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Background: In patients with metastatic breast cancer (mBC), Circulating Tumor Cells (CTC) counts have a strong prognostic impact on progression free survival (PFS) and overall survival (OS). Changes 4 weeks after the start of a new line of therapy, inform on treatment efficacy. Despite improvements in systemic treatment, metastatic BC remains mainly uncurable with alteration of health-related quality of life (HRQOL) during the course of the disease. The aim of this work was to assess impact of clinical factors and biological factors as CTC on HRQOL. Methods: The French cohort COMET is a prospective study including first line HER2 negative patients receiving weekly paclitaxel and bevacizumab according to EMA approved combination. The aim of this cohort was to evaluate clinical, biological and radiological parameters associated with patients’ outcome (CTC, CEC, serum markers, ctDNA, pharmacogenomic polymorphisms, metabolomic parameters, visceral fat assessed by initial CTscan, serum estradiol level, and quality of life). HRQOL was assessed at baseline, at every cycle until progression and then every 3 months up to death using the EORTC QLQ-C30 questionnaire and its breast cancer specific module, the EORTC QLQ-BR23. Five dimensions of HRQOL were analyzed for the primary analyses: Global health status (GHS), physical functioning (PF), Emotional functioning (EF), fatigue (FA) and pain (PA). Time until definitive deterioration (TUDD) in HRQOL was defined as the interval between inclusion and the first decrease in HRQOL score ≥ 5 compared to baseline HRQOL score with no further improvement or in case of death. CTC counts were determined using the standard CellSearch system [Menarini Silicon Biosystems]. Results: Out of 510 patients included in COMET study, 432 patients with available HRQOL data were analyzed in this study. At baseline, patients reported a mean score for GHS of 57.6 (SD=22.7), for PF of 75.8 (23.2), for EF of 62.2 (25.8), for FA of 42.2 (29.60) and for PA of 38.1 (31.5). The Median TUDDs for the 5 targeted dimensions was 10.1 months [7.5-16.9] for GHS, 6.1 months [4.1-8.9] for PF, 21.6 [18.7-31.2] for EF, 10.8 [6.2-16.6] for FA and 13.6[10.1-22.5] months for PA. CTC counts were available in 261 patients at base line and in 229 patients after 4 weeks of treatment, before second cycle of chemotherapy. CTC high count was independent of main clinical and biological characteristics except lobular subtype. We confirmed the poor outcome of patients with high CTC count at base line and after one cycle of treatment with the threshold of > 4CTC/7.5 ml of blood. Out of the 5 dimensions of HRQOL, TUDD of EF was significantly correlated with a high CTC level at base line (p=0.0262) and even more with still an elevated count of CTC after one cycle of chemotherapy(p=0.0137). There was no association of CTC with the other dimensions of HRQOL. Conclusion: This is the first study ever reporting an analysis of QoL and CTC. We observed an association of high CTC count with one component of HRQOL scale. This suggests that CTC could be complementary to clinical factors that could influence HRQOL in HER2 negative metastatic BC treated with first line chemotherapy. Citation Format: Jean-Yves Pierga, Oumar Billa, Sandrine Dabakuyo, Jérôme Lemonnier, Frédérique Berger, Olivier Trédan, William Jacot, Anthony Gonçalves, Marc Debled, Christelle Levy, Christelle Jouannaud, Marie-Ange Mouret-Reynier, Jean-Marc Ferrero, Florence Dalenc, Fatima-Zohra Toumi, Franck Bonnetain, Francois-Clement Bidard, Shufang Renault. Circulating tumor cells enumeration and Health Related Quality of Life of patients treated with first-line chemotherapy for HER2 negative 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 P4-07-24.

Background: High circulating tumor cell (CTC) count (CTChigh) is a strong adverse prognostic factor in patients with metastatic breast cancer (mBC). In the STIC CTC trial (NCT01710605), run before the introduction of CDK4/6 inhibitors for ER+/HER2- mBC, we showed that CTC count (CTC arm) was non inferior to clinician’s choice (standard arm) on progression-free survival (PFS) to guide first line treatment selection between chemotherapy (CT) and endocrine therapy (ET) (Bidard et al., JAMA Oncol 2021). Of note, patients who had treatment escalated from ET (a priori clinician choice) to CT in the CTC arm, had a significantly longer PFS. We report here overall survival (OS) results of this multicenter CTC clinical utility trial. Methods: In the CTC arm, N=377 patients had their treatment determined by baseline CTC count: CT if CTChigh (≥5 CTCs/7.5 mL, CellSearch®), ET if CTClow. In the standard arm (N=378 patients), the choice was left to the investigator: CT if clinical high risk (Clinhigh), ET if clinical low risk (Clinlow). Therefore, patients with discordant Clinlow/CTChigh or Clinhigh/CTClow profiles had their first line treatment escalated from ET (standard arm) to CT (CTC arm) or de-escalated from CT (standard arm) to ET (CTC arm), respectively. Patients with concordant Clinlow/CTClow and Clinhigh/CTChigh profiles received ET and CT in both arms, respectively. Results: Among 755 randomized patients, N=189 (25.0%) had a Clinlow/CTChigh profile, N=103 (13.6%) Clinhigh/CTClow, N=363 (48.2%) Clinlow/CTClow and N=100 (13.2%) Clinhigh/CTChigh. OS was analyzed after a median follow-up of 57 months and 382 events (50.6%). In the Clinlow/CTChigh subgroup, CT in the CTC arm led a longer OS (mOS: 51.8 months [43.3-NR]) than ET in the standard arm (35.4 months [30.4-45.4]; HR=0.53 [0.36-0.78], p=0.001). In patients Clinhigh/CTClow, no significant difference was observed whether they received CT (standard arm) or ET (CTC arm) (45.9 months [36.3-59.8] vs 49.4 months [35.4-65.4]; HR=0.88 [0.51-1.51], p=0.63). Pooling the two discordant groups (Clinlow/CTChigh or Clinhigh/CTClow), the CTC-driven strategy was superior to the clinician-driven treatment decision (HR=0.63 [0.46-0.86], p=0.02). Pooling all concordant and discordant groups together, a median OS of 45.5 (95%CI=[40.9-51.1]) and 51.3 months [46.8-55.1] was observed in the standard and CTC arms, respectively (HR=0.84 [0.69-1.03], p=0.10). Conclusions: Prognostic information brought by CTC or standard factors is discordant in 40% of patients with ER+ HER2- mBC. In case of a discordant estimate, the STIC CTC trial shows the superiority on OS of the CTC-driven treatment decision strategy. These results also suggest a possible clinical utility of CTC to adjust systemic treatment for mBC in second and later lines, after progression on CDK4/6 inhibitors. Funding:The study was funded by Institut Curie; the French National Cancer Institute (INCa), as part of the Programme de Soutien aux Techniques Innovantes Coûteuses 2011 (STIC 2011); and Menarini Silicon Biosystems (Castel Maggiore, Italy). Citation Format: Francois-Clement Bidard, Nicolas Kiavue, Catherine Alix-Panabières, Sylvain Dureau, Thomas Bachelot, Hugues Bourgeois, Anthony Gonçalves, Etienne Brain, Sylvain Ladoire, Florence Dalenc, Joseph Gligorov, Luis Teixeira, George Emile, Jean-Marc Ferrero, Delphine Loirat, Luc Cabel, Véronique Diéras, Frédérique Berger, William Jacot, Jean-Yves Pierga. GS3-09 Circulating Tumor Cells-driven choice of first line therapy for ER+ HER2- metastatic breast cancer: overall survival analysis of the randomized STIC CTC trial [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 GS3-09.

Background: Advances in screening and treatment have led to increase in breast cancer (BC) survival in recent years but prognoses for metastatic BC remain poor with poorer outcomes as health-related quality of life (HRQOL). Treatment as bevacizumab and paclitaxel for metastatic BC, although that can increase time to progression of disease, often carry toxicity and is not curative but rather palliative in intent with the goal to improve or maintain HRQOL. The aim of this work was to assess impact of clinical factors such as disease progression, toxicity on HRQOL. Methods: COMET study is a multicenter prospective single-arm cohort study in France whose main objective was to identify biological factor that could predict the clinical benefit of bevacizumab-paclitaxel combination therapy as first treatment in HER2 negative metastatic BC. HRQOL was assessed at baseline, at every cycle (every for 4 weeks) until progression and then every 3 months up to death using the EORTC QLQ-C30 questionnaire and its BC specific module, the EORTC QLQ-BR23. In this ancillary study, we targeted 5 dimensions HRQOL for the primary analyses: Global health status (GHS), physical functioning (PF), Emotional functioning (EF), fatigue (FA) and pain (PA). The primary endpoint was time until definitive deterioration (TUDD) in HRQOL scales that defined as time between inclusion and the first decrease HRQOL score ≥ 5 points compared to baseline score, with no further improvement of at least 5 points. Multivariable Cox model with time dependent covariate was performed to assess clinical factors associated with TUDD for each of the 5 target dimensions HRQOL. We performed 3 models for each dimension: model 1 including all covariate with p< 0.10 in univariable; model 2 including model 1 and adjusted on cancer subtype and model 3 included model 1 stratified by cancer subtype. P value < 0.01 were considered statistically significant. Results: Out of 510 patients included in COMET study, 432 patients with available HRQOL data were analyzed in this study. Median age at inclusion was 58 years (range: 29-83), and 24.4% of patients had triple negative tumor subtype. About 79 % of cancers were invasive ductal carcinoma and 43 % patients had least 3 metastasis sites at baseline. At baseline, patients reported a mean score for GHS of 57.6 (SD=22.7), for PF of 75.8 (23.2), for EF of 62.2 (25.8), for FA of 42.2 (29.60) and for PA of 38.1 (31.5). The Median TUDDs for the 5 targeted dimensions was 10.1 months [7.5-16.9] for GHS, 6.1 months [4.1-8.9] for PF, 21.6 [18.7-31.2] for EF, 10.8 [6.2-16.6] for FA and 13.6[10.1-22.5] months for PA. In multivariable analyses, Disease Progression was associated with TUDD of GHS (HR [99%CI] =2.4 [1.2-4.9] and TUDD of PF (2.1 [1.1-3.7]). After adjusted on cancer subtype, association persisted with TUDD of GHS (p=0.009). Performance Status was associated with TUDD of PF (1.6 [1.2-2.3]), and TUDD of Pain (1.6 [1.1-2.3]). Performance Status association with TUDD of PF continued after adjustment on cancer subtype (p=0.0003). Prior endocrine therapy was associated with TUDD of pain in patients with tumor with positive hormone receptor (HR+) (2.4 [1.2-4.7]). There was no factor associated with TUDD of EF and TUDD of FA. Conclusion: Results of this study have shown that among the 5 targeted dimensions HRQOL, Physical Functioning was deteriorated in the shortest time. Disease progression, base line performance status and prior endocrine therapy for HR+ subtype, are clinical factors that could influence HRQOL in HER2 negative metastatic BC treated with first line chemotherapy. Citation Format: Oumar Billa, Sandrine Dabakuyo, Marion Chevrier, Franck Bonnetain, Isabelle Desmoulins, William Jacot, Olivier Trédan, Marc Debled, Christelle Levy, Anthony Gonçalves, Jean-Marc Ferrero, Florence Dalenc, Christelle Jouannaud, Marie-Ange Mouret-Reynier, Mireille Mousseau, Julien Grenier, Jean-Philippe Jacquin, Fatima-Zohra Toumi, Frédérique Berger, Jérôme Lemonnier, Jean-Yves Pierga. Health related quality of life of patients treated with bevacizumab and paclitaxel as first-line treatment for HER2 negative metastatic breast cancer: impact of clinical factors [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 P4-07-54.

Background Obesity has previously been correlated with poorer survival in both early and metastatic breast cancer. Adipose tissues release proangiogenic factors such as Insulin-like Growth Factor and Vascular Endothelial Growth Factor that may ultimately promote tumor growth. CTscan can be used to measure the visceral fat area (VFA) and the subcutaneous fat area (SFA) on the same section. High VFA has been shown to independently predict poorer outcome in patients given first-line bevacizumab-based treatment for metastatic colorectal cancer and metastatic renal cell carcinoma. The prospective multicenter COMET trial included metastatic HER2 negative breast cancer patients receiving bevacizumab and paclitaxel as fist-line chemotherapy. This study was designed to identify and validate reliable factors to predict benefit of bevacizumab and allow for a more personalized use of this antiangiogenic agent. Our aim was to evaluate the prognostic value of BMI (Body Mass Index), VFA and SFA in the COMET cohort and their impact on the quality of life. Patients and Methods Out of the 510 patients included in the COMET trial from 9/2012 to 3/2016, 480 received bevacizumab and paclitaxel as first-line treatment and 360 had available CTscan data. VFA and SFA were measured retrospectively on the CTscans performed before chemotherapy initiation, at the level of the umbilicus with the patient in the supine position. ImageJ software was used to measure pixels with densities in the -190 HU to -30 HU range in order to delineate the subcutaneous and visceral compartments and to compute the cross-sectional area of each in cm2. These measurements were performed by a radiologist blinded to patients’ characteristics and outcomes. For VFA and SFA, we used a threshold at the median value. VFA and SFA levels were tested for their association with progression-free survival (PFS) and overall survival (OS). The impact on quality of life was based on the Global Health Status, the Physical functioning, the Emotional functioning, Fatigue and Pain scores. Results The mean age at inclusion was 57 years (range: 28-83). At initial diagnosis, the main histological type was invasive ductal carcinoma (n = 247, 80.7%). Most patients had received prior neoadjuvant/adjuvant chemotherapy (n = 245, 68.1%) and a large majority (95.4%) had less than 3 metastatic sites. One hundred and forty patients (46.7%) had histological grade II and 41% had grade III tumors. The majority of the patients had positive hormone receptor tumor (n = 238, 79.3 %) and 62 (20.7%) had triple-negative tumor subtype. The median BMI was 24.7 (range : 17-46). After a median follow-up of 60.6 months (95%CI, 60-61.3), median PFS was 9.5 months (95CI, 8.6-10.3). There was no significant correlation between BMI (p = 0.69), VFA (p = 0.24) or SFA (p = 0.58) and PFS in the univariate analysis. The median OS was 29.6 months (95CI, 25.9-32.4). BMI, VFA and SFA were not correlated with OS. Out of the 360 patients, 328 had available data regarding the quality of life. There was no impact of the VFA or the SFA on the different quality of life scores. Conclusions In our prospective cohort of 360 patients with metastatic breast cancer receiving bevacizumab and paclitaxel as first-line treatment, high VFA or high SFA were not associated with a poorer survival. VFA and SFA had no impact on quality of life. Citation Format: Séverine Guiu, Boris Guiu, Marion Chevrier, Oumar Billa, Christelle Levy, Olivier Trédan, Isabelle Desmoulins, Marc Debled, Jean-Marc Ferrero, Christelle Jouannaud, Anthony Gonçalves, Maria Rios, Marie-Ange Mouret-Reynier, Frédérique Berger, Fatima-Zohra TOUMI, Jérôme Lemonnier, Jean-Yves Pierga, Sandrine Dabakuyo, Sophie Gourgou. Visceral fat area as a predictive factor in metastatic HER2 negative breast cancer patients treated by first line chemotherapy with weekly paclitaxel and bevacizumab [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 P1-03-04.

ABSTRACT Background: Half of HER2-negative breast cancers (BC) show HER2-low expression. The strong efficacy of recent anti-HER2 antibody-drug conjugates (ADC) in HER2-low tumors has risen the interest of HER2-low as a proper BC subtype. Chemosensitivity and prognosis of this subtype are not clear when compared to HER2-0 tumors. We investigated the pathological complete response (pCR) and disease-free survival (DFS) rates in BC patients receiving neoadjuvant chemotherapy for HER2-low or HER2-0 tumors. Methods: Data were collected from the Institut Paoli-Calmettes European Comprehensive Cancer Center database. HER2-low tumors were defined by HER2 IHC score of 1+ or 2+ with negative FISH, and HER2-0 by IHC score of 0+. Clinicopathological characteristics, pCR (defined as [ypT0/ypTis] and [pN0sn or ypN0]) and DFS rates were compared between the two cohorts. Results: From Jan/2005 to Jun/2021, 1,111 patients receiving neoadjuvant chemotherapy were evaluable. The incidence of HER2-low was 41%, including 63% of hormone receptor (HR)-positive and 37% of HR-negative tumors (p< 0.001). In the whole population, the pCR rate was lower in HER2-low (23%) versus HER2-0 (30%) tumors (p=0.013), but this association was lost in multivariate analysis. In HR-positive patients, HER2-low negatively impacted pCR rates when compared to HER2-0 (10% vs. 16%, p=0.046), but not in HR-negatives (46% vs. 42%), and this result was maintained in multivariate analysis (OR 0.60 [95CI 0.36-1.00]; p=0.049, and OR 1.15 [95CI 0.77-1.71]; p=0.490, respectively. No correlation existed between DFS and HER2-status. Conclusion: HER2-low is associated with HR positivity. HER2 status did not impact pCR in HR-negative patients, whereas HER2-low was associated with lower pCR rate in HR-positive patients, supporting the development of anti-HER2 ADC in this setting. Citation Format: Alexandre de Nonneville, Gilles HOUVENAEGHEL, Monique Cohen, Laura SABIANI, Marie BANNIER, Frederic VIRET, Anthony Gonçalves, François BERTUCCI. Pathological complete response rate and disease-free survival after neoadjuvant chemotherapy in patients with HER2-low and HER2-0 breast cancers [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 P3-05-23.

Background: Half of HER2-negative breast cancers (BC) show HER2-low expres-sion. The strong efficacy of recent anti-HER2 antibody-drug conjugates (ADC) in HER2-low tumours has risen the interest of HER2-low as a proper BC subtype. Chemosensitivity and prognosis of this subtype are not clear when compared to HER2-0 tumours. We investigated the pathological complete response (pCR) and disease-free survival (DFS) rates in BC patients receiving neoadjuvant chemotherapy for HER2-low or HER2-0 tumours.Methods: Data were collected from the Institut Paoli-Calmettes database. HER2-low tumours were defined by HER2 IHC score of 1+ or 2+ with negative FISH, and HER2-0 by IHC score of 0. Clinicopathological characteristics, pCR (defined as [ypT0/ypTis] and [pN0sn or ypN0]) and DFS rates were compared between the two cohorts.Results: From Jan/2005 to Jun/2021, 1111 patients receiving neoadjuvant chemotherapy were evaluable. The incidence of HER2-low was 41%, including 63% of hormone receptor (HR) -positive and 37% of HR-negative tumours (p < 0.001). In the whole population, the pCR rate was lower in HER2-low (23%) versus HER2-0 (30%) tumours (p = 0.013), but this association was lost in multivariate analysis. In HR-positive patients, HER 2-low negatively impacted pCR rates when compared to HER2-0 (10% vs. 16%, p = 0.046), but not in HR-negatives (46% vs. 42%), and this result was maintained in multivariate analysis. No correlation existed between DFS and HER2-status. Conclusion: HER2-low is associated with HR positivity. HER2 status did not impact pCR in HR-negative patients, whereas HER2-low was associated with lower pCR rate in HR-positive patients. 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Introduction: Few data have been reported regarding endocrine therapy (ET) in patients with small pT1a-b ER-postive breast cancer (BC). Thus, we conducted a study to detect possible survival improvements due to ET in such patients. Methods: Our retrospective observational study included 5545 patients with pT1a-b ERpositive BC treated in 15 French centres, excluding patients with HER2-positive status, neoadjuvant chemotherapy, ER-negative status, unknown pN status or in situ BC. We estimated disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) via univariate analysis and multivariate Cox regression. Results: Most patients (80.3%: 4453) received ET and-when compared to those without ET -experienced increases of 2.5% and 3.3% in DFS and 1.9% and 4.3% in RFS after 5 and 7 years of follow-up, respectively, with little difference in OS. In Cox regression analysis, no ET was significantly associated with decreased DFS (hazard ratio, HR = 1.275, p = 0.047, 95% CI[1.003-1.620]) but not OS or RFS in all patients, while in 2363 patients with pT1ab ER-positive grade 2-3 BC, no ET was significantly associated with decreased DFS (HR = 1.502, p = 0.049, 95% CI[1.001-2.252]), but not OS (HR = 1.361, p = 0.272). ET omission was not significantly associated with decreased survival in 3047 patients with pT1a-b ER-positive grade 1 BC. Conclusion: Our results indicate that while ET provided a beneficial impact on survival to patients with pT1a-bN0 ER-positive BC-and especially in those with grade 2-3 tumours-no such impact was observed in grade 1 tumours. Consequently, ET should be discussed with these patients, particularly in those with pT1a grade 1 tumours. 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Purpose: Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non–small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. Experimental Design: We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis). Results: We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12–0.51; P < 0.0001). Conclusions: As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Antibody–drug conjugates (ADC) represent a fast-growing drug class in oncology. However, ADCs are associated with resistance, and therapies able to overcome it are of utmost importance. Recently, enfortumab vedotin-ejfv (EV) was approved in nectin-4+ metastatic urothelial cancer. We previously described PVRL4/nectin-4 as a new therapeutic target in breast cancer and produced an efficient EV-like ADC comprising a human anti–nectin-4 mAb conjugated to monomethyl auristatin-E (MMAE) named N41mab-vcMMAE. To study the consequence of the long-term treatment with this ADC, we developed a preclinical breast cancer model in mice, and report a mechanism of resistance to N41mab-vcMMAE after 9-month treatment and a way to reverse it. RNA-sequencing pointed to an upregulation in resistant tumors of ABCB1 expression, encoding the multidrug resistance protein MDR-1/P-glycoprotein (P-gp), associated with focal gene amplification and high protein expression. Sensitivity to N41mab-vcMMAE of the resistant model was restored in vitro by P-gp pharmacologic inhibitors, like tariquidar. P-gp is expressed in a variety of normal tissues. By delivering the drug to the tumor more specifically than classical chemotherapy, we hypothesized that the combined use of ADC with P-gp inhibitors might reverse resistance in vivo without toxicity. Indeed, we showed that the tariquidar/N41mab-vcMMAE combination was well tolerated and induced a rapid regression of ADC-resistant tumors in mice. In contrast, the tariquidar/docetaxel combination was toxic and poorly efficient. These results show that ABC transporter inhibitors can be safely used with ADC to reverse ADC-induced resistance and open new opportunities in the fight against multidrug resistance.

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.

Background: While studies have shown feasibility and reported preliminary evidence of utility, there is no evidence that multigene sequencing improves outcome in patients with metastatic cancer. The aim of the present study was to assess the clinical utility of multigene sequencing and DNA copy number analyses.. Methods: In SAFIR02-BREAST (NCT: 02299999) and SAFIR-PI3K (NCT: 03386162), open-label multicentric phase II randomized trials, patients were selected if they had a Her2-negative metastatic breast cancer eligible to 1st or 2nd line chemotherapy. Patients underwent a pre-treatment biopsy of metastatic disease when feasible, followed by genomic analysis by next generation sequencing and SNParray. After 6 to 8 cycles of induction chemotherapy, patients without progressive disease and presenting an actionable genomic alteration, were randomized between targeted therapies matched to genomic alterations or maintenance chemotherapy. The primary objective was to evaluate whether targeted therapies guided by genomics improves progression-free survival (PFS) as compared to maintenance chemotherapy, in a pooled analyses of SAFIR02-BREAST and SAFIR-PI3K populations. A hierarchical testing was applied. The efficacy of targeted therapies matched to genomic alterations was first tested in patients presenting an ESCAT I/II alteration (ESMO Scale of Actionability of Molecular Targets). If a p value Citation Format: Fabrice André, Anthony Gonçalves, Thomas Filleron, Florence Dalenc, Amélie Lusque, Mario Campone, Marie-Paule Sablin, Hervé Bonnefoi, Ivan Bieche, Ludovic Lacroix, Alicia Tran-Dien, Marta Jimenez, Alexandra Jacquet, Qing Wang, Etienne Rouleau, David Gentien, Isabelle Soubeyran, Alain Morel, Monica Arnedos, Thomas Bachelot. Clinical utility of molecular tumor profiling: Results from the randomized trial SAFIR02-BREAST [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS1-10.

Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA improved progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P Citation Format: Hope S. Rugo, Joanne L. Blum, A. Douglas Laird, Sara A. Hurvitz, Johannes Ettl, Lida A. Mina, Kyung-Hun Lee, Anthony Gonçalves, Rinat Yerushalmi, Young-Hyuck Im, Miguel Martin, Louis Fehrenbacher, Henri H. Roché, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Wolfgang Eiermann, Jennifer K. Litton. Identification of PD-L1+ status as a candidate predictive biomarker of response to talazoparib (TALA) in the phase 3 EMBRACA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-08.

IntroductionThe poor prognosis of ovarian carcinoma (OvC) is due to the advanced stage at diagnosis, a high risk of relapse after first-line therapies, and the lack of efficient treatments in the recurrence setting. Circulating tumor DNA (ctDNA) analysis is a promising tool to assess treatment-resistant OvC and may avoid iterative tissue biopsies. We aimed to evaluate the genomic profile of recurrent heavily pre-treated OvC.MethodsWe performed tumor panel-based sequencing as well as low-coverage whole-genome sequencing (LC-WGS) of tumor and plasma collected in patients with ovarian cancer included in the PERMED-01 trial. Whole-exome sequencing (WES) data of plasma samples were also analyzed and compared to mutation and copy number alteration (CNA) tumor profiles. The prognostic value [progression-free survival (PFS)] of these alterations was assessed in an exploratory analysis.ResultsTumor and plasma genomic analyses were done for 24 patients with heavily pretreated OvC [67% high-grade serous carcinoma (HGSC)]. Tumor mutation burden was low (median 2.04 mutations/Mb) and the most frequent mutated gene was TP53 (94% of HGSC). Tumor CNAs were frequent with a median of 50% of genome altered fraction. Plasma LC-WGS and WES detected ctDNA in 21/24 cases (88%) with a median tumor fraction of 12.7%. We observed a low correlation between plasma and tumor CNA profiles. However, this correlation was significant in cases with the highest circulating tumor fraction. Plasma genome altered fraction and plasma mutation burden (p = 0.011 and p = 0.041, respectively, log-rank tests) were associated with PFS.ConclusionsCombination of LC-WGS and WES can detect ctDNA in most pre-treated OvCs. Some ctDNA characteristics, such as genome altered fraction and plasma mutation burden, showed prognostic value. ctDNA assessment with LC-WGS may be a promising and non-expansive tool to evaluate disease evolution in this disease with high genomic instability.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02342158, identifier NCT02342158.

Recently, immune checkpoint inhibitors (ICI) have demonstrated survival benefits in triple-negative breast cancer (TNBC) patients, treated in both the advanced and the early settings.As monotherapy, ICI failed to demonstrate a superiority over chemotherapy in pretreated advanced TNBC. In the first-line setting, ICI in combination with chemotherapy have shown consistent gains in progression-free survival in programmed death-ligand 1-positive TNBC, but only pembrolizumab indisputably demonstrated a significant overall survival benefit. In early-stage TNBC patients treated with neoadjuvant chemotherapy (NAC), ICI may improve the pathological complete response (pCR) rate. In the KEYNOTE-522 trial enrolling stage II to III TNBC patients, pembrolizumab, in combination with a NAC composed of carboplatin-paclitaxel followed by anthracyclines, and continued in the adjuvant phase led to significant increases in both pCR and disease-free survival, a practice-changing result in the field. Importantly, no unexpected safety signal was observed, but the possibility of definitive ICI-related toxicities may be challenging in curable early disease.Immunotherapy is now an important component in the therapeutic management of TNBC. Unresolved issues include the best chemotherapy partners, additional biomarkers to maximize the clinical benefit, and the possible extension of its use to other breast cancer subtypes.

Background: PD-1 blockade (αPD-1) has shown limited efficacy in breast & gynecologic cancers. In other types of solid tumor, regulatory T cells (Tregs) harbouring markers of highly suppressive effector Tregs (eTregs) correlates with poor responses to PD-1 blockade, prompting combination therapy based on eTregs depletion. Yet, subsets of Tregs remain to be determined in breast & gynecologic cancers, in order to: (i) evaluate the role of eTregs in resistances to PD-1 blockade, (ii) identify the most selective target for eTregs depletion tailored to tumors context and combination strategy. Methods: We collected public single-cell RNA/TCR-sequencing data from primary tumors and metastases of Triple-Negative Breast Cancer patients (TNBC, N = 28) biopsied before and after αPD-1 (pembrolizumab). Microarray data from primary TNBC (N = 124) biopsied before and after αPD-1 were quired for association with clinical responses. Deep phenotyping of Tregs from normal breast tissues (N = 4) and primary breast tumors (N = 8) or gynecologic tumors (N = 17) was performed by mass cytometry. ALD2510 (αCD25NIB, Alderaan Biotechnology) is a novel non-IL-2 blocking Fc-optimized anti-CD25 mAb (1). αPD-1 and αCD25NIB combination was evaluated using: (i) a humanized αCD25NIB in CD34+ humanized NSG mice grafted with human TNBC cell lines, (ii) a murine surrogate of αCD25NIB in a syngeneic TNBC mouse model. Results: CD25high Tregs were accumulating in breast & gynecologic tumor tissues. In TNBC patients treated with αPD-1, fractions of CD25high Tregs were further increased. CD25high Tregs highly expressed eTregs-related molecules in primary tumors, invaded tumor-draining lymph nodes and distant metastases. Amongst the potential therapeutic targets for Treg depletion, only CD25, 4-1BB and CCR8 were largely restricted to intratumoral CD25high eTregs. Yet, CD25 was the best candidate for CD25high eTregs depletion with limited on-target off-Treg effects, as: (i) CCR8 marked a small fractions of CD25high eTregs in primary tumors and was not detected in metastasis, (ii) 4-1BB marked antigen-experienced αβCD8 T cell revigorated by PD-1 blockade, (iii) only CD25high eTregs expressed 4-1BB and CCR8, yet TCR clonotype analysis revealed that CD25high eTregs originate in part from activated CD25+ Tregs, suggesting that anti-CCR8/-4-1BB mAbs may be ineffective due to CD25high eTregs replenishment in tumors. In murine models resistant to αPD-1 alone, αCD25NIB effectively depleted intratumoral CD25high eTregs, with limited effects on peripheral Tregs, and synergized with αPD-1 by restoring a positive effector αβCD8 T cells/Tregs ratio, leading to tumor clearance without adverse effects. Conclusions: This study supports clinical evaluation of CD25high effector Tregs depletion by ALD2510 in patients with breast or gynecologic cancers resistant to PD-1 blockade. Citation Format: Stéphane FATTORI, Aude Le Roy, Jemila Houacine, Lucie Robert, Riad Abes, Laurent Gorvel, Samuel Granjeaud, Marie-Sarah Rouvière, Amira Ben Amara, Nicolas Boucherit, Carole Tarpin, Jihane Pakradouni, Emmanuelle Charafe-Jauffret, Julien Barrou, Gilles Houvenaeghel, Eric Lambaudie, François Bertucci, Philippe Rochigneux, Anthony Gonçalves, Arnaud Foussat, Anne-Sophie Chrétien, Daniel Olive. Selective depletion of regulatory T cells by ALD2510, a novel IL-2-sparing anti-CD25 antibody, synergizes with PD-1 blockade in breast and gynecologic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3239.

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 Tucatinib (TUC) is a highly selective oral tyrosine kinase inhibitor of HER2 with minimal inhibition of EGFR. It was recently approved by the FDA for patients (pts) with HER2+ metastatic breast cancer (MBC), including pts with brain metastases (BM) whose cancers have progressed on at least 1 prior anti-HER2 regimen in the metastatic setting. In the HER2CLIMB (NCT02614794) pivotal trial, pts with HER2+ MBC previously treated with trastuzumab (T), pertuzumab, and trastuzumab emtansine (T-DM1) were randomized to receive TUC or placebo in combination with T and capecitabine (C). The addition of TUC resulted in clinically meaningful and statistically significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in HER2+ MBC pts. Primary methods and outcomes have been reported previously (Murthy, NEJM 2019). Here we present an exploratory analysis describing the outcomes in the HER2CLIMB trial based on hormone receptor (HR) status. Methods Pts were randomized 2:1 to receive TUC or placebo in combination with T and C. All pts had a baseline brain MRI and randomization was stratified by presence of BM, ECOG status, and geographic region. All pts with HER2+ MBC who were positive for either or both estrogen receptor and progesterone receptor (> 1%) were assigned to the HR “positive” subgroup. Pts not meeting the above criteria were assigned to the HR “negative” subgroup. For the exploratory HR+/HR- efficacy analysis presented here, PFS per RECIST 1.1 by blinded independent central review was evaluated in the first 480 pts enrolled. OS, PFS in pts with baseline BM, and confirmed ORR in pts with measurable disease were evaluated in the total study population. P values presented for PFS are nominal. Results Overall, 612 pts were enrolled to HER2CLIMB; 370 pts (60%) had HR+ and 242 (40%) had HR- tumors. Baseline demographics and disease characteristics in HR+/HR- subgroups were generally balanced between treatment arms. In the HR+ group, there was a 42% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.58; 95% CI: 0.42, 0.80; P=0.0008); median (95% CI) PFS was 7.6 mo (7.4, 9.5) in the TUC arm vs 5.6 mo (4.3, 7.4) in the control arm. In the HR- group, there was a 46% reduction in the risk of progression or death in the TUC arm (hazard ratio: 0.54; 95% CI: 0.34, 0.86; P=0.008); median (95% CI) PFS was 8.1 mo (7.0, 11.6) in the TUC arm vs 4.2 mo (3.1, 8.6) in the control arm. In the total population, median OS was 21.7 mo vs 18.2 mo in HR+ in the TUC arm vs control arm, respectively; median OS in HR- was 31.1 mo in the TUC arm vs 14.1 mo in the control arm. In pts with BM in the HR+ group (n=166 [45%]), there was a 52% reduction in the risk of progression or death (hazard ratio: 0.48; 95% CI: 0.31, 0.75; P=0.0008); median (95% CI) PFS was 7.5 mo (5.6, 9.5) in the TUC arm vs 5.1 mo (4.1, 5.7) in the control arm, and median OS was 18.1 mo vs 12.8 mo, respectively. In pts with BM in the HR- group (n=125 [52%]), there was a 50% reduction in the risk of progression or death (hazard ratio: 0.50; 95% CI: 0.27, 0.95; P=0.03); median (95% CI) PFS was 7.8 mo (6.1, 11.6) in the TUC arm vs 5.4 mo (2.9, 8.6) in the control arm, and median OS was 18.5 mo vs 11.5 mo, respectively. In the total population, ORR was numerically higher in the TUC arm vs the control arm regardless of HR status (HR+: 37.4% [95% CI: 30.8, 44.5] vs 27.1% [95% CI: 19.0, 36.6], respectively and HR-: 45.3% [95% CI: 36.7, 54.0] vs 15.6% [95% CI: 7.8, 26.9], respectively). Conclusions Among pts with HER2+ MBC previously treated with T, pertuzumab, and T-DM1, the addition of TUC to T and C showed clinically meaningful improvements of PFS, OS, and ORR independent of HR status. Furthermore, pts with HR+ and HR- MBC with BM derived similar benefit from the addition of TUC to T and C. Citation Format: Erika Hamilton, Mattea Reinisch, Sherene Loi, Alicia Okines, Paula R. Pohlmann, Eva Harder Brix, Hugues Bourgeois, Belinda Yeo, Cheryl Aylesworth, Melody Cobleigh, Anthony Goncalves, Rebecca Moroose, Katherine H.R. Tkaczuk, Michaela Tsai, Christine Simmons, Michael Andersson, Hatem Soliman, Michelina Cairo, Lisa A. Carey, David Cameron, Jorge Ramos, Wentao Feng, Mafalda Oliveira. Tucatinib vs placebo in combination with trastuzumab and capecitabine for patients with locally advanced unresectable or HER2-positive metastatic breast cancer (HER2CLIMB): Outcomes by hormone receptor status [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 PD3-08.

Background: Triple negative breast cancer (TNBC) is an heterogeneous disease and encompasses at least 4 subtypes. One of these expresses the androgen receptor (AR). Several prospective trials demonstrated antitumour efficacy with anti-androgen treatment in patients with advanced breast cancer. Darolutamide is an androgen-receptor antagonist with a potent anti-tumour efficacy in metastatic prostate cancer with a favorable safety profile. We conducted a randomized non-comparative phase II trial to study the efficacy and tolerability of darolutamide and capecitabine in AR-positive TNBC (NCT03383679). Material and methods: Patients (Pts) with a metastatic, centrally reviewed, AR-positive (≥ 10% by immunohistochemistry) and TNBC who have received a maximum of one line of chemotherapy for advanced disease were eligible. They were randomised in a 2:1 ratio to receive darolutamide (D arm) 600 mg twice daily or capecitabine (C arm) at 1000 mg/m² twice daily 2 weeks on and 1-week off, until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) defined as the proportion of pts presenting a complete response (CR), partial response (PR), or stable disease (SD) at 16 weeks. Main secondary endpoints included objective response rate, overall survival, progression-free survival and safety. An interim statistical analysis was planned when 19 assessable pts will be available in the D arm. According to an optimal 2-stage Simon’s design,if Results: Out of 133 pts screened and centrally analyzed, from 37 centres, 54% (72/133) were AR-positive. 45 pts were randomized (29 in D arm and 16 in C arm) from April 2018 to December 2019. In arm D, median age was 60 years (range 47-88). and 13.8 % received a first line of chemotherapy for metastatic disease. A total of 19 pts were eligible and assessable for the primary endpoint in D arm. 5 CBR were confirmed at 16 weeks (26.3%; 95% CI: 9.2%-51.2 %) including 1 confirmed PR and 4 SD. In arm D, fatigue (23.8%), ASAT increased (23.8%), and blood alkaline phosphatase increased (23.8%) were the most common drug-related adverse events; the majority of them being grade 1 or 2. 6 pts presented with drug-related serious adverse events: one in D arm and 5 in C arm. Conclusions: According to the planned interim analysis, the efficacy objective is met (5 CBR) in D arm. Moreover, darolutamide is well tolerated. Thus, patients are now recruited in the second stage. Keywords: Androgen receptor,triple-negative breast cancer, darolutamide, advanced breast cancer Citation Format: Hervé Bonnefoi, Florence Lerebours, Olivier Tredan, Florence Dalenc, Christelle Levy, Mahasti Saghatchian, Marie Ange Mouret Reynier, Delphine Mollon, Severine Guiu, Laurence Venat Bouvet, Elisabeth Carola, Geraldine Martineau, Marina Pulido, Gaetan MacGrogan, Anthony Goncalves. First efficacy results of a 2-stage Simon’s design randomised phase 2 of darolutamide or capecitabine in patients with triple-negative, androgen receptor positive advanced breast cancer (UCBG06-3) [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 PS12-05.

OBJECTIVE The aim was to evaluate the impact of local surgery performed during the year following metastatic breast cancer (MBC) diagnosis on patients' outcomes from a large real-life cohort. SUMMARY BACKGROUND DATA Locoregional treatment for patients with MBC at the time of diagnosis remains debated. METHODS Women with newly diagnosed, de novo stage IV MBC and who started MBC treatment between January 2008 and December 2014 in one of the 18 French Comprehensive Cancer Centers were included (NCT03275311). The impact of local surgery performed during the first year on overall survival (OS) and progression-free survival (PFS) was evaluated by the Cox proportional hazards model in a 12 month-landmark analysis. RESULTS Out of 16,703 patients in the ESME database, 1,977 had stage IV MBC at diagnosis, were alive and progression-free at 12 months and eligible for this study. Among them, 530 (26.8%) had received primary breast cancer surgery within 12 months. A greater proportion of patients who received surgery had less than 3 metastatic sites than the no-surgery group (90.8% vs 78.2%, p < 0.0001). Surgery within 12 months was associated with treatment with chemotherapy, HER2-targeted therapy (89.1% vs 69.6%, p < 0.0001) and locoregional radiotherapy (81.7% vs 32.5%, p < 0.0001). Multivariable analyses showed that surgery performed within 12 months was associated with longer OS and PFS (adjusted HR [95%CI] = 0.75 [0.61 - 0.92] and 0.72 [0.63 - 0.83], respectively), which were also affected by pattern and number of metastatic sites, histological subtype and age. CONCLUSIONS In the large ESME cohort, surgery within one year after de novo MBC diagnosis was associated with a significantly better OS and PFS.

The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did not progress after six to eight cycles of chemotherapy. Patients (n = 199) were randomized to either durvalumab (10 mg kg−1 every 2 weeks) or maintenance chemotherapy. In the overall population, durvalumab did not improve progression-free survival (adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.00–1.96; P = 0.047) or overall survival (OS; adjusted HR: 0.84, 95% CI: 0.54–1.29; P = 0.423). In an exploratory subgroup analysis, durvalumab improved OS in patients with triple-negative breast cancer (TNBC; n = 82; HR: 0.54, 95% CI: 0.30–0.97, P = 0.0377). Exploratory analysis showed that the HR of death was 0.37 (95% CI: 0.12–1.13) for patients with PD-L1+ TNBC (n = 32) and 0.49 (95% CI: 0.18–1.34) for those with PD-L1− TNBC (n = 29). In patients with TNBC, exploratory analyses showed that the HR for durvalumab efficacy (OS) was 0.18 (95% CI: 0.05–0.71; log-rank test, P = 0.0059) in patients with CD274 gain/amplification (n = 23) and 1.12 (95% CI: 0.42–2.99; log-rank test, P = 0.8139) in patients with CD274 normal/loss (n = 32). Tumor infiltration by lymphocytes (CD8, FoxP3 and CD103 expressions) and homologous recombination deficiency did not predict sensitivity to durvalumab in exploratory analyses. This latter finding should be interpreted with caution since only one patient presented a germline BRCA mutation. The present study provides a rationale to evaluate single-agent durvalumab in maintenance therapy in patients with TNBC. Exploratory analyses identified CD274 amplification as a potential biomarker of sensitivity. Maintenance chemotherapy was more effective than durvalumab in patients with hormone receptor-positive and Her2-negative disease. Exploratory analyses from the phase 2 randomized SAFIR02-IMMUNO trial identify biomarkers associated with improved outcomes to durvalumab as compared to maintenance chemotherapy in patients with triple-negative breast cancer.

Simple Summary The goal of precision medicine is to deliver therapy matched to a relevant actionable genetic alteration (AGA) identified in the tumor. Few data are available regarding precision medicine in advanced urological cancers (AUC), the prognosis of which remains unfavorable. Sixty-four patients with refractory AUC were enrolled in the PERMED-01 clinical trial and underwent a tumor biopsy that was then profiled using sophisticated molecular analyses. The results were discussed in real-time during a weekly molecular tumor board meeting, and patients with a relevant AGA became candidates for an eventual matched therapy. A complete molecular profile was obtained in 77% of cases and an AGA was identified in 59%. Nineteen percent of patients received a matched therapy on progression, of which 42% showed a clinical benefit. The objective response, disease control rates, and the 6-year overall survival were higher in the ``matched therapy group'' than in the ``non-matched therapy group''. Introduction. The prognosis of advanced urological cancers (AUC) remains unfavorable, and few data are available regarding precision medicine. Methods: the PERMED-01 prospective clinical trial assessed the impact of molecular profiling in adults with refractory advanced solid cancer, in terms of number of patients with tumor actionable genetic alterations (AGA), feasibility, description of molecular alterations, treatment, and clinical outcome. We present here those results in the 64 patients enrolled with AUC. DNA extracted from a new tumor biopsy was profiled in real-time (targeted NGS, whole-genome array-comparative genomic hybridization), and the results were discussed during a weekly molecular tumor board meeting. Results: a complete molecular profile was obtained in 49 patients (77%). Thirty-eight (59%) had at least one AGA. Twelve (19%) received a matched therapy on progression, of which 42% had a PFS2/PFS1 ratio >= 1.3 versus 5% in the ``non-matched therapy group'' (n = 25). The objective response and disease control rates were higher in the ``matched therapy group'' (33% and 58%, respectively) than in the ``non-matched therapy group'' (13% and 22%), as was the 6-month OS (75% vs. 42%). Conclusion: the profiling of a newly biopsied tumor sample identified AGA in 59% of patients with AUC, led to ``matched therapy'' in 19%, and provided clinical benefit in 8%.

International audience; No abstract available

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.

Background: Prognosis of women with HER2+ metastatic breast cancer (MBC) has radically improved over the past 10 years, resulting from the implementation in clinical of anti-HER2 therapies. However, there are limited data regarding these trends in the older women, although they represent a growing segment of the population. Standard strategy being based mostly on combinations of anti-HER2 treatments with chemotherapy, under-treatment may be a specific issue in this population. Methods: Based on the ESME MBC Data Platform (NCT03275311),a unique national real-life database including individual data from all patients (pts) ≥18 years who initiated a first-line treatment for MBC between 2008 and 2016 in the 18 French Comprehensive Cancer Centers, the main objective of this work was the description of patients’ outcome in women with HER2+ MBC according to age: ≥70 vs Results: Of 22463 cases selected, 4045 (18%) women had HER2+ MBC with a 4.4-year median follow-up. Of those, 814 (20%) were aged ≥ 70 and had more often HR+ disease (Table 1). As 1st line treatment, anti-HER2 therapy was prescribed in 76% vs 92% of older vs younger pts, combined with chemotherapy in 65% vs 89%. Median OS and PFS (years) were 2.9 [2.6-3.1] and 0.9 [0.8 - 1.0] vs 4.5 [4.2-4.6] and 1.1 [1.1-1.2] in older vs younger patients. Multivariate analysis for OS identified the following variables as significant: age ≥ 70 (HR=1.57 IC95% [1.40-1.75]), 2 and ≥ 3 metastatic sites (HR=1.24 IC95% [1.10-1.39] and HR=1.92 IC95% [1.70-2.17] respectively), de novo MBC (HR 0.70 IC95% [0.63 - 0.77]), visceral disease with a time-varying effect (HR=2.67 IC95% [2.11-3.39] and 5.98 IC95% [4.64-7.46] at 1 and 5 years) and first-line treatment with a time-varying effect, better prognosis for combination of chemotherapy + anti-HER2 agent + endocrine therapy vs any other. Except for de novo MBC, similar results were observed for PFS. Conclusions: In this large real-life database, older HER2+ MBC patients received significantly less frequently “standard” first-line anti-HER2 treatment, defined as a combination of chemotherapy and anti-HER2 treatment. Age was a strong risk factor for both PFS and OS. Given the lack of information on geriatric assessment (e.g. general health status, functional status, comorbidity, etc.), confounding factors and usual selection biases cannot be ruled out. These results stress the importance to study older populations with specific approaches, not based on the usual transfer of those developed in younger ones, in order to avoid under and overtreatments, both that are not acceptable. Table 1: Patients’ characteristics and first-line treatment≥70 Citation Format: Mylène Annonay, Morgane Abiven, Etienne Brain, Mony Ung, Laurence Cristol-Dalstein, Marie-Ange Mouret-Reynier, Anthony Goncalves, Sophie Abadie-Lacourtoisie, Eric Francois, Claudia Lefeuvre-Plesse, Johann Le Fel, Veronique Lorgis, Veronique Servent, Lionel Uwer, Christelle Jouannaud, Marianne Leheurteur, Loic Campion, Coralie Courtinard, Olivier Villacroux, Thierry Petit, Pierre Soubeyran, Thomas Bachelot, Carine Bellera, Suzette Delaloge. Treatments and outcome in older versus younger women with HER2-positive metastatic breast cancer in the multicenter national observational 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 P1-19-19.

Background: Insulin-like growth factor receptor-1 (IGF-1R) signaling is implicated in cancer progression, prognosis, and treatment resistance. Cross-talk between IGF-1R signaling and cyclin-dependent kinase (CDK) 4 & 6 was reported in preclinical studies, and synergy was shown with concurrent inhibition of IGF-1R signaling and CDK 4 & 6. The CDK 4 & 6 inhibitor, abemaciclib, is FDA approved for hormone receptor-positive [HR+], HER2- advanced BC (ABC) in combination with an aromatase inhibitor as initial endocrine-based therapy, with fulvestrant for progression following endocrine therapy (ET), and as monotherapy for progression following ET and prior chemotherapy in the metastatic setting. NCT03099174 is a prospective, open-label study investigating the safety and tolerability of concurrent inhibition of IGF/IGF-1R signaling with the IGF-1/2-neutralizing monoclonal antibody, xentuzumab, plus abemaciclib (provided by Eli Lilly), with or without ET. Methods: 4 dose-finding cohorts were evaluated in 2 parts using a Bayesian Logistic Regression Model with overdose control, fitted to toxicity outcomes. Part 1 (Cohort A) included pts with solid tumors who had failed/were intolerant of prior treatments, or had no other option available. The starting dose was xentuzumab 1000 mg i.v. weekly plus abemaciclib 150 mg orally (p.o.) every 12 h (Q12h). Part 1 determined the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) prior to starting Part 2. Part 2 included postmenopausal women with HR+, HER2- BC who had received 0-2 prior lines of chemotherapy in the metastatic setting and were eligible for ET. One of 3 ETs was combined with xentuzumab plus abemaciclib (doses determined in Part 1): Cohort B, letrozole; Cohort C, anastrozole; Cohort D, fulvestrant. Previous CDK 4 & 6 inhibitor therapy was not permitted. Treatment was given until progression, lack of tolerability, or withdrawal. Primary endpoints were MTD and dose-limiting toxicities (DLTs) during the first 28-day cycle. Tumor response and progression-free survival (PFS) were also assessed. Results: 27 pts were treated (26 female [96.3%]; median age, 58 years [range 34-70]); 9 pts remained on treatment at the time of analysis. Cohorts A/B/C/D included 6/7/6/8 pts. Cohort A included pts with ABC (n=3), and lung cancer, sarcoma, and colorectal cancer (n=1 each). In total, 23 pts were evaluable for MTD. MTD was xentuzumab 1000 mg i.v. weekly plus abemaciclib 150 mg p.o. Q12h in Cohorts A, B, and D (Cohort C is ongoing). During Cycle 1, 4 DLTs were reported (Cohort A: grade 3 neutrophil count decrease, n=1; Cohort B: grade 3 neutrophil count decrease, n=1; Cohort C: grade 4 thrombocytopenia, n=1; Cohort D: grade 3 neutropenia, n=1). The most common drug-related AEs (DRAEs) in Cohort A were diarrhea and decreased appetite (66.7% each), and nausea, vomiting, and asthenia (50% each). The most common DRAEs in Cohorts B/C/D were diarrhea (90.5%), asthenia (66.7%), anemia (61.9%), neutropenia (57.1%), and nausea (52.4%). Most were reversible and grade 1/2. The most common grade 3/4 DRAEs were diarrhea (16.7/0%) in Cohort A, and neutropenia (19.0/14.3%) and diarrhea (14.3/0%) in Cohorts B/C/D. 4 pts had a best overall response of partial response (Cohorts A and B, n=1; Cohort D, n=2) and 10 pts had stable disease (Cohort A/B/C/D, n=1/3/1/5; duration currently Citation Format: Douglas Yee, Mafalda Oliveira, Hiroji Iwata, Anthony Gonçalves, Javier García-Corbacho, Marie Paule Sablin, Aleix Prat, Molly Catherine Hardebeck, Marta Puig, Dennis Chin-Lun Huang, Mingchi Hsu, Patricia LoRusso. A phase Ib multi-cohort study of xentuzumab and abemaciclib in patients (pts) with solid tumors and breast cancer (BC) - Initial report of four dose-finding cohorts [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 P3-11-05.

To heal otherwise in oncology has become an imperative of Public Health and an economic imperative in France. Patients can therefore receive live most of their care outside of hospital with more ambulatory care. This ambulatory shift will benefit from the digital revolution and the development of digital health or e-health. Cancer research will also benefit with Big Data and artificial intelligence, which gather and analyze a huge amount of data. In this synthesis, we describe the different e-health tools and their potential impacts in oncology, at the levels of education and information of patients and caregivers, prevention, screening and diagnosis, treatment, follow-up, and research. A few randomized studies have already demonstrated clinical benefits. Large Big Data projects such as ConSoRe and Health Data Hub have been launched in France. We also discuss the issues and limitations of "cancer outside the hospital walls and e-health" from the point of view of patients, health care professionals, health facilities and government. This new organization will have to provide remote support "outside the walls" with care and follow-up of quality, continuous and prolonged in total safety and equity. Ongoing and future randomized clinical trials will need to definitively demonstrate areas of interest, advantages and drawbacks not only for patients, but also for caregivers, health facilities and governments., Soigner autrement en Cancérologie est devenu un impératif de Santé Publique et un impératif économique en France. Aujourd’hui, les patients peuvent vivre l’essentiel de leurs soins hors des murs de l’hôpital avec une prise en charge de plus en plus ambulatoire. Ce virage ambulatoire va bénéficier de la révolution numérique et du développement de la santé numérique ou e-santé. La recherche va également en bénéficier avec le Big Data et l’intelligence artificielle qui collectent en réseau et analysent une masse de données considérable. Dans cette Synthèse, nous décrivons les différents outils d’e-santé et leurs impacts potentiels en Cancérologie aux niveaux de l’éducation et l’information des patients et soignants, la prévention, le dépistage et le diagnostic, le suivi sous traitement, la surveillance et la recherche. Quelques études randomisées ont déjà démontré le bénéfice clinique. Des gros projets de Big Data tels que ConSoRe et Health Data Hub ont été mis en place en France. Nous discutons les enjeux et les limites du « cancer hors les murs et e-santé » du point de vue des patients, des professionnels de la santé, des établissements de santé et des pouvoirs publics. Cette nouvelle organisation devra permettre un accompagnement à distance « hors des murs » assurant soins et suivi de qualité, continus et prolongés en toute sécurité et équité. Les essais cliniques randomisés en cours et futurs devront démontrer de manière définitive les domaines d’intérêt, les avantages et inconvénients non seulement pour les patients, mais également pour les soignants, les établissements de santé et les pouvoirs publics.

The number of cancer survivors is growing increasingly worldwide. The long-term negative consequences of the disease are now better known. Cancer may also foster positive outcomes. Some survivors consider life after cancer as the start of a new life and experience positive changes called post-traumatic growth (PTG) measured by a scale developed by Tedeschi and Calhoun.The purpose of this article was to explore actionable factors affecting PTG, particularly those in relation with health care management and those that reflected health behavior changes.This study included the 1,982 participants in the VICAN cohort who responded to the questionnaire on living conditions 2 and 5 years after diagnosis. Factors associated with a moderate or high PTG (score ≥ 63) were identified using logistic regressions.Factors positively associated with moderate or high PTG were being satisfied with the time spent by health care team on information (OR:1.35 [1.08;1.70]), increased physical activity (OR:1.42 [1.04;1.95]) and healthier diet (OR:1.85 [1.44;2.36]) since diagnosis, and having benefited from psychological support at diagnosis (OR:1.53 [1.16;2.01]).High PTG is positively associated with health behavior and time spent on information. Our findings suggest that appropriate clinical and educational interventions can help foster growth after the experience of cancer. Even if we do not know what causes what, it is admitted that the interventions leading to an increase of physical activity, for example, are good from all points of view.

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BackgroundCirculating tumor cells (CTCs) have a strong potential as a quasi-non-invasive tool to set up precision medicine strategy for cancer patients. Tremendous efforts have been made to develop the second-generation of “filtration-based” technologies to detect CTCs, revealing a surprising heterogeneity among those cells. Here, we performed the largest and simultaneous analysis of all atypical circulating tumor cells (aCTCs) detected with a filtration-based technology, in a cohort of metastatic breast cancer (mBC) patients, and correlated their presence with clinicopathological and survival data.MethodsThe PERMED-01 study enrolled patients with mBC refractory to systemic therapy. We prospectively analyzed aCTCs present at the time of inclusion in the study, using the Screencell®Cyto device (n=91). Subsets cut-offs were established and evaluated for correlation with clinicopathological data, including progression-free survival (PFS) and overall survival (OS).ResultsThe median number of aCTCs found in mBC was 8.3 per mL of blood. Three subsets of aCTCs, absent from controls, were observed in mBC patients: single (s-aCTCs), circulating tumor micro-emboli (CTM), and giant-aCTCs (g-aCTCs). The presence of g-aCTCs was associated with shorter PFS and OS in multivariate analyses. For 23 cases, the analysis was completed with advanced immunofluorescence staining and showed that CTM and g-aCTCs displayed a hybrid phenotype for epithelial and mesenchymal markers.ConclusionsThis study highlights the heterogeneity of aCTCs in mBC patients both at the cytomorphological and molecular levels when using a Screencell®Cyto device. It reveals the g-aCTC subset as a prognostic factor and a potential stratification tool that might help to orientate late-stage mBC patients’ therapeutic care.

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.

The phosphatidylinositol 3-kinase (PI3K) pathway is one of the most altered pathways in human cancers, and it plays a central role in cellular growth, survival, metabolism, and cellular mobility, making it a particularly interesting therapeutic target. Recently, pan-inhibitors and then selective p110α subunit inhibitors of PI3K were developed. Breast cancer is the most frequent cancer in women and, despite therapeutic progress in recent years, advanced breast cancers remain incurable and early breast cancers are at risk of relapse. Breast cancer is divided in three molecular subtypes, each with its own molecular biology. However, PI3K mutations are found in all breast cancer subtypes in three main “hotspots”. In this review, we report the results of the most recent and main ongoing studies evaluating pan-PI3K inhibitors and selective PI3K inhibitors in each breast cancer subtype. In addition, we discuss the future of their development, the various potential mechanisms of resistance to these inhibitors and the ways to circumvent them.

Background Xentuzumab—a humanised IgG1 monoclonal antibody—binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). Methods Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). Results MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3–not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7–9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57–1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05–0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). Conclusions Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). Trial registration ClinicalTrials.gov, NCT02123823. Prospectively registered, 8 March 2013.

Background The benefit of precision medicine based on relatively limited gene sets and often-archived samples remains unproven. PERMED-01 (NCT02342158) was a prospective monocentric clinical trial assessing, in adults with advanced solid cancer, the feasibility and impact of extensive molecular profiling applied to newly biopsied tumor sample and based on targeted NGS (t-NGS) of the largest gene panel to date and whole-genome array-comparative genomic hybridization (aCGH) with assessment of single-gene alterations and clinically relevant genomic scores. Methods Eligible patients with refractory cancer had one tumor lesion accessible to biopsy. Extracted tumor DNA was profiled by t-NGS and aCGH. We assessed alterations of 802 “candidate cancer” genes and global genomic scores, such as homologous recombination deficiency (HRD) score and tumor mutational burden. The primary endpoint was the number of patients with actionable genetic alterations (AGAs). Secondary endpoints herein reported included a description of patients with AGA who received a “matched therapy” and their clinical outcome, and a comparison of AGA identification with t-NGS and aCGH versus whole-exome sequencing (WES). Results Between November 2014 and September 2019, we enrolled 550 patients heavily pretreated. An exploitable complete molecular profile was obtained in 441/550 patients (80%). At least one AGA, defined in real time by our molecular tumor board, was found in 393/550 patients (71%, two-sided 90%CI 68–75%). Only 94/550 patients (17%, 95%CI 14–21) received an “AGA-matched therapy” on progression. The most frequent AGAs leading to “matched therapy” included PIK3CA mutations, KRAS mutations/amplifications, PTEN deletions/mutations, ERBB2 amplifications/mutations, and BRCA1/2 mutations. Such “matched therapy” improved by at least 1.3-fold the progression-free survival on matched therapy (PFS2) compared to PFS on prior therapy (PFS1) in 36% of cases, representing 6% of the enrolled patients. Within patients with AGA treated on progression, the use of “matched therapy” was the sole variable associated with an improved PFS2/PFS1 ratio. Objective responses were observed in 19% of patients treated with “matched therapy,” and 6-month overall survival (OS) was 62% (95%CI 52–73). In a subset of 112 metastatic breast cancers, WES did not provide benefit in term of AGA identification when compared with t-NGS/aCGH. Conclusions Extensive molecular profiling of a newly biopsied tumor sample identified AGA in most of cases, leading to delivery of a “matched therapy” in 17% of screened patients, of which 36% derived clinical benefit. WES did not seem to improve these results. Trial registration ID-RCB identifier: 2014-A00966-41; ClinicalTrials.gov identifier: NCT02342158.

International audience; Background: Hormone-resistant HER2-negative or triple-negative advanced breast cancers (ABC) are routinely treated with paclitaxel chemotherapy. LY2780301 is a dual inhibitor of p70 ribosomal protein S6 kinase and AKT. The TAKTIC study aimed at exploring the combination of paclitaxel and LY2780301 in this population.Methods: In this multicentric phase Ib/II trial, we enrolled patients with HER2-negative ABC, with (phase IB) or without (phase II) prior to cytotoxic treatment for advanced disease. Oral LY2780301 was administered once daily in combination with intravenous weekly paclitaxel. Primary endpoints were to determine the recommended phase II dose (RP2D) of the combination of LY2780301 with weekly paclitaxel (phase Ib), and to estimate a 6 months objective response rate (ORR) (phase II) in patients with HER2-negative ABC, both in the overall patient population and in cases with activation of the PI3K/AKT pathway (PI3KAKT+).Results: A total of 51 patients were enrolled; RP2D was LY2780301 500 mg QD+ paclitaxel 80 mg/m2. Main drug-related adverse events noted in phase Ib included neuropathy (75% of patients, grade 3-4 in 8%), asthenia (58% of patients, no grade 3-4), and ungual toxicity (50% of patients, grade 3-4 in 25%). They were similar in the phase II part, except that 14% of patients experienced pneumonia (grade 3-4 in 6%). In the phase II part, 6-month ORR in the overall population and in PI3KAKT+ subgroup were, respectively, 63.9% [48.8-76.8] and 55% [35-73.7].Conclusion: Combining LY2780301 and weekly paclitaxel in patients with HER2-negative ABC was feasible with preliminary evidence of efficacy in both the overall population and the PI3KAKT+ subgroup.Trial registration id: NCT01980277.

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.

PURPOSE: A major question when treating HR+/HER2- metastatic breast cancer (MBC) is whether early introduction of chemotherapy (CT) increases endocrine resistance. We aimed to describe progression-free survival (PFS) under first endocrine therapy (ET) depending on whether given before or after CT in a large nationwide cohort, in the pre-CDK era. METHODS: The real-life retrospective ESME database includes all patients with MBC whose first-line treatment was initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. Our primary objective was to compare PFS from start of first ET in patients with HR+/HER2- MBC who received ET or CT first. RESULTS: We identified 6293 patients who received at least one ET line during their first two therapeutic lines for MBC. As first-line therapy, 3832 (60.9%) received ET alone (ET1 1st group), whilst 2461 (39.1%) received CT, including 2024 patients (32.2%) with maintenance ET after CT (ET1 after CT group). Median PFS under first ET was 12.4 months (95% CI 11.9-13.1) in ET 1st group vs. 12.6 months in ET1 after CT group (95% CI 12.1-13.4), HR 0.96 (95% CI 0.90-1.01, P = 0.1277). CONCLUSIONS: PFS under first ET appears identical whether prescribed before or after chemotherapy. These data suggest chemotherapy does not promote endocrine resistance.

International audience; We developed a high spatial resolution and sensitive detector particularly suitable for radiation dose measurements in radiotherapy at small fields and X-ray imaging applications. The detector is based on a silica optical fiber whose sensitive terminal is functionalized by grafting Ag-doped ZnS scintillating materials that emit blue luminescence under X-ray irradiation. Due to the small scintillating head of the detector, the acquisition signal is quite low, and it is measured by a sensitive photon counter plugged at the other terminal of the fiber. The weaker signal can be enhanced significantly by adding a metal coating over the scintillator. Therefore, this study presents the effect of metal thickness and density on the signal amplification at high irradiation energies of 6 MeV and 15 MeV using a Linear Accelerator (LINAC). In addition, the stem effect was characterized for regular to small field beam size and shows that the detector is almost free from stem contribution during high energy irradiation.

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.

International audience; Background. Anti-PD1/PDL1 immune checkpoint inhibitors (ICIs) showed promising results in breast cancer, and exploration of additional actionable immune checkpoints is ongoing. Inflammatory breast cancer (IBC) is an aggressive form of disease, the immune tumor microenvironment (TME) of which is poorly known. We aimed at providing the first comprehensive immune portrait of IBCs. Methods. From the gene expression profiles of 137 IBC and 252 non-IBC clinical samples, we measured the fractions of 22 immune cell types, expression of signatures associated with tertiary lymphoid structures (TLS) and with the response to ICIs (T cell-inflamed signature: TIS) and of 18 genes coding for major actionable immune checkpoints. The IBC/non-IBC comparison was adjusted upon the clinicopathological variables. Results. The immune profiles of IBCs were heterogeneous. CIBERSORT analysis showed profiles rich in macrophages, CD8+ and CD4 + T-cells, with remarkable similarity with melanoma TME. The comparison with non-IBCs showed significant enrichment in M1 macrophages, γδ T-cells, and memory B-cells. IBCs showed higher expression of TLS and TIS signatures. The TIS signature displayed values in IBCs close to those observed in other cancers sensitive to ICIs. Two-thirds of actionable immune genes (HAVCR2/TIM3, CD27, CD70, CTLA4, ICOS, IDO1, LAG3, PDCD1, TNFRSF9, PVRIG, CD274/PDL1, and TIGIT) were overexpressed in IBCs as compared to normal breast and two-thirds were overexpressed in IBCs versus non-IBCs, with very frequent co-overexpression. For most of them, the overexpression was associated with better pathological response to chemotherapy. Conclusion. Our results suggest the potential higher vulnerability of IBC to ICIs. Clinical trials.

BackgroundHead and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting.MethodsThe phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria.ResultsFrom November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III–IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3–4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR.ConclusionsNeoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach.Trial registration numberClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759.

Background: Inflammatory breast cancer (IBC) represents a rare but aggressive form of locally advanced BC. In spite of multimodality therapy including neoadjuvant chemotherapy (NAC), radical surgery and radiotherapy, prognosis remains poor, notably in HER2-negative subtypes. Whole-genome and gene expression profiling studies in IBC have identified an immune-enriched signature predicting for pathological complete response (pCR), suggesting a critical role for T-cell cytotoxicity in reaching complete tumor cell elimination after NAC. In addition, overexpression of programmed cell death ligand 1 (PD-L1) mRNA in IBC is more frequent than in non-IBC and has significant correlation with pCR. Pembrolizumab (PEM), an anti- programmed cell death 1 (PD 1) receptor antibody, inhibiting its interaction with PD-L1, is registered or in development across a large range of malignancies. PEM may boost anti-tumor immunity, eradicating residual tumor cells and thus improving pCR and outcome in HER2-negative IBC. Trial design: PELICAN-IPC 2015-016 trial (NCT03515798), sponsored by Institut Paoli-Calmettes with financial support of MSD, is a multicenter, randomized phase II, non-comparative study evaluating the addition of PEM to anthracyclines/taxanes NAC in non-metastatic HER2-negative IBC. Patients will receive 4 cycles of Q3W FEC100 (5FU 500 mg/m², Epirubicin 100 mg/m², Cyclophosphamide 500 mg/m²; non-triple negative) or 4 cycles of Q2W EC (Epirubicin 90 mg/m², Cyclophosphamide 600 mg/m²; triple-negative) followed by Q1W paclitaxel 80 mg/m² x 12, with (arm B) or without (arm A) Q3W IV PEM 200 mg started with C2 FEC/EC. The primary endpoint will be pCR in the experimental arm. The study also includes a run-in safety phase. Secondary endpoints include tolerance, invasive disease-free, event-free and overall survivals in each arms and collection of pre- and post-treatment tissue and blood samples for pharmacodynamics measurements and biological correlates. Following Simon’s 2-stage optimal procedure a total of 54 patients in arm B is required to reject the null hypothesis of a truly ineffective experimental arm (H0: p Citation Format: Anthony Gonçalves. A prospective, multicentre, open-label, randomized phase II study of PEmbroLizumab in combination with neo-adjuvant (F)EC-paclitaxel regimen in HER2-negative Inflammatory 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 OT2-04-01.

Proof of concept studies has reported that circulating endothelial cell (CEC) count may be associated with the outcome of HER2-negative metastatic breast cancer (mBC) patients treated by chemotherapy and the anti-VEGF antibody bevacizumab. We report the results obtained in an independent prospective validation cohort (COMET study, NCT01745757). The main baseline criteria were HER2-negative mBC, performance status 0–2 and no prior chemotherapy for metastatic disease. CECs were detected by CellSearch® from 4 ml of blood at baseline and after 4 weeks of weekly paclitaxel and bevacizumab therapy. CEC counts (considered both as a continuous variable and using the previously described 20 CEC/4 ml cutoff) were associated with clinical characteristics and progression-free survival (PFS). CEC count was obtained in 251 patients at baseline and in 207 patients at 4 weeks. Median baseline CEC count was 22 CEC/4 ml (range 0–2231). Baseline CEC counts were associated with performance status (p = 0.02). No statistically significant change in CEC counts was observed between baseline and 4 weeks of therapy. High baseline CEC count was associated with shorter PFS in univariate and multivariate analyses (continuous: p

Background In the EMBRACA phase III study (NCT01945775), talazoparib was associated with a significantly prolonged progression‐free survival (PFS) compared with physician's choice of chemotherapy (PCT) in germline BRCA1/2‐mutated HER2‐negative advanced breast cancer (ABC). Herein, the safety profile of talazoparib is explored in detail. Materials and Methods Overall, 412 patients received ≥1 dose of talazoparib (n = 286) or PCT (n = 126). Adverse events (AEs) were evaluated, including timing, duration, and potential overlap of selected AEs. The relationship between talazoparib plasma exposure and grade ≥3 anemia was analyzed. Time‐varying Cox proportional hazard models assessed the impact of dose reductions on PFS. Patient‐reported outcomes (PROs) in patients with common AEs and health resource utilization (HRU) were assessed in both treatment arms. Results The most common AEs with talazoparib were hematologic (195 [68.2%] patients) and typically occurred within the first 3–4 months of receiving talazoparib. Grade 3‐4 anemia lasted approximately 7 days for both arms. Overlapping grade 3‐4 hematologic AEs were infrequent with talazoparib. Higher talazoparib exposure was associated with grade ≥3 anemia. Permanent discontinuation of talazoparib due to hematologic AEs was low (, Talazoparib is a viable option for patients with germline BRCA‐mutated advanced breast cancer. This article presents detailed safety analyses for talazoparib, as a follow‐up to reported results from the EMBRACA trial, to highlight patterns of toxicity compared with chemotherapy and to outline guidelines for management of talazoparib toxicity in clinical practice via dose modifications and/or standard supportive care.

Background Metastatic breast cancer (MBC) behaviour differs depending on hormone receptors (HR) and human epidermal growth factor receptor (HER2) statuses. Methods The kinetics of central nervous system (CNS) metastases (CNS metastasis-free survival, CNSM-FS) and subsequent patient’s prognosis (overall survival, OS) according to the molecular subtype were retrospectively assessed in 16703 MBC patients of the ESME nationwide multicentre MBC database (Kaplan–Meier method). Results CNS metastases occurred in 4118 patients (24.6%) (7.2% at MBC diagnosis and 17.5% later during follow-up). Tumours were HER2−/HR+ (45.3%), HER2+/HR+ (14.5%), HER2+/HR− (14.9%) and triple negative (25.4%). Median age at CNS metastasis diagnosis was 58.1 years (range: 22.8–92.0). The median CNSM-FS was 10.8 months (95% CI: 16.5–17.9) among patients who developed CNS metastases. Molecular subtype was independently associated with CNSM-FS (HR = 3.45, 95% CI: 3.18–3.75, triple-negative and HER2−/HR+ tumours). After a 30-month follow-up, median OS after CNS metastasis diagnosis was 7.9 months (95% CI: 7.2–8.4). OS was independently associated with subtypes: median OS was 18.9 months (HR = 0.57, 95% CI: 0.50–0.64) for HER2+/HR+ , 13.1 months (HR = 0.72, 95% CI: 0.65–0.81) for HER2+/HR−, 4.4 months (HR = 1.55, 95% CI: 1.42–1.69) for triple-negative and 7.1 months for HER2−/HR+ patients (p Conclusions Tumour molecular subtypes strongly impact incidence, kinetics and prognosis of CNS metastases in MBC patients. Clinical trial registration NCT03275311.

PURPOSE The prevalence of breast cancer is increasing in low- to middle-income countries such as Senegal. Our prospective study assessed the quality of life (QoL) of patients with breast cancer undergoing chemotherapy in Senegal. PATIENTS AND METHODS Our study included women with breast cancer undergoing chemotherapy as initial treatment at the Center Aristide Le Dantec University Hospital in Dakar. Clinical, sociodemographic, and QoL data were collected and analyzed at three different times: baseline, 3 months, and 6 months after the start of systemic therapy. Health-related QoL was assessed using a Functional Assessment of Cancer Therapies-Breast (FACT-B) questionnaire after translation into the Wolof language. Linear mixed-effects models were performed to assess the changes in QoL scores. RESULTS Between July 2017 and February 2018, 120 patients were included in the study. Their median age was 45 years. Most patients (n = 105; 92%) had locally advanced disease (T3 to T4 stage) and lymph node involvement (n = 103; 88%), and half had metastatic disease. The FACT-B total scores significantly improved over time (β = 1.58; 95% CI, 0.50 to 2.67; P < .01). Nausea and vomiting were significantly associated with a decrease in FACT-B total scores (β = −16.89, 95% CI, −29.58 to −4.24, P = .012; and β = −13.44, 95% CI, −25.15 to −1.72, P = .028, respectively). CONCLUSION Our study confirmed the feasibility of standardized QoL assessment in Senegalese patients with breast cancer. Our results indicated a potential improvement of QoL over the course of chemotherapy. Optimizing nausea and vomiting prevention may improve QoL.

International audience; Eribulin mesylate (EM) was recently approved for metastatic breast cancer (MBC) chemotherapy (CT) in late lines by the FDA, with debated results in second line. We evaluated outcomes in breast cancer patients receiving EM as second, third and fourth line in a national real-life cohort of 16,703 consecutive MBC patients initiating their first metastatic therapeutic line between 2008 and 2014. Primary and secondary objectives were overall survival (OS) and progression-free survival (PFS). An imbalance was seen for HER2+ tumors and concomitant anti-HER2 targeted therapies use, we thus performed a subanalysis in HER2- patients. PFS and OS were significantly better in EM patients in third and fourth lines, compared to "Other chemotherapies" patients (PFS: 4.14 vs. 3.02 months, p = 0.0010; 3.61 vs. 2.53 months, p = 0.0102, third and fourth-line; OS: 11.27 vs. 7.65 months, p = 0.0001; 10.91 vs. 5.95 months, p

Le cancer du sein triple-négatif (CSTN), défini par l’absence d’expression des récepteurs hormonaux et d’HER2 (human epidermal growth factor receptor-2), représente 15 à 20 % des cancers du sein. Cependant, cette définition, essentiellement négative, masque la très grande hétérogénéité des entités biologiques qui constituent ce soustype. Si la chimiothérapie est le principal traitement systémique établi de la maladie à la fois dans la prise en charge des stades précoces et avancés, la compréhension progressive des composantes moléculaires impliquées dans la pathogenèse des CSTN permet des perspectives thérapeutiques novatrices. L’objectif de cette synthèse est de décrire ces cibles potentielles et d’explorer les traitements d’aujourd’hui et de demain qui permettront de lutter contre ce cancer au comportement particulièrement agressif.