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CONTEXT: Endocrine therapy combined with CDK4/6 inhibitor is the standard frontline treatment for the vast majority of HR+/HER2- metastatic breast cancer (MBC) patients. Despite an overall survival benefit, patients eventually progress and mechanisms of resistance to this combination are not well identified. Non-invasive monitoring of the efficacy of treatment could help into tailoring therapeutic regimen. Extracellular vesicles (EVs) are a group of heterogeneous nanosized bioparticles (30-1000nm), released by almost all cell types - including tumor, platelets, and immune cells – carrying informative biological material emanating from the mother cell and circulating in the blood stream. In this project, we ambition to assess whether the vesiclemia, i.e. plasmatic extracellular vesicle concentration can be used as a clinic-biological parameter to assist in the monitoring of patients. METHODS: EPICURE is an ongoing pilot prospective cohort study of heterogeneous and massive data integration, i.e. multi-omics approaches in MBC patients. The present study focused on patients with HR+/HER2- MBC receiving frontline endocrine therapy+iCDK4/6. Plasma samples were drawn every 3 months during the treatment until progression. The workflow for the enrichment of circulating EVs was developed from frozen plasma. A semi-automatized isolation procedure using size exclusion chromatography combined with the newly developed interference light microscopy apparatus Videodrop allowed to routinely separate plasmatic EVs and quantify vesiclemia in a fast and reliable manner for a large number of samples (longitudinal follow-up of MBC patients). RESULTS: 26 patients were included and monitored for vesiclemia. Median age was 58.5y (±13.7). Metastatic disease sites were distributed as follows: bone metastases (21; 84%), liver (21; 84%), thoracic (10; 40%), node (2; 8%), brain (1; 4%), others (2; 8%). Endocrine therapy included aromatase inhibitors (20; 77%), fulvestrant (6; 29%), GnRH agonists (5; 19%) and CDK4/6 inhibitors palbocilib (15; 57%), abemaciclib (8; 31%) and ribociclib (3; 11%). With a median follow-up time of 22.1 months (95%CI 21.2 - not reached), median progression free survival was 21.8 months (95%CI 18.1 - not reached). Median time on treatment was 19.4 months (IQR 11.6 - 22.1). Objective response rate was confirmed in 12 patients (6 with complete response). Out of the 26 patients, 12 stopped the frontline treatment due to disease progression. 135 longitudinal follow-up samples were analyzed for EVs. All patients who progressed rapidly after treatment initiation (i.e median PFS< 6 months) had an increased vesiclemia at the months 2 and 6 after inclusion. Conversely, patients who had a median PFS >18m had a stable vesiclemia during this period. CONCLUSION This study aims to use circulating EVs as a therapeutic companion to anticipate treatment resistance and tumor progression in MBC patients. Our preliminary data suggest that the vesiclemia could be used as a predictive tool to anticipate treatment failure, and thus might be used to tailor treatments in time. Citation Format: Mathilde Richard, Jean Sebastien FRENEL, Laurent Mathiot, Mario Campone, Mathilde Colombie, Marie Robert, Anne Patsouris, Frederic Bigot, Julie Gavard, Gwennan André-Grégoire, Laetitia Guevel. Extracellular vesicle-based biomarker assay for the monitoring of the efficacy of frontline endocrine therapy + CDK4-6 inhibitors in metastatic breast cancer. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-11-09.

The efficacy and added benefit of platinum-based chemotherapy (PtCT) for metastatic breast cancer (MBC) remain unclear in patients with and without germline BRCA1 or BRCA2 mutations (gBRCA1/2m and gBRCA1/2wt, respectively).We selected from the French national real-world multicentre ESME cohort (2008-2016) all patients with HER2-negative MBC with known gBRCA1/2 status at first-line chemotherapy initiation. Using multivariable Cox models, we compared the outcome (progression-free (PFS) and overall survival (OS)) of first-line PtCT and non-PtCT regimens based on the patients' gBRCA1/2 status and tumour subtype.Patients who received PtCT had more aggressive tumour features. In the multivariable analysis, first-line PtCT was associated with better adjusted PFS and OS in gBRCA1/2m carriers (N = 300), compared with non-PtCT (HR 0.54, 95% CI 0.4-0.73, P 0.001, and HR 0.70, 95% CI 0.49-0.99, P = 0.047, respectively). Conversely, outcomes were similar in gBRCA1/2wt patients (N = 922) treated with PtCT and non-PtCT, whatever the tumour subtype. Landmark analyses at months 3 and 6 post treatment initiation supported these results.In this pre-PARP inhibitor real-world cohort, PFS and OS were better after PtCT than non-PtCT in patients with gBRCA1/2m, but not in those with gBRCA1/2wt. These results emphasise the need of early gBRCA1/2 testing in patients with MBC.NCT03275311.

The impact of the histological lobular subtype on overall survival (OS) in metastatic breast cancer (MBC) is still under debate, with very few data available.Using the French national multicentre Epidemiological Strategy and Medico Economics [ESME]) data platform, the primary objective was to compare the OS of patients with invasive lobular carcinoma (ILC) versus invasive ductal carcinoma (IDC) MBC, with adjustment on the main prognostic factors using two approaches: multivariable analysis and matching with a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1) and describe patients and tumour characteristics.Of the 16,703 patients with MBC in the ESME database, 13,111 met all inclusion criteria for the present analysis. One-thousand eight-hundred and four (13.8%) patients had ILC and 11.307 (86.2%) IDC. In the multivariable analysis, patients with ILC had a worse OS [hazard ratio (HR): 1.31; 95%CI 1.20-1.42; p 0.0001] and a worse PFS1 (HR: 1.15; 95%CI 1.07-1.22; p 0.0001) as compared with those with IDC, independently of hormone receptor and HER2 status. Interestingly, OS was better (HR 0.79; 95% confidence interval [CI] 0.64-0.98; p = 0.0302), worse (HR: 1.17; 95%CI 1.08-1.27; p = 0.0001) or similar (HR: 0.88; 95%CI 0.67-1.15; p = 0.3455) in patients with ILC with triple-negative, hormone receptor-positive/HER2-negative and HER2-positive MBC, respectively, compared with patients with IDC.Lobular histology is an independent adverse prognostic factor among women with MBC. ILC MBC could be considered a specific entity. Dedicated prospective studies are needed to tailor the management of these patients.

IntroductionThe direction of the causal link between solid cancers and elevated plasma vitamin B12 (B12) remains uncertain.Material and methodsWe retrospectively included patients having two B12 measurements with a B12 initially ≥ 1000 ng/l and a solid cancer diagnosed between the measurements. Patients were included in the Curative or Supportive group according to their treatments.ResultsB12 changes over time differed among groups (p = 0.001): +157.4 ng/L/month in the Supportive care group versus -171.6 ng/L/month in the Curative care group.ConclusionsThe decrease of plasma B12 in cases of curative care could suggest that this B12 elevation is secondary to solid cancers.

s Introduction During the COVID-19 pandemic, teleconsultation was implemented in clinical practice to limit patient exposure to COVID-19 while monitoring their treatment and follow-up. We sought to examine the satisfaction of patients with breast cancer (BC) who underwent teleconsultations during this period. Methods Eighteen centres in France and Italy invited patients with BC who had at least one teleconsultation during the first wave of the COVID-19 pandemic to participate in a web-based survey that evaluated their satisfaction (EORTC OUT-PATSAT 35 and Telemedicine Satisfaction Questionnaire [TSQ] scores) with teleconsultation. Results Among the 1299 participants eligible for this analysis, 53% of participants were undergoing standard post-treatment follow-up while 22 and 17% were currently receiving active anticancer therapy for metastatic and localised cancers, respectively. The mean satisfaction scores were 77.4 and 73.3 for the EORTC OUT-PATSAT 35 and TSQ scores, respectively. In all, 52.6% of participants had low/no anxiety. Multivariable analysis showed that the EORTC OUT-PATSAT 35 score correlated to age, anxiety score and teleconsultation modality. The TSQ score correlated to disease status and anxiety score. Conclusion Patients with BC were satisfied with oncology teleconsultations during the COVID-19 pandemic. Teleconsultation may be an acceptable alternative follow-up modality in specific circumstances.

Elevated plasma vitamin B12 has been associated with solid cancers, based on a single B12 measurement. We evaluated the incidence of solid cancers following B12 measurement in patients with persistent elevated B12, compared to patients without elevated B12 and to patients with non-persistent elevated B12. The study population included patients with at least two plasma B12 measurements without already known elevated-B12-related causes. Patients with elevated plasma B12 (≥ 1000 ng/L) at first measurement (n = 344) were matched for age and sex with patients having 2 normal B12 measurements (

Breast cancer is the most common cancer in women worldwide. The number of childbearing-age women diagnosed with early breast cancer (eBC) is increasing, raising questions over their subsequent fertility. The main objective of this study was therefore to assess, in a cohort of eBC patients with pregnancy desire, the rate of live births achieved spontaneously or by assisted reproductive technology. We conducted an observational, descriptive, retrospective study including patients aged 18–40, treated for eBC at the Institut de Cancerologie de l’Ouest (ICO) Pays de Loire between July 2010 and July 2016, with pregnancy desire. The primary outcome was the rate of live births. Secondary outcomes were overall survival, disease-free survival, time to conception, and spontaneous or assisted pregnancy rate. 61 patients were included, with a live birth rate of 19.7% (12/61). We observed no recurrence or death in women with a pregnancy. Pregnancy started with a median time of 36.4 months after the end of treatment (4.1–51.3 months). All pregnancies in this cohort were achieved spontaneously. The results of our cohort are consistent with previous results showing that spontaneous pregnancy remains possible after treatment for eBC without increasing the risk of recurrence or death.

Background: About 40% of breast cancer cases occur in women 65 years old (yo) or older and 20% in women over 75 yo. These numbers are expected to increase in the near future. Ironically, older patients remain underrepresented in clinical trials with no improvement in the past decade, although they may present different efficacy/toxicity profiles compared with younger adults. In this context, real life cohorts may bring valuable insight to identify potential barriers to recruitment of older patients with metastatic breast cancer (MBC) in clinical trials. Methods: We used the national Epidemio-Strategy and Medical Economics (ESME) MBC Data Platform, a multi-center real life database using a retrospective data collection process in 18 French Cancer Centers. Cases selected were adult patients with MBC whose first metastasis was treated between January 1st, 2008 and December 31st, 2016. We selected MBC women over 70 yo at the time of MBC diagnosis, with at least one line of systemic treatment and no other cancer in the 5 years before MBC. The primary objective was to describe factors associated with enrollment in clinical trials in older patients, using a multivariable Cox model. Factors included in this model were age (continuous, and by class), period (2008-2011 vs 2012-2016), phenotype (ER+, HER2+, or ER- HER2-), ECOG Performance Status (PS), treatment, metastatic sites (brain, visceral, nodes/bone only) and number, and volume of hospital activity. No geriatric description could be extracted from the database. Results: There were 5846 patients ≥70yo (median age 77) and 15892 patients < 70 yo. Of the older ones, 245 (4.2%) were enrolled in a clinical trial in first line compared with 1602 (10%) for younger ones. Most of the older patients in this cohort (66%) had ER+ HER2+ disease, half had visceral metastases (< 3 metastatic sites in 82%). Median follow-up of older patients was 46.3 months; 95%CI 44.8-49.0. Cause of death was related to disease in 1155 (33.9%) older patients, and related to another cause or unknown in 2156 (63.3%), data were missing for 2441 patients. Median overall survival (OS) was 34.1 months in the older population, 95%CI 32.9-35.4, and specific overall survival was 70.8 months, 95%CI 66.3-80.0. Significant factors identified in the multivariable analysis for enrollment in 1st line treatment clinical trial ≥70 are shown in table. Volume of activity was not identified as one. By multivariate analysis, participation of older patients to a clinical trial was associated with an increased OS (HR 0.7; 95% CI 0.6-0.8) but not with a better breast cancer specific survival (HR 0.94; 95%CI 0.68-1.29). Conclusions: In this large real-life database, few older MBC patients were enrolled in a trial compared with younger ones. Factors associated with such participation to clinical research were younger age (< 80 yo), good PS, HER2+ disease, and investigational treatment consisting of chemotherapy or targeted therapy. There was a small improvement in accruing older patients between 2007-2011 and 2012-2016 (2.6% versus 5.5%). Most of these factors raise questions on drug availability and perceived potential benefits by investigators and medical teams. Accrual of older patients with cancer in other disease types should be more encouraged. VariableOR95%CIAge vs 70-75 75-80 80-85 85+0.74 0.47 0.170.54-1 0.31-0.71 0.06-0.37MBC diagnosis period vs 2008-2011 2012-20161.671.23-2.27Phenotype vs Others HER2+1.761.26-2.45PS vs 0 1 2-40.71 0.150.5-1 0.08-0.26Treatment4.88 5.253.08-7.9 3.48-8.14Chemotherapy vs others4.883.08-7.9Targeted treatment vs others5.253.48-8.14 Citation Format: Michael Bringuier, Matthieu Carton, Christelle Levy, Anne Patsouris, David Pasquier, Marc Debled, Olivier Rigal, William Jacot, Anthony Gonçalves, Isabelle Desmoulins, Thibault De La Motte Rouge, Thomas Bachelot, Jean-Marc Ferrero, Jean-Christophe Eymard, Florence Dalenc, Marie-Ange Mouret-Reynier, Thierry Petit, Michael Chevrot, Coralie Courtinard, Lionel Uwer, Jean-Sebastien Frenel, Capucine Baldini. Enrollment of older metastatic breast cancer patients in clinical trials [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 PS7-46.

Background : Triple negative breast cancer (TNBC) represents 10-17 % of all diagnosed early breast cancers, occurs more frequently in young women (< 50 years old) and has a poor prognosis. TNBC remains a clinical and therapeutic challenge dealing with a paradox: a high-risk of metastatic relapse despite a high rate of clinical and histological response after neoadjuvant chemotherapy with contrasting but disappointing results of targeted therapies. However, TNBCs are treated as a single entity and due to their phenotypic heterogeneity and various molecular pathogenesis, this subtype has a very different profile in terms of prognosis and response to treatment. Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18FDG) is gaining importance for the staging of patients with large or locally advanced breast cancer. TNBCs often show high 18FDG uptake and several studies demonstrate correlations between standard uptake value (SUV) and histoprognostic factors such as grade or KI67%. Recently, a new approach is growing interest in medical imaging: textural analysis. Some studies have shown correlations between metabolic parameters with overall survival (OS) and disease free survival (DFS) in other carcinoma, such as lung and head-and-neck cancers. Few studies analyzed textural features with potentially promising prognostic value that has to be confirmed. The objective of this study is to evaluate the association between metabolic and textural parameters measured at the initial 18FDG-PET/CT, disease-free survival (DFS) and overall survival (OS) in patients with non-metastatic TBNC. Patients and Methods: All consecutive non-metastatic TNBC women who underwent 18FDG-PET/CT at diagnosis between 2012 and 2018 were retrospectively included. Metabolic parameters (SUVmax, SUVmean, SUVpeak, MTV, TLG) in the primary tumor and lymph nodes and textural features (entropy, homogeneity, SRE, LRE, LGZE, HGZE) in the primary tumor were collected. Regression models were used to assess the correlations between PET parameters and histoprognostic factors. Cox regression models were computed to identify association with DFS and OS. Results : One hundred and eleven patients were enrolled. The median follow-up was 53.6 months. Thirty-six patients experienced relapse and 20 died. Homogeneity was associated with no axillary lymph node involvement and lower grade. Entropy was associated with higher grade, lymph node involvement and inflammatory tumors. SRE was only associated with higher grade. TLG and MTV were highly correlated (r =0.98, 95%CI = 0.97-0.99). TLG, MTV and Entropy of the primary tumor were associated with lower DFS (p = 0.008, p = 0.006, and p = 0.025, respectively) and lower OS (p = 0.002, p = 0.001 and p = 0.046, respectively). In the 50 patients with positive PET axillary lymph nodes, all metabolic parameters except SUVmean were correlated with DFS whereas no correlation was seen with OS. Conclusion: Textural associated with metabolic features of baseline 18FDG-PET/CT add prognosis value interesting to identify high risk group of relapse in early TNBC patients. Citation Format: Clément Bouron, Clara Mathie, Valérie Seegers, Camille Guillerminet, Mario Campone, Olivier Morel, Pascal Jézéquel, Anne Patsouris, Aude Testard. Prognostic value of textural associated with metabolic parameters of baseline 18FDG-PET/CT in early triple-negative breast cancer (TNBC) [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 PS3-19.

CONTEXT: Endocrine therapy combined with CDK4/6 inhibitor is the standard frontline treatment for the vast majority of HR+/HER2- MBC patients. Despite an overall survival benefit, patients eventually progress and mechanisms of resistance to this combination are not well identified. METHODS: EPICURE is an ongoing pilot prospective cohort study of heterogeneous and massive data integration, ie. multi-omics approach in MBC patients. The present study aims at identifying progression markers in patients with HR+/HER2- MBC receiving frontline endocrine therapy+iCDK4/6 by means of transcriptomics, genomics and proteomics data. All patients had a tumor biopsy at the entry in the study (B1) and a biopsy was repeated at progression if feasible (B2). Transcriptomic (RNAseq: NextSeq550, Illumina), genomic (whole exome sequencing: NextSeq550, Illumina) and proteomic (DIA mass spectrometry: TimsTOFPro2, Bruker) were performed on B1 and B2 according to available tumor tissue. RESULTS: Fifty-one patients matching inclusion criteria were included. B1 was done at inclusion for all patients (B1) (n = 51) and B2 was performed in 8 patients. (B2) (n = 8). Eight metastatic sites were biopsied: node (n = 17); liver (n = 16); bone (n = 8); breast local recurrence (n = 5); chest wall (n = 5); skin (n = 4); pleural (n = 3); ovary (n = 1). Transcriptomic, genomic and proteomic analysis of paired biopsies (B1 and B2) was performed in parallel and separately for 8, 7 and 2 patients, respectively. Exploratory data analysis of transcriptomic and proteomic data showed that liver biopsies clustered together. In order to eliminate this anatomic bias, specific genes and proteins of liver metastases were identified by means of DESeq2 analysis (12 liver vs 39 other sites) for transcriptomic data (n = 2654) and LIMMA (4 liver vs 14 other sites) for proteomic data (n = 227), and excluded for the rest of the analysis. Differential analyses (ie. gene expression, non-synonymous mutations and protein expression) between B1 and B2 were performed for each patient. These three kind of lists were finally submitted to ToppGene, DAVID and GOrilla for Gene Ontology terms enrichment analyses. Transcriptomic analyses of the 8 paired biopsies highlighted immune response (IR) in seven B1, IR in four B2 and neurogenesis in three B2. Genomics data evaluation between B1 and B2 pointed out “transposon integration” as an important pathway. Proteomic data of the 2 paired biopsies analysed underlined high immune response in B1, and muscle development/contraction and response to tumor necrosis factor in B2 for one patient. For the second one, liver metabolism in B1 and extracellular matrix and p38 MAPK cascade were emphasised. CONCLUSION: This preliminary study based on transcriptomic, genomic and proteomic data represents an encouraging first step of the EPICURE project. In a near future, additional paired biopsies and other kinds of omics data (epigenetics, radiomics, microbiomics, exposomics) will be available. Furthermore, omics data will be analysed in an integrated manner (ie. artificial intelligence), which will make it possible to detect synergies across the different omics data. Citation Format: Jean Sebastien FRENEL, Fadoua Ben Azzouz, Frederic Bigot, Jonathan Dauve, Marie Francoise Heymann, Wilfried Gouraud, Catherine Guette, Hamza Lasla, Bertrand Michel, Alain Morel, Anne Patsouris, Marie Robert, Grégoire Siekaniec, Mathilde Colombie, Pascal Jézéquel, Mario Campone. Multi-omics approach to identify markers of resistance to endocrine therapy + CDK4/6 inhibitors in first line HR+/HER2- metastatic breast cancer (MBC) patients. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-37.

Background: Breast cancer (BC) in young women merits a specific approach given the associated fertility, genetic and psychosocial issues. De novo metastatic breast cancer (MBC) in young women is an even more serious condition, with limited data available. Methods: We evaluated management of women aged ⩽40 years with de novo MBC in a real-life national multicentre cohort of 22,463 patients treated between 2008 and 2016 (NCT0327531). Our primary objective was to compare overall survival (OS) in young women versus women aged 41–69 years. The secondary objectives were to compare first-line progression-free survival (PFS1) and to describe treatment patterns. Results: Of the 4524 women included, 598 (13%) were ⩽40 years. Median age at MBC diagnosis was 36 years (range = 20–40). Compared with women aged 41–69 years, young women had more grade III tumours (49% versus 35.7%, p Conclusion: De novo MBC affects a significant proportion of young women. A subgroup of these patients achieves long OS and merits multidisciplinary care.

Le cancer du sein est le plus frequent et la premiere cause de mortalite par cancer chez la femme. En cas de presentation locoregionale, l’objectif therapeutique est curatif, mais en presence de metastases, le traitement vise a prolonger la survie, tout en conservant la qualite de vie. L’orientation therapeutique est determinee en fonction du profil phenotypique de la tumeur.

Background: Bone-only (BO) metastatic breast cancer (MBC), defined as bone as unique site of metastasis at MBC diagnosis, is thought to carry a better prognosis among MBC. However, only small retrospective series and data from selected randomized controlled trials have been reported so far. Based on a national database, we aimed at providing a large comprehensive analysis of BO MBC, and at evaluating its impact on clinical outcome. Methods: The ESME MBC platform (NCT03275311) is a French multicenter retrospective real-life database using a clinical trial-like methodology to collect data from 18 French Comprehensive Cancer Centers. It includes data from each newly diagnosed MBC patient having initiated at least one treatment between 2008 and 2016. BO cases occurring in women were retrieved and compared to the overall non-BO population, regarding treatment effects and survival. Results: Of the 22,463 women selected in the database, 5,041 (22.4%) patients with BO disease were identified. Most (N=4,102, 81.4%) had HR+/HER2- disease while 644 (12.8%) and 295 (5.9%) patients had HER2+ or HR-/HER2- disease, respectively. Compared to non-BO MBC, BO MBC patients were older in the global cohort and in HR-/HER2- patients (mean age 61.0y versus 59.5y, and 59.3y vs 56.4y, all p Conclusion: This large comprehensive study is the largest cohort of BO MBC to date. BO MBC has a distinct presentation from non-BO MBC and carry a better prognosis compared to non-BO MBC. A significant proportion of BO MBC patients have a very long survival and may benefit from aggressive local therapy, as stereotactic radiotherapy. Dedicated studies are warranted to tailor the management of these patients. Funding: This work was supported by UNICANCER. The ESME MBC database is supported by an industrial consortium (Roche, Pfizer, AstraZeneca, MSD, Eisai and Daiichi Sankyo). Data collection, analyses and publications are totally managed by R&D UNICANCER independently of the industrial consortium. TableBOBOBOBOnon-BOnon-BOnon-BOnon-BON (%)median OS monthsmedian PFS1 months5-year OS rate %N (%)median OS monthsmedian PFS1 months5-year OS rate %(95% CI)(95% CI)(95% CI)(95% CI)(95% CI)(95% CI)Overall population5,041 (100%)52.1 (50.3-54.1) 13.1 (12.6-13.8) 43.41 (41.66-45.15)15,054 (100%)34.7 (34.0-35.6) 8.5 (8.3-8.7) 30.55 (29.62-31.48)HR+/HER-4,102 (81.4%)52.6 (50.5-54.8)13.6 (13.0-14.3)43.52 (41.56-45.46)9,127 (60.6%) 39.0 (37.8-40.1)9.6 (9.3-9.9)32.69 (31.47-33.93)HER2+644 (12.8%)66.4 (59.8-71.9) 14.9 (12.9-17.3) 54.49 (49.54-59.16)3,265 (21.7%) 46.5 (44.2-48.9)10.6 (10.1-11.3)39.88 (37.77-41.98)HR-/HER2-295 (5.9%)20.8 (18.3-27.4) 5.6 (4.9-7.5)16.21 (11.21-22.02)2,662 (17.7%) 14.3 (13.6-15.1)4.8 (4.6-5.0)10.89 (9.4-12.5)De novo MBC patients1,909 (37.9%)58.6 (55.4-62.1)17.9 (17.0-18.9)48.24 (45.28-51.14)4,399 (29.2%) ---Relapsed MBC patients3,132 (62.1%)48.3 (46.5-50.5)10.7 (10.2-11.2)40.51 (38.34-42.67)10,655 (70.8%)--- Citation Format: Marion Bertho, Julien Fraisse, Anne Patsouris, Paul Cottu, Suzette Delaloge, David Pérol, Anne Jaffré, Anthony Goncalves, Marie-Paule Lebitasy, Véronique D'Hondt, Florence Dalenc, Jean-Marc Ferrero, Christelle Levy, Patrick Arveux, Roman Rouzier, Frédérique Penault-Llorca, Lionel Uwer, Jean-Christophe Eymard, Mathias Breton, Michaël Chevrot, Marianne Leheurteur, Michel Velten, Gaëtane Simon, Jean-Sébastien Frenel. Impact of bone-only metastatic breast cancer on outcome in a real-life setting: A comprehensive analysis of 5,041 women from the ESME database [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 P2-19-01.

(1) Background: triple-negative breast cancer (TNBC) remains a clinical and therapeutic challenge primarily affecting young women with poor prognosis. TNBC is currently treated as a single entity but presents a very diverse profile in terms of prognosis and response to treatment. Positron emission tomography/computed tomography (PET/CT) with

Background: Breast cancer (BC) in young women merits a specific approach given the associated fertility, genetic and psychosocial issues. De novo metastatic breast cancer (MBC) in young women is an even more serious condition, with limited data available. Methods: We evaluated management of women aged ⩽40 years with de novo MBC in a real-life national multicentre cohort of 22,463 patients treated between 2008 and 2016 (NCT0327531). Our primary objective was to compare overall survival (OS) in young women versus women aged 41–69 years. The secondary objectives were to compare first-line progression-free survival (PFS1) and to describe treatment patterns. Results: Of the 4524 women included, 598 (13%) were ⩽40 years. Median age at MBC diagnosis was 36 years (range = 20–40). Compared with women aged 41–69 years, young women had more grade III tumours (49% versus 35.7%, p

Purpose: Older cancer patients are underrepresented in clinical trials. We aimed to understand barriers to clinical trial recruitment in women aged 70 years old (yo) or over with metastatic breast cancer (MBC).Methods: We used the national Epidemio-Strategy and Medical Economics MBC Data Platform, a French multi-center real life database. We selected MBC women over 70yo, without central nervous system metastases, with at least one line of systemic treatment, between January 1st, 2008 and December 31st, 2016, and had no other cancer in the 5 years before MBC. The primary objective was to evaluate the proportion of patients enrolled in clinical trials according to their age. Secondary objective was to identify variables associated with enrollment.Results: 5552 women were aged ≥ 70 (median 74yo; IQR72-77). 14611 were less than 70. Of the older ones, 239 (4%) were enrolled in a clinical trial during first line of treatment, compared with 1529 (10.5%) for younger ones. Multivariable analysis of variables predicting for enrollment during first line of treatment in older patients were younger age (OR 0.50 [95%CI; 0.33-0.76] for the 80-85yo class; OR 0.17 [95%CI; 0.06-0.39] for the 85yo and more class), good ECOG Performance Status (PS 0-1) (OR 0.15 [95%CI; 0.08-0.27] for the PS 2-4 class), HER2+ disease (OR 1.78 [95%CI; 1.27-2.48]), type of treatment (chemotherapy/targeted therapy/immunotherapy OR 5.01 [95%CI; 3.13-8.18]), and period (OR 1.65 [95%CI; 1.22–2.26] for 2012-2016, compared to 2008-2011).Conclusions: In this large database, few older MBC patients were enrolled in a trial compared with younger ones.

Background Breast cancer may present genomic alterations leading to homologous recombination deficiency (HRD). PARP inhibitors have proven their efficacy in patients with HER2-negative (HER2-) metastatic breast cancer (mBC) harbouring germline (g) BRCA1/2 mutations in 3 phases III trials. The single-arm phase II RUBY trial included 42 patients, 40 of whom received at least one dose of rucaparib. RUBY study assessed the efficacy of rucaparib in HER2-mBC with either high genomic loss of heterozygosity (LOH) score or non-germline BRCA1/2 mutation. Patients and methods The primary objective was the clinical benefit rate (CBR), and the study was powered to see 20% CBR using a 2-stage Simon design. Results The primary-end point was not reached with a CBR of 13.5%. Two LOH-high patients, without somatic BRCA1/2 mutation, presented a complete and durable response (12 and 28.5 months). Whole-genome analysis was performed on 24 samples, including 5 patients who presented a clinical benefit from rucaparib. HRDetect tended to be associated with response to rucaparib, without reaching statistical significance (median HRDetect responders versus non-responders: 0.465 versus 0.040; p = 0.2135). Finally, 220 of 711 patients with mBC screened for LOH upstream from RUBY presented a high LOH score associated with a higher likelihood of death (hazard ratio = 1.39; 95% CI: 1.11–1.75; p = 0.005). Conclusion Our data suggest that a small subset of patients with high LOH scores without germline BRCA1/2 mutation could derive benefit from PARP inhibitors. However, the RUBY study underlines the need to develop additional biomarkers to identify selectively potential responders.

Aim of the study To evaluate correlation between metabolic and textural parameters on baseline 18F-FDG PET/CT and pathological response after neoadjuvant chemotherapy in non-metastatic triple negative breast cancer (TNBC). Methods All consecutive non-metastatic TNBC women treated by neoadjuvant chemotherapy followed by breast surgery who underwent 18F-FDG PET/CT examination at diagnosis between 2012 and 2018 were retrospectively included. Metabolic parameters (SUVmax, SUVmean, SUVpeak, MTV, TLG) of the primary tumour and lymph nodes, and textural features (entropy, homogeneity, SRE, LRE, LGZE, HGZE) of the primary tumour were collected. Pathological response was defined according to Sataloff classification. Results Seventy-four patients were enrolled. In univariate analysis, metabolic and textural features of the primary breast lesion or metabolic parameters of regional lymph nodes were not predictive of pathological complete response after neoadjuvant chemotherapy. Conclusion Metabolic and textural features of baseline PET/CT do not seem to predict pathological response after neoadjuvant chemotherapy in non-metastatic triple negative breast cancer.

Introduction: Pertuzumab, a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2), inhibits the heterodimerization of HER2 with other HER receptors. It has been approved both by the Food and Drug Administration and the European Medicine Agency in the metastatic, neoadjuvant and adjuvant setting.Areas covered: This review analyses and discusses preclinical and clinical studies of pertuzumab in breast cancer. In this article, we review the status of pertuzumab, the completed and ongoing trials, and its safety.Expert opinion: Pertuzumab is a key drug for the treatment of HER2-positive metastatic or early breast cancer. However, it is imperative to identify patients that will need dual-targeting and mechanisms of resistance. Moreover, the value of pertuzumab beyond progression needs to be evaluated.

INTRODUCTION The combination of cyclin-dependent kinases 4 and 6 (CDK 4 and 6) inhibitors with endocrine therapy represents a new standard of care for endocrine-receptor positive metastatic breast cancer. Currently, three compounds are approved. Abemaciclib is the latest CDK4/6 inhibitor approved by the US Food and Drug Administration in view of the results of the MONARCH1 and 2 trials. Area covered: In this article, we review the preclinical and clinical development of abemaciclib in advanced breast cancer, describing current therapeutic indications and open questions. Expert opinion: Results of phase III trials investigating abemaciclib in patients with endocrine-receptor positive metastatic breast cancer have shown a substantial improvement in progression-free-survival, with a safe and manageable toxicity profile. In order to better select patients who will more likely respond to CDK4/6 inhibitors, biomarkers need to be identified. To optimize CDK4/6 targeting, combination therapies are being tested in several ongoing trials.

International audience; Introduction: In most cases, metastatic breast cancer remains an incurable disease. A PIK3CA mutation is detected in 30-40% of all hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancers. PIK3CA activating mutations have been linked to endocrine resistance. PI3K inhibitors therefore offer promising new therapeutic options for this disease. Areas covered: This review discusses the pharmacologic properties, preclinical development, clinical efficacy, and safety profile of alpelisib, a PI3K inhibitor indicated in HR+/HER2 - PIK3CA-mutated advanced breast cancer, describing current therapeutic indication and open questions. Expert opinion: Following results of the SOLAR-1 trial, alpelisib became the first PI3K inhibitor approved by the U.S. Food and Drug Administration, in combination with fulvestrant, for postmenopausal women and men with HR+/HER2 - PIK3CA-mutated advanced breast cancer following progression on or after an endocrine-based regimen. This trial showed a substantial improvement in progression-free survival. However, given the side effects of alpelisib, the treatment decision should follow a thorough benefit-risk assessment. The BYLieve trial suggests alpelisib-fulvestrant benefit after progression on CDK 4/6 inhibitors. The identification of patients that are likely to benefit the most from PI3K inhibitors is still eagerly sought.

Background High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC). Methods The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers. Results Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m2 (range 12.1–66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2–48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02–1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect. Conclusion Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor., Highlights • This is the first large multicenter cohort reporting BMI’s effect on outcomes among patients with metastatic breast cancer. • Overweight or obese status does not negatively influence outcome of metastatic breast cancer patients, whatever the subtype. • Underweight is a strong negative independent prognostic factor on outcomes, whatever the subtype.

Background: Bone-only (BO) metastatic breast cancer (MBC) is considered a more favorable entity than other MBC presentations. However, only few retrospective series and data from selected randomized controlled trials have been reported so far. Methods: Using the French national multicenter ESME (Epidemiological Strategy and Medico Economics) Data Platform, the primary objective of our study was to compare the overall survival (OS) of patients with BO versus non-BO MBC at diagnosis, with adjustment on main prognostic factors using a propensity score. Secondary objectives were to compare first-line progression-free survival (PFS1), describe treatment patterns, and estimate factors associated with OS. Results: Out of 20,095 eligible women, 5041 (22.4%) patients had BO disease [hormone-receptor positive (HR+)/human epidermal growth-factor-receptor-2 negative (HER2−), n = 4 102/13,229 (31%); HER2+, n = 644/3909 (16.5%); HR−/HER2−, n = 295/2 957 (10%)]. BO MBC patients had a better adjusted OS compared with non-BO MBC [52.1 months (95% confidence interval (CI) 50.3–54.1) versus 34.7 months (95% CI 34.0–35.6) respectively]. The 5-year OS rate of BO MBC patients was 43.4% (95% CI 41.7–45.2). They also had a better PFS1 [13.1 months (95% CI 12.6–13.8) versus 8.5 months (95% CI 8.3–8.7), respectively]. This observation could be repeated in all subtypes. BO disease was an independent prognostic factor of OS [hazard ratio 0.68 (95% CI 0.65–0.72), p Conclusion: BO MBC patients have better outcomes compared with non-BO MBC, consistently, through all MBC subtypes.

Background In the phase III OlympiAD trial, olaparib significantly increased progression-free survival (PFS) compared with chemotherapy of physician's choice in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (mBC). The phase IIIb LUCY trial assessed the clinical effectiveness of olaparib in similar patients, in a setting reflecting clinical practice. Methods This open-label, single-arm trial of olaparib (300 mg, twice daily) enrolled patients with BRCAm, HER2-negative mBC who had received taxane and/or anthracycline in the (neo)adjuvant/metastatic setting and not more than two lines of prior chemotherapy for mBC. Patients with hormone receptor–positive mBC had progressed on at least one line of endocrine therapy in an adjuvant/metastatic setting and were unsuitable for further endocrine treatment. This interim analysis was planned after 160 PFS events. Results Of 563 patients screened, 252 patients with gBRCAm were enrolled and received at least one dose of olaparib. The median investigator-assessed PFS was 8.11 months (95% confidence interval [CI], 6.93–8.67; 166/252 events [65.9% maturity]). The investigator-assessed clinical response rate was 48.6%, and median time to first subsequent treatment or death was 9.66 months (95% CI, 8.67–11.14). The most common treatment-emergent adverse events (TEAEs; >20% patients) were nausea, anaemia, asthenia, vomiting and fatigue. Eleven patients (4.4%) discontinued treatment because of a TEAE. Grade 3 or higher TEAEs occurred in 64 patients (25.4%), including anaemia (33 patients; 13.1%). Conclusion Olaparib was clinically effective in patients with gBRCAm, HER2-negative mBC with safety outcomes consistent with previous findings. ClinicalTrials.gov identifier: NCT03286842 .

Background Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008. Patients and methods We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2−; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD). Results The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2– MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2– and TNBC cohorts, respectively, whatever YOD. Conclusion OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed., Highlights • OS of HER2+ MBC patients keeps improving over time [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. • This effect seems timely related to the release of drugs demonstrated to improve survival in clinical trials. • OS gains observed in real life among HER2+ MBC patients are at least equivalent to those observed in clinical trials. • YOD had no sustained impact on OS among patients with TNBC and luminal MBC. • The impact of CDK4/6 inhibitors cannot yet be assessed in this cohort.

Patients with metastatic breast cancer (MBC) often require inpatient palliative care (IPC). However, mounting evidence suggests age-related disparities in palliative care delivery. This study aimed to assess the cumulative incidence function (CIF) of IPC delivery, as well as the influence of age.The national ESME (Epidemio-Strategy-Medical-Economical)-MBC cohort includes consecutive MBC patients treated in 18 French Comprehensive Cancer Centres. ICD-10 palliative care coding was used for IPC identification.Our analysis included 12,375 patients, 5093 (41.2%) of whom were aged 65 or over. The median follow-up was 41.5 months (95% confidence interval [CI], 40.5-42.5). The CIF of IPC was 10.3% (95% CI, 10.2-10.4) and 24.8% (95% CI, 24.7-24.8) at 2 and 8 years, respectively. At 2 years, among triple-negative patients, young patients (65 yo) had a higher CIF of IPC than older patients after adjusting for cancer characteristics, centre and period (65+/65: β = -0.05; 95% CI, -0.08 to -0.01). Among other tumour sub-types, older patients received short-term IPC more frequently than young patients (65+/65: β = 0.02; 95% CI, 0.01 to 0.03). At 8 years, outside large centres, IPC was delivered less frequently to older patients adjusted to cancer characteristics and period (65+/65: β = -0.03; 95% CI, -0.06 to -0.01).We found a relatively low CIF of IPC and that age influenced IPC delivery. Young triple-negative and older non-triple-negative patients needed more short-term IPCs. Older patients diagnosed outside large centres received less long-term IPC. These findings highlight the need for a wider implementation of IPC facilities and for more age-specific interventions.

Background Cancer-related microangiopathic haemolytic anaemia (MAHA) is a rare but life-threatening paraneoplastic syndrome. Only single cases or small series have been reported to date. We set up a retrospective multicentre study focusing on breast cancer-related MAHA. Methods Main inclusion criteria were known diagnosis of breast cancer, presence of schistocytes and either low haptoglobin or cytopenia and absence of any causes of MAHA other than breast cancer, including gemcitabine- or bevacizumab-based treatment. Patient characteristics, treatments and outcome were retrieved from digital medical records. Results Individual data from 54 patients with breast cancer-related MAHA were obtained from 7 centres. Twenty-three (44%) patients had a breast tumour with lobular features, and most primary tumours were low grade (grade I/II, N = 39, 75%). ER+/HER2−, HER2+ and triple-negative phenotypes accounted for N = 33 (69%), N = 7 (15%) and N = 8 (17%) cases, respectively. All patients had stage IV cancer at the time of MAHA diagnosis. Median overall survival (OS) was 28 days (range 0–1035; Q1:10, Q3:186). Independent prognostic factors for early death (≤ 28 days) were PS > 2 (OR = 7.0 [1.6; 31.8]), elevated bilirubin (OR = 6.9 [1.1; 42.6]), haemoglobin Conclusions Breast cancer-related MAHA appears to be a new feature of invasive lobular breast carcinoma. Prognostic factors and scores may guide clinical decision-making in this serious but not always fatal condition.

Aim Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC). Methods Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients’ characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2−, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours. Results The median OS of the whole cohort was 39.5 months (95% confidence interval [CI], 38.7–40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p Conclusions The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients. Database registration clinicaltrials.gov Identifier NCT032753.

International audience; no abstract

Background: Estrogen positive/HER2 negative (ER+/HER2-) early (e) breast carcinoma (BC) is an heterogeneous entity, on the prognostic and predictive plan. Several prognostic multigene tests have been developed to identify patients in whom chemotherapy could be safely avoided. Proteomic is a complementary approach as variations in mRNA expression only account for ≈40% of the tumor-encoded protein range and it is taking into account, as other OMICs the tumoral microenvironment Sequential Windowed Acquisition of All Theoretical fragment (SWATH-MS) proteomic approach let an accurate and reproducible label-free quantification of large proteome. To our knowledge, no study has been conducted in a large cohort of luminal BC by SWATH-MS. The aim of this study was to establish a proteomic cartography of ER+/HER2- eBC and identify prognostic biomarkers. Methods: Frozen primary tumors were collected from 157 ER+/HER2- eBC treated in the ICO cancer center between 2006 and 2009. Patients were included if they fulfilled the following criteria: 1) ductal carcinoma; 2) unilateral; 3) first occurrence; 4) have received adjuvant chemotherapy. Clinicopathologic characteristics as outcomes were collected. Each sample was analyzed using SWATH-MS acquisition method as previously described (Aebersold et al, 2012). Peak extraction of the SWATH data was performed using either the Spectronaut software (ver 8.0, Biognosys, Switzerland). Peptide identification results were filtered with a q-value of < 1%. We performed clustering analysis (fuzzy clustering method) based on the 15% of most variant proteins. Functional annotation of clusters based on GO biological process terms enrichment (GOEA) was performed by means of ToppGene and GORILLA web tools. Results: The median of follow-up was 8.34 years. Respectively 32, 4 and 7 patients presented a metastatic, locoregional and controlateral recurrence. 684 among 4555 proteins represented the 15% of most variants proteins.Two ER+/HER2- eBC clusters were identified (C1 [23%] and C2 [77%]) by means of fuzzy clustering and GOEA. Two significant clinicopathological differences were observed between the two subgroups: more unifocal tumors in C1 (P = 0.0415) and mostly a clear better outcome in term of Disease Free Survival (DFS), Distant DFS (DDFS) and Overall survival (OS) in patients belonging to C2 (cf table 1). Functional annotation found that C1 was characterized by mRNA processing and protein synthesis (GO:0006396: RNA processing; GO:0008380: RNA splicing; GO:0016071: mRNA metabolic process; GO:0022613: ribonucleoprotein complex biogenesis), and C2 by a high immune response (GO:0002757: immune response-activating signal transduction; GO:0050778: positive regulation of immune response; GO:0002253: activation of immune response; GO:0050776: regulation of immune response). Differential protein expression according to the C1-C2 clusters will be presented at the meeting. Conclusion: Proteomic cartography by SWATH-MS can clearly distinguish two ER+/HER2- eBC subgroups with clear different prognosis with a better outcome for C2 patients compared to C1 patients. High immune response observed in C2 could underlie this difference with results that must be confirmed on external cohort. Nevertheless this approach could be considered as a complementary approach, helpful for clinical decision for administration of adjuvant treatment. All (n=157)Cluster 1 (n = 36)Cluster 2 (n = 121)PDisease-free survival72%55.5%77.6%0.0016Distant disease-free survival79.6%66.6%83.4%0.0063Overall survival81%61%87%0.0009Specific overall survival86%69%91%0.0012 Citation Format: Anne Patsouris, Hamza Lasla, Pascal Jézéquel, Philippe Juin, Alice Boissard, Cécile Henry, Mario Campone, Catherine Guette. High immune response identified as a good prognostic factor by proteomic SWATH-MS approach in 157 ER+/HER2- early breast cancer [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 P4-06-11.

Background: to determine the distribution and evolution of mutational processes in metastatic breast cancers (mBC), together with their clinical relevance Methods: Whole exome sequencing (Hi-Seq, Illumina) and determination of copy number alterations (CNA) (CGH array / SNP6.0) were performed in 240 and 692 metastatic breast cancers respectively. Mutational processes were defined according to Alexandrov (Nature, 2013). Homologous Recombination Deficiency (HRD) was determined by genome wide assessment of loss-of-heteroygosity (LOH) on SNP6.0 (n = 210). Finally, genomic instability was assessed by the % of genome altered assessed by CGH / SNP6.0 Results: Whole exome sequencing showed that HR+/Her2- metastatic breast cancer presented an increased contribution of APOBEC-related signatures, as compared to early breast cancer (TCGA) (58% of the mutations vs 31%, p < 0.0001). Twelve percent of the HR+/Her2- mBC acquired an hypermutator genotype ( > 200 non-synonymous mutations). This acquisition of an hypermutator genotype was confirmed in five paired primary-metastatic samples. An operational APOBEC-related signature 13 was associated with a poor outcome in a multivariate analysis (HR: 1.75, 95%CI: 1.1-2.7, p = 0.017). High LOH score (HRD) was observed in 30% of HR+/Her2- mBC as compared to 13% of early HR+/Her2- early BC (p < 0.0001). The opposite was observed in TNBC (43% in mTNBC versus 58% in early TNBC ,p = 0.032). High LOH score was associated with a trend for poor outcome in HR+/Her2- mBC (multivariate 1.67, 95%CI: 0.949-2.951, p = 0.075).The % of genome altered was associated with a poor outcome in multivariate analyses both in the overall and HR+/Her2- mBC (HR / 10 increase:1.144, 95%CI:1.038-1.261, p = 0.007 and HR:1.18, 95%CI:1.037-1.344, p = 0.012 respectively). Copy number analyses identified 143 genes that are more frequently amplified as compared to early breast cancers (FDR < 0.01) Conclusions: metastatic HR+/Her2- metastatic breast cancer present an increased in APOBEC-related mutational burden and in LOH score as compared to early breast cancers. APOBEC-related signature 13 and genome instability are associated with a poor outcome and could be used in the future to better stratify metastatic breast cancer patients. Citation Format: Patsouris A, Filleron T, Jacquet A, Goncalves A, Bonnefoi H, Letourneau C, Bachelot T, Jimenez M, Andre F. Mutational processes, genome evolution and outcome in metastatic breast cancers [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 PD8-12.