[2021 update of the GEFPICS' recommendations for HER2 status assessment in invasive breast cancer in France]. / Mise à jour 2021 des recommandations du GEFPICS pour l'évaluation du statut HER2 dans les cancers infiltrants du sein en France.

The last international guidelines on HER2 determination in breast cancer have been updated in 2018 by the American Society of Clinical Oncology and College of American Pathologists, on the basis of a twenty-year practice and results of numerous clinical trials. Moreover, the emerging HER2-low concept for 1+ and 2+ non amplified breast cancers lead to refine French practices for HER2 status assessment. The GEFPICS group, composed of expert pathologists, herein presents the latest French recommendations for HER2 status evaluation in breast cancer, taking into account the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, HER2 status assessment remains one of the most important biomarkers in breast cancer and its quality guaranties the optimal patients' care. French pathologists' commitment in theranostic biomarker quality is more than ever required to provide the most efficient cares in oncology.

Identification of a tumor-promoter cholesterol metabolite in human breast cancers acting through the glucocorticoid receptor.

Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3ß,5α,6ß-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3ß,5α-diol (OCDO) by 11ß-hydroxysteroid-dehydrogenase-type-2 (11ßHSD2). 11ßHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11ßHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11ßHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11ßHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC.

[Report of a mucoepidermoid breast carcinoma: Presentation of a rare entity]. / À propos d'un cas de carcinome muco-épidermoïde du sein : présentation d'une entité rare.

Salivary gland-like tumours are described in the breast but remain very rare and difficult to diagnose in this location. Only 37 cases of mucoepidermoid carcinoma have been described in the literature. We report the challenging diagnosis of a mucoepidermoid carcinoma sampled by core biopsy in a 51-year-old woman.

[GEFPICS' guidelines for management of breast cancer tissue samples in the neoadjuvant setting]. / Recommandations du GEFPICS pour la prise en charge des prélèvements dans le cadre du traitement néoadjuvant du cancer du sein.

Neoadjuvant therapy is an increasing treatment option in the management of breast cancer. The tumor response to neoadjuvant therapy, especially the pathological complete response, is a validated endpoint frequently used in clinical trials. However, there is still a lack of standardization for the surgical specimen management in the neoadjuvant setting. This leads to heterogeneity in the specimen handling and might lead to significant bias for the prognostic assessment of patients or in clinical trials. The GEFPICS group, composed of expert breast cancer pathologists, herein presents guidelines for the management of breast and axillary specimen before treatment (management of biopsy, items of the pathological report) and after neoadjuvant therapy (specimen handling, histological assessment of response, items of the pathological report and response grading systems).

Outcome of pN0 Triple-Negative Breast Cancer with or without Lymph Node Irradiation: A Single Institution Experience.

The optimal management of patients with pathologically node-negative triple-negative breast cancer (pN0 TNBC) remains unclear. We hypothesized that lymph node irradiation (LNI; internal mammary chain/periclavicular irradiation) had an impact on outcomes of pN0 TNBC. A cohort of 126 consecutive patients with pN0 TNBC treated between 2007 and 2010 at a single institute were included. All radiotherapy (breast/chest wall, ±LNI) was delivered adjuvantly, following completion of surgery ± chemotherapy. Tumors were reviewed and histologic features were described. Tissue microarrays were constructed and tumors were assessed by immunohistochemistry using antibodies against ER, PR, HER2, Ki-67, cytokeratins 5/6, 14, epidermal growth factor receptor and androgen receptor. Patients were divided into two groups for statistical analysis: LNI (LNI+) or no LNI (LNI-). We focused on disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). Fifty-seven and 69 patients received or not LNI, respectively. Median age was 52 (range [25-76]) and 55 (range [29-79]) in LNI+ and LNI- group (p = 0.23). LNI was associated with larger tumors (p = 0.033), central/internal tumors (33 versus 4, p < 0.01) and more chemotherapy (86% versus 59.4% p < 0.01). The median follow-up was 53.5 months. The rate of first regional relapse (associated or not with distant relapse) was low in both groups. There was no difference in 4-year DFS (82.2% versus 89.9%; p = 0.266), MFS (87.0% versus 91.1%; p = 0.286) and OS (85.8% versus 89.9%; p = 0.322) between LNI+ and LNI- group, respectively. In univariate analysis, only clinical size (T >10 mm versus ≤10 mm), histologic size (pT >10 mm versus ≤10 mm) and grade 3 (versus grade 2) were found to be significantly associated with shorter DFS. Omission of LNI in patients with pN0 TNBC does not seem to result in poorer outcome. Further studies are needed to specifically evaluate LNI in pN0 TNBC with histologic grade 3 and/or (p)T >10 mm.

[Tumor microenvironment and the pathologist: looking at what we just see]. / Microenvironnement tumoral - la vision du pathologiste.

Owing to the phenomenal advances in molecular technology, the past few years have seen drastic improvements in the knowledge of tumor biology. Whilst efforts are still focused on the cancer cell, it is now clear that analysis of the tumor microenvironment plays a major role in the management of cancer. Known for years as the "stroma reaction", tumor microenvironment was commonly used by pathologists as helpful criteria to establish the diagnostic of histological subtypes. More recently however, research on tumor microenvironment (and immune response in particular) has provided numerous evidences to support a leading role in the assessment of cancer prognosis, and open new avenues in treatment of cancer patients. Prognostic and/or predictive biomarkers issued from this research will have to get through the validation process required by international consensus conferences before any implementation in clinical practice.

Delayed Hypersensitivity Reaction to Titanium-coated Polypropylene Mesh in Breast Reconstruction.

Breast implant reconstructions increasingly incorporate meshes like the synthetic nonresorbable titanium-coated polypropylene mesh commercialized as Tiloop (Pfm medical). We report the case of a 48-year-old woman, with a medical history of nickel allergy, who presented with an extensive erythematous eruption, a periprosthetic reaction, and an axillary node reaction, 18 months after a unilateral prophylactic mastectomy. We excluded infectious, sarcoidosis and carcinomatosis. The patient's medical history, the clinical evolution, and the particularly fast and complete healing after removal of the mesh were suggestive of an unusual allergic reaction to the titanium in the titanium-coated polypropylene mesh. Titanium allergies are very rare events, predominantly described in the dental and orthopedic fields. We also discussed the hypothesis of a tardive red breast syndrome related to a synthetic mesh, also mediated by immunological response as described recently in another case report.

Thrombospondin-1 Silencing Improves Lymphocyte Infiltration in Tumors and Response to Anti-PD-1 in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is notoriously aggressive with a high metastatic potential, and targeted therapies are lacking. Using transcriptomic and histologic analysis of TNBC samples, we found that a high expression of thrombospondin-1 (TSP1), a potent endogenous inhibitor of angiogenesis and an activator of latent transforming growth factor beta (TGF-ß), is associated with (i) gene signatures of epithelial-mesenchymal transition and TGF-ß signaling, (ii) metastasis and (iii) a reduced survival in TNBC patients. In contrast, in tumors expressing low levels of TSP1, gene signatures of interferon gamma (IFN-γ) signaling and lymphocyte activation were enriched. In TNBC biopsies, TSP1 expression inversely correlated with the CD8+ tumor-infiltrating lymphocytes (TILs) content. In the 4T1 metastatic mouse model of TNBC, TSP1 silencing did not affect primary tumor development but, strikingly, impaired metastasis in immunocompetent but not in immunodeficient nude mice. Moreover, TSP1 knockdown increased tumor vascularization and T lymphocyte infiltration and decreased TGF-ß activation in immunocompetent mice. Noteworthy was the finding that TSP1 knockdown increased CD8+ TILs and their programmed cell death 1 (PD-1) expression and sensitized 4T1 tumors to anti-PD-1 therapy. TSP1 inhibition might thus represent an innovative targeted approach to impair TGF-ß activation and breast cancer cell metastasis and improve lymphocyte infiltration in tumors, and immunotherapy efficacy in TNBC.

[Molecular taxonomy of luminal breast cancer in 2015]. / Cancer du sein luminal et apport des classifications intrinsèques moléculaires: comment identifier les tumeurs luminales A et B en 2015 ?

Luminal breast cancers (i.e. displaying œstrogen receptor expression) account for 70 to 80% of all breast cancers. It encompasses a heterogeneous population of tumors, differing by their clinical course, histopathological characteristics, phenotypes and molecular features. As a continuum of lesions, luminal breast tumors are critically challenged by the recent evolution in treatment decision making. Indeed, whilst about half of luminal breast cancers are associated with a very good prognosis (so-called luminal A tumors with regard to the intrinsic molecular classification), 20% of luminal tumors display a poor clinical outcome (i.e. luminal B tumors), the remaining tumors corresponding to intermediate lesions that are very difficult to accurately classify. Clearly, therapeutic issues are critical, since according to the vast majority of international consensus guidelines luminal A tumors are best treated by endocrine therapy, whilst an additional adjuvant chemotherapy will be proposed to patients harbouring luminal B breast cancer. By providing precise histopathological, phenotypic and molecular characterization of luminal breast tumors, the pathologist is actually the cornerstone of this therapeutic decision. Herein we aim to review the state-of-the-art knowledge on luminal breast carcinomas, with a perspective of routine clinical practice in 2015.

[Improving practice in breast pathology: 34-months experience of the regional SENOPATH network and webinars as a tool for diagnosis of difficult lesions of the breast]. / Amélioration des pratiques en pathologie mammaire : bilan à 34 mois du groupe régional de relecture SENOPATH et télépathologie pour les lésions de diagnostic difficile.

Pathologists commonly face breast lesions that are difficult to diagnose. To reduce second opinion delay, erase geographical barrier and provide continuing education, we aimed to develop a telepathology-based regional network of pathologists. With the support of ONCOMIP network, we founded a peer-group named SENOPATH, composed of experienced breast pathologists practising in private laboratories, university hospitals or comprehensive cancer center in the region of Midi-Pyrénées in France. Submitted cases are digitalized at the University Hospital, stored in a shared space with a possible access via Internet prior to the SENOPATH sessions. The group meets monthly, via a synchronized webinar and multihead microscope session. A consensual diagnosis and final pathology report is issued for each case, and sent to the referring clinician via the patient medical file securely hosted by ONCOMIP. Between 2012 and 2014, 142 cases were reviewed, for either diagnostic 'routine' difficulty or rare histological type. The SENOPATH group, also regularly called by oncologists to solve difficult cases, has considerably improved the pathologist network in Southern France. Supported by the webinar tool, its educational impact is prominent, with a considerable progress in the region with regards to standardization of pathology processes, literature review and knowledge sharing.