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IntroductionReturn to work (RTW) after breast cancer (BC) is still a new field of research. The factors determining shorter sick leave duration of patients with BC have not been clearly identified. The aim of this study was to describe work during BC treatment and to identify factors associated with sick leave duration.Materials and methodsAn observational, prospective, multicentre study was conducted among women with operable BC. A logbook was given to all working patients to record sociodemographic and work-related data over a 1-year period.ResultsWork-related data after BC were available for 178 patients (60%). The median age at diagnosis was 50 years (27–77), 87.9% of patients had an invasive form of BC and 25.3% a lymph node involvement. 25.9% had a radical surgery and 24.2% had an axillary dissection. Radiotherapy was performed in 90.9% of patients and chemotherapy in 48.1%. Sick leave was prescribed for 165 patients (92.7%) for a median of 155 days. On univariate analysis, invasive BC (p=0.025), lymph node involvement (p=0.005), radical surgery (p=0.025), axillary dissection (p=0.004), chemotherapy (pConclusionAdvanced disease and chemotherapy are major factors that influence sick leave duration during the management of BC.Trial registration numberNCT02813317.

BACKGROUND Cancer research participation today is unfortunately not optimally effective. Only a few citizens of the population in France are involved in clinical trials. The participation of a wide number of people in cancer research is crucial to increase speed and optimize quality in cancer research. OBJECTIVE In order to remove this barrier and connect the public with researchers a national online platform called Seintinelles has been created in 2014. METHODS Participants subscribed voluntarily to a website and were afterwards recruited by email for studies suitable to their baseline profile. Participants were given the possibility to register for the newsletter or to participate in social events. Once a researcher needed volunteers the participants in the database received an email with the terms and criteria of the study and interested participants could give their permission to be included. RESULTS Currently more than 20.504 participants, healthy people and people with a specific cancer type, with a mean age of 46 years old and spread out all over France, have subscribed to the website Seintinelles. The main cancer type that is represented is breast cancer (5962 participants), followed by colorectal cancer (136 participants) and lung cancer (78 participants). A group of researchers (n: 277) contributed to successfully match patients with the appropriate studies 10 studies have been successfully conducted and 7 are currently ongoing. CONCLUSIONS Seintinelles successfully started a national online platform in 2014 that connects researchers and citizens of France in order to improve the efficacy of cancer research. Within 2 years time the website has been able to recruit 20.504 citizens eligible to participate in important nation-wide cancer studies. Seinitelles has shown to be an effective way to speed up cancer research. The future goal is to expand the platform and involve up to 50.000 patients and 10 yearly studies by 2018.

Background: We conducted a meta-analysis in nonmetastatic breast cancer patients treated by neoadjuvant chemotherapy (NCT) to assess the clinical validity of circulating tumor cell (CTC) detection as a prognostic marker. Methods: We collected individual patient data from 21 studies in which CTC detection by CellSearch was performed in early breast cancer patients treated with NCT. The primary end point was overall survival, analyzed according to CTC detection, using Cox regression models stratified by study. Secondary end points included distant disease-free survival, locoregional relapse-free interval, and pathological complete response. All statistical tests were two-sided. Results: Data from patients were collected before NCT (n = 1574) and before surgery (n = 1200). CTC detection revealed one or more CTCs in 25.2% of patients before NCT; this was associated with tumor size (P < .001). The number of CTCs detected had a detrimental and decremental impact on overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P < .001), but not on pathological complete response. Patients with one, two, three to four, and five or more CTCs before NCT displayed hazard ratios of death of 1.09 (95% confidence interval [CI] = 0.65 to 1.69), 2.63 (95% CI = 1.42 to 4.54), 3.83 (95% CI = 2.08 to 6.66), and 6.25 (95% CI = 4.34 to 9.09), respectively. In 861 patients with full data available, adding CTC detection before NCT increased the prognostic ability of multivariable prognostic models for overall survival (P < .001), distant disease-free survival (P < .001), and locoregional relapse-free interval (P = .008). Conclusions: CTC count is an independent and quantitative prognostic factor in early breast cancer patients treated by NCT. It complements current prognostic models based on tumor characteristics and response to therapy.

Purpose: Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines- and taxanes-based treatments. Experimental Design: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins, and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistologic analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX. Results: Residual TNBC PDX were characterized by a high tumor take, a short latency, and a poor prognosis of the corresponding patients. With the exception of BRCA1/2-mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX, with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB1 and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment. Conclusions: We identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes, and platins. RB1 positivity and high expression of TYMP were significantly associated with capecitabine response. Clin Cancer Res; 24(11); 2605–15. ©2018 AACR.

Background: Trastuzumab was introduced a decade ago and has improved outcomes for HER2-positive breast cancer. We investigated the factors predictive of pathological complete response (pCR), prognostic factors for disease-free survival (DFS), and interactions between pCR and DFS after neoadjuvant treatment. Methods: We identified 287 patients with primary HER2-positive breast cancers given neoadjuvant chemotherapy (NAC) between 2002 and 2011. Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were performed. Results: pCR rates differed between patients receiving neoadjuvant trastuzumab treatment or not (47.7% versus 19.3%, P

Le malformazioni e le deformita acquisite della mammella hanno origini molto varie. A seconda della deformita da trattare, sia essa derivante da esiti chirurgici o dalla radioterapia o sia essa legata ad agenesia mammaria o a una mammella tuberosa, l’approccio chirurgico e differente. Le tecniche di rimodellamento (riduzione, impianto di protesi, lipofilling, lembi) sono le stesse per tutte queste deformita. L’elemento essenziale della strategia si basa sulla comprensione della deformita e sulla scelta dell’indicazione chirurgica.

Invasion of cancer cells into collagen-rich extracellular matrix requires membrane-tethered membrane type 1–matrix metalloproteinase (MT1-MMP) as the key protease for collagen breakdown. Understanding how MT1-MMP is delivered to the surface of tumor cells is essential for cancer cell biology. In this study, we identify ARF6 together with c-Jun NH2-terminal kinase–interacting protein 3 and 4 (JIP3 and JIP4) effectors as critical regulators of this process. Silencing ARF6 or JIP3/JIP4 in breast tumor cells results in MT1-MMP endosome mispositioning and reduces MT1-MMP exocytosis and tumor cell invasion. JIPs are recruited by Wiskott-Aldrich syndrome protein and scar homologue (WASH) on MT1-MMP endosomes on which they recruit dynein–dynactin and kinesin-1. The interaction of plasma membrane ARF6 with endosomal JIPs coordinates dynactin–dynein and kinesin-1 activity in a tug-of-war mechanism, leading to MT1-MMP endosome tubulation and exocytosis. In addition, we find that ARF6, MT1-MMP, and kinesin-1 are up-regulated in high-grade triple-negative breast cancers. These data identify a critical ARF6–JIP–MT1-MMP–dynein–dynactin–kinesin-1 axis promoting an invasive phenotype of breast cancer cells.

Reciprocal interactions between tumor cells and their microenvironment vitally impact tumor progression. In this study, we show that GM-CSF produced by primary breast tumor cells induced the activation of plasmacytoid predendritic cells (pDC), a cell type critical to anti-viral immunity. pDC that expressed the GM-CSF receptor were increased in breast tumors compared with noninvolved adjacent breast tissue. Tumor-activated pDC acquired naïve CD4+ T-cell stimulatory capacity and promoted a regulatory Th2 response. Finally, the concomitant increase of GM-CSF and pDC was significantly associated with relatively more aggressive breast cancer subtypes. Our results characterize the first tumor-derived factor that can activate pDC to promote a regulatory Th2 response, with implications for therapeutic targeting of a tumor-immune axis of growing recognition in its significance to cancer. Cancer Res; 75(14); 2775–87. ©2015 AACR.

Background Filter feature selection methods compute molecular signatures by selecting subsets of genes in the ranking of a valuation function. The motivations of the valuation functions choice are almost always clearly stated, but those for selecting the genes according to their ranking are hardly ever explicit. Method We addressed the computation of molecular signatures by searching the optima of a bi-objective function whose solution space was the set of all possible molecular signatures, ie, the set of subsets of genes. The two objectives were the size of the signature-to be minimized–and the interclass distance induced by the signature-to be maximized–. Results We showed that: 1) the convex combination of the two objectives had exactly n optimal non empty signatures where n was the number of genes, 2) the n optimal signatures were nested, and 3) the optimal signature of size k was the subset of k top ranked genes that contributed the most to the interclass distance. We applied our feature selection method on five public datasets in oncology, and assessed the prediction performances of the optimal signatures as input to the diagonal linear discriminant analysis (DLDA) classifier. They were at the same level or better than the best-reported ones. The predictions were robust, and the signatures were almost always significantly smaller. We studied in more details the performances of our predictive modeling on two breast cancer datasets to predict the response to a preoperative chemotherapy: the performances were higher than the previously reported ones, the signatures were three times smaller (11 versus 30 gene signatures), and the genes member of the signature were known to be involved in the response to chemotherapy. Conclusions Defining molecular signatures as the optima of a bi-objective function that combined the signature size and the interclass distance was well founded and efficient for prediction in oncogenomics. The complexity of the computation was very low because the optimal signatures were the sets of genes in the ranking of their valuation. Software can be freely downloaded from http://gardeux-vincent.eu/DeltaRanking.php

Background The role of tumor-infiltrating lymphocytes (TILs) in breast cancer has been extensively studied over the last decade. High TILs levels have been associated with pathological response rate in the neoadjuvant setting and with better outcomes in the adjuvant setting. However, little attention has been paid to changes in TILs and residual TIL levels after neoadjuvant chemotherapy (NAC). We investigated TIL levels before, after chemotherapy, and their dynamics during treatment; and we assessed the correlation of these levels with response to NAC and prognosis. Materials and methods We identified 175 patients with primary HER2-positive breast cancers receiving NAC+/− trastuzumab between 2002 and 2011. Microbiopsy specimens and paired surgical samples were evaluated for stromal lymphocyte infiltration. Univariate and multivariate analyses were carried out to assess the association of clinical and pathological factors with pathological complete response (pCR) and disease-free survival. Results Baseline TIL levels were not significantly associated with pCR. TIL levels decreased during treatment in 78% of the patients. The magnitude of the decrease was strongly associated with pCR. After chemotherapy, TIL levels were high in tumors displaying aggressive patterns (high residual cancer burden score, mitotic index >22, tumor cellularity >5%). In the population with residual disease, TIL levels >25% at the end of NAC were significantly associated with an adverse outcome (TILs >25%, HR = 7.98, P = 0.009) after multivariate analyses including BMI, post-NAC mitotic index and tumor grade. Conclusion A decrease in TIL levels during chemotherapy was positively associated with response to treatment. In tumor failing to achieve pCR, post-NAC lymphocytic infiltration was associated with higher residual tumor burden and adverse clinical outcome. Further studies are required to characterize immune infiltration in residual disease to identify candidates who could benefit from second-line therapy trials including immune checkpoint inhibitors.

Benefit of adjuvant trastuzumab-based chemotherapy for node-positive and/or1 cm human epidermal growth factor receptor 2-positive (HER2+) breast carcinomas has been clearly demonstrated in randomized clinical trials. Yet, evidence that adjuvant chemotherapy with or without trastuzumab is effective in pT1abN0 HER2+ tumors is still limited. The primary objective of this study was to investigate the impact of adjuvant chemotherapy ± trastuzumab on outcome in this subpopulation.A total of 356 cases of pT1abN0M0 HER2 + breast cancers were retrospectively identified from a large cohort of 22,334 patients, including 1248 HER2+ patients who underwent primary surgery at 17 French centers, between December 1994 and January 2014. The primary end point was disease-free survival (DFS). A multivariate Cox model was built, including adjuvant chemotherapy, tumor size, hormone receptor status, and Scarff Bloom Richardson (SBR) grade.A total of 138 cases (39%) were treated with trastuzumab-based chemotherapy, 29 (8%) with chemotherapy alone, and 189 (53%) received neither trastuzumab nor chemotherapy. Adjuvant chemotherapy ± trastuzumab was associated with a significant DFS benefit (3-year 99 vs. 90%, and 5-year 96 vs. 84%, Hazard ratio, HR 0.26 [0.10-0.67]; p = 0.003, logrank test) which was maintained in multivariate analysis (HR 0.19 [0.07-0.52]; p = 0.001). Metastasis-free survival was also increased (HR 0.25 [0.07-0.86]; p = 0.018, logrank test) at 3-year (99 vs. 95%) and 5-year (98 vs. 89%) censoring. Exploratory subgroup analysis found DFS benefit to be significant in hormone receptor-negative, hormone receptor-positive, and pT1b tumors, but not in pT1a tumors.Adjuvant chemotherapy ± trastuzumab is associated with a significantly reduced risk of recurrence in subcentimeter node-negative HER2+ breast cancers. Most of the benefit may be driven by pT1b tumors.

Background Avoiding axillary lymph node dissection (ALND) for invasive breast cancers with isolated tumor cells or micrometastatic sentinel node biopsy (SNB) could decrease morbidity with minimal clinical significance. Purpose The aim of this study is to simulate the medico-economic impact of the routine use of the MSKCC non-sentinel node (NSN) prediction nomogram for ER+ HER2- breast cancer patients. Methods We studied 1036 ER+ HER2- breast cancer patients with a metastatic SNB. All had a complementary ALND. For each patient, we calculated the probability of the NSN positivity using the MSKCC nomogram. After validation of this nomogram in the population, we described how the patients' characteristics spread as the threshold value changed. Then, we performed an economic simulation study to estimate the total cost of caring for patients treated according to the MSKCC predictive nomogram results. Results A 0.3 threshold discriminate the type of sentinel node (SN) metastases: 98.8% of patients with pN0(i+) and 91.6% of patients with pN1(mic) had a MSKCC score under 0.3 (false negative rate = 6.4%). If we use the 0.3 threshold for economic simulation, 43% of ALND could be avoided, reducing the costs of caring by 1 051 980 EUROS among the 1036 patients. Conclusion We demonstrated the cost-effectiveness of using the MSKCC NSN prediction nomogram by avoiding ALND for the pN0(i+) or pN1(mic) ER+ HER2- breast cancer patients with a MSKCC score of less than or equal to 0.3.

Analysis and interpretation of stained tumor sections is one of the main tools in cancer diagnosis and prognosis, which is mainly carried out manually by pathologists. The avent of digital pathology provides us with the challenging opportunity to automatically analyze large amounts of these complex image data in order to draw biological conclusions from them and to study cellular and tissular phenotypes at a large scale. One of the bottlenecks for such approaches is the automatic segmentation of cell nuclei from this type of image data. Here, we present a fully automated workflow to segment nuclei from histopathology image data by using deep neural networks trained from a set of manually annotated images and by processing the posterior probability maps in order to split jointly segmented nuclei. Further, we provide the image data set that has been generated for this study as a benchmark set to the scientific community.

Resume La mastectomie avec conservation de la plaque areolo-mamelonnaire (PAM) dans la prise en charge du cancer du sein est controversee. Les risques oncologiques ainsi que les risques de complications sont aux premiers plans. Nous nous sommes interesses a identifier l’incidence des atteintes de la PAM, les facteurs predictifs d’atteinte de celle-ci, le taux de recidive locoregionale ainsi que le taux de complications. Nous avons realise une revue de la litterature via PubMed en utilisant les termes : « mastectomy », « nipple involvement », « nipple-sparing mastectomy », « skin-sparing » « Mastectomy » « occult nipple malignancy » « occult nipple disease » « breast cancer recurrence ». Les articles ont ete analyses en portant attention sur l’incidence des atteintes de la PAM, les facteurs associes a une atteinte de la PAM, les taux de recidives et de complications. Les taux d’incidence ont ete compares entre les groupes par les tests de Chi 2 ou de Fisher pour les variables categorielles et par test de Student pour les variables continues. Les differences etaient considerees comme significatives avec un p 5 cm, une localisation retro-areolaire et les lesions multicentriques. Le taux de recidive apres mastectomie avec conservation de la PAM est de 0,9 % au niveau de la PAM et de 4,2 % au niveau de l’etui cutane. Les taux de necrose partielle et totale de la PAM sont respectivement de 2,9 % et 6,3 %. La mastectomie avec conservation de la plaque areolo-mamelonnaire est une solution appropriee chez des patientes bien selectionnees. Il doit etre realise une recoupe retro-areolaire systematique. La mastectomie avec conservation de la PAM doit etre proposee dans le cas de lesions uni- ou multicentriques bien circonscrites a plus de 2 cm de la PAM, de grade 1 ou 2, HER2 negatif, sans embole ni atteinte ganglionnaire.

Aim To identify predictors for infiltrating carcinoma and lymph node involvement, before immediate breast reconstructive surgery, in patients with an initial diagnosis of extensive pure ductal carcinoma in situ of the breast (DCIS). Patients and methods Between January 2000 and December 2009, 241 patients with pure extensive DCIS in preoperative biopsy had underwent mastectomy. Axillary staging (sentinel node and/or axillary dissection) was performed in 92% ( n = 221) of patients. Patients with micro-invasive lesions at initial diagnosis, recurrence or contralateral breast cancer were excluded. Results Respectively 14% and 21% of patients had a final diagnosis of micro-invasive carcinoma (MIC) and invasive ductal carcinoma (IDC). Univariate analysis showed that the following variables at diagnosis were significantly correlated with the presence of either MIC or IDC in the mastectomy specimen: palpable tumor ( p = 0.002), high grade DCIS ( p = 0.002) and detection of an opacity by mammography ( p = 0.019). Axillary lymph node (ALN) involvement was reported in 9% of patients. Univariate analysis suggested that a body mass index higher than 25 ( p = 0.007), a palpable tumor ( p = 0.012) and the detection of an opacity by mammography ( p = 0.044) were associated with an increased rate of ALN involvement. Conclusion Skin-sparing mastectomy and immediate breast reconstruction (IBRS) has become increasingly popular, especially for patients with extended DCIS of the breast. This study confirmed that extended DCIS is associated with a substantial risk of finding MIC or IDC on the surgical specimen but also ALN involvement. Adjuvant systemic treatment and/or radiotherapy could be indicated for some of these patients after the surgery. Patients should be informed of the rate of 1) complications associated to IBRS that will potentially delay the introduction of systemic or local therapy 2) complications associated to radiotherapy after IBRS.

Background: BIA-ALCL is a rare subtype of T cell lymphomas associated with textured breast implants which has recently been recognized. The pathogenesis of this entity remains elusive even if mutations in the JAK/STAT pathway have been identified. Little is known about the causes, prognostic factors of this disease, and treatment outcome. Methods: since 2016, a WebEx national multidisciplinary meeting has been implemented by the French Cancer Agency in order to better define therapeutic strategies for newly diagnosed cases after histologic confirmation. In the same time, BIA-ALCL registry was funded by LYSA in order to collect ambispectively, in France and Belgium, patient clinical data including reasons for breast implantation (breast augmentation, reconstruction), implant manufacturer, treatments and outcome. A biological program aiming molecular characterization of this T-cell lymphoma subtype has been set in coordination with the registry. Results: Fifty-eight patients (pts) have been analyzed so far among the 88 (67 in France and 21 in Belgium) identified from 2009 to 2019. Median age was 58 years (range 29-82) at diagnosis. In 29 out of the 58 pts (50%) the first implant followed a mastectomy for breast cancer. In this analysis, only implants in the breast(s) where the lymphoma occurred have been considered. Four pts (6.9%) had bilateral lymphoma and 54 pts had unilateral lymphoma (50% left side and 50% right side), 25 pts were implanted once (43.1%), 24 twice (41.4%) and 9 pts (15.5%) 3 times or more. The median delay between first implant and BIA-ALCL diagnosis was 11.9 years (range 4.1-37), and median delay from last implant to diagnosis was 6.5 years (range 0.2-25.4). The two clinical presentations i.e. seroma (n = 43, 74.1%) and breast tumor mass with or without seroma (n = 12, 20.7%) were most often correlated with the two distinct histological subtypes (in situ /mixed (n=41) or infiltrative (n=17). Three pts were diagnosed without any mass or seroma (1 lymph node involvement, 2 in the context of systematic implant removal). The majority of pts were stage I-II (n=45, 77.6%), and 13 (22.4%) pts were stage IV. One hundred and five implants have been used on lymphoma associated breast for these 58 patients. Considering available information regarding the type of implants, almost all patients had at least one silicone-filled (n=51) and at least one textured implant (n=49) with Biocell texturation (n=40, 69%). No patient had only smooth implant. Implant removal with total capsulectomy was performed in 49 patients and 17 underwent chemotherapy based mostly on CHOP or CHOP-like chemotherapy regimens (n=12) and brentuximab vedotin CHP (n=3). After 21 months of median follow-up, 52 pts are alive and free of evolutive disease and one was lost to follow up. Five pts have died, either from lymphoma progression alone (n=2), or associated with concomitant active breast cancer (n=2) and one due to another disease. All had an infiltrative histology, and the 2 patients who died from lymphoma were stage IV. All but one received systemic chemotherapy and one received palliative care only due to concomitant active breast cancer. One of these patients early relapsed after a first complete remission. After the BIA-ALCL diagnosis, breast reconstruction was performed in in 23 pts (39.7%), 17 with a new implant, lipofilling in 4 pts, with a flap in 4 pts, and one benefit from combined approaches. Whole exome sequencing and/or targeted deep sequencing was performed in 29 of these patients. Recurrent mutation of epigenetic modifiers were seen in 22 pts (76%) involving notably KMT2C (28%), CM2D (14%) and CREBBP (14%). Eighteen pts (62%) showed mutations in at least one member of JAK STAT signaling pathway including STAT3 (38%) and JAK1(21%). Conclusions: We here confirm that in situ BIA-ALCLs have an indolent clinical course and remain in complete remission mainly after implant removal. Infiltrative histological subtype which have a more aggressive clinical course should be precisely identified at baseline. In our series, most BIA-ALCL cases were associated with macrotextured implants with Biocell texturation observed in 69% of the cases. The molecular characterization of these cases highlights the key role of the JAK/STAT pathway, and the importance of epigenomics. Such observation provide basis to develop novel targeted therapies for patients with aggressive disease. Disclosures Le Bras: Takeda: Research Funding; Pfizer: Other: Travel grant; Jansen: Other: Travel grant. Haioun:novartis: Honoraria; celgene: Honoraria; roche: Consultancy; celgene: Consultancy; gilead: Consultancy; takeda: Consultancy; janssen cilag: Consultancy; amgen: Honoraria; servier: Honoraria. Bachy:Janssen Cilag: Honoraria; Janssen Cilag: Other: Travel, accomodation, Expense; Roche: Honoraria; Amgen: Honoraria; Roche: Consultancy; Gilead Science: Honoraria. Oberic:Roche: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria. Tilly:Roche: Consultancy; roche: Membership on an entity's Board of Directors or advisory committees; servier: Honoraria; merck: Honoraria; Gilead: Honoraria; Janssen: Honoraria; BMS: Honoraria; Karyopharm: Consultancy; Astra-Zeneca: Consultancy; Celgene: Consultancy, Research Funding.

Background Elderly breast cancer (BC) patients have been underrepresented in clinical trials whereas ∼60% of deaths from BC occur in women aged 65 years and older. The management of elderly women with early BC requires careful evaluation of risks and benefits of available treatment options. Clinical trials for elderly patients in the adjuvant setting are lacking, and efficacy results obtained in general population cannot be directly extrapolated to elderly patients without specific evidences. Therefore, we examined factors associated with the prescription of adjuvant chemotherapy (aCT) and the impact of this treatment on overall survival (OS) in a large cohort of patients aged 65 years and older. Methods Patients were retrospectively identified from a large cohort of 23,134 early BC patients who underwent primary surgery in 18 academic centres between 1990 and 2014. A binary logistic regression was built to identify the factors associated with aCT administration. The impact of aCT on OS was analysed using a multivariate Cox regression model including age, histology, grade, tumour size, lymphovascular invasion (LVI), nodal status and endocrine therapy (ET) and endocrine receptors (ER). A propensity score-based matching analysis was performed. Results Of 6605 patients aged 65 years and older, 1493 received aCT (22.6%). Administration of aCT was predominantly associated with macroscopic lymph node involvement (LNi) and ER-negative status but common predictors, such as age Conclusions The factors associated with aCT use in the elderly are similar to those usually found in younger age groups. By highlighting an OS benefit, even in the “very old” subgroup, our results may help clarifying the role of aCT in elderly patients. Legal entity responsible for the study Houvenaeghel Gilles. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

e12095 Background: The aim of this study was to compare the value of 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET/CT) with CGFL/Curie nomogram to predict a pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor 2 (HER2)-positive breast cancer treated by trastuzumab. Methods: Fifty-one women with HER2-positive breast cancer treated with trastuzumab plus taxane-based NAC, were retrospectively included from January 2005 to December 2015. For 18F-FDG PET/CT, the analyzed predictor was the maximum standardized uptake value of the primary tumor and axillary nodes after the first course of NAC (PET2.SUVmax). pCR was defined by no residual infiltrative tumor but in situ tumor was accepted. Accuracy of CGFL/Curie nomogram and PET2.SUVmax was evaluated measuring sensitivity (Se), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV). For each predictor, receiver operating characteristic (ROC) curve was created. To evaluate the correlation between predictors, the Spearman coefficient was calculated. Combined prediction was evaluated testing predictor’s associations. Results: For CGFL/Curie nomogram’s performances, Se, Sp, PPV and NPV were respectively: 76% (CI95%: 58-90%), 57% (CI95%: 43-66%), 55% (CI95%: 42-65), 77% (CI95%: 59-90%). For PET2.SUVmax’s performances, Se, Sp, PPV and NPV were respectively: 67% (CI95%: 48-81%), 77% (CI95%: 64-97%), 67% (CI95%: 48-82%), 77% (CI95%: 64-87%). ROC curves for these predictors were similar; the areas under the curve were 0.6 (CI95%: 0.56-0.64) for PET2.SUVmax and 0.55 (CI95%: 0.50-0.59) for CGFL/Curie nomogram. Spearman coefficient was 0.23. Combined prediction was more efficient with Se at 80%, VPN at 76%, Sp at 78% and VPP at 81 %. Conclusions: CGFL/Curie nomogram and PET2.SUVmax were two efficient predictors of pCR in patients with HER2-positive breast cancer. Combined prediction has an improved accuracy.

Aim To determine whether, in a highly selected patient population, medical treatment combined with surgical resection of liver metastases from breast cancer is associated with improved survival compared with medical treatment alone. Patients and methods Between 1988 and 2007, 100 liver resections for metastatic breast cancer were performed at Institut Curie, 51 of which met the criteria for inclusion in this case-control study. With the exception of bone metastases, patients with other distant metastasis sites were excluded. Surgery was only performed in patients with stable disease or disease responding to medical treatment evaluated by imaging evaluation. Surgical cases were individually matched with 51 patients receiving medical treatment only. All patients had 4 or fewer resectable liver metastases. The study group was matched with the control group for age, year of breast cancer diagnosis, time to metastasis, TNM stage, hormone receptor status and breast cancer tumour pathology. Results Univariate analysis confirmed a survival advantage for patients lacking bone metastases and axillary lymphadenopathy at the time of breast cancer diagnosis and for surgically treated patients. Multivariate analysis indicated that surgery and the absence of bone metastases were associated with a better prognosis. A multivariate Cox model adapted for paired data showed a RR = 3.04 (CI: 1.87–4.92) ( p Conclusion Surgical resection of liver metastases from primary breast cancer appears to provide a survival benefit for highly selected patients.

RNA interference has boosted the field of functional genomics, by making it possible to carry out 'loss-of-function' screens in cultured cells. Here, we performed a small interfering RNA screening, in three breast cancer cell lines, for 101 candidate driver genes overexpressed in amplified breast tumors and belonging to eight amplicons on chromosomes 8q and 17q, investigating their role in cell survival/proliferation. This screening identified eight driver genes that were amplified, overexpressed and critical for breast tumor cell proliferation or survival. They included the well-described oncogenic driver genes for the 17q12 amplicon, ERBB2 and GRB7. Four of six other candidate driver genes-RAD21 and EIF3H, both on chromosome 8q23, CHRAC1 on chromosome 8q24.3 and TANC2 on chromosome 17q23-were confirmed to be driver genes regulating the proliferation/survival of clonogenic breast cancer cells presenting an amplification of the corresponding region. Indeed, knockdown of the expression of these genes decreased cell viability, through both cell cycle arrest and apoptosis induction, and inhibited the formation of colonies in anchorage-independent conditions, in soft agar. Strategies for inhibiting the expression of these genes or the function of the proteins they encode are therefore of potential value for the treatment of breast cancers presenting amplifications of the corresponding genomic region.

The role of nipple-sparing mastectomy for breast cancer is controversial, as there is concern regarding its oncologic safety and complication rate. The authors reviewed the literature to quantify the incidence of occult nipple malignancy in breast cancer, identify the factors influencing occult nipple malignancy, quantify locoregional recurrence rates, and quantify nipple-sparing mastectomy complication rates.A search of the literature was performed using PubMed. Key words used were "mastectomy," "nipple involvement," "nipple-sparing mastectomy," "skin-sparing mastectomy," "occult nipple malignancy," "occult nipple disease," and "breast cancer recurrence." Articles were analyzed regarding incidence of occult nipple malignancy, potential factors influencing the incidence of occult malignancy, and recurrence/complications following nipple-sparing mastectomy. The incidence of occult nipple disease was compared between groups using chi-square or Fisher's exact tests for categorical variables and t tests for continuous variables. Values of p0.05 were considered significant.The overall rate of occult nipple malignancy was 11.5 percent. Primary tumor characteristics influencing occult nipple malignancy were tumor-nipple distance less than 2 cm, grade, lymph node metastasis, lymphovascular invasion, human epidermal growth factor receptor-2-positive, estrogen receptor/progesterone receptor-negative, tumor size greater than 5 cm, retroareolar/central location, and multicentric tumors. The overall nipple recurrence rate considered significant was 0.9 percent, and the skin flap recurrence rate was 4.2 percent. Full- and partial-thickness nipple necrosis rates were 2.9 and 6.3 percent, respectively.Nipple-sparing mastectomy for primary breast cancer is appropriate in carefully selected patients. All patients should have retroareolar sampling. There is strong evidence to suggest that suitable cases are well circumscribed single or multifocal lesions that have a tumor-to-nipple distance greater than 2 cm. Tumors should be grade 1 to 2 and not have lymphovascular invasion, axillary node metastasis, or human epidermal growth factor receptor-2 positivity.

In March of 2010, French authorities suspended the use of breast implants made by the company Poly Implant Prothèse. Institut Curie is a large cancer center, and Poly Implant Prothèse was one major silicone-filled breast implant brand used. This report describes the impact of the fraudulent implants worldwide and more specifically on patient care at the authors' unit. From 2002 to 2009, the median number of Poly Implant Prothèse implants removed per year was 32. Since the first alert in March of 2010, 252 of these breast implants were removed in 2010 and 2011. The breast implants removed were mainly reported as normal, with a rupture rate of less than 5 percent before 2008. However, the annual rupture rate has increased from 2008 to 2011 (8, 14, 20, and 23 percent, respectively). The Institut Curie, in conjunction with breast cancer patients, has organized a management plan to deal with this major industrial fraud. Its surveillance program of breast cancer patients facilitated the management of patients during this difficult time.

Metastasis confronts clinicians with two major challenges: estimating the patient's risk of metastasis and identifying therapeutic targets. Because they are key signal integrators connecting cellular processes to clinical outcome, we aimed to identify transcriptional nodes regulating cancer cell metastasis. Using rodent xenograft models that we previously developed, we identified the transcription factor Fos-related antigen-1 (Fra-1) as a key coordinator of metastasis. Because Fra-1 often is overexpressed in human metastatic breast cancers and has been shown to control their invasive potential in vitro, we aimed to assess the implication and prognostic significance of the Fra-1–dependent genetic program in breast cancer metastasis and to identify potential Fra-1–dependent therapeutic targets. In several in vivo assays in mice, we demonstrate that stable RNAi depletion of Fra-1 from human breast cancer cells strongly suppresses their ability to metastasize. These results support a clinically important role for Fra-1 and the genetic program it controls. We show that a Fra-1–dependent gene-expression signature accurately predicts recurrence of breast cancer. Furthermore, a synthetic lethal drug screen revealed that antagonists of the adenosine receptor A 2B (ADORA2B) are preferentially toxic to breast tumor cells expressing Fra-1. Both RNAi silencing and pharmacologic blockade of ADORA2B inhibited filopodia formation and invasive activity of breast cancer cells and correspondingly reduced tumor outgrowth in the lungs. These data show that Fra-1 activity is causally involved in and is a prognostic indicator of breast cancer metastasis. They suggest that Fra-1 activity predicts responsiveness to inhibition of pharmacologically tractable targets, such as ADORA2B, which may be used for clinical interference of metastatic breast cancer.

Background The REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS). Patients and methods From 2004 to 2007, 340 stage II–III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin–cyclophosphamide followed by four cycles of docetaxel) +/− celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106). Results Median follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36–0.92], p = 0.021). Conclusion Celecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.

Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that primes dendritic cells for Th2 induction. It has been implicated in different types of allergic diseases. Recent work suggested that TSLP could play an important role in the tumor microenvironment and influence tumor progression, in particular in breast cancer. In this study we systematically assessed the production of TSLP at the mRNA and protein levels in several human breast cancer cell lines, large-scale public transcriptomics data sets, and primary human breast tumors. We found that TSLP production was marginal, and concerned less than 10% of the tumors, with very low mRNA and protein levels. In most cases TSLP was undetectable and found to be expressed at lower levels in breast cancer as compared to normal breast tissue. Last, we could not detect any functional TSLP receptor (TSLPR) expression neither on hematopoietic cells nor on stromal cells within the primary tumor microenvironment. We conclude that TSLP-TSLPR pathway activity is not significantly detected within human breast cancer. Taken together, these observations do not support TSLP targeting in breast cancer.

Controversy exists about the prognosis of breast cancer in young women. Our objective was to describe clinicopathological and prognostic features to improve adjuvant treatment indications.We conducted a retrospective multi centre study including fifteen French hospitals. Disease-free survival's data, clinical and pathological criteria were collected.5815 patients were included, 15.6% of them where between 35 and 40 years old and 8.7% below 35. In 94% of the cases, a palpable masse was found in patients ≤35 years old. Triple negative and HER2 tumors were predominantly found in patients ≤35 (22.2% and 22.1%, p 0.01). A young age ≤40 years (p 0.001; hazard ratio [HR]: 2.05; 95% confidence limit [CL]: 1.60-2.63) or ≤35 years (p 0.001; [HR]: 3.86; 95% [CL]: 2.69-5.53) impacted on the indication of chemotherapy. Age ≤35 (p 0.001; [HR]: 2.01; 95% [CL]: 1.36-2.95) was a significantly negative factor on disease-free survival. Chemotherapy (p 0.006; [HR]: 0.6; 95% [CL]: 0.40-0.86) and positive hormone receptor status (p 0.001; [HR]: 0.6; 95% [CL]: 0.54-0.79) appeared to be protector factors. Patients under 36, had a significantly higher rate of local recurrence and distant metastasis compared to patients35-40 (21.5 vs. 15.4% and 21.8 vs. 12.6%, p 0.01).Young women present a different distribution of molecular phenotypes with more luminal B and triple negative tumors with a higher grade and more lymph node involvement. A young age, must be taken as a pejorative prognostic factor and must play a part in indication of adjuvant therapy.

Background The poor prognosis of patients who experience ipsilateral breast tumor recurrence (IBTR) after breast conserving surgery (BCS) is established. A short time between primary cancer and IBTR is a prognostic factor but no clinically relevant threshold was determined. Classification of IBTR may help tailor treatment strategies. Purpose We determined a specific time frame, which differentiates IBTR into early and late recurrence, and identified prognostic factors for patients with IBTR at time of the recurrence. Methods We analyzed 2209 patients with IBTR after BCS. We applied the optimal cut-points method for survival data to determine the cut-off times to IBTR. A subgroup analysis was performed by hormone receptor (HR) status. Survival analyses were performed using a Cox proportional hazard model to determine clinical features associated with distant-disease-free survival (DDFS) after IBTR. We therefor built decision trees. Results On the 828 metastatic events observed, the majority occurred within the first 3 months after IBTR: 157 in the HR positive group, 98 in the HR negative group. We found different prognostic times to IBTR: 49 months in the HR positive group, 33 in the HR negative group. After multivariate analysis, time to IBTR was the first discriminant prognostic factor in both groups (HR 0.65 CI95% [0.54–0.79] and 0.42 [0.30–0.57] respectively). The other following variables were significantly correlated with the DDFS: the initial number of positive lymph nodes for both groups, the initial tumor size and grade for HR positive tumors. Conclusion A short interval time to IBTR is the strongest factor of poor prognosis and reflects occult distant disease. It would appear that prognosis after IBTR depends more on clinical and histological parameters than on surgical treatment. A prospective trial in a low-risk group of patients to validate the safety of salvage BCS instead of mastectomy in IBTR is needed.

Aims The aim of this study was to analyse a series of borderline and malignant phyllodes tumours (PTs) of the breast by whole-genome profiling to identify genomic markers that could help to recognise potentially malignant tumours within borderline tumours. Methods We evaluated the genetic imbalances of a series of 53 PTs (30 borderline, 23 malignant) using the Human CNV370 BeadChip microarray (Illumina), containing 370 000 SNP markers and correlate this alterations with clinicopathological features. Results Forty-five PTs (85%) showed chromosome copy number variations (CNVs). Twenty PTs (37%) showed five or more chromosomal imbalances (8/30 borderline (27%) and 12/23 malignant (52%)). The large-scale genetic changes associated with malignant were+7p (9/23), +1q (8/23), −10p (8/23), −13q14 (7/23), +8q (6/23) and +10q (6/23) and borderline were+1q (13/30), −13q14 (9/30), −6q (8/30) and −10p (8/30). Losses in 9p21.3, encompassing CDKN2A/B gene, were present in three tumours (malignant), whereas deletions of 13q, with a minimal region in 13q14.2 encompassing the RB1 gene, were found in 9/30 borderline and 7/28 malignant tumours. High-level amplifications were seen in eight tumours (seven malignant and one borderline): in 7p in three tumours (including EGFR in two), 7q31.2 (including TFEC and MET ), 8q24.21 (including MYC ) and 8q23.3 (including CSMD3 ) in one tumour each. Conclusions Whole-genome profiling by SNP arrays in PTs leads to identify a high number of CNV, gains of 7p and 8q, losses of 13q and 10, losses in 9p21.3 ( CDKN2A/B ) and the presence of amplifications, especially involving EGFR , as markers of potentially malignant tumours.

Triple-negative breast cancers (TNBC) are a specific subtype of breast cancers with a particularly poor prognosis. However, it is a very heterogeneous subgroup in terms of clinical behavior and sensitivity to systemic treatments. Thus, the identification of risk factors specifically associated with those tumors still represents a major challenge. A therapeutic strategy increasingly used for TNBC patients is neoadjuvant chemotherapy (NAC). Only a subset of patients achieves a pathologic complete response (pCR) after NAC and have a better outcome than patients with residual disease.The aim of this study is to identify clinical factors associated with the metastatic-free survival in TNBC patients who received NAC.We analyzed 326 cT1-3N1-3M0 patients with ductal infiltrating TNBC treated by NAC. The survival analysis was performed using a Cox proportional hazard model to determine clinical features associated with prognosis on the whole TNBC dataset. In addition, we built a recursive partitioning tree in order to identify additional clinical features associated with prognosis in specific subgroups of TNBC patients.We identified the lymph node involvement after NAC as the only clinical feature significantly associated with a poor prognosis using a Cox multivariate model (HR = 3.89 [2.42-6.25], p0.0001). Using our recursive partitioning tree, we were able to distinguish 5 subgroups of TNBC patients with different prognosis. For patients without lymph node involvement after NAC, obesity was significantly associated with a poor prognosis (HR = 2.64 [1.28-5.55]). As for patients with lymph node involvement after NAC, the pre-menopausal status in grade III tumors was associated with poor prognosis (HR = 9.68 [5.71-18.31]).This study demonstrates that axillary lymph node status after NAC is the major prognostic factor for triple-negative breast cancers. Moreover, we identified body mass index and menopausal status as two other promising prognostic factors in this breast cancer subgroup. Using these clinical factors, we were able to classify TNBC patients in 5 subgroups, for which pre-menopausal patients with grade III tumors and lymph node involvement after NAC have the worse prognosis.

Resume Objectif de l’etude L’objectif de notre etude etait d’evaluer les caracteristiques des cancers du sein survenant apres un lymphome hodgkinien et notamment le pronostic apres chirurgie conservatrice. Patientes et methodes Il s’agit d’une etude retrospective concernant 72 femmes qui ont vu se developper un cancer du sein in situ ou invasif de stade I–III apres un lymphome de Hodgkin, entre 1978 et 2009. Resultats L’âge median au moment du diagnostic du lymphome de Hodgkin etait de 23 ans. La dose totale mediane recue par le mediastin etait de 40 Gy, principalement par une technique en mantelet. Les cancers du sein sont survenus apres un intervalle median de 21 ans apres le lymphome de Hodgkin. Les carcinomes canalaires infiltrants et in situ representaient respectivement 71 % et 19 % des cas. Le traitement locoregional des cancers du sein a comporte une mastectomie avec (3) ou sans (36) radiotherapie adjuvante chez 39 patientes et une tumorectomie avec (30) ou sans (2) ou sans radiotherapie adjuvante chez 32 patientes. La technique de decubitus lateral isocentrique a ete utilisee chez 17 patientes (57 %). Avec un suivi en mediane de sept ans, les taux de survie globale et de controle locoregional a cinq ans etaient respectivement de 74,5 % et 82 % pour les cancers invasifs et de 100 % et 92 % pour les cancers in situ. Treize patientes sont decedees d’une progression du cancer du sein et un cancer du sein controlateral a ete diagnostique chez dix patientes (14 %). Conclusions La chirurgie conservatrice peut etre une option pour les cancers du sein survenant apres lymphome de Hodgkin, malgre l’irradiation thoracique anterieure. Elle doit associer une mastectomie partielle et une irradiation avec utilisation d’une technique adequate telle que le lateral isocentrique.

Purpose To report clinical and pathologic characteristics and outcome of breast cancer (BC) after irradiation for Hodgkin's lymphoma (HL) in women treated at the Institut Curie, with a special focus on the breast-conserving option. Methods and Materials Medical records of 72 women who developed either ductal carcinoma in situ or Stage I–III invasive carcinoma of the breast after HL between 1978 and 2009 were retrospectively reviewed. Results Median age at HL diagnosis was 23 years (range, 14–53 years). Median total dose received by the mediastinum was 40 Gy, mostly by a mantle-field technique. Breast cancers occurred after a median interval of 21 years (range, 5–40 years). Ductal invasive carcinoma and ductal carcinoma in situ represented, respectively, 51 cases (71%) and 14 cases (19%). Invasive BCs consisted of 47 cT0–2 tumors (82%), 5 cN1–3 tumors (9%), and 20 Grade 3 tumors (35%). Locoregional treatment for BCs consisted of mastectomy with (3) or without (36) radiotherapy in 39 patients and lumpectomy with (30) or without (2) adjuvant radiotherapy in 32 patients. The isocentric lateral decubitus radiation technique was used in 17 patients after breast-conserving surgery (57%). With a median follow-up of 7 years, 5-year overall survival rate and locoregional control rate were, respectively, 74.5% (95% confidence interval [CI], 64–88%) and 82% (95% CI, 72–93%) for invasive carcinoma and 100% (95% CI, 100 –100%) and 92% (95% CI, 79–100%) for in situ carcinoma. In patients with invasive tumors, the 5-year distant disease-free survival rate was 79% (95% CI, 69–91%), and 13 patients died of progressive BC. Contralateral BC was diagnosed in 10 patients (14%). Conclusions Breast-conserving treatment can be an option for BCs that occur after HL, despite prior thoracic irradiation. It should consist of lumpectomy and adjuvant breast radiotherapy with use of adequate techniques, such as the lateral decubitus isocentric position, to protect the underlying heart and lung.

Background This study aimed to evaluate the potential impact of social inequalities on stage at diagnosis and long-term outcome of breast cancer patients attending the Institut Curie in Paris (France). Methods The study population included 14,610 breast cancer patients diagnosed and treated in the Institut Curie between 1981 and 2001. The socioeconomic status was determined from district of residence, median income for town of residence corrected by the consumption unit and body mass index. Logistic regression models adjusted on socioeconomic factors were used to evaluate clinical and pathologic features at diagnosis. Overall survival and distant metastasis were analysed with log-rank tests and Cox proportional hazards regression models. Results Patients living in lower income districts were more likely to be diagnosed with breast tumors size greater than 20 mm (P = 0.01). Residents of high-income urban areas (> 15,770 €) exhibited a significant overall survival and distant metastasis advantage (respectively HR = 0.93 [0.86–0.99]; P = 0.02 and HR = 0.91 [0.85–0.98]; P = 0.01). Breast cancer screening with mammography was independent of district of residence (P = 0.61) or income (P = 0.14). After adjusting for age at diagnosis and period, the risk of having breast cancer with unfavorable prognostic factors such as tumor size greater than 20 mm decreased with 1000 € increase in district income (OR = 0.986 [0.98–0.99]; P Conclusion Despite the limitations of the study (aggregate data used to assess socioeconomic status, non representative cohort of French women), we observed that poorer breast cancer prognosis with advanced disease diagnosis and increased risk of breast cancer mortality was related to low socioeconomic status.

Purpose This phase II trial aimed to investigate the efficacy of concurrent radio- (RT) and chemotherapy (CT) in the preoperative setting for operable, non-metastatic breast cancer (BC) not amenable to initial breast-conserving surgery (BCS). Patients and methods From 2001 to 2003, 59 women were included. CT consisted of four cycles of 5-FU, 500 mg/m2/d, continuous infusion (d1–d5) and vinorelbine, 25 mg/m2 (d1 and d6). Starting concurrently with the second cycle, RT delivered 50 Gy to the breast and 46 Gy to the internal mammary and supra/infra-clavicular areas. Breast surgery and lymph node dissection were then performed. Adjuvant treatment consisted of a 16 Gy boost to the tumor bed after BCS, FEC (four cycles of fluorouracil 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 100 mg/m2, d1; d21) for pN1-3 and hormone-therapy for positive hormone receptors BC. Results The in-breast pathological complete response rate was 27%. BCS was performed in 41 (69%) pts. Overall and distant-disease free survivals at 5 years were respectively 88% [95% CI 80–98] and 83% [95% CI 74–93] whereas locoregional and local controls were 90% [95% CI 82–97] and 97% [95% CI 92–100]. Late toxicity (CTCAE-V3) was assessed in 51 pts (86%) with a median follow-up of 7 years [5–8]. Four (8%) experienced at least one grade III toxicities (one telangectasia and three fibroses). Cosmetic results, assessed in 35 of the 41 pts (85%) who retained their breasts, were poor in four pts (11%). Conclusion Preoperative concurrent administration of RT and CT is an effective regimen. Long-term toxicity is moderate. This association deserves further evaluations in prospective trials.

Background: The molecular subtypes of breast cancer have different axillary status. A new nomogram including the interaction covariate between estrogen receptor (ER) and HER2 status has been recently published (Reyal et al. PLOSone, may 2011) and allows to identify before surgery the patients with a high risk of positive sentinel lymph node (SLN). The purpose of our study was to validate this model on an independent population. Patients and methods: We studied 755 consecutive patients treated for operable breast cancer with sentinel node biopsies in 2009, from the Institut Curie breast cancer prospective database. Baseline characteristics were compared between our population and the population used to build the model, using Chi-square test for categorical variables and Kruskal-Wallis test for continuous variables. The multivariate model, including age, tumor size, lymphovascular invasion and interaction covariate between ER and HER2 status, was used to calculate the theoretical risk of positive sentinel lymph node (SLN) for all patients. The performance of the model on our population was then evaluated in terms of discrimination (area under the curve AUC) and of calibration (Hosmer-Lemeshow HL test). Results: Characteristics of our population were significantly different from the training population for the following variables: tumor size (median 12mm [1-60] versus 13mm [1-100] p=0.005), lymphovascular invasion (18.6% versus 23.7% p=0.006), positive ER (91.4% versus 87% p=0.002) and age as followed: 56.7% of patients ≤ 60 versus 63.1%, 17.5% of patients between 60 and 65 versus 14.1% and 25.8% of patients above 65 versus 22.8% p=0.01. The nomogram showed similar results in our population than in the training population in terms of discrimination (AUC= 0.72 [0.68−0.76] versus 0.73 [0.7−0.75] and calibration (HL p= 0.4 versus p=0.35). Conclusions: Despite significant differences between the two populations concerning variables which are part of the nomogram, the model was validated in our population. Our study shows that this nomogram is efficient and robust over time to predict the likelihood of positive SLN according to molecular subtypes defined by surrogate markers ER and HER2 determined by immunohistochemistry in clinical practice. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD02-08.

Background: To identify ER+ve ERBB2-ve ductal T1T2N0 carcinomas associated with a poor prognosis remains challenging. We have previously demonstrated that the number of chromosomal breakpoints assessed by CGH could be a marker of worse outcome for breast carcinomas. Our aim was to validate the CGH based signature in a series of luminal ductal and T1T2 N0 carcinoma patients with long-term clinical follow-up. Patients and methods: We analyzed 214 patients treated for an invasive ductal ER+ve ERBB2-ve carcinomas, smaller than 30mm. The training set was composed of 109 patients (10.9 years of median follow-up; 30 cases associated with a metastatic event within less than 4 years/79 control cases with no metastastic event at 5 years) and the validation set of 105 patients (10.5 years of median follow-up; 30 relapses including contra-lateral breast carcinomas, loco-regional relapses and 8 metastatic events). None of the patient received adjuvant chemotherapy. 16 received an adjuvant hormonotherapy (10 in the training and 6 in the validation groups). We genotyped the sample set with the SNP6.0 affymetrix array. After RMA normalisation using Genotyping console, segmentation was performed according to the Zhang and Siegmund maximum method. In the training data set, the number of breakpoints was assessed, linked to outcome and the threshold optimising the sensitivity and specificity was determined (ROC curve). The threshold prognostic value was then tested on the validation series (Kaplan Meier analysis, log rank test, determination of relative risk and its confidence interval with a Cox model). Results: In the training set, median numbers of breakpoints were 7 in cases that experienced a metastatic event after more than 5 years and 40.5 in cases that experienced a metastatic event in less than 4 years. The threshold (Younden index ) was 34 breakpoints with a sensitivity of 0.57 and a specificity of 0.94 (AUC: 0.81[0.71;0.91]). In the validation set, the outcome of patients with more than 34 breakpoints was poorer than that of patients with less than 34 breakpoints (34 breakpoints: 11 events out of 22 patients with a median time to progression of 108 months; p34 versus 34 breakpoints: 4 events out of 22 patients with a median time to progression of 108 months; p=0.009 (logrank test); RR: 5.29 [1.32; 21.26]). Conclusion: We demonstated that patients with T1T2 ( Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-01.

Resume Objectif de l’etude Evaluer le benefice de la chirurgie mammaire chez les patientes traitees pour un cancer du sein inflammatoire. Patientes et methodes Cette etude retrospective a ete basee sur 232 patientes traitees pour des cancers du sein inflammatoire. Toutes les patientes ont recu une chimiotherapie premiere suivie soit de radiotherapie exclusive (118 patientes, 51 %) soit de chirurgie avec ou sans radiotherapie (114 patientes, 49 %). La duree mediane de surveillance etait de 11 ans. Resultats Les deux groupes etaient comparables en dehors de l’existence d’un plus petit nombre de tumeurs de moins de 70 mm (43 % contre 33 %, p = 0,003), un plus grand taux de tumeurs classees N2 cliniquement (15 % contre 5 %, p = 0,04) et un plus petit nombre de tumeurs de grade 3 (46 % contre 61 %, p Conclusion L’analyse des resultats indique que la chirurgie associee a la chimiotherapie et a la radiotherapie augmente le taux de controle local chez les patientes traitees pour un cancer du sein inflammatoire.

Background Digestive metastasis of breast cancer are rare but when they do occur the stomach is one of the commoner sites. Aim To describe the clinical, endoscopic, pathological features and treatment. Methods 35 cases of gastric metastasis were identified retrospectively between 1980 and 2008. Results The location of the gastric metastasis was fundus (n = 15, 43%), antrum (n = 15, 43%) or both (n = 5, 14%). The histological subtype of primary breast cancer was invasive lobular carcinoma in 34 patients (97%). Hormonal receptors were positive in 19 out of 24 cases (79%), two out of 22 analysed were HER2 positive (9%). There were 16 (46%) patients with peritoneal carcinosis. The treatment was chemotherapy (n = 13, 37%), hormonotherapy (n = 2, 6%) or both (n = 13, 37%). The 2-year survival rate after gastric metastasis diagnosis was 53% with a median follow up of 31 months [7–84 months]. Conclusion Ninety-seven percent of gastric metastasis from breast cancers are derived from invasive lobular carcinoma. Seventy-nine percent of these are HER+ and comparison with the original histopathological slides of primary breast carcinoma should be performed to differentiate gastric metastasis from primary gastric carcinoma. Peritoneal carcinomatosis accompanied gastric metastasis in almost half the cases in this series and treatment was generally chemotherapy.

The increasing incidence of breast cancer brain metastasis in patients with otherwise well-controlled systemic cancer is a key challenge in cancer research. It is necessary to understand the properties of brain-tropic tumor cells to identify patients at risk for brain metastasis. Here we attempt to identify functional phenotypes that might enhance brain metastasis. To obtain an accurate classification of brain metastasis proteins, we mapped organ-specific brain metastasis gene expression signatures onto an experimental protein-protein interaction network based on brain metastatic cells. Thirty-seven proteins were differentially expressed between brain metastases and non-brain metastases. Analysis of metastatic tissues, the use of bioinformatic approaches, and the characterization of protein expression in tumors with or without metastasis identified candidate markers. A multivariate analysis based on stepwise logistic regression revealed GRP94, FN14, and inhibin as the best combination to discriminate between brain and non-brain metastases (ROC AUC = 0.85, 95% CI = 0.73 to 0.96 for the combination of the three proteins). These markers substantially improve the discrimination of brain metastasis compared with ErbB-2 alone (AUC = 0.76, 95% CI = 0.60 to 0.93). Furthermore, GRP94 was a better negative marker (LR = 0.16) than ErbB-2 (LR = 0.42). We conclude that, in breast carcinomas, certain proteins associated with the endoplasmic reticulum stress phenotype are candidate markers of brain metastasis. Supported by grants from the Spanish Ministry of Health and Consumer Affairs FIS/PI041937 and FIS/PI071245, by the European Commission MetaBre contract No. LSHC-CT-2004-506049, and by the Spanish Ministry of Education and Science SAF2004-0188-E. B.O. and R.A. acknowledge grants from the Spanish Ministry of Education and Science (MEC BIO2005-00533 and MCyT BIO2002-0369), and P.L.F. from the Marató-TV3, RETICC from Instituto Carlos III, and Xarxa de Bancs de Tumors de Catalunya

Resume Objectif de l’etude Evaluer la radiotherapie exclusive comme option therapeutique apres reponse clinique complete a une chimiotherapie neoadjuvante pour des cancers du sein de stade II-IIIA. Patientes et methodes Entre 1985 et 1999, 1477 patients ont recu une chimiotherapie neoadjuvante pour un cancer du sein de stade II-IIIA considere trop volumineux pour etre opere de facon conservatrice. Parmi les 165 patientes en situation d’une reponse clinique complete apres la chimiotherapie neoadjuvante, 65 ont ete traitees par chirurgie mammaire et irradiation et 100 par irradiation exclusive. Resultats Les deux groupes etaient comparables en termes de caracteristiques initiales, excepte pour le diametre tumoral au diagnostic (plus grand dans le groupe exclusivement irradie). Aucune difference statistiquement significative n’a ete observee en termes de survie globale, de survie sans maladie ni de survie sans metastase. Les taux de survie globale a cinq et dix ans etaient respectivement de 91 et 77 % dans le groupe exclusivement irradie et de 82 et 79 % dans le groupe opere et irradie ( p = 0,9). Cependant, une tendance en faveur d’un taux plus eleve de recidive locoregionale a ete observee dans le groupe exclusivement irradie (31 contre 17 % a dix ans ; p = 0,06). Chez les patientes en situation de remission complete d’apres la mammographie et/ou l’echographie, il n’y avait pas de difference statistiquement significative de taux de recidive locoregionale (a dix ans : 21 dans le groupe opere et irradie contre 26 % dans le groupe exclusivement irradie, p = 0,45). Aucune difference n’a ete observee en termes de toxicite cutanee, cardiaque et pulmonaire. Conclusion La chirurgie est une etape incontournable du traitement locoregional des cancers du sein ayant repondu completement a une chimiotherapie neoadjuvante.

Phyllodes tumors are a rare distinctive fibroepithelial tumors of the breast and their management continues to be questioned. The aim of our study was to examine the treatment and outcome of 165 patients with phyllodes tumors and to review the options for surgical management. This is a retrospective study of 165 patients who presented to the Institut Curie between January 1994 and November 2008 for benign, borderline or malignant phyllodes tumors. The median follow-up was 12.65 months [range 0-149.8]. The median age at diagnosis was 44 years [range 17-79]. One hundred and sixty patients (97%) had breast-conserving treatment, of whom 3 patients (1.8%) had oncoplastic breast surgery. Younger women had a significantly higher chance of having a benign phyllodes tumor (p = 0.0001) or a tumor of small size (p < 0.0001). Histologic examination showed 114 benign (69%), 37 borderline (22%) and 14 malignant tumors (9%). The median tumor size was 30 mm [range 5-150]. The tumor margins were considered incomplete (< 10 mm) in 46 out of 165 cases (28%) with 52% revision surgery. Only the tumor grade was a significant risk factor for incomplete tumor margins (p = 0.005). Fifteen patients developed local recurrence (10%) and two, metastases. In univariate analysis, the histologic grade (p = 0.008), and tumor size (p = 0.02) were significative risk factors for local recurrence with an accentuated risk for "borderline" tumors and tumors of large size.).Similar results were obtained using multivariate analysis (p = 0.07). The mainstay of treatment for phyllodes tumors remains excision with a safe surgical margin, taking advantage breast conserving surgery where amenable. For borderline or malignant phyllodes tumors or in cases of local tumor recurrence, mastectomy, and immediate breast reconstruction may become the preferred option. Genetic analysis will potentially supplement classical histologic examination in order to improve our management of these tumors. The role of adjuvant treatments is unproven and must be considered on a case-by-case basis.

MicroRNAs (miRNA) regulate many genes critical for tumorigenesis. We profiled miRNAs from 11 normal breast tissues, 17 noninvasive, 151 invasive breast carcinomas, and 6 cell lines by in-house–developed barcoded Solexa sequencing. miRNAs were organized in genomic clusters representing promoter-controlled miRNA expression and sequence families representing seed sequence–dependent miRNA target regulation. Unsupervised clustering of samples by miRNA sequence families best reflected the clustering based on mRNA expression available for this sample set. Clustering and comparative analysis of miRNA read frequencies showed that normal breast samples were separated from most noninvasive ductal carcinoma in situ and invasive carcinomas by increased miR-21 (the most abundant miRNA in carcinomas) and multiple decreased miRNA families (including miR-98/let-7), with most miRNA changes apparent already in the noninvasive carcinomas. In addition, patients that went on to develop metastasis showed increased expression of mir-423, and triple-negative breast carcinomas were most distinct from other tumor subtypes due to upregulation of the mir∼17–92 cluster. However, absolute miRNA levels between normal breast and carcinomas did not reveal any significant differences. We also discovered two polymorphic nucleotide variations among the more abundant miRNAs miR-181a (T19G) and miR-185 (T16G), but we did not identify nucleotide variations expected for classical tumor suppressor function associated with miRNAs. The differentiation of tumor subtypes and prediction of metastasis based on miRNA levels is statistically possible but is not driven by deregulation of abundant miRNAs, implicating far fewer miRNAs in tumorigenic processes than previously suggested. Cancer Res; 71(13); 4443–53. ©2011 AACR.

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Aim:The aim of our study was to examine the treatment and outcome of 165 patients with phyllodes tumours and to review the options for surgical management. Patients and Methods: This is a retrospective study of 165 patients who presented to the Institut Curie between January 1994 and November 2008 for benign, borderline or malignant phyllodes tumours. Results: The median follow-up was 12.65 months [range 0 to 149.8]. The median age at diagnosis was 44 years [range 17 to 79]. One hundred and sixty patients (97%) had breast conserving treatment, of whom 3 patients (1. 8%) had oncoplastic breast surgery. Younger women had a significantly higher chance of having a benign phyllodes tumor (p = 0.0001) or a tumour of small size (< 0.0001). Histological examination showed 114 benign (69%), 37 borderline (22%) and 14 malignant tumours (9%). The median tumour size was 30 mm [range 5 to 150]. The tumour margins were considered incomplete (< 10 mm) in 46 out of 165 cases (28%) with 52% revision surgery. Only the tumour grade was a significant risk factor for incomplete tumour margins (p = 0.005). Fifteen patients developed local recurrence (10%) and two, metastases. In univariate analysis, the histological grade (p = 0.008) and tumour size (p=0.02) were significative risk factors for local recurrence with an accentuated risk for borderline tumours and tumours of large size. Similar results were obtained using multivariate analysis (p=0.07) Conclusion: The mainstay of treatment for phyllodes tumours remains excision with a safe surgical margin, taking advantage breast conserving surgery where amenable. For borderline or malignant phyllodes tumours or in cases of local tumour recurrence, mastectomy and immediate breast reconstruction may become the preferred option.Genetic analysis will potentially supplement classical histological examination in order to improve our management of these tumours. The role of adjuvant treatments is unproven and must be considered on a case-by-case basis. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-12.

Predicting evolution of small node-negative breast carcinoma is a real challenge in clinical practice. The aim of this study was to search whether qualitative or quantitative DNA changes may help to predict metastasis of small node-negative breast carcinoma. Small invasive ductal carcinomas without axillary lymph node involvement (T1T2N0) from 168 patients with either good (111 patients with no event at 5 years after diagnosis) or poor (57 patients with early metastasis) outcome were analyzed with comparative genomic hybridization (CGH) array. A CGH classifier, identifying low- and high-risk groups of metastatic recurrence, was established in a training set of 78 patients, then validated, and compared with clinicopathological parameters in a distinct set of 90 patients. The genomic status of regions located on 2p22.2, 3p23, and 8q21-24 and the number of segmental alterations were defined in the training set to classify tumors into low- or high-risk groups. In the validation set, in addition to estrogen receptors and grade, this CGH classifier provided significant prognostic information in multivariate analysis (odds ratio, 3.34; 95% confidence interval 1.01-11.02; P = 4.78 × 10(-2), Wald test). This study shows that tumor DNA contains important prognostic information that may help to predict metastasis in T1T2N0 tumors of the breast.