pN+. Histological subtypes (mixed, squamous, mesenchymal, and spindle cell) were 40%, 35.5%, 15.5%, and 9%, respectively. Tumour-infiltrating lymphocytes were low or moderate except when squamous differentiation was present. Most tumours were triple-negative (92%). AR and TROP2 were positive in 34% and 85% of the cases, respectively. PD-L1 was positive in tumour cells in 18% (cutoff: 1% of positive tumour cells) of the cases and in tumour-infiltrating immune cells in 40% (cutoff: 1% of tumour area) of the cases. Notably, spindle cell and mesenchymal metaplastic breast carcinomas were mostly PDL1-negative. Lastly, 21 (32.3%) cases were HER2-low, all being HER2 1+, with no HER2 2+. CONCLUSION: Metaplastic breast carcinoma could benefit from tailored therapeutic strategies adapted to the phenotypic specificities of histological subtypes.

[Pathological complete response of a metastatic MisMatch Repair deficient/MicroSatellite Instable colon cancer after immunotherapy: A case report]. / Réponse histologique complète d'un cancer colique métastatique de phénotype MisMatch Repair déficient/MicroSatellite Instable après immunothérapie : à propos d'un cas.

Immunotherapies are part of the therapeutic strategy in many cancers and are indicated for metastatic colorectal adenocarcinoma with loss of expression of MisMatch Repair system proteins or with microsatelite instability (dMMR/MSI) in the United States. The rate of pathological response to immunotherapy remains poorly documented, but several cases of complete or major pathological response have recently been described. We decided to report the case of a complete pathological response to immunotherapy of a dMMR/MSI colorectal adenocarcinoma in a 74-year-old patient, initially inoperable due to duodenal invasion. Three months after the introduction of immunotherapy, the patient developed drug-induced colitis that contraindicated further treatment. Histological examination of the subtotal colectomy specimen revealed no residual tumour cells. The patterns of tumour regression were mainly represented by colloid regression, infarctoid-type necrosis and a resorptive inflammatory reaction. Although the operative indications for patients with metastatic dMMR/MSI colorectal cancer treated by immunotherapy are still very limited, the number of such specimens is expected to increase rapidly. The management of these specimens, as well as the possibility of a complete histological response, must be known by pathologists who play a key role in the pathophysiological knowledge of these lesions.

Uterine metastasis from invasive ductal breast carcinoma: A case report with literature review.

Breast cancer is the leading cause of cancer death in women, and most breast cancer related deaths are due to metastases. Uterine metastases from breast cancer are uncommon and rarely reported in the literature. We described the case of a 50 years-old-woman who developed a uterine metastasis, 6 years after the diagnosis of an invasive ductal breast carcinoma. Indeed, although the patient was asymptomatic, the monitoring imaging examinations, particularly the computed tomography (CT) and the positron emission tomography/computed tomography (PET/CT), showed a myometrial lesion. Non-conservative total hysterectomy was performed. The anatomo-pathological examination revealed a myometrial metastasis from an invasive ductal breast carcinoma. Seventeen months after surgery, the patient had no pelvic recurrence, but lungs and bones metastases progressed despite chemotherapy. In the lack of guidelines of uterine metastases from breast cancer's management, we reviewed the existing literature with the aim to provide a rational framework for clinical presentation, diagnostic approach, histological findings and treatment of this rare and heterogeneous pathology. Uterine metastases of breast cancer are frequently revealed with metrorrhagia. They occur preferentially in tumours with initial lobular carcinoma, initial lymph node involvement and positive hormonal receptors.

HPV Detection in Head and Neck Squamous Cell Carcinomas: What Is the Issue?

Besides classic tobacco and alcohol risk factors, human papillomavirus (HPV) plays a role in the development of a subset of head and neck squamous cell carcinomas (HNSCCs), and notably oropharynx squamous cell carcinomas (OPSCCs). HPV-induced OPSCCs have a different biological behavior and a better prognosis compared to non-HPV-induced OPSCCs and the eighth-edition TNM classification now separates these two entities. Therefore, determining the HPV status of patients with OPSCC is now essential for treatment, prognosis, and development of clinical trials. In this review, after reminding essential steps of HPV implication in the cell cycle, we describe the existing tools that are currently feasible in routine practice according to facilities available in health structures, with their benefits and drawbacks: HPV PCR, E6/E7 mRNA RT-PCR, E6/E7 mRNA in situ hybridization, HPV DNA in situ hybridization, and P16 immunochemistry. Besides these traditional HPV detection tools, novel diagnostic approaches are being evaluated for HPV-induced OPSCC "ultrastaging." E6 humoral response and ddPCR-detecting HPVct DNA are two techniques performed on blood and are therefore non-invasive. Baseline E6 humoral levels could have a prognostic value, and HPVct DNA could be helpful for HPV OPSCC recurrence monitoring. At last, next-generation sequencing (NGS)-based "capture HPV" is a technique feasible on biopsies and circulating DNA material. It helps characterize HPV integration status and sites, and it could define prognostic subgroups in HPV-induced OPSCC. These novel precision detection tools could be further integrated in the care of patients with HPV-induced OPSCC.