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Purpose: Although a potential role of the Epstein-Barr virus (EBV) in the pathogenesis of breast cancer (BC) has been underlined, results remain conflicting. Particularly, the impact of EBV infection on biological markers of BC has received little investigation.Methods: In this study, we established the frequency of EBV-infected BC using real-time quantitative PCR (RT-PCR) in 196 BC specimens. Biological and pathological characteristics according to EBV status were evaluated.Results: EBV DNA was present in 65 of the 196 (33.2%) cases studied. EBV-positive BCs tended to be tumours with a more aggressive phenotype, more frequently oestrogen receptor negative (P=0.05) and with high histological grade (P=0.01). Overexpression of thymidine kinase activity was higher in EBV-infected BC (P=0.007). The presence of EBV was weakly associated with HER2 gene amplification (P=0.08).Conclusion: Our study provides evidence for EBV-associated BC undergoing distinct carcinogenic processes, with more aggressive features. [ABSTRACT FROM AUTHOR]

Background: In University hospitals or Comprehensive Cancer Centers (CCC), breast cancer (BC) patients have a theoretically large access to clinical trials as part of the management and treatment of their localized or advanced disease. Though, most patients are not proposed inclusion into suitable trials or studies or do not accept them. We aimed at determining the factors that influence physicians and patient's choice to respectively propose or enter clinical trials for which the patients were considered eligible by MTM. Methods: Patients who were considered eligible for a clinical trial by a BC-specific multidisciplinary team meeting (MTM) assessing their cases were prospectively registered during a 6 months period. The complete files of these patients were prospectively registered following initial written proposal by the MTM. The 27 clinical trials proposed were classified in 5 categories: cognitive studies, imaging, radiation therapy, diagnostic/prognostic biology, or interventional therapeutic studies. Detailed analysis of factors predicting physician's proposal and patient's final inclusion was conducted. Candidate factors were age, socio-demographic characteristics, PS, type of clinician, time intervals, stage of disease, type of disease, type of study, single vs multiple study proposal. Results: MTM proposed 547 inclusions into clinical trials for 397 patients between March 3rd and Sept 21st, 2011. 267 pts were considered eligible for 1 trial, 100 for 2, 25 for 3, 4 for 4 and 1 for 5 trials; 211 for cognitive studies, 13 for imaging, 71 for radiation therapy, 136 for diagnostic/prognostic biology, 116 for interventional therapeutic studies. Upon referral physician's visit, the trial was only proposed in 39.3% and pts were finally included in 29.1% of the cases. Reasons for non inclusion were patients' refusal in only 5-11%, but absence of proposal by physician in 45-81 %, according to the types of studies. The only factor predicting both proposal by the referral physician's and final inclusion into trials was type of study (both p < 0.001). Diagnostic/prognostic biology trials were proposed in 71 %, while interventional therapeutic and cognitive studies were only respectively proposed in 35 and 19% of the cases. The factors predicting non-inclusion upon physicians' proposal were professional status (p = 0.03) and type of study (p = 0.0007). The highest inclusion rates were among retired pts and those with executive work (84 and 76% respectively). Conclusion: The main reason for non inclusion into clinical trials remains absence of physicians' proposal, while professional status and type of study influence both the physicians' and the patients' decision. Educative measures dedicated mostly to treating physicians might be proposed. [ABSTRACT FROM AUTHOR]

Background: Population-based mammography screening has resulted in the increased detection of suspicious, non-palpable lesions that require histopathological assessment. When a "pre-malignant" lesion, such as lobular carcinoma in situ (LCIS), atypical ductal or lobular hyperplasia (ADH and ALH) or flat epithelial atypia (FEA), is discovered on the primary biopsy, a surgical excision is recommended due to the risk of underestimation of the lesion. DCIS or invasive carcinoma is finally retrieved in 10-30% of the patients, meaning a large part receive unnecessary surgery. The aim of this study was to define a nomogram integrating clinical, imaging and histological data to predict for the risk of underestimation of the lesion. Intentionally, we decided to include all the premalignant lesions which implied the same management, whereas most of the previous models of the literature are focused in only one or another type of atypia. Patients and Methods: We collected complete clinical, radiological and double-reading histological data on all patients with a diagnosis of pure atypical lesion (CLIS, ADH, ALH, FEA) on image-guided biopsy performed at the One-Stop Unjt of our breast care center from 2004 to 2011. Univariate and multivariate logistic regression analyses were used to develop a model predicting for the presence of DCIS or invasive carcinoma on the final surgical sample, and build a nomogram. This nomogram was evaluated on a training set of 205 patients treated at IGR. Results: 205 patients were eligible for the study. Of these 205 patients, 50 cancers (24.4%) were diagnosed at definitive surgery (21 DCIS, 20 ductal and 9 lobular invasive carcinoma). Univariate analysis retrieved age (p = 0.03), number of biopsy cores (p = 0.02) and type of radiological anomalies (p = 0.02) as factors associated with cancer at surgery. The presence of microcalcifications on biopsies of limit significance was included in the multivariate analysis (p = 0.09). The final most informative nomogram included information on patient age (p = 0.03), type of radiological anomalies (p = 0.02) and number of biopsy cores (p = 0.04). The predictive accuracy of the nomogram was 0.71 and 0.68 in the training set before and after bootstrapping, respectively. The calibration of the nomogram was good. The sensitivity, specificity, positive predictive value, and negative predictive values were 68%, 73%, 45%, and 88%, respectively. Conclusion: This nomogram could help identify a subset of patients with premalignant disease for whom surgery could be spared and who would be eligible for exclusive clinical follow-up. A validation study is currently undergoing in an external dataset. [ABSTRACT FROM AUTHOR]

Background: Lymphocele is the principal post-operative morbidity following axillary node dissection. According to the literature, the incidence can vary from 4% to 89%. Encouraging results in terms of reducing postoperative lymphoceles as well as the volume and duration of drainage using octreotide LAR has been recently reported. Pasireotide LAR, a long acting drug designed to target multiple somatostatin receptors, was evaluated in this trial. Trial design: A phase II, two centers, randomized, double-blind, non-comparative pilot study was carried out in order to evaluate efficacy and safety of a single injection of pasireotide LAR 60 mg administered 7-10 days before scheduled mastectomy with axillary dissection surgery. This study included a parallel placebo arm to assess the natural course of the disease. Eligibility criteria: Adult female breast cancer patients planned to undergo a mastectomy (without reconstruction at the same time) and axillary node dissection. Specific aims: To assess the efficacy and safety of a single injection of pasireotide LAR 60 mg or placebo prior to mastectomy with axillary lymph node dissection surgery in reducing symptomatic lymphocele development. Symptomatic lymphocele was evaluated and was defined as: 1. total lymphocele drainage/aspiration volume (unique or iterative) >60 cc inclusive within the 28 days after surgery (excluding post-surgery drain) or; 2. a systematic aspiration volume at day 28 > 120 cc. Statistical methods: The statistical analysis was carried out sequentially after observing the absence of symptomatic lymphocele for each patient. It involves estimating the probability of a response in each group using a Bayesian design based on a beta-binomial model. The probability of response was considered random and its prior distribution was centered on 80% in the pasireotide group and 60% in the placebo group according to the investigators initial guesses. The distribution of the probability of response was updated after the observation of the patients included in the trial. Results: A total of 90 patients were included over 18 months: 42 in the treatment group and 48 in the placebo group. In the treatment group, the posterior mean estimation of the response rate (i.e. patients who did not experience a symptomatic lymphocele) was 62.4% (95% CI: 48.6%-75.3%) and 50.2% in the placebo group (95% CI: 37.6%-62.8%%). In the treatment group, one serious adverse event occurred in a patient with known insulin dependent diabetes requiring hospitalization for hyperglycaemia. Conclusion: A one time injection of pasireotide LAR to prevent symptomatic lymphocele development in women undergoing mastectomy with axillary dissection is promising. Further clinical studies are warranted. [ABSTRACT FROM AUTHOR]

Background: Despite early diagnosis, approximately 20% of patients with ER-positive and HER2-negative breast cancer (BC) will experience disease recurrence. Improved survival has been reported with adjuvant treatment combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy, in high-risk patients with ER-positive and HER2-negative BC, regardless of age. Older patients have higher rates of ER-positive/HER2-negative BC than younger patients. Methods: In this real-world data analysis, MonarchE and NataLEE high-risk patients accounted for 9.5% and 33% of patients undergoing upfront surgery, respectively. Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. Results: Eligibility rates in patients ≤40 years and >80 years who underwent mastectomy were 27.8% and 24.7% for abemaciclib, respectively, and 56.6% and 65.2% for ribociclib, respectively. A higher discontinuation rate for abemaciclib was reported in patients aged ≥65 years and it can be assumed that discontinuation rates may increase in even older patients. Conclusions: If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population.

Background: There is a scarcity of data exploring early breast cancer (eBC) in very young patients. We assessed shared and intrinsic prognostic factors in a large cohort of patients aged ≤35, compared to a control group aged 36 to 50., Methods: Patients ≤50 were retrospectively identified from a multicentric cohort of 23,134 eBC patients who underwent primary surgery between 1990 and 2014. Multivariate Cox analyses for DFS and OS were built. To assess the independent impact of age, 1 to 3 case-control analysis was performed by matching ≤35 and 36-50 years patients., Results: Of 6481 patients, 556 were aged ≤35, and 5925 from 36 to 50. Age ≤35 was associated with larger tumors, higher grade, ER-negativity, macroscopic lymph node involvement (pN + macro), lymphovascular invasion (LVI), mastectomy, and chemotherapy (CT) use. In multivariate analysis, age ≤35 was associated with worse DFS [HR 1.56, 95% CI 1.32-1.84; p < 0.001], and OS [HR 1.29, 95% CI 1.03-1.60; p = 0.025], as were high grade, large tumor, LVI, pN + macro, ER-negativity, period of diagnostic, and absence of ET or CT (for DFS). Adverse prognostic impact of age ≤35 was maintained in the case control-matched analysis for DFS [HR 1.56, 95%CI 1.28-1.91, p < 0.001], and OS [HR 1.33, 95%CI 1.02-1.73, p = 0.032]. When only considering patients ≤35, ER, tumor size, nodal status, and LVI were independently associated with survival in this subgroup., Conclusions: Age ≤35 is associated with less favorable presentation and more aggressive treatment strategies. Our results support the poor prognosis value of young age, which independently persisted when adjusting for other prognostic factors and treatments., Competing Interests: Declaration of competing interest Alexandre de Nonneville declares Gilead (lecture fees, congress invitations), Daiichi Sankyo (lecture fees, congress invitations), Seagen (consulting fees), Lilly (lecture fees, congress invitations, consulting fees, research grants paid to institution), Novartis (consulting fees), MSD (congress invitations, lecture fees), Pfizer (research grants paid to institution). No conflict of interest declared by others authors., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Results of IBCSG-23-01-trial which included breast cancer patients with involved sentinel nodes (SN) by isolated-tumor-cells or micro-metastases supported the non-inferiority of completion axillary-lymph-node-dissection (cALND) omission. However, current data are considered insufficient to avoid cALND for all patients with SN-micro-metastases., Methods: To investigate the impact of cALND omission on disease-free-survival (DFS) and overall survival (OS), we analyzed a cohort of 1421 patients <75 years old with SN-micro-metastases who underwent breast conservative surgery (BCS). We used inverse probability of treatment weighting (IPTW) to obtain adjusted Kaplan-Meier estimators representing the experience in the analysis cohort, based on whether all or none had been subject to cALND omission., Results: Weighted log-rank tests comparing adjusted Kaplan-Meier survival curves showed significant differences in OS (p-value = 0.002) and borderline significant differences in DFS (p-value = 0.090) between cALND omission versus cALND. Cox's regression using stabilized IPTW evidenced an average increase in the risk of death associated with cALND omission (HR = 2.77, CI95% = 1.36-5.66). Subgroup analyses suggest that the rates of recurrence and death associated with cALND omission increase substantially after a large period of time in the half sample of women less likely to miss cALND., Conclusions: Using IPTW to estimate the causal treatment effect of cALND in a large retrospective cohort, we concluded cALND omission is associated with an increased risk of recurrence and death in women of <75 years old treated by BCS in the absence of a large consensus in favor of omitting cALND. These results are particularly contributive for patients treated by BCS where cALND omission rates increase over time., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The near-infrared (NIR) fluorescence axillary reverse mapping (ARM) procedure is a promising tool to identify and preserve arm lymphatic drainage during axillary lymph node dissection (ALND). The ARMONIC clinical trial was conducted to validate the technique on a large cohort of patients and to analyze the predictive clinical factors for ARM lymph node metastasis. For the first time, the fluorescence signal intensity from the ARM lymph nodes was measured and correlated with clinical findings. A total of 109 patients with invasive breast cancer and indications of mastectomy and ALND underwent the NIR fluorescence ARM procedure. Indocyanine green was administered by intradermal injection followed by intraoperative identification and resection of the ARM lymph nodes with NIR fluorescence camera guidance. The fluorescence signal intensity and signal distribution were then measured ex vivo and compared with clinical outcomes. ARM lymph nodes were successfully identified by fluorescence in 94.5% of cases. The mean normalized fluorescence signal intensity value was 0.47 with no significant signal difference between metastatic and non-metastatic ARM lymph nodes ( p = 0.3728). At the microscopic level, the fluorescence signal distribution was focally intense in lymphoid tissue areas. Only the preoperative diagnosis of metastasis in the axillary nodes of patients was significantly associated with a higher ARM node fluorescence signal intensity ( p = 0.0253), though it was not significantly associated with the pathological nodal (pN) status ( p = 0.8081). Based on an optimal cut-off fluorescence value, the final sensitivity and specificity of the NIR fluorescence ARM procedure for ARM lymph node metastatic involvement were 64.7% and 47.3%, respectively. Although our preliminary results did not show that fluorescence signal intensity is a reliable diagnostic tool, the NIR fluorescence ARM procedure may be useful for ARM lymph node identification. Clinical trial registration: NCT02994225.

The tissue stroma plays a major role in tumors' natural history. Most programs for tumor progression are not activated as cell-autonomous processes but under the conditions of cross-talks between tumor and stroma. Adipose tissue is a major component of breast stroma. This study compares adipose tissues in tumor-bearing breasts to those in tumor-free breasts with the intention of defining a signature that could translate into markers of cancer risk. In tumor-bearing breasts, we sampled adipose tissues adjacent to, or distant from the tumor. Parameters studied included: adipocytes size and density, immune cell infiltration, vascularization, secretome and gene expression. Adipose tissues from tumor-bearing breasts, whether adjacent to or distant from the tumor, do not differ from each other by any of these parameters. By contrast, adipose tissues from tumor-bearing breasts have the capacity to secrete twice as much interleukin 8 (IL-8) than those from tumor-free breasts and differentially express a set of 137 genes of which a significant fraction belongs to inflammation, integrin and wnt signaling pathways. These observations show that adipose tissues from tumor-bearing breasts have a distinct physiological status from those from tumor-free breasts. We propose that this constitutive status contributes as a non-cell autonomous process to determine permissiveness for tumor growth., (Copyright © 2020 Miran, Scherer, Ostyn, Mazouni, Drusch, Bernard, Louvet, Adam, Mathieu, Haffa, Antignac, Le Bizec, Vielh, Dessen, Perdry, Delaloge and Feunteun.)

Background: A strong correlation between breast cancer (BC) molecular subtypes and axillary status has been shown. It would be useful to predict the probability of lymph node (LN) positivity., Objective: To develop the performance of multivariable models to predict LN metastases, including nomograms derived from logistic regression with clinical, pathologic variables provided by tumor surgical results or only by biopsy., Methods: A retrospective cohort was randomly divided into two separate patient sets: a training set and a validation set. In the training set, we used multivariable logistic regression techniques to build different predictive nomograms for the risk of developing LN metastases. The discrimination ability and calibration accuracy of the resulting nomograms were evaluated on the training and validation set., Results: Consecutive sample of 12,572 early BC patients with sentinel node biopsies and no neoadjuvant therapy. In our predictive macro metastases LN model, the areas under curve (AUC) values were 0.780 and 0.717 respectively for pathologic and pre-operative model, with a good calibration, and results with validation data set were similar: AUC respectively of 0.796 and 0.725. Among the list of candidate's regression variables, on the training set we identified age, tumor size, LVI, and molecular subtype as statistically significant factors for predicting the risk of LN metastases., Conclusions: Several nomograms were reported to predict risk of SLN involvement and NSN involvement. We propose a new calculation model to assess this risk of positive LN with similar performance which could be useful to choose management strategies, to avoid axillary LN staging or to propose ALND for patients with high level probability of major axillary LN involvement but also to propose immediate breast reconstruction when post mastectomy radiotherapy is not required for patients without LN macro metastasis.

Background: Sentinel lymph node biopsy (SLNB) remains under discussion for large size tumors. The aim of this work has been to study the false negative rate (FNR) of SLNB for large tumors and predictive factors of false negative (FN)., Materials and Methods: A study of a multicentric cohort, involved patients presenting N0 breast cancer with a SLNB eventually completed by complementary axillary lymph node dissection (cALND). The main criteria were the FNR and the predictive factors of FN., Results: 12.415 patients were included: 748 with tumors ≥30 mm, 1101 with tumors >20 and < 30 mm and 10.566 with tumors ≤20 mm, with a cALND respectively for 501 patients (67%), 523 (62.1%) and 2775 (26.3%). The FNR were respectively: 3.05% (IC95%: 1.3-4.8) for tumors ≥30 mm*, 3.5% (1.8-5.2) for tumors >20 and < 30 mm*, 1.8% (1-2.4) for tumors ≤20 mm (p < 0.05) (*Not significant). At multivariate analysis, SN number harvested ≤2 (OR:2.0, p = 0.023) and tumor size >20 and < 30 mm (OR:2.07, p = 0.017) were significant predictive factors of FN, without significant value for tumor size ≥30 mm (OR:1.83, p = 0.073)., Conclusion: The FNR of SLNB was not higher amongst large size tumors compared to tumors of a smaller size. These results support the validation of SNLB for tumors up to 50 mm., (Copyright © 2017. Published by Elsevier Ltd.)