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Background: There is a lack of data on the use of breast implants and the path of patients reconstructed after breast cancer in France. This study aims to identify the paths of patients reconstructed by breast implant in France and assess their impact on survival, but also estimate the quality of the reconstruction, determined by early removal or replacement of implants.Methods : We performed a multicentric retrospective cohort study on women who underwent immediate or delayed implant-based reconstruction after curative or prophylactic mastectomy between 2002 and 2010 in three French private health institutions of public interest.Results : We identified 9 care pathways according to the type of disease, the type of surgery, the addition or not of adjuvant radiotherapy, and the timing of reconstruction. Theses courses concern 2,499 patients, and 3,191 breasts on which at least one implant has been placed. Five implant brands were mainly used during this period: PIP, Mentor, Allergan, Sebbin, and Perthese - with a total of 4,106 implants. The median of follow-up is 6 years [0 ;12 ;1]. The number of implants per breast is significantly different according to the reconstruction pathways (p Citation Format: Lea Pauly, Benoit Couturaud, Fabien Reyal. Current practice in implant-based breast reconstruction: A french long-term follow-up study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-66.

Background : Silicone breast implants from the French manufacturer Poly Implant Prothese (PIP) were recalled from the French market after the use of a non-medical silicone filler has been established. The systematic explantation of the implants had been proposed to women with PIP implants in France, a preventive measure concerning approximately 30,000 patients.Objectives : This study aimed to evaluate the consequences of having at least one PIP breast implant on overall and disease-free survival after breast reconstruction for cancer or prophylactic surgery.Materials and Methods : We performed a multicentric retrospective cohort study on women who underwent immediate or delayed implant-based reconstruction after curative or prophylactic mastectomy between January 01,2002 and March 30,2010 in three French private health institutions of public interest. These dates correspond respectively to the arrival of PIP breast implants on the French market and the decision to withdraw them by the French government. The primary endpoints were disease-free and overall survival, depending on whether or not having a PIP breast implant used during breast reconstruction of prophylactic surgery.Results : We identified 2499 patients with the use of 4106 breast implants between 2002 and 2010.The median age of cancer diagnosis was 47 years (19-77). This patient population selected for breast reconstruction had good prognosis criteria (77% T1 and 68% N0). PIP was the most common brand used between 2002 and 2010 and represented 45% of all breast implants (1764 implants). PIP has been preferentially used in courses with immediate breast reconstruction. On the 1764 PIP, 1408 (80%) were removed, mainly after the preventive measure recommending systematic explantation. Censored data on March 30, 2010, showed that the incidence of PIP implants removal is lower than other brands (Log-rank test : p Citation Format: Lea Pauly, Benoit Couturaud, Fabien Reyal. What lessons can be learned from the poly implant prothese scandal ? A french retrospective study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-65.

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.

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. Citation Format: Laura Vincent, Clémentine Jankowski, Marion Cortet, Laurent Arnould, Sylvain Ladoire, Bruno Coudert, Isabelle Desmoulins, Céline Charron-Barra, Françoise Beltjens, Roman Rouzier, Fabien Reyal, Olivier Humbert, Alexandre Cochet, Charles Coutant. HER2-positive breast cancer: Combined 18F-FDG PET and CGFL/Curie nomogram to predict pathologic complete response after preoperative chemotherapy with trastuzumab [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 P2-16-14.

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.

Background We determined the prognostic impact of lymphovascular invasion (LVI) in a large, national, multicenter, retrospective cohort of patients with early breast cancer (BC) according to numerous factors. Patients and methods We collected data on 17 322 early BC patients treated in 13 French cancer centers from 1991 to 2013. Survival functions were calculated using the Kaplan–Meier method and multivariate survival analyses were carried out using the Cox proportional hazards regression model adjusted for significant variables associated with LVI or not. Two propensity score-based matching approaches were used to balance differences in known prognostic variables associated with LVI status and to assess the impact of adjuvant chemotherapy (AC) in LVI-positive luminal A-like patients. Results LVI was present in 24.3% (4205) of patients. LVI was significantly and independently associated with all clinical and pathological characteristics analyzed in the entire population and according to endocrine receptor (ER) status except for the time period in binary logistic regression. According to multivariate analyses including ER status, AC, grade, and tumor subtypes, the presence of LVI was significantly associated with a negative prognostic impact on overall (OS), disease-free (DFS), and metastasis-free survival (MFS) in all patients [hazard ratio (HR) = 1.345, HR = 1.312, and HR = 1.415, respectively; P < 0.0001], which was also observed in the propensity score-based analysis in addition to the association of AC with a significant increase in both OS and DFS in LVI-positive luminal A-like patients. LVI did not have a significant impact in either patients with ER-positive grade 3 tumors or those with AC-treated luminal A-like tumors. Conclusion The presence of LVI has an independent negative prognostic impact on OS, DFS, and MFS in early BC patients, except in ER-positive grade 3 tumors and in those with luminal A-like tumors treated with AC. Therefore, LVI may indicate the existence of a subset of luminal A-like patients who may still benefit from adjuvant therapy., Highlights • In a study of 17 322 early BC patients, LVI had a significant independent negative prognostic impact on survival. • LVI negatively impacted survival in almost every patient category and cancer subtype, with and without AC. • LVI did not have a negative survival impact in patients with ER+ grade 3 or with luminal A-like tumors with chemotherapy. • Results suggest a possible benefit of AC in LVI-positive luminal A-like patients.

Malignant adenomyoepithelioma (AME) of the breast is an exceptionally rare form of breast cancer, with a significant metastatic potential. Chemotherapy has been used in the management of advanced AME patients, however the majority of treatments are not effective. Recent studies report recurrent mutations in the HRAS Q61 hotspot in small series of AMEs, but there are no preclinical or clinical data showing H-Ras protein as a potential therapeutic target in malignant AMEs. We performed targeted sequencing of tumours’ samples from new series of 13 AMEs, including 9 benign and 4 malignant forms. Samples from the breast tumour and the matched axillary metastasis of one malignant HRAS mutated AME were engrafted and two patient-derived xenografts (PDX) were established that reproduced the typical AME morphology. The metastasis-derived PDX was treated in vivo by different chemotherapies and a combination of MEK and BRAF inhibitors (trametinib and dabrafenib). All malignant AMEs presented a recurrent mutation in the HRAS G13R or G12S hotspot. Mutation of PIK3CA were found in both benign and malignant AMEs, while AKT1 mutations were restricted to benign AMEs. Treatment of the PDX by the MEK inhibitor trametinib, resulted in a marked anti-tumor activity, in contrast to the BRAF inhibitor and the different chemotherapies that were ineffective. Overall, these findings further expand on the genetic features of AMEs and suggest that patients carrying advanced HRAS-mutated AMEs could potentially be treated with MEK inhibitors.

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.

Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. Novel strategies are needed to stimulate the immune response and increase the response rate to ICB in luminal B BC., info:eu-repo/semantics/published

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.

Metastatic phyllodes tumors have poor prognosis with median overall survival of 11.5 months. The objective of this study is to identify prognostic factors and the best options for management of metastatic malignant phyllode tumors (MMPTs). A multicentric retrospective study, including cases of MMPT from 10 sarcoma centers, was conducted. The primary end-point was overall survival (OS), and the secondary end-point was the clinical benefit of chemotherapy (CBCT) rate. 51 MMPT patients were included. Median time from diagnosis to metastatic recurrence was 13 months. Management of MMPT consisted in surgery of the metastatic disease for 16 patients (31.3%), radiation therapy of the metastatic disease for 15 patients (31.9%), and chemotherapy for 37 patients (72.5%). Median follow-up was 62.1 months [95% confidence interval (CI) 31–80 months]. Median OS was 11.5 months (95% CI 7.5–18.7 months). On multivariate analysis, two or more metastatic sites [hazard ratio (HR) 2.81, 95% CI 1.27–6.19; p = 0.01] and surgery of metastasis (HR 0.33, 95% CI 0.14–0.78; p = 0.01) were independently associated with OS. The CBCT rate was 31.4% and 16.7% for the first and second lines. Polychemotherapy was not superior to single-agent therapy. Alkylating-agent-based chemotherapy, possibly associated with anthracyclines, was associated with a better CBCT rate than anthracyclines alone (p = 0.049). The results of this study emphasize the impact of the number of metastatic sites on survival of MMPT patients and the leading role of metastasis surgery in MMPT management. If systemic therapy is used, it should include alkylating agents, which are associated with a better clinical benefit.

Background Tumour features associated with isolated invasive breast cancer ipsilateral local recurrence (ILR) after breast conservative treatment (BCT) and consequences on overall survival (OS) are still debated. The aim of our study was to examine predictive factors of isolated ILR after BCT with in sano resection and whole breast irradiation as well as the impact of such an ILR on overall survival in a large multi-institutional cohort. Methods Patients were retrospectively identified from a large cohort of 23,375 consecutive patients who underwent BCT for invasive breast cancer in 16 cancer centres. End-points were ILR rate and OS. The impact of ILR on OS was assessed through multivariate analysis by logistic regression and Cox model, adjusted on ERs/Grade status (ERs+/Grade 1, ERs+/Grade 2, ERs+/Grade 3 and ERs-) and then on tumour subtypes. Results Of 15,570 patients, ILR rate was 3.1%. Cumulative ILR rates differed according to ERs/grade (ERs+/Grade2: HR=1.42, p=0.010; ERs+/Grade3: HR=1.41, p=0.067; ERs-: HR=2.14, p Impact of free interval time on OS among patients with ILR and among all patients p-valueHRInfSupILRno ILR 1 Conclusion ERs/Grade status, lack of endocrine therapy and tumour subtypes predict isolated ILR risk in patients treated with BCT. Short ILR-free-intervals represent a strong pejorative factor for OS. These results may help selecting initial treatment as well as tailoring ILR systemic chemotherapy. Citation Format: Houvenaeghel G, de Nonneville A, Cohen M, Classe J-M, Reyal F, Mazouni C, Chopin N, Martinez A, Daraï E, Coutant C, Colombo P-E, Gimbergues P, Chauvet M-P, Azuar A-S, Rouzier R, Tunon de Lara C, Murraciole X, Agostini A, Gonçalves A, Lambaudie E. Isolated ipsilateral local recurrence of breast cancer: Predictive factors and prognostic impact [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-08.

Objective The objective of our study was to analyze quality of life (QOL) in an e-cohort of patients treated for breast cancer (BC) by endocrine therapy (ET), by means of validated quality of life questionnaires. Study design and setting A retrospective, observational, e-cohort study was conducted (Seintinelles platform). Female patients treated for nonmetastatic and nonrecurrent BC, treated in France after 2005, filled in online questionnaires concerning: QOL (QLQ-C30 and QLQ-BR23), tolerability of treatment and demographic characteristics. A multivariate analysis including variables significant on univariate analysis (P Results We included 1,198 patients, 1140 of whom declared that they were taking ET (37.7% tamoxifen, 17.1% aromatase inhibitor (AI), 5.6% LHRH-agonist and 39.6% sequential tamoxifen and AI). Different tolerability profiles were observed when comparing the tamoxifen and AI groups. Treatment adherence was similar in the 2 groups. QOL varied slightly according to the type of ET. On multivariate analysis, ET had no impact on QOL. However, individual patient characteristics (socioeconomic, education and age) were significantly associated with QOL Conclusion Using a real-life study questionnaire on a large e-cohort, individual patient characteristics were strongly associated with deterioration of QOL. The use of e-cohorts must be encouraged to modulate the conclusions of randomized trials.

ObjectiveTo study fertility concerns and oncofertility practices at time of breast cancer (BC) diagnosis.DesignThe FEERIC study (Fertility, Pregnancy, Contraception after BC in France) is a prospective, multicenter study.SettingWeb-based collaborative research platform Seintinelles.Patients517 patients with prior BC diagnosis free from relapse and aged 18 to 43 years at inclusion (from 12th March 2018 to 27th June 2019).InterventionBaseline online self-administered questionnaires.Main Outcome MeasureFertility preservation procedures at BC diagnosis.ResultsMedian age at BC diagnosis was 33.6 years and 424 patients (82.0%) received chemotherapy. Overall, 236 (45.6%) patients were offered specialized oncofertility counseling, 124 (24.0%) underwent one or more FP procedures with material preservation (oocytes n=108, 20.9%; embryos n=31, 6.0%; both oocytes and embryos n=13, 2.5%; ovarian cryopreservation n=6, 1.2%) and 78 patients received gonadotropin-releasing hormone agonists (15.1%). With a median follow-up of 26.7 months after the end of treatments,133 pregnancies (25.7%) had occurred in 85 patients (16.4%), including 20 unplanned pregnancies (15.0%). Most of the pregnancies were spontaneous (n=113, 87.6%), while 16 (12.4%) required medical interventions. Patients who had an unplanned pregnancy were less likely to have received fertility counseling (p=0.02) and contraceptive counseling (p=0.08) at BC diagnosis.ConclusionMost of the patients were not offered proper specialized oncofertility counseling at the time of BC diagnosis. Spontaneous pregnancies after BC were very much more frequent than pregnancies resulting from the use of cryopreserved gametes. Adequate contraceptive counseling seems as important as information about fertility and might prevent unplanned pregnancies.

OTC deficiency, an inherited urea cycle disorder, is caused by mutations in the X-linked OTC gene. Phenotype-genotype correlations are well understood in males but still poorly known in females. Taking advantage of a cohort of 130 families (289 females), we assessed the relative contribution of OTC enzyme activity, X chromosome inactivation , and OTC gene sequencing to genetic counselling in heterozygous females. Twenty two percent of the heterozygous females were clinically affected, with episodic (11 %), chronic (7.5%), or neonatal forms of the disease (3.5%). Overall mortality rate was 4%. OTC activity, ranging from 0% to 60 %, did not correlate with phenotype at the individual level. Analysis of multiple samples from 4 mutant livers showed intra-hepatic variability of OTC activity and X inactivation profile (range of variability: 30 % and 20 %, respectively) without correlation between both parameters for 3 of the 4 livers Ninety disease-causing variants were found, 27 of which were novel. Mutations were classified as "mild" or "severe", based on male phenotypes and/or in silico prediction. In our cohort, a serious disease occurred in 32% of females with a severe mutation, compared to 4% in females with a mild mutation (odds ratio = 1.365; p=1.6e-06). These data should help prenatal diagnosis for heterozygous females and genetic counseling after fortuitous findings of OTC variants in pangenomic sequencing. This article is protected by copyright. All rights reserved.

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.

Simple Summary Breast cancer induces sequelae even years after diagnosis, but little is currently known about long-term sequelae patterns. This study aimed to (1) assess the evolution of the main sequelae and treatment two and five years after diagnosis in women with early-stage breast cancer, (2) explore patterns of sequelae associated with given sociodemographic, clinical, and lifestyle factors. Our results show that six main classes of sequelae were identified and remain constant over time except for fatigue and cognitive sequelae. The latent class analysis identified two main classes of sequelae (functional and esthetic patterns) and we have highlighted that different risk factors such as treatment, sociodemographic level, and physical activity level were associated with an increased risk of long-term sequelae. Abstract Breast cancer (BC) remains complex for women both physically and psychologically. The objectives of this study were to (1) assess the evolution of the main sequelae and treatment two and five years after diagnosis in women with early-stage breast cancer, (2) explore patterns of sequelae associated with given sociodemographic, clinical, and lifestyle factors. The current analysis was based on 654 localized BC patients enrolled in the French nationwide longitudinal survey “vie après cancer” VICAN (January–June 2010). Information about study participants was collected at enrollment, two and five years after diagnosis. Changes over time of the main sequelae were analyzed and latent class analysis was performed to identify patterns of sequelae related to BC five years after diagnosis. The mean age (±SD) of study participants at inclusion was 49.7 (±10.5) years old. Six main classes of sequelae were identified two years and five years post-diagnosis (functional, pain, esthetic, fatigue, psychological, and gynecological). A significant decrease was observed for fatigue (p = 0.03) and an increase in cognitive sequelae was reported (p = 0.03). Two latent classes were identified—functional and esthetic patterns. Substantial sequelae remain up to five years after BC diagnosis. Changes in patient care pathways are needed to identify BC patients at a high risk.

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.

Simple Summary Immune checkpoint inhibitors (ICI) are now part of the therapeutical arsenal for cancers at several sites and in several settings. PD-L1 expression is assessed to predict treatment response. We used immunohistochemistry (E1L3N clone) to assess PD-L1 expression on tumor and immune cells from a cohort of 89 surgical specimens of T1-T3NxM0 triple-negative breast cancers (TNBC) from patients treated with neoadjuvant chemotherapy (NAC) with residual disease. PD-L1 expression levels were low in tumor and immune cells from post-NAC surgical specimens. PD-L1 positivity in tumor cells was significantly associated with aggressive post-NAC tumor characteristics. A small subset of TNBC patients displaying PD-L1 expression in the context of a more extensive post-NAC tumor burden could benefit from ICI treatment after NAC. Abstract The consequences of neoadjuvant chemotherapy (NAC) for PD-L1 activity in triple-negative breast cancers (TNBC) are not well-understood. This is an important issue as PD-LI might act as a biomarker for immune checkpoint inhibitors’ (ICI) efficacy, at a time where ICI are undergoing rapid development and could be beneficial in patients who do not achieve a pathological complete response. We used immunohistochemistry to assess PD-L1 expression in surgical specimens (E1L3N clone, cutoff for positivity: ≥1%) on both tumor (PD-L1-TC) and immune cells (PD-L1-IC) from a cohort of T1-T3NxM0 TNBCs treated with NAC. PD-L1-TC was detected in 17 cases (19.1%) and PD-L1-IC in 14 cases (15.7%). None of the baseline characteristics of the tumor or the patient were associated with PD-L1 positivity, except for pre-NAC stromal TIL levels, which were higher in post-NAC PD-L1-TC-positive than in negative tumors. PD-L1-TC were significantly associated with a higher residual cancer burden (p = 0.035) and aggressive post-NAC tumor characteristics, whereas PD-L1-IC were not. PD-L1 expression was not associated with relapse-free survival (RFS) (PD-L1-TC, p = 0.25, and PD-L1-IC, p = 0.95) or overall survival (OS) (PD-L1-TC, p = 0.48, and PD-L1-IC, p = 0.58), but high Ki67 levels after NAC were strongly associated with a poor prognosis (RFS, p = 0.0014, and OS, p = 0.001). A small subset of TNBC patients displaying PD-L1 expression in the context of an extensive post-NAC tumor burden could benefit from ICI treatment after standard NAC.

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.

The consequences of neoadjuvant chemotherapy (NAC) for PD-L1 activity in triple-negative breast cancers (TNBC) are not well understood. This is an important issue as immune checkpoint inhibitors (ICI) are undergoing rapid development and could be beneficial in patients who do not achieve a pathological complete response. We used immunohistochemistry to assess PD-L1 expression (E1L3N clone, cutoff for positivity: ≥ 1%) on both tumor (PD-L1-TC) and immune cells (PD-L1-IC) from a cohort of surgical specimens of T1-T3NxM0 TNBCs treated with NAC. PD-L1-TC was detected in 17 cases (19.1%) and PD-L1-IC in 14 cases (15.7%). None of the baseline characteristics of the tumor or the patient were associated with PD-L1 positivity, except for pre-NAC stromal TIL levels, which were higher in post-NAC PD-L1-TC-positive than in negative tumors. PD-L1-TC were significantly associated with a higher residual cancer burden (p=0.035) and aggressive post-NAC tumor characteristics, whereas PD-L1-IC were not. PD-L1 expression was not associated with DFS (p=0.38) or OS (p=0.48), but high Ki67 levels after NAC were strongly associated with a poor prognosis (DFS p=0.0014 and OS p=0.001). A small subset of TNBC patients displaying PD-L1 expression in the context of an extensive post-NAC tumor burden could benefit from ICI treatment after standard NAC.

IntroductionThe three different breast cancer subtypes (Luminal,HER2-positive and triple negative (TNBCs) display different natural history and sensitivity to treatment, but little is known about whether residual axillary disease after neoadjuvant chemotherapy (NAC) carries a different prognostic value by BC subtype.MethodsWe retrospectively evaluated axillary involvement (0, 1 to 3 positive nodes, ≥ 4 positive nodes) on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between nodal involvement (ypN) binned into 3 classes (0; [1-3];4 or more), relapse-free survival (RFS) and overall survival (OS) among the global population, and according to BC subtypes.Results1197 patients were included in the analysis (luminal (n = 526, 43.9%), TNBCs (n = 376, 31.4%),HER2-positive BCs (n = 295, 24.6%)). After a median follow-up of 110.5 months, ypN was significantly associated with RFS, but this effect was different by BC subtype (Pinteraction= 0.004), and this effect was nonlinear. In the luminal subgroup, RFS was impaired in patients with 4 or more nodes involved (HR=2.8; 95% CI [1.93;4.06],pversusypN0,p< 0.001). Similar decreased prognosis were observed among patients withHER2-positive BC (1-3N+: HR=2.7, 95%CI= [1.64; 4.43] and ≥ 4 N+: HR=2.69, 95%CI= [1.24; 5.8] respectively,p=0.003).ConclusionThe prognostic value of residual axillary disease should be considered differently in the 3 BC subtypes to accurately stratify patients with a high risk of recurrence after NAC who should be offered second line therapies.

Introduction: Five to 10% of breast cancers (BCs) occur in a genetic predisposition context (mainly BRCA pathogenic variant). Nevertheless, little is known about immune tumor infiltration, response to neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) and adverse events according to BRCA status. Material and Methods: Out of 1199 invasive BC patients treated with NAC between 2002 and 2012, we identified 267 patients tested for a germline BRCA pathogenic variant. We evaluated pre-NAC and post-NAC immune infiltration (TILs). Response to chemotherapy was assessed by pCR rates. Association of clinical and pathological factors with TILs, pCR and survival was assessed by univariate and multivariate analyses. Results: Among 1199 BC patients: 46 were BRCA-deficient and 221 BRCA-proficient or wild type (WT). At NAC completion, pCR was observed in 84/266 (31%) patients and pCR rates were significantly higher in BRCA-deficient BC (p = 0.001), and this association remained statistically significant only in the luminal BC subtype (p = 0.006). The interaction test between BC subtype and BRCA status was nearly significant (Pinteraction = 0.056). Pre and post-NAC TILs were not significantly different between BRCA-deficient and BRCA-proficient carriers, however, in the luminal BC group, post-NAC TILs were significantly higher in BRCA-deficient BC. Survival analysis were not different between BRCA-carriers and non-carriers. Conclusions: BRCA mutation status is associated with higher pCR rates and post-NAC TILs in patients with luminal BC. BRCA-carriers with luminal BCs may represent a subset of patients deriving higher benefit from NAC. Second line therapies, including immunotherapy after NAC, could be of interest in non-responders to NAC.

IntroductionFive to 10% of breast cancers (BCs) occur in a genetic predisposition context (mainly BRCA pathogenic variant). Nevertheless, little is known about immune tumor infiltration, response to neoadjuvant chemotherapy (NAC), pathologic complete response (pCR) and adverse events according to BRCA status.Material and methodsOut of 1199 invasive BC patients treated with NAC between 2002 and 2012, we identified 267 patients tested for a germline BRCA pathogenic variant. We evaluated pre-NAC and post-NAC immune infiltration (TILs). Response to chemotherapy was assessed by pCR rates. Association of clinical and pathological factors with TILs, pCR and survival was assessed by univariate and multivariate analyses.ResultsAmong 1199 BC patients: 46 were BRCA-deficient and 221 BRCA-proficient or wild type (WT). At NAC completion, pCR was observed in 84/266 (31%) patients and pCR rates were significantly higher in BRCA-deficient BC (p= 0.001), and this association remained statistically significant only in the luminal BC subtype (p= 0.006). The interaction test between BC subtype and BRCA status was nearly significant (Pinteraction=0.056). Pre and post-NAC TILs were not significantly different between BRCA-deficient and BRCA-proficient carriers; however, in the luminal BC group, post-NAC TILs were significantly higher in BRCA-deficient BC. Survival analysis were not different between BRCA-carriers and non-carriers.ConclusionBRCA mutation status is associated with higher pCR rates and post-NAC TILs in patients with luminal BC. BRCA-carriers with luminal BCs may represent a subset of patients deriving higher benefit from NAC. Second line therapies, including immunotherapy after NAC, could be of interest in non-responders to NAC.Translational relevanceHigh lymphocytic infiltration (TILs) seem to reflect favorable host antitumor immune responses. In breast cancer, the variation of TILs before and after neoadjuvant chemotherapy (NAC) according to BRCA status has been poorly described. Little data is available on their value after treatment. We investigated TIL levels before and after NAC and response to treatment in 267 paired biopsy and surgical specimens.In our study, luminal BCs were associated with pathologic complete response (pCR) and higher TIL levels after chemotherapy completion in patients with BRCA pathogenic mutations. Our data supports that (i) NAC should be reconsidered in luminal BCs with BRCA pathogenic mutation, (ii) TILs could be a biomarker for response to immune checkpoint blockade in luminal BCs with BRCA pathogenic variant who did not achieve a pCR and (iii) exploiting the antitumor immune response in luminal BCs could be an area of active research.

International audience

Tobacco use is associated with an increase in breast cancer (BC) mortality. Pathologic complete response (pCR) rate to neoadjuvant chemotherapy (NAC) is influenced by tumor-infiltrating lymphocyte (TIL) levels and is associated with a better long-term survival outcome. The aim of our study is to evaluate the impact of smoking status on TIL levels, response to NAC and prognosis for BC patients. We retrospectively evaluated pre- and post-NAC stromal and intra tumoral TIL levels and pCR rates on a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012 at Institut Curie. Smoking status (current, ever, never smokers) was collected in clinical records. We analyzed the association between smoking status, TIL levels, pCR rates and survival outcomes among the whole population, and according to BC subtype. Nine hundred and fifty-six BC patients with available smoking status information were included in our analysis (current smokers, n = 179 (18.7%), ever smokers, n = 154 (16.1%) and never smokers, n = 623 (65.2%)). Median pre-NAC TIL levels, pCR rates, or median post-NAC TIL levels were not significantly different according to smoking status, neither in the whole population, nor in any BC subtype group. With a median follow-up of 101.4 months, relapse-free survival (RFS) and overall survival (OS) were not significantly different by smoking status. We did not find any significant effect of tobacco use on pre- and post-NAC TILs nor response to NAC. Though our data seem reassuring, BC treatment should still be considered as a window of opportunity to offer BC patients accurate smoking cessation interventions.

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.

INTRODUCTIONTobacco use is associated with an increase in breast cancer (BC) mortality. Pathologic complete response rate to neoadjuvant chemotherapy (NAC) is influenced by tumor-infiltrating lymphocytes (TILs) levels and is associated with a better long-term survival outcome. Whether tobacco modifies either tumoral microenvironment such as TIL levels, either pCR rates remains unclear. The aim of our study is to evaluate the impact of smoking status on TIL levels, response to NAC and prognosis for BC patients.METHODSWe retrospectively evaluated pre and post NAC stromal and intra tumoral TIL levels and pCR rates on a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012 at Institut Curie. Smoking status (current, ever, never smokers) was collected in clinical records. We analyzed the association between smoking status, TIL levels, pCR rates and survival outcomes among the whole population, and after stratification by BC subtype.RESULTSA total of 956 BC patients with available smoking status information were included in our analysis [current smokers, n=179 (18.7%); ever smokers, n=154 (16.1%) and never smokers, n = 623 (65.2%)]. Median pre-NAC TIL levels, pCR rates, or median post-NAC TIL levels were not significantly different according to smoking status, neither in the whole population, nor after stratification by BC subtype. With a median follow-up of 101.4 months, relapse free survival (RFS) and overall survival (OS) were not significantly different by smoking status.CONCLUSIONIn this study, we did not find any significant effect of tobacco use on pre and post NAC TILs nor response to NAC and. Though our data seem reassuring, BC treatment should still be considered as a window of opportunity to offer BC patients accurate smoking cessation interventions.

The optimal threshold of surgical margins for breast malignant phyllodes tumors (MPTs) and the impact of adjuvant chemotherapy and radiotherapy were investigated.We conducted a multicenter nationwide retrospective study of all MPT cases with central pathological review within the French Sarcoma Group. Endpoints were local recurrence-free survival (LRFS), metastasis-free survival (MFS), and overall survival (OS) rates.Overall, 212 patients were included in the study. All non-metastatic patients underwent primary surgical treatment, including 58.6% of conservative surgeries. An R0 resection was achieved in 117 patients (59.4%: 26.9% of patients with 1-2 mm margins, 12.2% of patients with 3-7 mm margins, 20.3% of patients with ≥ 8 mm margins). Ninety-four patients (45%) underwent a second surgery (SS) to obtain R0 margins, with a final mastectomy rate of 72.6%. Radiotherapy and chemotherapy were performed in 91 (43.1%) and 23 patients (10.9%), respectively, but were not associated with better outcomes. Mastectomy was significantly associated with better LRFS (p 0.001). Margins of 0, 1, or 2 mm with SS were associated with better MFS (hazard ratio [HR] 0.3, p = 0.005) and OS (HR 0.32, p = 0.005) compared with margins of 0-1-2 mm without SS. Wider margins ( 8 mm) were not superior to margins of 3-7 mm (3-7 mm vs. 8 mm; HR 0.81, p = 0.69). Age (HR 2.14, p = 0.038) and tumor necrosis (HR 1.96, p = 0.047) were found to be poor prognostic factors and were associated with MFS.This study suggests that 3 mm margins are necessary and sufficient for surgical management of MPTs, and emphasizes the importance of SS to obtain clear margins in case of 0-1-2 mm margins. No impact of adjuvant chemotherapy or radiotherapy was detected in this study.

International audience; Although identified to be at a higher risk of relapse, no consensus exists on the treatment of breast cancer (BC) patients with no pathological complete response after neoadjuvant chemotherapy (NAC). The benefit of adjuvant chemotherapy (ADJ) in this context has scarcely been studied. We evaluated the benefit of administrating adjuvant chemotherapy in a real life cohort of BC patients with invasive residual disease after NAC. 1199 female BC patients with T1-3NxM0 invasive tumors receiving NAC at Institut Curie from 2002 to 2012 were included in the analysis. 1061 had been treated by NAC only, whereas 138 had received additional adjuvant chemotherapy after NAC (FUN protocol: 5-FU-Vinorelbine). We compared disease-free survival (DFS) and overall survival (OS) rates between patients having received NAC only and patients having received NAC+ADJ. To ensure comparability of our populations, we used a propensity score (which defines the probability of treatment assignment conditional on observed baseline covariates) and matched each patient having received NAC+ADJ (n = 138) with a patient having received NAC only that had a similar propensity score value. Before propensity score matching, DFS and OS rates were significantly lower in the NAC+ADJ group compared to NAC only, after 3 years, 5 years and 10 years follow-up (p

Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.

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.

Aim: To assess the value of Post-mastectomy radiation therapy (PMRT) in breast cancer patients with no or minimal lymph nodes involvement. Materials and methods: We retrospectively analyzed a French multi-centric cohort of 4283 patients treated between 1980 and 2013, by mastectomy and axillary dissection with or without PMRT. Practices were analyzed according 3 treatment periods (1980-1999, 2000-2005; 2006-2013). The value of PMRT on loco-regional recurrence, disease-free survival, breast cancer specific survival and overall survival was assessed in pN0-1mi patients, using multivariate analyses (logistic regression and Cox model). It was subsequently assessed according to the number of clinicopathologic recurrence-risk factors, generating a prognostic index (f-PMRT index), in an attempt to isolate a pN0-1mi patients subgroup deriving benefit from PMRT. We tested the accuracy of the Cambridge-PMRT (c-PMRT) index in the discrimination of patients with significantly different outcomes, as well as the value of PMRT in each c-PMRT prognostic group. Results: PMRT was considered in more than half pN0-1mi patients of our cohort. Whereas matching pN0-1mi patients according to the number of clinicopathologic recurrence-risk factors led to isolate a higher-risk subpopulation (≥ 3 RR factors), PMRT had no significant impact on patients' outcomes, on multivariate analysis. Whereas the Cambridge-PMRT index had the potential to discriminate 3 patient populations with significantly different outcomes, its use did not help to the decision making for PMRT. Conclusion: Despite a large cohort, we failed to isolate a subgroup of early breast cancer patients suitable for PMRT, in the absence of lymph node involvement. Citation Format: Forissier V, Tallet A, Cohen M, Classe J-M, Reyal F, Chopin N, Mazouni C, Gimbergues P, Daraï E, Colombo PE, Azuar P, Lambaudie E, Houvenaeghel G. Is post mastectomy radiotherapy contributive in pN0-1mi breast cancers patients? Results of a French multi-centric cohort [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-17.

Background: Recent updated analysis of the HERA (HERceptin Adjuvant) trial indicate that tumor hormone receptor status (HR)remains a major determinant of outcome in HER2-positive (HER2+) early breast cancer (BC) patients, with higher rates of recurrence and death in women with HR-negative (HR-) disease, even after 11 years' median follow-up. Furthermore, data reported from the HERA trial suggest that the timing of recurrences is different, with an initial higher frequency of disease-free survival (DFS) events in patients with HR- disease than those with HR-positive disease (HR+). No evidence of a different trastuzumab efficacy according to the HR of the primary tumor was found. In this study, we examined the impact of HR on outcome in a large, multicenter, “real-world”, retrospective cohort of HER2+ early breast cancer patients Methods: HER2+ BC were retrospectively identified from a large cohort of 23,375 consecutive patients who underwent primary surgery at 17 French centers between Dec 1987 and Jan 2014. A multivariate Cox model was built including age, tumor size, SBR grade, lymphovascular invasion, lymph node involvement, hormonal receptors status, adjuvant chemotherapy, adjuvant hormone therapy, trastuzumab, radiotherapy and type of surgery. Results: A total of 1308 cases were identified, including 829 (63%) HR+ and 479 (47%) HR- patients. Median follow-up was 52 months (range 0 to 201). Compared with HR+, HR- patients had significantly smaller tumors (37 vs. 31% ≤ 10mm, p=0.027; information for multifocal tumors was not available), with higher SBR grade (58 vs. 40% grade 3, p Conclusions: Our results suggest that HR status remains a major determinant of outcome in HER2+ BC, including the timing of recurrence. Yet, this prognostic impact appears to be mitigated by trastuzumab-based adjuvant treatment. Citation Format: de Nonneville A, Gonçalves A, Cohen M, Reyal F, Classe JM, Giard S, Colombo PE, Muracciole X, Chopin N, Lambaudie E, Houvenaeghel G. Impact of hormone receptor status in HER2-Positive early breast cancer in the trastuzumab era: Results of a National multi-institutional study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-13-04.

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

Aim To assess the value of post-mastectomy radiation therapy (PMRT) to breast cancer (BC) patients with no or minimal lymph node (LN) involvement. Materials and methods We retrospectively analysed a French multi-centric cohort of 4283 patients treated by mastectomy and axillary dissection, with or without PMRT, between 1980 and 2013. Practices were analysed for three treatment periods (1980–1999, 2000–2005 and 2006–2013). The impact of PMRT on loco-regional recurrence (LRR), disease-free survival (DFS), BC-specific survival and overall survival was assessed in pN0-1mi patients using multivariate analyses (logistic regression and Cox model). It was subsequently assessed based on the number of clinicopathological recurrence-risk factors, generating a prognostic index (French-PMRT index), to isolate a pN0-1mi patients subgroup that might derive a benefit from PMRT. We tested the accuracy of the Cambridge-PMRT (c-PMRT) index to discriminate between patients with significantly different outcomes and the value of PMRT in each c-PMRT prognostic group. Results More than half of the pN0-1mi patients of our cohort underwent PMRT, which almost significantly improved LRR-free survival and DFS. Matching pN0-1mi patients based on the number of clinicopathologic recurrence-risk factors identified a higher risk subpopulation (≥3 recurrence-risk factors), but PMRT did not improve patient outcomes. Although the c-PMRT index had the potential to predict patient outcomes, its use did not help in making the decision of whether or not to use PMRT. Conclusion We failed to isolate a subgroup of early BC patients without LN involvement suitable for PMRT, despite studying a large cohort.

Introduction The aim of this study was to examine changes in therapeutic practices for early breast cancer T0-2 N0 managed by upfront surgery and SLNB. Population Between 1999 and 2012, 15.508 patients were treated. Four periods were determined: 1999–2003, 2004–2006, 2007–2009 and > 2009. Five tumor subtypes were defined according to hormonal receptors (HR) and Her2: Luminal A (HR + Her2- Grade 1–2), Her2 (Her2+ HR-), Triple-negative (HR- Her2-), Luminal B Her2- (HR + Her2- Grade 3), Luminal B Her2+ (HR + HER2+). Methods Rates of axillary lymph node dissection (ALND), adjuvant chemotherapy ± trastuzumab, endocrine treatment, mastectomy and post mastectomy radiotherapy (PMRT) were analyzed according to treatment periods with univariate and multivariate analysis. Overall and disease-free survivals were analyzed according to treatment periods adjusted for HR and then for tumor subtypes. Results Rates of ALND, adjuvant chemotherapy and endocrine treatment varied significantly according to treatment periods, for HR positive and negative tumors. ALND rate decreased for all tumor subtypes with a decrease of adjuvant chemotherapy rate for Luminal A tumors and an increase for Luminal B Her2+ and Her2-tumors. Endocrine treatment rate decreased for Luminal A and increased for Luminal B Her2+ tumors. In multivariate analysis, these modifications with time remained significant. Mastectomy and PMRT rates increased. In multivariate analysis, overall and disease-free survivals increased during successive periods. Conclusion A global therapeutic de-escalation in ALND and adjuvant systemic treatment, combined with an actual escalation in some specific subsets was demonstrated, but without negative impact on survival.

Background: The European Society of Breast Cancer Specialists (EUSOMA) has defined quality indicators for breast cancer (BC). The aim of this study was to describe the preoperative clinical pathway of breast cancer patients and evaluate the determinants of compliance with EUSOMA quality indicators in the Optisoins01 cohort. Methods: Optisoins01 is a prospective, multicentric study. Data from operable BC patients were collected, including results from before surgery to 1 year follow-up. Seven preoperative EUSOMA quality indicators were compared with the clinical pathways Optisoins01. Results: Six hundred and four patients were included. European Society of Breast Cancer Specialists targets were reached for indicator 1 (completeness of clinical and imaging diagnostic work-up), 3 (preoperative definitive diagnosis) and 5 (waiting time). For indicator 8 (multidisciplinary discussion), the minimum standard of 90% of the patients was reached only in general hospitals and comprehensive cancer centres. Having more than 1 medical examination within the centre was associated with an increased waiting time for surgery, whereas it was reduced by having an outpatient breast biopsy. The comprehensive cancer centre type was the only parameter associated with the other quality indicators. Conclusions: European Society of Breast Cancer Specialists quality indicators are a useful tool to evaluate care organisations. This study highlights the need for a standardised and coordinated preoperative clinical pathway.

The Breast Surgery theoretical and practical knowledge curriculum comprehensively describes the knowledge and skills expected of a fully trained breast surgeon practicing in the European Union and European Economic Area (EEA). It forms part of a range of factors that contribute to the delivery of high quality cancer care. It has been developed by a panel of experts from across Europe and has been validated by professional breast surgery societies in Europe. The curriculum maps closely to the syllabus of the Union of European Medical Specialists (UEMS) Breast Surgery Exam, the UK FRCS (breast specialist interest) curriculum and other professional standards across Europe and globally (USA Society of Surgical Oncology, SSO). It is envisioned that this will serve as the basis for breast surgery training, examination and accreditation across Europe to harmonise and raise standards as breast surgery develops as a separate discipline from its parent specialties (general surgery, gynaecology, surgical oncology and plastic surgery). The curriculum is not static but will be revised and updated by the curriculum development group of the European Breast Surgical Oncology Certification group (BRESO) every 2 years.

Immunosurveillance plays an important role in breast cancer (BC) prognosis and progression, and can be geared by immunogenic chemotherapy. In a cohort of 1023 BC patients treated with neoadjuvant chemotherapy (NAC), 40% of the individuals took comedications mostly linked to aging and comorbidities. We systematically analyzed the off-target effects of 1178 concurrent comedications (classified according to the Anatomical Therapeutic Chemical (ATC) Classification System) on the density of tumor-infiltrating lymphocytes (TILs) and pathological complete responses (pCR). At level 1 of the ATC system, the main anatomical classes of drugs were those targeting the nervous system (class N, 39.1%), cardiovascular disorders (class C, 26.6%), alimentary and metabolism (class A, 16.9%), or hormonal preparations (class H, 6.5%). At level 2, the most frequent therapeutic classes were psycholeptics (N05), analgesics (N02), and psychoanaleptics (N06). Pre-NAC TIL density in triple-negative BC (TNBC) was influenced by medications from class H, N, and A, while TIL density in HER2+ BC was associated with the use of class C. Psycholeptics (N05) and agents acting on the renin-angiotensin system (C09) were independently associated with pCR in the whole population of BC or TNBC, and in HER2-positive BC, respectively. Importantly, level 3 hypnotics (N05C) alone were able to reduce tumor growth in BC bearing mice and increased the anti-cancer activity of cyclophosphamide in a T cell-dependent manner. These findings prompt for further exploration of drugs interactions in cancer, and for prospective drug-repositioning strategies to improve the efficacy of NAC in BC.

A diversity of T helper (Th) subsets (Th1, Th2, Th17) has been identified in the human tumor microenvironment. In breast cancer, the role of Th subsets remains controversial, and a systematic study integrating Th subset diversity, T cell inflammation, breast cancer molecular subtypes, and patient prognosis, is lacking. In primary untreated breast cancer samples, we analyzed 19 Th cytokines at the protein level. Eight were T cell-specific, and subsequently measured in 106 prospectively-collected untreated samples. The dominant Th cytokines across all breast cancer samples were IFN-γ and IL-2. Th2 cytokines (IL-4, IL-5, IL-13) were expressed at low levels and not associated with any breast cancer subtype. Th17 cytokines (IL-17A and IL-17F) were up-regulated in triple negative breast cancer (TNBC), specifically in T cell non-inflamed tumors. In order to get insight into prognosis, we exploited the METABRIC transcriptomic dataset. We derived Th1, Th2, and Th17 metagenes based on manually curated Th signatures, and found that a high Th17 metagene was of good prognosis in T cell non-inflamed TNBC. Multivariate Cox modeling selected the Nottingham Prognostic Index (NPI), Th2 and Th17 metagenes as additive predictors of breast cancer-specific survival, which defined novel and highly distinct prognostic groups within TNBC. Our results reveal that Th17 is a novel prognostic composite biomarker in T cell non-inflamed TNBC. Integrating immune cell and tumor molecular diversity is an efficient strategy for prognostic stratification of cancer patients.

SCOPUS: ed.j, info:eu-repo/semantics/published

International audience; Analysis and interpretation of stained histopathology sections is one of the main tools in cancer diagnosis and prognosis. In addition to the information which is typically extracted by trained pathologists, there is also information that is not yet exploited, simply because we do not yet understand the impact of all cellular and tissular features that could be predictive of outcome. In this paper, we address a question that can currently not be solved by pathologists: the prediction of treatment efficiency for Triple Negative Breast Cancer (TNBC) patients from biopsy data.

Objectives: To analyze axillary lymph node involvement (ALNI) rate and survival for mucinous (MC) and tubular (TC) breast carcinomas considered being of very good prognosis and for which an axillary surgical exploration could be questioned. Methods: Our multicentric cohort consisted of 21,135 patients with clinically node-negative invasive breast cancer, without neoadjuvant therapy, between 1999 and 2013 in 10 French centers. ALNI rate and survival were analyzed according to patient and tumor characteristics. Results: Our cohort consisted of 672 TC and 245 MC. Patients were older and tumor size greater for MC and pathologic factors were more pejorative. The rate of mastectomies and adjuvant chemotherapy was higher in the MC group. Axillary lymph node status was determined by SLNB alone in 71.2% of patients. ALNI rates were 17.9% and 18% for TC and MC, respectively. ALNI rate was lesser for MC (OR 0.503, p = 0.024) and greater in case of lympho-vascular invasion (OR 5.0, p < 0.0001) and for tumors >10 mm (OR 2.17, p = 0.042). Median follow-up was 58 months. The 5- and 7-year overall survival rates were 97.1% and 95% for TC, respectively; 92.3% and 91.2% for MC ( p = 0.043); 5- and 7-year disease-free survival rates were 97.9% and 97.2% versus 95.2 and 93.6% ( p = 0.041). Lympho-vascular invasion was the only predictive factor for overall survival (hazard ratio [HR] = 2.70)’ grade 2 (HR = 10) and HR-negative (HR = 4.9) were the two predictive factors for disease-free survival. Conclusion: This study confirms the need for an axillary exploration for these tumors even for a tumor size

International audience; BACKGROUND:Tumour features associated with isolated invasive breast cancer (BC) ipsilateral local recurrence (ILR) after breast conservative treatment (BCT) and consequences on overall survival (OS) are still debated. Our objective was to investigate these points.METHODS:Patients were retrospectively identified from a cohort of patients who underwent BCT for invasive BC in 16 cancer centres. End-points were ILR rate and OS. The impact of ILR on OS was assessed by multivariate analysis (MVA) for all patients and according to endocrine receptors (ERs) and grade or tumour subtypes.RESULTS:Of 15,570 patients, ILR rate was 3.1%. Cumulative ILR rates differed according to ERs/grade (ERs+/Grade2: HR 1.42, p = 0.010; ERs+/Grade3: HR 1.41, p = 0.067; ERs-: HR 2.14, p

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 Prognostic impact of lymph node micro-metastases (pN1mi) has been discordantly reported in the literature. The need to clarify this point for decision-making regarding adjuvant therapy, particularly for patients with endocrine receptor (ER)-positive status and HER2-negative tumors, is further reinforced by the generalization of gene expression signatures using pN status in their recommendation algorithm. Patients and methods We retrospectively analyzed 13 773 patients treated for ER-positive breast cancer in 13 French cancer centers from 1999 to 2014. Five categories of axillary lymph node (LN) status were defined: negative LN (pN0i−), isolated tumor cells [pN0(i+)], pN1mi, and pN1 divided into single (pN1 = 1) and multiple (pN1 > 1) macro-metastases (>2 mm). The effect of LN micro-metastases on outcomes was investigated both in the entire cohort of patients and in clinically relevant subgroups according to tumor subtypes. Propensity-score-based matching was used to balance differences in known prognostic variables associated with pN status. Results As determined by sentinel LN biopsy, 9427 patients were pN0 (68.4%), 546 pN0(i+) (4.0%), 1446 pN1mi (10.5%) and 2354 pN1 with macro-metastases (17.1%). With a median follow-up of 61.25 months, pN1 status, but not pN1mi, significantly impacted overall survival (OS), disease-free survival (DFS), metastasis-free survival (MFS), and breast-cancer-specific survival. In the subgroup of patients with known tumor subtype, pN1 = 1, as pN1 > 1, but not pN1mi, had a significant prognostic impact on OS. DFS and MFS were only impacted by pN1 > 1. Similar results were observed in the subgroup of patients with luminal A-like tumors (n = 7101). In the matched population analysis, pN1macro, but not pN1mi, had a statistically significant negative impact on MFS and OS. Conclusion LN micro-metastases have no detectable prognostic impact and should not be considered as a determining factor in indicating adjuvant chemotherapy. The evaluation of the risk of recurrence using second-generation signatures should be calculated considering micro-metastases as pN0., Highlights • LN micro-metastases have no detectable prognostic impact. • pN1 status, but not pN1mi, significantly impacted overall survival, disease-free survival, metastasis-free survival. • In the subgroup of patients with known tumor subtype, pN1=1, as pN1>1, but not pN1mi, had a significant prognostic impact on OS. • LN micro-metastases should not be considered as a determining factor in indicating adjuvant chemotherapy.