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Background To compare RCB (Residual Cancer Burden) and Neo-Bioscore in terms of prognostic performance and see if adding pathological variables improve these scores. Methods We analysed 750 female patients with invasive breast cancer (BC) treated with neoadjuvant chemotherapy (NAC) at Institut Curie between 2002 and 2012. Scores were compared in global population and by BC subtype using Akaike information criterion (AIC), C-Index (concordance index), calibration curves and after adding lymphovascular invasion (LVI) and pre-/post-NAC TILs levels. Results RCB and Neo-Bioscore were significantly associated to disease-free and overall survival in global population and for triple-negative BC. RCB had the lowest AICs in every BC subtype, corresponding to a better prognostic performance. In global population, C-Index values were poor for RCB (0.66; CI [0.61–0.71]) and fair for Neo-Bioscore (0.70; CI [0.65–0.75]). Scores were well calibrated in global population, but RCB yielded better prognostic performances in each BC subtype. Concordance between the two scores was poor. Adding LVI and TILs improved the performance of both scores. Conclusions Although RCB and Neo-Bioscore had similar prognostic performances, RCB showed better performance in BC subtypes, especially in luminal and TNBC. By generating fewer prognostic categories, RCB enables an easier use in everyday clinical practice.

BACKGROUND: Although no survival benefit has been demonstrated by treating early breast cancer (BC) with neoadjuvant chemotherapy (NAC), it is now widely accepted as first intention strategy in triple negative and HER2-positive BC. However, the benefit of the neoadjuvant strategy is controversial in luminal tumours. The latter are considered as poor responder to chemotherapy and it remains unknown if delaying time to surgery by providing NAC as first treatment might be deleterious. The aim of this study was to compare the prognosis of patients with Luminal B BC treated with either NAC, either adjuvant chemotherapy. MATERIALS AND METHODS: We retrospectively identified in our institutional database 188 patients with grade 3 luminal B BC treated with NAC and 1203 patients treated with the same adjuvant chemotherapy (AC). To deal with the selection bias, the contribution of each subject was weighted by a propensity score (PS): 1/PS for patient with the NAC strategy and 1/(1-PS) for patients with the AC strategy. This enables to generate a pseudo-population with a balanced covariates combination between groups. We evaluated the disease free survival (DFS), the distant metastasis free survival (DMFS) and the overall survival (OS) using a weighted Cox model. To analyse the effect of NAC in high-risk subgroups, we introduced in the model interaction effects with the initial tumour size and the initial clinical nodal status. RESULTS: By construction, patients, tumor characteristics and trastuzumab use were similar between the population treated with NAC and the population treated with adjuvant CT. After PS weighting and adjustment on confounding factors, DFS (HR = 2.56, 95%IC [1.73 - 3.78]; p< 0.001), DMFS (HR = 1.28, 95%IC [1 - 1.63]; p < 0.001) and OS were lower in the NAC group (HR = 1.51, 95%IC [1.10-2.09]]; p = 0.01) when compared with the group of patients treated with adjuvant chemotherapy.The interaction test between the initial clinical nodal status, initial clinical tumour size and survival endpoints was significant, highlighting a different prognostic effect of NAC versus AC in nodes-positive than in node-negative patients, and a different prognostic effect of NAC versus AC in small than in large tumours. No significant DFS nor OS difference was found in node-negative patients. In node-positive patients with tumour larger than 20mm, the risk of death was nearly doubled when comparing NAC strategy to AC strategy (HR=2.30, 95%CI [1.34-3.4]), while the highest deleterious impact on OS of the NAC strategy against the AC strategy was observed in node-positive patients with a tumour size smaller than ≤20mm (HR=3.52, 95%CI [1.59-7.8]). CONCLUSION: In node-positive, grade 3, luminal B tumours, receiving NAC seems associated with an impaired survival when compared with receiving the same treatment in the adjuvant setting. Our results suggest that surgery as first treatment could be the preferred option, even if breast-conserving surgery cannot be obtained. In tumors smaller than 20mm, NAC strategy should be avoided irrespective of the nodal status. Citation Format: Enora Laas, Thomas Gaillard, Jean Guillaume Feron, Jean-Yves Pierga, Florence Coussy, Beatriz Grandal, Audrey Bellesoeur, Eléonore De Guillebon, Sonia Rozette, Clemence Evrevin, Lucie Laot, Marick Lae, Anne Sophie Hamy, Fabien Reyal. Impact of neoadjuvant chemotherapy on survival in luminal B tumours: A propensity score weighted analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-35.

INTRODUCTION: Neoadjuvant chemotherapy (NAC) is increasingly being used for locally advanced breast cancers (BCs) or aggressive BC tumors. However, no survival benefit of the neoadjuvant approach over receiving chemotherapy in the adjuvant setting has been proven so far in HER2-positive early breast cancer (BC) patients. The objective of this study was to compare the prognosis of patients with an HER2-positive BC treated with NAC to patients treated with adjuvant chemotherapy (AC). MATERIALS AND METHODS: We retrospectively identified in our institutional database 203 patients with HER2-positive BCs treated with NAC plus trastuzumab and 701 patients treated with adjuvant chemotherapy. As the treatment was not randomly allocated, we used a propensity score with an Inverse probability of received treatment weighting (IPTW) to generate a pseudo-population in which each covariate combination was balanced between treatment groups. The disease free (DFS), distant metastasis free (DMFS) and overall survival (OS) were evaluated using a weighted Cox model. The interactions with poor prognosis factors (initial tumour size, tumour grade, hormone receptor status and initial clinical nodal status) were tested to evaluate the effect of the NAC in high-risk tumours. RESULTS: By construction, patients, tumor characteristics and trastuzumab use were similar between the population treated with NAC and the population treated with adjuvant CT. No difference was found regarding DFS (p=0.3) neither DMFS (p=0.4) in the global population. However, there was a significant interaction effect between the strategy and the initial clinical nodal status, with a DFS benefit of NAC over AC in the node-positive group (HR 0.53 CI95% [0.31- 0.89]), as well as for DMFS (HR 0.39 95%CI [0.20-0.77]). We found a significant benefit in OS with the neoadjuvant strategy when compared with the adjuvant strategy (HR = 0.12 95%CI [0.03-0.47], p=0.002) and this difference was significant irrespective of tumour size, initial clinical nodal status and hormone receptor status. CONCLUSION: In patients with HER2-positive BCs, receiving NAC is associated with an improved OS when compared with chemotherapy received in the adjuvant setting. Our results support the fact that NAC should become a standard of care in HER2-positive tumours. Citation Format: Enora Laas, Arnaud Bresset, Jean Guillaume Feron, Jean-Yves Pierga, Florence Coussy, Audrey Bellesoeur, Beatriz Grandal, Eléonore De Guillebon, Sonia Rozette, Clemence Evrevin, Thomas Gaillard, Marick Lae, Anne Sophie Hamy, Fabien Reyal. Survival benefit of neoadjuvant chemotherapy versus adjuvant chemotherapy in HER2-positive early breast cancer: A propensity score-weighted analysis [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-36.

PURPOSE To apply text mining (TM) technology on electronic medical records (EMRs) of patients with breast cancer (BC) to retrieve the occurrence of a pregnancy after BC diagnosis and compare its performance to manual curation. MATERIALS AND METHODS The training cohort (Cohort A) comprised 344 patients with BC age ≤ 40 years old treated at Institut Curie between 2005 and 2007. Manual curation consisted in manually reviewing each EMR to retrieve pregnancies. TM consisted of first applying a keyword filter (“accouch*” or “enceinte,” French terms for “deliver*” and “pregnant,” respectively) to select a subset of EMRs, and, second, checking manually EMRs to confirm the pregnancy. Then, we applied our TM algorithm on an independent cohort of patients with BC treated between 2008 and 2012 (Cohort B). RESULTS In Cohort A, 36 pregnancies were identified among 344 patients (10.5%; 2,829 person-years of EMR). Thirty were identified by manual review versus 35 by TM. TM resulted in a lower percentage of manual checking (26.7% v 100%, respectively) and substantial time gains (time to identify a pregnancy: 13 minutes for TM v 244 minutes for manual curation, respectively). Presence of any of the two TM filters showed excellent sensitivity (97%) and negative predictive value (100%). In Cohort B, 67 pregnancies were identified among 1,226 patients (5.5%; 7,349 person-years of EMR). Similarly, for Cohort B, TM spared 904 (73.7%) EMRs from manual review and quickly generated a cohort of 67 pregnancies after BC. Incidence rate of pregnancy after BC was 0.01 pregnancy per person-year of EMR in both cohorts. CONCLUSION TM is highly efficient to quickly identify rare events and is a promising tool to improve rapidity, efficiency, and costs of medical research.

PurposeFemale breast cancer (BC) patients exposed to gonadotoxic chemotherapy are at risk of future infertility. There is evidence of disparities in the discussion of fertility preservation for these patients. The aim of the study was to identify factors influencing the discussion of fertility preservation (FP).Material and MethodsWe analyzed consecutive BC patients treated by chemotherapy at Institut Curie from 2011-2017 and aged 18-43 years at BC diagnosis. The discussion of FP was classified in a binary manner (discussion/no discussion), based on mentions present in the patient’s electronic health record (EHR) before the initiation of chemotherapy. The associations between FP discussion and the characteristics of patients/tumors and healthcare practitioners were investigated by logistic regression analysis.ResultsThe median age of the 1357 patients included in the cohort was 38.7 years, and median tumor size was 30.3 mm. The distribution of BC subtypes was as follows: 702 luminal BCs (58%), 241 triple-negative breast cancers (TNBCs) (20%), 193 HER2+/HR+ (16%) and 81 HER2+/HR- (6%). All patients received chemotherapy in a neoadjuvant (n=611, 45%) or adjuvant (n= 744, 55%) setting. A discussion of FP was mentioned for 447 patients (33%). Earlier age at diagnosis (discussion: 34.4 years versus no discussion: 40.5 years), nulliparity (discussion: 62% versus no discussion: 38%), and year of BC diagnosis were the patient characteristics significantly associated with the mention of FP discussion. Surgeons and female physicians were the most likely to mention FP during the consultation before the initiation of chemotherapy (discussion: 22% and 21%, respectively). The likelihood of FP discussion increased significantly over time, from 15% in 2011 to 45% in 2017. After multivariate analysis, FP discussion was significantly associated with younger age, number of children before BC diagnosis, physicians’ gender and physicians’ specialty.ConclusionFP discussion rates are low and are influenced by patient and physician characteristics. There is therefore room for improvement in the promotion and systematization of FP discussion.

Simple Summary There is little available evidence concerning smoking behaviors among breast cancer (BC) patients. This large study addresses smoking-related issues at BC diagnosis and smoking cessation in women with a history of BC. This study suggests that (i) tobacco mention is missing from electronic health records in approximately one-third of patients; (ii) tobacco is not assessed nor addressed systematically during the BC care pathway, and this information depends on the practitioner’s specialty; (iii) approximately one-third of patients stop smoking in BC follow-up. These findings call to consider BC treatment and follow-up as a window of opportunity to promote smoking cessation. Abstract Breast cancer (BC) is the most commonly diagnosed type of cancer and the leading cause of cancer deaths in women. Smoking is the principal modifiable risk factor for cancers and has a negative influence on long-term survival. We conducted a retrospective study on consecutive BC survivors seen at follow-up consultations between 3 June and 30 October 2019 at Institut Curie, Paris, France. Smoking behaviors were evaluated prospectively via interviewer-administered questionnaires. The aim of this study was to describe smoking-related patient care at diagnosis and smoking cessation patterns in women with a history of BC. A total of 1234 patients were included in the study. Smoking status at diagnosis was missing from electronic health records in 32% of cases, including 13% of patients who smoke. Only 20% of the 197 patients currently smoking at diagnosis recalled having a discussion about smoking with a healthcare professional. Radiotherapists and surgeons were more likely to talk about complications than other practitioners. The main type of information provided was general advice to stop smoking (n = 110), followed by treatment complications (n = 48), while only five patients were referred to tobaccologists. Since diagnosis, 33% (n = 65) of the patients currently smoking had quit. Patients who quit had a lower alcohol consumption, but no other factor was associated with smoking cessation. The main motivation for tobacco withdrawal was the fear of BC relapse (63%). This study highlights room for improvement in the assessment of smoking behavior. Our data raise important perspectives for considering BC treatment and follow-up as a window of opportunity for smoking cessation.

Although an increasing number of young breast cancer (BC) patients have a pregnancy desire after BC, the time necessary to obtain a pregnancy after treatment and subsequent outcomes remain unknown. We aimed to determine the time to evolutive pregnancy in a cohort of BC survivors and subsequent obstetrical and neonatal outcomes. We analyzed BC patients treated at Institut Curie from 2005–2017, aged 18–43 years old (y.o.) at diagnosis having at least one subsequent pregnancy. 133 patients were included, representing 197 pregnancies. Mean age at BC diagnosis was 32.8 y.o. and at pregnancy beginning was 36.8 y.o. 71% pregnancies were planned, 18% unplanned and 86% spontaneous. 64% pregnancies resulted in live birth (n = 131). Median time from BC diagnosis to pregnancy beginning was 48 months and was significantly associated with endocrine therapy (p &lt, 0.001). Median time to pregnancy was 4.3 months. Median time to evolutive pregnancy 5.6 months. In multivariate analysis, menstrual cycles before pregnancy remained significantly associated with time to pregnancy and endocrine therapy with time evolutive to pregnancy. None of the BC treatments (chemotherapy/endocrine therapy/trastuzumab) was significantly associated with obstetrical nor neonatal outcomes, that seemed comparable to global population. Our findings provide reassuring data for pregnancy counseling both in terms of delay and outcome.

IntroductionComprehensive updated information on cervical cancer surgical treatment in Europe is scarce.ObjectiveTo evaluate baseline characteristics of women with early cervical cancer and to analyze the outcomes of the ESGO quality indicators after radical hysterectomy in the SUCCOR database.MethodsThe SUCCOR database consisted of 1272 patients who underwent radical hysterectomy for stage IB1 cervical cancer (FIGO 2009) between January 2013 and December 2014. After exclusion criteria, the final sample included 1156 patients. This study first described the clinical, surgical, pathological, and follow-up variables of this population and then analyzed the outcomes (disease-free survival and overall survival) after radical hysterectomy. Surgical-related ESGO quality indicators were assessed and the accomplishment of the stated recommendations was verified.ResultsThe mean age of the patients was 47.1 years (SD 10.8), with a mean body mass index of 25.4 kg/m2 (SD 4.9). A total of 423 (36.6%) patients had a previous cone biopsy. Tumor size (clinical examination) ConclusionsIn this European cohort, the rate of adjuvant therapy after radical hysterectomy is higher than for most similar patients reported in the literature. The majority of centers were already following the European recommendations even 5 years prior to the ESGO quality indicator implementations.

Background: No survival benefit has yet been demonstrated for neoadjuvant chemotherapy (NAC) against HER2-positive tumors in patients with early breast cancer (BC). The objective of this study was to compare the prognosis of HER2-positive BC patients treated with NAC to that of patients treated with adjuvant chemotherapy (AC). Materials and methods: We retrospectively analyzed disease-free (DFS) and overall survival (OS) in 202 HER2-positive patients treated with NAC and 701 patients treated with AC. All patients received trastuzumab in addition to chemotherapy. Patient data were weighted by a propensity score to overcome selection bias. Results: After inverse probability of treatment weights (IPTW) adjustment, no difference in DFS (p = 0.3) was found between treatments for the total population. However, after multivariate analysis, an interaction was found between cN status and chemotherapy strategy (IPTW-corrected corrected Hazard ratio cHR = 0.52, 95% CI (0.3&ndash, 0.9), pinteraction = 0.08) and between menopausal status and chemotherapy (CT) strategy (cHR = 0.35, 95%CI (0.18&ndash, 0.7)) pinteraction &lt, 0.01). NAC was more beneficial than AC strategy in cN-positive patients and in postmenopausal patients. Moreover, after IPTW adjustment, the multivariate analysis showed that the neoadjuvant strategy conferred a significant OS benefit (cHR = 0.09, 95%CI [0.02&ndash, 0.35], p &lt, 0.001). Conclusion: In patients with HER2-positive BC, the NAC strategy is more beneficial than the AC strategy, particularly in cN-positive and postmenopausal patients. NAC should be used as a first-line treatment for HER2-positive tumors.

BACKGROUND: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. METHODS: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. FINDINGS: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. INTERPRETATION: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810.

IntroductionThe Residual Cancer Burden (RCB) quantifies residual disease after neoadjuvant chemotherapy (NAC). Its predictive value has not been validated on large cohorts with long-term follow up. The objective of this work is to independently evaluate the prognostic value of the RCB index depending on BC subtypes (Luminal, HER2-positive and triple negative (TNBCs)).MethodsWe retrospectively evaluated the RCB index on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between RCB index and relapse-free survival (RFS), overall survival (OS) among the global population, after stratification by BC subtypes.Results717 patients were included (luminal BC (n = 222, 31%), TNBC (n = 319, 44.5%), HER2-positive (n = 176, 24.5%)). After a median follow-up of 99.9 months, RCB index was significantly associated with RFS. The RCB-0 patients displayed similar prognosis when compared to the RCB-I group, while patients from the RCB-II and RCB-III classes were at increased risk of relapse (RCB-II versus RCB-0: HR=3.25 CI [2.1-5.1] pversus RCB-0: HR=5.6 CI [3.5-8.9] pHER2-positive cancers; but not for luminal cancers (Pinteraction = 0.07). The prognosis of RCB-III patients was poor (8-years RFS: 52.7%, 95% CI [44.8 – 62.0]) particularly in the TNBC subgroup, where the median RFS was 12.7 months.ConclusionRCB index is a reliable prognostic score. RCB accurately identifies patients at a high risk of recurrence (RCB-III) with TNBC or HER2-positive BC who must be offered second-line adjuvant therapies.

Oncoplastic approach has become increasingly popular as a strategy for the surgical management of breast cancer, for either palpable or subclinical tumors. Historically, the superior pedicle technique has been considered as the reference for the treatment of tumors located in the lower breast quadrants. This technique enables optimum oncologic outcomes by improving the security of excision margins and by decreasing the breast volume that facilitates adjuvant radiotherapy. In addition to providing potential relief for physical discomfort, it enables to obtain excellent cosmetic results after excision for large tumors that would have been otherwise treated by total mastectomy. When its principles have been perfectly understood and with some experience, the superior pedicle technique represents a simple and reproducible technique. This article aims to give a step by step description of the technique and a detailed report of its indications, complications, and results.

Few studies evaluated the prognostic value of the presence of lymphovascular invasion (LVI) after neoadjuvant chemotherapy (NAC) for breast cancer (BC). The association between LVI and survival was evaluated in a cohort of BC patients treated by NAC between 2002 and 2011. Five post-NAC prognostic scores (ypAJCC, RCB, CPS, CPS + EG and Neo-Bioscore) were evaluated and compared with or without the addition of LVI. Out of 1033 tumors, LVI was present on surgical specimens in 29.2% and absent in 70.8% of the cases. Post-NAC LVI was associated with impaired disease-free survival (DFS) (HR 2.54; 95% CI 1.96–3.31; P

Background There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium ( www.raids-fp7.eu ), conducted a prospectively monitored trial, [BioRAIDs ( NCT02428842 )] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. Fund European Union's Seventh Program grant agreement No 304810.

BackgroundWe studied the relationship between time to ipsilateral breast tumor recurrence (IBTR) and distant metastasis-free survival (DMFS) in patients with breast cancer treated by neoadjuvant chemotherapy (NAC).MethodsBetween 2002 and 2012, 1199 patients with primary breast cancer were treated with NAC. Clinical, radiological and pathological data were retrieved from medical records. Multivariate analysis was performed with the random survival forest (RSF) method, to evaluate the relationship between time to local recurrence and DMFS.ResultsTime to IBTR, local recurrence and molecular subtype were the factors most strongly associated with DMFS. In the total population, DMFS increased linearly with recurrence time, up to 50 months. For recurrences after 50 months, DMFS was similar for all times to recurrence. Considering molecular subtypes separately, the threshold was similar for the TNBC subtype (50 months), but appeared to occur later for the luminal and HER2-positive subtypes (75 months).ConclusionA threshold of 50 months seems to differentiate between early and late recurrences and could be used to guide the medical management of local breast tumour recurrences.

Background: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods: Between 2013-2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings: At a median FU of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were 65*4% [CI95%: 60*2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulatorgene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harbouring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. Funding: European Union's Seventh Program grant agreement No 304810. Declaration of Interest: All authors declared: No conflict of interest. Ethical Approval: Ethical review was conducted according to national requirements and in accordance with the Declaration of Helsinki. All tumour and serum samples and clinical data were registered in a common database using a unique barcode system assuring data privacy.

A ductal in situ (DCIS) component is often associated with invasive breast carcinoma (BC), and its effect on response to treatment is unknown. We assessed the predictive value of the DCIS component for pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC). We analyzed a cohort of 1148 T1&ndash, 3NxM0 breast cancer (BC) patients treated by NAC at Institut Curie between 2002 and 2012. The presence of a DCIS component was retrospectively recorded from both the pre-NAC biopsy pathological report and surgical specimens. We included 1148 BC patients treated by NAC for whom pre- and post-NAC data concerning the in situ component were available. DCIS was present before NAC in 19.6% of the population. Overall, 283 patients (19.4%) achieved pCR after NAC. There was no significant association between the presence of DCIS on pre-NAC biopsy and pCR. In a multivariate analysis including subtype, tumor size, grade, mitotic index, and Ki67 index, only BC subtype (luminal/TNBC/HER2-positive) and Ki67 were significantly associated with pCR. The presence of a DCIS component on pre-NAC biopsy is not associated with pCR and does not seem to be a critical factor for predicting response to NAC.

Resume Introduction La chirurgie du cancer du sein est adaptee a une pratique ambulatoire car il s’agit d’une chirurgie programmee, a faible risque operatoire. L’objectif de cette etude a ete d’evaluer les indicateurs de reussite reconnus : taux de conversion en hospitalisation conventionnelle, taux de complications et de re-hospitalisations dans le mois suivant l’intervention. Methodes Analyse descriptive des cas consecutifs de patientes operees d’un cancer du sein en ambulatoire entre le 25 novembre 2012 et le 31 decembre 2013, a partir d’une base de donnees constituee prospectivement. Les caracteristiques sociodemographiques des patientes et clinico-biologiques des tumeurs ont ete relevees ainsi que le type de chirurgie et les actes preoperatoires. Resultats Trois cent quatre-vingt-seize patientes ont ete incluses. L’âge moyen des patientes etait de 54 ans [2–84], ont ete effectuees : 382 chirurgies conservatrices du sein (98,2 %), 238 ganglions sentinelles (60,1 %) et 40 curages axillaires (10,1 %). Trente-neuf patientes prevues en chirurgie ambulatoire ont ete hospitalisees en chirurgie conventionnelle, soit un taux de conversion de 9,8 % IC 95 % [6,7–9,12], dont 24 pour drainage axillaire (61,5 %). Ont ete observees 15 complications dans le mois suivant l’intervention, soit 3,7 % IC 95 % [1,8–5,6], et 5 re-hospitalisations ont eu lieu dans le mois suivant l’intervention soit 1,2 % IC 95 % [0,1–2,3]. Conclusion Les taux de complication et de re-hopitalisation apres chirurgie du sein en ambulatoire sont tres faibles (

BackgroundPerfusion-related complications remain the most common concern in DIEP flap breast reconstruction. Indocyanine green-based fluorescence angiography can be used for the real-time intra operative assessment of flap perfusion. The SPY Elite system is the most widely used device in this setting. The main objective was to describe the use of SPY-Q proprietary software to perform qualitative and quantitative analysis of flap perfusion.MethodsThis retrospective cohort study was performed at the Curie Institute between 2013 and 2017. We included patients undergoing unilateral DIEP flap breast reconstruction for whom indocyanine green-based angiography videos were of sufficient quality for analysis. Videos were recorded with the SPY Elite System and analyzed with SPY-Q proprietary software.ResultsWe included 40 patients. We used real-time dynamic color analysis to describe three different patterns of flap perfusion. SPY-Q proprietary software provides quantitative flap perfusion parameters. Our quantitative analysis confirmed that zone I is the best perfused part of the flap and zone IV the less perfused one. There was no significant association between flap perfusion pattern and perforator anatomy, patients' clinical characteristics or postoperative outcomes. After exploratory univariate analysis, quantitative perfusion parameters were significantly impaired in young patients with diabetes mellitus or under hormone therapy by tamoxifen.ConclusionsWe here describe a new approach to assess DIEP flap perfusion using the SPY Elite System proprietary software. It provides interesting qualitative and quantitative analysis that can be used in further studies to precisely assess DIEP flap perfusion.

Purpose: High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. We investigated the value of TIL levels by evaluating lymphocyte infiltration before and after NAC. Experimental Design: We assessed stromal TIL levels in 716 pre- and posttreatment matched paired specimens, according to the guidelines of the International TIL Working Group. Results: Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases with residual disease (33.9% vs. 20.3%, P = 0.001). This was observed in luminal tumors and TNBCs, but not in HER2-positive breast cancers (PInteraction = 0.001). The association between pre-NAC TIL levels and pCR was nonlinear in TNBCs (P = 0.005). Mean TIL levels decreased after chemotherapy completion (pre-NAC TILs: 24.1% vs. post-NAC TILs: 13.0%, P < 0.001). This decrease was strongly associated with high pCR rates, and the variation of TIL levels was strongly inversely correlated with pre-NAC TIL levels (r = −0.80, P < 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner (P < 0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in HER2-positive breast cancers (HR, 1.04; confidence interval, 1.02–1.06; P = 0.001), but not in luminal tumors or TNBCs (PInteraction = 0.04). Conclusions: The associations of pre- and post-NAC TIL levels with response to treatment and DFS differ between breast cancer subtypes. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, breast cancer subtype, response to treatment, and prognosis.

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.

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.

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.

A close relationship between tumor angiogenesis, growth, and carcinomatosis has been observed. Netrin-4 (NT-4) has been shown to regulate angiogenic responses. We aimed to examine the effects of NT-4 on colon tumor angiogenesis, growth, and carcinomatosis. We showed that NT-4 was expressed in human colon cancer cells (LS174). A 20-fold increase in NT-4 expression was stably induced by NT-4 pcDNA in LS174 cells. In vivo, a Matrigel angiogenesis assay showed that NT-4 overexpression altered vascular endothelial growth factor (VEGF)/basic fibroblast growth factor-induced angiogenesis. In nude mice with LS174 xenografts, NT-4 overexpression inhibited tumor angiogenesis and growth. In addition, these NT-4-involved inhibitory effects were associated with decreased tumor cell proliferation and increased tumor cell apoptosis. Using an orthotopic peritoneal carcinomatosis model, we demonstrated that NT-4 overexpression decreased colorectal cancer carcinomatosis. Moreover, carcinomatosis-related ascites formation was significantly decreased in mice transplanted with NT-4 LS174 cells versus control LS174 cells. The antiangiogenic activity of NT-4 was probably mediated by binding to its receptor neogenin. Netrin-4 had a direct effect on neither in vitro apoptosis and proliferation of cultured LS174 cells nor the VEGF-induced acute increase in vascular permeability in vivo. We propose that NT-4 overexpression decreases tumor growth and carcinomatosis, probably via an antiangiogenic effect, underlying the potential therapeutic interest in NT-4 in the treatment of colorectal cancer growth and carcinomatosis.

The purpose of this study was to evaluate the outcome of breast conserving surgery comparing oncoplastic surgery (OS) and standard lumpectomy (SL) after preoperative bracketing wire localization of large neoplastic lesions.We retrospectively reviewed the medical records and the mammograms of patients operated on at the Institut Curie between May 2005 and September 2011 after bracketing wire localization under mammographic and/or sonographic guidance.113 patients underwent surgery for a pre-operative diagnosis of DCIS (n = 80), micro-invasive carcinoma (n = 9) or invasive carcinoma (n = 24), by OS (n = 73) or SL (n = 40). In the OS group, radiological size (52 mm vs 39 mm, p0.001) and resection volumes (246 cc vs 88 cc, p0.00001) were significantly higher than in the SL group. Rates of clear histologic margins (60 vs 62%, NS), complete excision of microcalcifications (78% vs 72%, NS) and re-intervention rate (40% vs 42%, NS) were equivalent. The rate of local recurrence at 24 months was 3% [0-7.1] in patients with conservative treatment (n = 3). With a median follow-up of 40 months, 5 local relapses (two with axillary metastatic involvement), two distant metastatic evolution, one contralateral breast cancer and one death unrelated to cancer occurred.Following bracketing wire localization, OS allowed the conserving management of significantly larger lesions with wider resection volumes, without significant increase in margin involvement or re-intervention rate, and equivalent rate of microcalcifications clearance compared to SL.

Summary: A woman in her 50s underwent delayed bilateral Poly Implant Prothese implant reconstruction following mastectomy for breast cancer. Symptoms of implant rupture developed 43 months after surgery with an erythematous rash on her trunk. The rash then spread to her reconstructed breast mounds. Initial ultrasound scan and magnetic resonance imaging were normal; however, subsequent magnetic resonance imaging demonstrated left implant rupture only. In theater, following removal of both implants, both were found to be ruptured. The rash on her trunk resolved within 3 weeks in the postoperative period. Chemical analyses of silicone in both implants confirmed a nonauthorized silicone source; in addition, the chemical structure was significantly different between the left and right implant, perhaps explaining the variation in presentation.

Background The aims of the study were to investigate the factors associated with not having breast reconstruction following mastectomy and to assess patient satisfaction with information on reconstruction. Patients and methods We analysed a historical cohort of 1937 consecutive patients who underwent mastectomy at Institut Curie between January 2004 and February 2007. Their sociodemographic and clinicobiological characteristics were recorded in a prospective database. A questionnaire was sent to 10% of nonreconstructed patients. Results The proportion of patients with invasive cancer was 82.7%. The rate of nonreconstruction in patients with in situ and invasive cancer was 34.6% and 74.9%, respectively. On multivariate analysis, only employment outside the home was associated with reconstruction in patients with in situ cancer (p 50, ASA score >1, radiotherapy (p Conclusion Better understanding the factors that influence decision of nonreconstruction can help us adapt the information to serve the patient’s personal needs.

Introduction To decipher the interaction between the molecular subtype classification and the probability of a non-sentinel node metastasis in breast cancer patients with a metastatic sentinel lymph-node, we applied two validated predictors (Tenon Score and MSKCC Nomogram) on two large independent datasets. Materials and Methods Our datasets consisted of 656 and 574 early-stage breast cancer patients with a metastatic sentinel lymph-node biopsy treated at first by surgery. We applied both predictors on the whole dataset and on each molecular immune-phenotype subgroups. The performances of the two predictors were analyzed in terms of discrimination and calibration. Probability of non-sentinel lymph node metastasis was detailed for each molecular subtype. Results Similar results were obtained with both predictors. We showed that the performance in terms of discrimination was as expected in ER Positive HER2 negative subgroup in both datasets (MSKCC AUC Dataset 1 = 0.73 [0.69–0.78], MSKCC AUC Dataset 2 = 0.71 (0.65–0.76), Tenon Score AUC Dataset 1 = 0.7 (0.65–0.75), Tenon Score AUC Dataset 2 = 0.72 (0.66–0.76)). Probability of non-sentinel node metastatic involvement was slightly under-estimated. Contradictory results were obtained in other subgroups (ER negative HER2 negative, HER2 positive subgroups) in both datasets probably due to a small sample size issue. We showed that merging the two datasets shifted the performance close to the ER positive HER2 negative subgroup. Discussion We showed that validated predictors like the Tenon Score or the MSKCC nomogram built on heterogeneous population of breast cancer performed equally on the different subgroups analyzed. Our present study re-enforce the idea that performing subgroup analysis of such predictors within less than 200 samples subgroup is at major risk of misleading conclusions.

Background Lymph node status is an important prognostic factor and a criterion for adjuvant therapy in uterine cancers. While detection of micrometastases by ultrastaging techniques is correlated to prognosis in several other cancers, this remains a matter of debate for uterine cancers. The objective of this review on sentinel nodes (SN) in uterine cancers was to determine the contribution of ultrastaging to detect micrometastases. Methods Review of the English literature on SN procedure in cervical and endometrial cancers and histological techniques including hematoxylin and eosin (H&E) staining, serial sectioning, immunohistochemistry (IHC) and molecular techniques to detect micrometastases. Results In both cervical and endometrial cancers, H&E and IHC appeared insufficient to detect micrometastases. In cervical cancer, using H&E, serial sectioning and IHC, the rate of macrometastases varied between 7.1% and 36.3% with a mean value of 25.8%. The percentage of women with micrometastases ranged from 0% and 47.4% with a mean value of 28.3%. In endometrial cancer, the rate of macrometastases varied from 0% to 22%. Using H&E, serial sectioning and IHC, the rate of micrometastases varied from 0% to 15% with a mean value of 5.8%. In both cervical and endometrial cancers, data on the contribution of molecular techniques to detect micrometastases are insufficient to clarify their role in SN ultrastaging. Conclusion In uterine cancers, H&E, serial sectioning and IHC appears the best histological combined technique to detect micrometastases. Although accumulating data have proved the relation between the risk of recurrence and the presence of micrometastases, their clinical implications on indications for adjuvant therapy has to be clarified.

Background Molecular signatures may become of use in clinical practice to assess the prognosis of breast cancers. However, although international consensus conferences sustain the use of these new markers in the near future, concerns remain about their degree of discordance and cost-effectiveness in different international settings. The present study aims to validate Ki67 as prognostic factor in a large cohort of early-stage (pT1–pT2, pN0) breast cancer patients. Methods 456 patients treated in 1995–1996 were identified in the Institut Curie database. Ki67 (MIB1) was retrospectively assessed by immunohistochemistry for all cases. The prognostic value of this index was compared to that of histological grade (HG), Estrogen receptor (ER) and HER2 status. Distant disease free interval, loco-regional recurrence, time-lapse from first metastatic diagnosis to death were analyzed. Results All 456 patients were treated by lumpectomy plus axillary dissection and radiotherapy. 27 patients (5.9%) received systemic treatment. Tumors were classified as HG1 in 35%, HG2 in 42% and HG3 in 23% of cases. ER was expressed in 86% of the tumors, HER2 in 5% and 14% were triple negative. The median follow-up was 151 [5–191] months. Distant and loco-regional disease recurrences were observed in 16% and 18%, respectively. High (>20%) Ki67 rate [HR = 3 (1.8–4.8), p