Clinical behavior and outcomes of breast cancer in young women with germline BRCA pathogenic variants

Càncer de mama; Genètica del càncerCáncer de mama; Genética del cáncerBreast cancer; Cancer geneticsYoung breast cancer (BC) patients carrying a germline BRCA pathogenic variant (mBRCA) have similar outcomes as non-carriers. However, the impact of the type of gene (BRCA1 vs. BRCA2) and hormone receptor status (positive [HR+] vs. negative [HR−]) on clinical behavior and outcomes of mBRCA BC remains largely unknown. This is an international, multicenter, hospital-based, retrospective cohort study that included mBRCA patients diagnosed, between January 2000 and December 2012, with stage I–III invasive early BC at age ≤40 years. From 30 centers worldwide, 1236 young mBRCA BC patients were included. Among 808 and 428 patients with mBRCA1 or mBRCA2, 191 (23.6%) and 356 (83.2%) had HR+tumors, respectively (P < 0.001). Median follow-up was 7.9 years. Second primary BC (P = 0.009) and non-BC malignancies (P = 0.02) were more frequent among mBRCA1 patients while distant recurrences were less frequent (P = 0.02). Irrespective of hormone receptor status, mBRCA1 patients had worse disease-free survival (DFS; adjusted HR = 0.76, 95% CI = 0.60–0.96), with no difference in distant recurrence-free interval (DRFI) and overall survival (OS). Patients with HR+ disease had more frequent distant recurrences (P < 0.001) and less frequent second primary malignancies (BC: P = 0.005; non-BC: P = 0.18). No differences in DFS and OS were observed according to hormone receptor status, with a tendency for worse DRFI (adjusted HR = 1.39, 95% CI = 0.94–2.05) in patients with HR+ BC. Type of mBRCA gene and hormone receptor status strongly impact BC clinical behavior and outcomes in mBRCA young patients. These results provide important information for patients’ counseling on treatment, prevention, and surveillance strategies.This study received partial financial support by grants from the Italian Ministry of Health - 5 × 1000 funds 2017 (no grant number), the Italian Association for Cancer Research (AIRC; MFAG 2020 ID 24698), and “Les Amis de l’Institut Bordet” foundation (no grant number). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. M.L. acknowledges the support from the European Society for Medical Oncology (ESMO) for a Translational Research Fellowship at the Institut Jules Bordet in Brussels (Belgium) at the time of study conduction. K.P. acknowledges the support from a predoctoral clinical ‘KOOR’ mandate from the University Hospitals Leuven (Leuven, Belgium). F.P.D. acknowledges the support for a postdoctoral clinical mandate (2017-034) from the not-for-profit organization ‘Foundation Against Cancer’ (Brussels, Belgium). A.H.P. acknowledges the support from Susan G. Komen and Breast Cancer Research Foundation (BCRF). J.H. acknowledges the support from the Carlos III National Health Institute funded by FEDER funds—a way to build Europe (PI16/11363). This research was presented in the Poster Spotlight session at the 2020 San Antonio Breast Cancer Symposium (SABCS), San Antonio, TX, United States of America, on 8–12 December 2020

Safety of assisted reproductive techniques in young women harboring germline pathogenic variants in BRCA1/2 with a pregnancy after prior history of breast cancer

Breast cancer fertility; Pregnancy; SurvivalFertilidad y cáncer de mama; Embarazo; SupervivenciaFertilitat i càncer de mama; Embaràs; SupervivènciaBackground Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants. Patients and methods This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy. Results Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group. Conclusion This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing.The present work was supported by the Italian Association for Cancer Research (‘Associazione Italiana per la Ricerca sul Cancro’, AIRC; MFAG 2020 ID 24698) and the Italian Ministry of Health (5 × 1000 funds 2017). MC and ID acknowledge the Fonds National de la Recherche Scientifique (FNRS and Télévie 7.6508.20) and Fonds Erasme for their financial support

Clinical spectrum and evolution of immune-checkpoint inhibitors toxicities over a decade-a worldwide perspective.

BACKGROUND: Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ. METHODS: We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes. FINDINGS: We distinguished 25 types of irAE (n&nbsp;=&nbsp;50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3&nbsp;±&nbsp;12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (&lt;1%) in the studied timeframe. After 2020, over 14 different cancer types were treated vs. almost exclusively melanoma and lung cancers before 2016. Overall, the most reported irAE were skin reactions (22.9%), pneumonitis (18.5%), enterocolitis (14.4%) and thyroiditis (12.1%). ICI-myotoxicities (6.6%) included myositis, myocarditis and myasthenia-gravis like syndrome and were the most overlapping irAE (up to 30% overlap, vs. &lt;3% in general for other inter-irAE overlap). The top factors associated with specific irAE (odds-ratio&gt;5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis&nbsp;=&nbsp;27.6%, myasthenia&nbsp;=&nbsp;23.1%, severe cutaneous adverse reactions (SCAR)&nbsp;=&nbsp;22.1%, myositis&nbsp;=&nbsp;21.9%, pneumonitis&nbsp;=&nbsp;21%, and encephalomyelitis&nbsp;=&nbsp;18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n&nbsp;=&nbsp;275/951). INTERPRETATION: This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research. FUNDING: Paul Gougis was supported by the academic program: Contrats ED: Programme blanc Institut Curie PSL for the conduct of his PhD. Baptiste Abbar was supported by the Fondation ARC Pour le Rechercher Sur le Cancer. The RT2L research group (Institut Curie) was supported by the academic program SHS INCa, Sanofi iTech award, and by Monoprix∗

Identification des facteurs prédictifs de sensibilité ou résistance à la chimiothérapie néoadjuvante dans le cancer du sein

Neoadjuvant chemotherapy (NAC i.e. chemotherapy before surgery) is increasingly being used for aggressive or locally advanced breast cancer (BCs). Beyond clinical benefits, it represents an opportunity to monitor in vivo sensitivity to treatment. Based on the analysis of datasets of BCs patients treated with NAC, we aimed at identifying mechanisms associated with resistance or sensitivity to treatment.In the first part, we evaluated biological, clinical, pathological and transcriptomic patterns. We demonstrated that unexplored pathological features such as post-NAC lymphovascular invasion may carried an important prognostic information.In a second part, we analyzed impact of imune infiltration in BC and we described extensively the changes of tumor infiltrating lymphocytes(TILs) between pre and post-NAC samples. We showed that the prognostic impact of TILs was different before and after NAC, and was opposite in TNBC and HER2-positive BCs. Finally, we investigated the impact of comedications use during NAC. We found both positive effects - while enhancing immune infiltration and response to treatment - and negative effects with deleterisous oncologic outcomes in specific patients subgroups. In conclusion, the neoadjuvant setting represents a platform to both generate and potentially validate research hypotheses aiming at increasing the efficacy of treatment. The public release of real-life datasets of BC patients treated with NAC would represent a major resource to accelerate BC research.La chimiothérapie néoadjuvante (CNA) est utilisée dans les cancers du sein agressifs ou localement avancés (CS). Au delà des bénéfices cliniques, elle représente une opportunité pour monitorer in vivo la sensibilité d’une tumeur à un traitement.A partir de l’analyse de sets de données de patients traités par CNA, nous souhaitons identifier des mécanismes associes à la résistance ou sensibilité au traitement. Dans la première partie, nous avons évalué des paramètres, cliniques, anatomopathologiques et transcriptomiques. Nous avons démontré que des éléments non explorés comme la présence d’embols après CNA revêtaient une information pronostique importante. Dans une 2ème partie, nous avons analysé l’impact de l’infiltrat immunitaire dans le cancer du sein, et avons décrit les changements observés entre des échantillons avant et après CNA. Nous avons montré que l’impact pronostique des TILs était différent avant et après CNA, et était opposé dans les CS triple négatif ou HER2-positif. Finalement, nous avons analysé l’impact des comédications pendant la CNA. Nous avons trouvé des effets positifs – via l’augmentation de l’infiltrat immunitaire et la réponse au traitement – et des effets négatifs avec des effets délétères dans certains sous groupes de patients. En conclusion, la situation néoadjuvante représente une plateforme pour générer et potentiellement valider des hypothèses de recherche. La mise à disposition de jeux de données de patients traités par chimiothérapie néoadjuvante constituerait une ressource majeure pour accélérer la recherche contre le cancer du sein

Neoadjuvant treatment for intermediate/high-risk HER2-positive and triple-negative breast cancers: No longer an option' but an ethical obligation

SCOPUS: ed.jinfo:eu-repo/semantics/publishe

Primary versus delayed repair for bile duct injuries sustained during cholecystectomy: results of a survey of the Association Francaise de Chirurgie

AbstractBackgroundBile duct injuries (BDIs) sustained during a cholecystectomy still remain a major surgical problem, and it is still not clear whether the injury should be repaired immediately or a delayed repair is preferred.MethodsA retrospective national French survey was conducted to compare the results of immediate (at time of cholecystectomy), early (within 45 days after a cholecystectomy) and late (beyond 45 days after a cholecystectomy) surgical repair for BDI sustained during a cholecystectomy.ResultsForty‐seven surgical centres provided 640 cases of bile duct injury sustained during a cholecystectomy of which 543 were analysed for the purpose of the present study. The timing of repair was immediate in 194 cases (35.7%), early in 216 cases (39.8%) and late in 133 cases (24.5%). The type of repair was a suture repair in 157 cases (81%), and a bilio‐digestive reconstruction in 37 cases (19%) for immediate repair; a suture repair in 119 cases (55.1%) and a bilio‐digestive anastomosis in 96 cases (44.9%) for the early repair; and a bilio‐digestive reconstruction in 129 cases (97%) and a suture repair in 4 cases (3%) for late repair. A second procedure was required in 110 cases (56.7%) for immediate repair, 80 cases (40.7%) for early repair (P < 0.05) and in 9 cases (6.8%) for late repair (P < 0.001).ConclusionThe timing of surgical repair for a bile duct injury sustained during a cholecystectomy influences significantly the rate of a second procedure and a late repair should be preferred option

Neural network for the prediction of treatment response in Triple Negative Breast Cancer *

A bstract The automatic analysis of stained histological sections is becoming increasingly popular. Deep Learning is today the method of choice for the computational analysis of such data, and has shown spectacular results for large datasets for a large variety of cancer types and prediction tasks. On the other hand, many scientific questions relate to small, highly specific cohorts. Such cohorts pose serious challenges for Deep Learning, typically trained on large datasets. In this article, we propose a modification of the standard nested cross-validation procedure for hyper-parameter tuning and model selection, dedicated to the analysis of small cohorts. We also propose a new architecture for the particularly challenging question of treatment prediction, and apply this workflow to the prediction of response to neoadjuvant chemotherapy for Triple Negative Breast Cancer