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Benoîte Mery,1,2,* Christine Ménétrier-Caux,2,3,* Laure Montané,4 Pierre-Etienne Heudel,1 Isabelle Ray-Coquard,1 Thomas Bachelot,1 Olfa Derbel,5 Paule Augereau,6 Isabelle Treilleux,2,7 Justine Berthet,2,3 Axelle Nkodia,3 Christine Bardin-Dit-Courageot,3 Valery Attignon,8 Anthony Ferrari,9 Gwenaele Garin,4 David Perol,4 Christophe Caux,2,3 Bertrand Dubois,2,3,* Olivier Trédan1,2,* 1Department of Medical Oncology, Centre Léon Bérard, Lyon, France; 2Inserm U1052, CNRS 5286, Cancer Research Center of Lyon, Université Claude Bernard Lyon 1, Lyon, France; 3Laboratory of Cancer Immunotherapy of LYON (LICL), Centre Léon Bérard, Lyon, France; 4Clinical Research Platform (DRCI), Centre Léon Bérard, Lyon, France; 5Department of Medical Oncology, Hôpital Privé Jean-Mermoz, Lyon, France; 6Department of Medical Oncology, Institut de Cancérologie de L’ouest- Paul Papin, Angers, France; 7Biopathology Department, Centre Léon Bérard, Lyon, France; 8Genomic of Cancer Platform, Centre Léon Bérard, Lyon, France; 9Gilles Thomas Bioinformatics Platform, Synergie Lyon Cancer Foundation, Centre Léon Bérard, Lyon, France*These authors contributed equally to this workCorrespondence: Benoîte Mery, Department of Medical Oncology, Centre Léon Bérard, 28 Rue Laennec, Lyon, 69008, France, Tel +33 4 78 78 26 44, Fax +33 4 78 78 27 15, Email Benoite.mery@lyon.unicancer.frPurpose: Metastatic endocrine-resistant breast cancer (MBC) is a disease with poor prognosis and few treatment options. Low lymphocyte count is associated with limited overall survival. In a prospective cohort of lymphopenic patients with HER-2 negative MBC, we assessed the clinical and biological impact of pembrolizumab combined with metronomic cyclophosphamide.Experimental Design: This multicenter Phase II study evaluated the safety and clinical activity of pembrolizumab (intravenous (IV), 200mg, every 3 weeks) combined with metronomic cyclophosphamide (50mg/day, per os) in lymphopenic adult patients with HER2-negative MBC previously treated by at least one line of chemotherapy in this setting according to a Simon’s minimax two-stage design. Blood and tumor samples were collected to assess the impact of the combined treatment on circulating immune cells and the tumor immune microenvironment through multiparametric flow cytometry and multiplex immunofluorescence analyses. Primary endpoint was the clinical benefit rate at 6 months of treatment (CBR-6M). Secondary endpoints were objective response rate (ORR), duration of response, progression free survival (PFS), and overall survival (OS).Results: Two out of the twenty treated patients presented clinical benefit (one Tumor Mutational Burden (TMB)-high patient with complete response (CR) and one patient with objective response (OR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) associated with a strong increase of cytokine-producing and proliferating CD4+ T cells and higher CD8+ T cells to macrophage ratios in the tumor. This impact on CD4+ and CD8+ T cell polyfunctionality was still observed more than one year for the patient with CR. A decreased in their absolute number of CD4+ and CD8+ memory T cells was observed in other patients.Conclusion: Pembrolizumab combined with metronomic cyclophosphamide was well tolerated, and displayed limited anti-tumoral activity in lymphopenic MBC. Correlative translational data of our trial advocates for additional studies with other chemotherapy combinations.Keywords: metastatic breast cancer, lymphopenia, immunotherapy, chemotherapy, immunomonitoring

Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene affects the clinical outcome of ovarian cancer patients.Experimental Design: A study cohort of 353 women with ovarian cancer who underwent genetic germline testing for BRCA1 and BRCA2 genes was identified. Progression-free survival (PFS), platinum-free interval (PFI), and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of ovarian cancer (n = 316) was used as a validation cohort.Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2. After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS [58%; adjusted HR, 0.36; 95% confidence interval (CI), 0.20–0.64; P = 0.001] and prolonged PFI (29.7 vs. 15.5 months, P = 0.011), compared with noncarriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42–1.07; P = 0.094) or PFI (19 vs. 15.5 months, P = 0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13–0.68; P = 0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02–0.38; P = 0.001).Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged PFS, PFI, and OS. Clin Cancer Res; 24(2); 326–33. ©2017 AACR.

Table S1: Multivariate Model of progression-free survival in the study cohort; Table S2: Multivariate Model of overall survival in the study cohort; Table S3: BRCA2 mutations in the study cohort; Figure S1: Flow diagram for selection of patients in the study cohort; Figure S2: A model for double-strand breaks repair by homologous recombination that depends on the location of mutation in BRCA2 gene.

Resistance of advanced hormone-dependent endometrial carcinoma to endocrine therapy remains a worldwide clinical issue. We recently reported that the combination of Vistusertib (V, mTOR inhibitor) and Anastrozole (A, aromatase inhibitor) improves the progression-free rate compared to Anastrozole alone. However, a better patient selection based on biomarkers would improve patient outcome. We evaluate for the first time the usage of ribosome biogenesis (RiBi) factors as a source of innovative markers. Using 47 FFPE tumours (A n = 18; V + A n = 29), 32 blood samples (A n = 13; V + A n = 19) and 30 samples of total RNAs (A n = 12; V + A n = 18) from the VICTORIA clinical trial, we observed an association between RiBi-associated markers and drug activity or prediction of treatment response. NOP10 and NHP2 mRNA levels were significantly higher in non-responders compared to responders in the Vistusertib + Anastrozole arm (P = 0.0194 and P = 0.0002 respectively; i.e. 8 weeks progression-free survival as endpoint). This study provides RiBi-based markers relevant for a better selection of patients with advanced endometrial carcinoma by predicting the response of endocrine therapy combined with mTOR inhibitor.

Second primary cancers (SPC) account for 18% of all cancers. We used the enhanced medical/health data mining tool ConSoRe to search aggregated data, analyze electronic patient records (EPR), and better characterize patients with SPC. This retrospective cohort study used ConSoRe to identify EPRs from patients with SPC referred to the regional cancer center Leon Berard from 1993 to 2017, and examined characteristics of patients with SPC, frequencies of first primary cancer (FPC) localization in the global population of patients with SPC, and time to SPC. Data set was extracted on January 1, 2018. Among 296,530 EPRs, we identified 157,187 patients with FPC, including 13,002 (8%) patients with SPC. Between 2000 and 2010, the rate of SPC was 34%, and 52% of SPC were identified in the last years (2010–2017). In men, main cancers were head and neck cancer, lymphoma, and prostate carcinoma accounting for 15.6%, 12.8%, and 10.5% of FPC, while the three most common SPC were head and neck cancer (13.2%), lung cancer (11.8%) and lymphoma (9.2%). In women, breast cancers, lymphoma, and skin cancers accounted for 48.8%, 8%, and 5.1% of first cancers, and for 31.1%, 7% and 6% of SPC. The data mining tool ConSoRe contributes to access to real world data, and to better characterize patients with SPC. Expanding such approach to any comprehensive center will allow a global overview of the follow-up of patients with cancer, and help to improve long-term management and adapt surveillance.

Background Trabectedin and pegylated liposomal doxorubicin (PLD) is an effective combination therapy for platinum-sensitive recurrent ovarian cancer (ROC), particularly for disease relapsing within 6-12 months of platinum therapy. The non-interventional PROSPECTYON study evaluated trabectedin/PLD in French clinical practice. Patients and methods Patients with ROC after at least one platinum-based regimen received 1.1 mg/m2 trabectedin plus 30 mg/m2 PLD every 3 weeks. Efficacy and safety were evaluated in subgroups according to platinum-free interval [6-12 versus ≥12 months (partially or fully platinum sensitive, respectively)]. Results Recurrent disease was partially platinum-sensitive in 58 patients and fully sensitive in 33 patients treated between July 2014 and June 2016. Patients in both subgroups received a median of six cycles of trabectedin and PLD. The most common grade 3 or more toxicities were haematological. Median progression-free survival was 6 months for both subgroups. Conclusion Trabectedin/PLD is a valuable treatment option for partially or fully platinum-sensitive ROC.

Background The objective of the CHEOPS trial was to assess the benefit of adding aromatase inhibitor (AI) to metronomic chemotherapy, oral vinorelbine, 50 mg, three times a week for pre-treated, HR + /HER2- metastatic breast cancer patients. Methods In this multicentric phase II study, patients had to have progressed on AI and one or two lines of chemotherapy. They were randomized between oral vinorelbine (Arm A) and oral vinorelbine with non-steroidal AI (Arm B). Results 121 patients were included, 61 patients in Arm A and 60 patients in Arm B. The median age was 68 years. 109 patients had visceral metastases. They all had previously received an AI. The study had been prematurely stopped following the third death due to febrile neutropenia. Median PFS trend was found to be different with 2.3 months and 3.7 months in Arm A and Arm B, respectively (HR 0.73, 95%CI 0.50–1.06, p value = 0.0929). No statistical difference was shown in OS and better tumor response. 56 serious adverse events corresponding to 25 patients (21%) were reported (respectively, 12 (20%) versus 13 (22%) for arms A and B) (NS). Conclusion The addition of AI to oral vinorelbine over oral vinorelbine alone in aromatase inhibitor-resistant metastatic breast cancer was associated with a non-significant improvement of PFS. Several unexpected serious adverse events were reported. Metronomic oral vinorelbine schedule, at 50 mg three times a week, requires close biological monitoring. The question of hormonal treatment and chemotherapy combination remains open.

Introduction/Background* Endometrial cancer (EC) patients (Pts) with advanced and recurrent disease relapse despite treatment with combination chemotherapy and have a short progression-free survival (PFS). Nintedanib (N) is a potent, orally available triple receptor tyrosine kinase inhibitor targeting VEGFR 1–3, PDGFR α/β, and FGFR 1–3. This study explored the preliminary efficacy of nintedanib in EC. Methodology The primary objective of this placebo-controlled, randomized study was to evaluate efficacy defined by median PFS of concomitant and maintenance N against placebo (P) in combination with chemotherapy. Patients with histologically confirmed stage IIIC2 or IVA & B or relapsed after adjuvant therapy for stage I-III disease; prior surgery; adjuvant chemotherapy; radiation therapy; hormonal therapy in metastatic setting; with measurable/non-measurable disease were permitted. Pts were randomized 1:1 to receive N 200mg or P, twice daily days 2–21 during chemotherapy (six cycles of Carboplatin (AUC5) and paclitaxel (175mg/m2) every 21 days) and continuously in maintenance phase. N/P was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification by stage of disease, prior adjuvant chemotherapy and measurable/non-measurable disease. This is an ENGOT Model A study. Clinical trial information: NCT02730416. Result(s)* 146 of 148 pts were eligible for PFS: 72N/74P; mean age 66yrs; FIGO stage III 18%, IV 42%, recurrent 40%; follow-up 30 mo. N added to chemotherapy did not improve PFS (119 events) as compared to chemotherapy plus P: median for N 8.3 vs. for P 7.2 mo; hazard ratio (HR) adjusted for stratification factors 1.03; 95% confidence interval (CI),[0.71 to 1.48]; p0.879. Median overall survival (85 events) for N 20 vs. for P 22 mo; HR: 1.10; CI: 0.72–1.69; p0.665. Treatment-emerged grade 3–4 adverse events were higher in N vs P arm: liver function tests 13%/0%; diarrhea 12%/6%; neutropenia 21%/14%; asthenia 4%/1%. Patient-reported outcomes will be reported. Conclusion* Addition of nintedanib to chemotherapy did not improve PFS nor OS. This regimen cannot be recommended to undergo further testing in a phase III trial.

Purpose Sarcopenia has been identified as an important prognostic factor for patients with cancer. This study aimed at exploring the potential associations between a 6-month physical activity intervention and muscle characteristics, sarcopenia, oxidative stress and toxicities in patients with metastatic breast cancer. Methods Women newly diagnosed with metastatic breast cancer (N = 49) participated in an unsupervised, personalized, 6-month physical activity intervention with activity tracker. Computerized tomography images at the third lumbar vertebra were analysed at baseline, three months and six months to assess sarcopenia (muscle mass index 2/m2) and muscle quality (poor if muscle attenuation Results At baseline 53% (mean age 55 years (SD 10.41)) were sarcopenic and 75% had poor muscle quality. Muscle cross sectional area, skeletal muscle radiodensity, lean body mass remained constant over the six months (p = 0.75, p = 0.07 and p = 0.75 respectively), but differed significantly between sarcopenic and non-sarcopenic patients at baseline and 6-months. Sarcopenic patients at baseline were more likely to have an increase of MDA (p = 0.02) at 6 months. Being sarcopenic during at least one moment during the 6-month study was associated with a higher risk of developing severe toxicities (grade > 2) (p = 0.02). Conclusions This study suggests potential benefits of physical activity for maintenance of muscle mass. Sarcopenia can alter many parameters and disturb the pro and antioxidant balance.

International audience; Purpose. Regular physical activity (PA) can affect oxidative stress, known to be involved in carcinogenesis. The objective of this study was to evaluate the associations between a six-month PA intervention and oxidative stress biomarkers, PA, and clinical outcomes in patients with metastatic breast cancer. Methods. Forty-nine newly diagnosed patients with metastatic breast cancer were recruited for a single-arm, unsupervised, and personalized six-month walking intervention with activity tracker. PA level and PA fitness, plasma concentrations of DNA oxidation (8OhdG), lipid peroxidation (MDA), and protein oxidation (AOPP), plasma activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase, plasma and leucocyte activities of myeloperoxidase (MPO) and NADPH oxidase (NOX), and clinical markers of tumor progression (RECIST criteria) were measured at baseline and after the six-month intervention. Results. GPX activity (+17%) and MDA (+9%) significantly increased between baseline and the end of the intervention. Changes in PA level and fitness were significantly positively correlated with changes in plasma GPX and significantly negatively with changes in NOX in the leucocytes. Plasma MDA was significantly higher (+20%) whereas plasma AOPP was lower (-46%) for patients with tumor progression or that died during the six months as compared to patients without progression. Conclusion. A six-month PA intervention may be potentially beneficial in metastatic breast cancer patients for enhancing antioxidant enzyme activity and decreasing prooxidant enzyme activity. Moreover, AOPP and MDA could also be favorable and unfavorable biomarkers, respectively, since they are associated with disease progression and fitness level in this population. This trial is registered with NCT number: NCT03148886.

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

5572 Background: AcSé Pembrolizumab is a Phase 2, non-randomized parallel arms, multicentric basket trial investigating the efficacy and safety of pembrolizumab monotherapy in different cohorts of patients with rare cancers (NCT03012620). Here we report the results in the rare ovarian tumors cohort. Methods: Selected histotypes were all rare ovarian cancers (incidence < 6/100,000/year). Main inclusion criteria were age > 18, ECOG PS≤1, resistant disease to platinum based chemotherapy, and systematic histological central review by expert pathologist from TMRG network. Patients (pts) received pembrolizumab 200 mg IV on Day 1 of every 21-day cycle for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to RECIST v1.1 at 12 weeks. Secondary endpoints included best response rate, duration of response, progression-free survival (PFS), overall survival (OS), and safety. The 7 subgroups of pts analyzed were carcinosarcoma (CS), clear cell carcinoma (CCC), low grade serous carcinoma (LGSC), mucinous carcinoma (MEOC), sex cord tumors (SCT), germ cell tumor (GCT), and smarcA4 deficient hypercalcemic ovarian tumor (SCHOCCT). Results: 62 pts from 22 centers, were included from 08/2017 to 12/2020. Median Age was 53.5 years old [36-64]. Median number of previous lines of chemotherapy was 2 (range 1-4). The median number of cycles was 8 (range, 1-35) with 44 pts (70.9%) who discontinued the trial after a mean number of 6.8 cycles. There were 2 pts (3.2%) with partial response (PR) at 12 weeks. The best response in ITT was complete response (CR) in 1 patient (1%), PR in 3 (14.3%), and stable disease (SD) in 21 (33.8%). The occurrence of best response depended on the histotype with 1 CR (33%) in GCT (cancerized teratoma), 2 PR (20%) in CCC, and 1 PR (4%) in LGSC. 4/4 pts (100%) reported PD as best response in SCOOHT (Table 1). Median duration of response or stabilized disease was 7.8 months [IQR, 4.1 to 9.0]. At the data cut off, 6-month PFS was 29% [19.7-42.8] and 6-month OS was 77.8% [67.7-89.3] on the overall population. Outcomes differed according to subgroups and will be presented. There were a total of 62 adverse events (AEs) reported in 28 pts. For 5 pts (8%) AEs lead to drug discontinuation. AEs were of grade 1 (n = 9), grade 2 (n = 8), or grade ≥ 3 (n = 45: 42 grade 3, 2 grade 4, and 1 grade 5). Conclusions: Pembrolizumab is safe and well tolerate in this population of rare ovarian cancer pts. AcSé study reports prolonged responses in very selected subtypes of rare ovarian tumor (CCC, cancerized teratoma, and LGCS). Acknowledgements: TMRG (national cancer network dedicated to rare gynecological tumors), GINECO group for partnership, La Ligue Nationale contre le Cancer, INCa and MSD. Clinical trial information: NCT03012620. [Table: see text]

590 Background: Triple-Negative Breast Cancer (TNBC) is characterized by high metastatic potential and poor prognosis with limited treatment options. Neoadjuvant chemotherapy (NACT) is the standard of care in non-metastastic setting due to the ability to assess pathologic responses providing important prognostic information and guidance in adjuvant therapy decisions. However, the histological response heterogeneity is still poorly understood. We investigate the use of Machine Learning (ML) to predict from diagnosis Whole-Slide Images (WSI) of early TNBC the positive histological Complete Response (pCR) to NACT on surgical specimens. To overcome the known biases of small scale studies while respecting data privacy, we conduct a study in a multi-centric fashion behind hospitals’ firewalls using collaborative Federated Learning (FL). Thereby allowing access to enough TNBC data to sustain a complete response heterogeneity investigation. Methods: We collected in both comprehensive cancer centers: Centre Léon Bérard (A)(n=99) and Institut Curie (B) (n=420), WSI of biopsies performed at diagnosis and relevant clinical variables. We use traditional Multiple Instance Learning pipelines by tiling the matter on each WSI with a pre-trained Neural Network (NN). We train a second NN to predict the NACT pCR using the mean feature of each WSI. ML trainings are performed using either one cohort in isolation (NN Local) or both cohorts using FL. We compare the performance of this federated WSI based model to the best clinical model (Clin.) simulating clinical practice (using grade and Tumor-Infiltrating Lymphocytes (TILs) percentage) on both centers. Results: Performance of models to predict NACT pCR (AUC). All results are evaluated in 5 repeated 4-folds cross validations. Conclusions: The final ML model, that was trained in a privacy preserving fashion on both hospitals, provides better prediction of NACT pCR than current clinical standards. This study shows that 1. Not all relevant information is routinely extracted from WSI and 2. Non simulated FL is possible in Healthcare and gives better results than siloed studies on open medical questions. Additional interpretability results of the model show that it has re-discovered known biomarkers such as TILs and apocrine tumor cells without any tile-level annotation, and hints at potential new biomarkers. [Table: see text]

Background Palbociclib is a CDK4/6 inhibitor with demonstrated efficacy and safety in combination with endocrine therapy in advanced luminal breast cancer (LBC). We evaluated the respective efficacy and safety of chemotherapy and letrozole–palbociclib (LETPAL) combination as neoadjuvant treatment in patients with high-risk LBC. Patients and methods NeoPAL (UCBG10/4, NCT02400567) is a randomised, parallel, non-comparative phase II study. Patients with ER-positive, HER2-negative, Prosigna®-defined luminal B, or luminal A and node-positive, stage II–III breast cancer, not candidate for breast-conserving surgery, were randomly assigned to either letrozole (2.5 mg daily) and palbociclib (125 mg daily, 3 weeks/4) during 19 weeks, or to FEC100 (5FU 500 mg/m2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)×3 21-day courses followed by docetaxel 100 mg/m2×3 21-day courses. Primary end point was residual cancer burden (RCB 0–I rate). Secondary end points included clinical response, proliferation-based markers, and safety. Results Overall, 106 patients were randomised [median Prosigna® ROR Score 71 (22–93)]. RCB 0–I was observed in four and eight patients in LETPAL [7.7% (95% CI 0.4–14.9)] and chemotherapy [15.7% (95% CI 5.7–25.7)] arms, respectively. Pathological complete response rates were 3.8% and 5.9%. Clinical response (75%) and breast-conserving surgery rates (69%) were similar in both arms. Preoperative Endocrine Prognostic Index 0 scores (breast cancer-specific survival) were observed in 17.6% and 8.0% of patients in LETPAL and chemotherapy arms, respectively. Safety profile was as expected, with 2 versus 17 serious adverse events (including 11 grade 4 serious AEs in the chemotherapy arm). Conclusion LETPAL combination was associated with poor pathological response but encouraging clinical and biomarker responses in Prosigna®-defined high-risk LBC. Contemporary chemotherapy regimen was associated with poor pathological and biomarker responses, with a much less favourable safety profile. LETPAL combination might represent an alternative to chemotherapy in early high-risk LBC. Clinical Trial Number NCT02400567.

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

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

Additional file 2: Supp Mat 2. Kaplan-Meier survival curves corresponding to 2A: Time from first cancer diagnosis until development of MAHA. 2B: Time from first metastasis until development of MAHA.

Additional file 1: Supp Mat 1. Clinical and biological parameters included in statistical analysis. 1A: Data requested from participating centres. 1B: Predictive score construction according to statistical analysis.

Benefits of physical activity are widely demonstrated for early stage cancers but few studies have focused on metastatic disease. The purpose of this study was to determine the impact of physical activity on survival in patients with metastatic breast cancer. We conducted a secondary analysis of the national, multicentric, non-randomized, prospective cohort SNPs to Risk of Metastasis (StoRM) study. The level of physical activity was self-reported at inclusion and divided into three categories of physical activity: light level, moderate level, and vigorous level. Overall, 833 patients (56.2%) completed the physical activity questionnaire at baseline on average physical activity during the previous year: 11.6% had a light level of physical activity, 69.0% achieved moderate levels of physical activity and 19.3% reported vigorous levels of physical activity. After adjustment for confounding, physical activity was not statistically significantly associated with overall survival in the whole population. Subgroup analysis identified that both vigorous and moderate physical activity were associated with statistically significantly improved overall survival compared to light physical activity level only in the HER2 positive subgroup (HR 0.23; 95% CI 0.07–0.70, p = 0.01 and HR 0.38; 95% CI 0.15–0.96, p = 0.04). Physical activity done during the previous year was associated with survival in HER2 positive metastatic breast cancer patients. These results suggest that overall survival in metastatic breast cancer patients could be improved through physical activity which should be considered as a complementary intervention for these individuals. The study showed that moderate/vigorous levels of physical activity were associated with better overall survival, and that these associations remained statistically significant in multivariate analysis in the HER2 positive subgroup. These results have clinical relevance and justify the recommendations for physical activity interventions in metastatic breast cancer.

Breast cancer with HER2-amplification accounts for 20% of breast cancers. The management of patients has dramatically changed with the advent of anti-HER2 treatment, especially the monoclonal antibodies since 2000 in the metastatic and (neo)-adjuvant setting, leading to an improvement of patient outcomes. If therapeutic arsenal has been gradually enhanced with the targeting of HER receptors family, resistances to these treatments are observed, hence the development of new therapeutic strategies. This review provides an updated look of novel therapeutic strategies in HER2-positive breast cancer, as well as future perspectives, both in the adjuvant and metastatic setting.

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

International audience; Introduction :To assess pre-therapeutic MRI-based radiomic analysis to predict the pathological complete response to neoadjuvant chemotherapy (NAC) in women with early triple negative breast cancer (TN).Materials and methods :This monocentric retrospective study included 75 TN female patients with MRI (T1-weighted, T2-weighted, diffusion-weighted and dynamic contrast enhancement images) performed before NAC. For each patient, the tumor(s) and the parenchyma were independently segmented and analyzed with radiomic analysis to extract shape, size, and texture features. Several sets of features were realized based on the 4 different sequence images. Performances of 4 classifiers (random forest, multilayer perceptron, support vector machine (SVM) with linear or quadratic kernel) were compared based on pathological complete response (defined on the excised tissues), on 100 draws with 75% as training set and 25% as test.Results : The combination of features extracted from different MR images improved the classifier performance (more precisely, the features from T1W, T2W and DWI). The SVM with quadratic kernel showed the best performance with a mean AUC of 0.83, a sensitivity of 0.85 and a specificity of 0.75 in the test set.Conclusion :MRI-based radiomics may be relevant to predict NAC response in TN cancer. Our results promote the use of multi-contrast MRI sources for radiomics, providing enrich source of information to enhance model generalization.

Objective This secondary analysis of the ABLE Trial (ClinicalTrials.gov NCT03148886) aimed to assess physical activity preferences before and after a 6-month physical activity intervention for women recently diagnosed with metastatic breast cancer and to investigate demographic and clinical correlates of these preferences. Methods Forty-nine patients participated in the ABLE Trial, a single-arm, unsupervised 6-month physical activity intervention with activity trackers. At baseline and 6 months, physical activity preferences, physical activity level, clinical variables, demographics and social vulnerability were assessed. Results At baseline, 49 participants were included, among whom 85% were interested in receiving physical activity counselling and 89% were interested in following a physical activity programme designed for metastatic breast cancer. At the end of the study, more participants preferred practising in a community fitness centre (66%) rather than at home (19% vs. 44% at baseline, p = .03). A higher social vulnerability score and not being treated by chemotherapy at baseline were significantly associated with lower desire to receive physical activity counselling (p = .01 and p = .04 respectively). Conclusions This study will help design future studies within patients with metastatic breast cancer in accordance with their preferences. Designing tailored physical activity interventions according to the participant's preferences may be one key to success for adherence.

Aim The goal of the present study was to further refine how polygenic risk scores may be used in a large population and to quantify the transmission of risk score through generations. Methods Allele frequencies from the 1000 Genomes data for 159 single nucleotide polymorphisms associated with breast cancer risk were used. A breast cancer risk score was calculated among 100,000 people. Choosing two “parents” and the alleles they transmit at random, 100,000 “daughters” were simulated. The population was divided by deciles of risk score. Comparing mean risk score in the mother and daughter populations provided information regarding the general relationship at a population level. By examining the distribution of daughter's risk score within each decile of maternal risk score, the transmission was evaluated at the subject level. Results Mean values of risk score were 85.1 (St Dev = 7.5) and 85.0 (St Dev = 7.5) for the populations of mothers and daughters, respectively (mean absolute difference = 0.02, p = 0.48). When examining the transmission of risk score from mothers to daughters in specific deciles of risk, statistically significant differences were observed in all deciles (ranged between 0.001 and Conclusion The relationship at the subject level will not provide information regarding prevention and screening of offspring based on the knowledge of parents' risk score alone. The present results show that risk estimation by polygenic risk scores is personal, and evaluation of risk score is required for each individual.

Les 40es Journées de la SFSPM se sont tenues à Avignon du 7 au 9 novembre 2018. Le thème abordé—Cancer du sein : optimisation du parcours de soins — a réuni plus de 1 200 participants sous les voûtes du Palais des Papes. La fluidité de chaque segment du parcours a été analysée en termes de risques de rupture de continuité des soins tant au sein du segment lui-même qu’en amont et en aval. Dans un parcours par essence pluridisciplinaire et plurimétiers, la nécessité d’une réflexion globale et d’une coordination active réalisées par des professionnels formés a été rappelée à chaque session. Chacun des intervenants a esquissé de potentiels indicateurs de qualité tenant compte à la fois de son implication dans son segment d’intervention, mais tenant compte aussi d’une vision plus globale de ce que devrait être le parcours au travers de la maladie et des soins. La parole a été très largement partagée entre soignants et associations de malades, entre paramédicaux et acteurs en sciences humaines et sociales, entre responsables de la santé publique HAS, ARS, CNAM–CPAM 84 et représentants des différents modes d’hospitalisation publique/privée et ESPIC. La session grand public a été l’occasion d’échanges fructueux et instructifs sur la perception des difficultés comme des satisfactions rencontrées que nous ont fait partager les malades, leurs proches et les représentantes des associations. Au total, un congrès de réflexion partagé par de nombreux acteurs qui cherchent tous à améliorer le parcours de soins des malades atteintes de cancer du sein. La publication le 21 janvier par l’INCa de dix indicateurs de qualité du parcours de soins pour les malades atteints de cancer du sein est une étape importante qu’attendaient tous les participants d’Avignon — SFSPM 2018.

In premenopausal women treated for breast cancer, endocrine therapy combining an aromatase inhibitor (AI) and a gonadotropin-releasing hormone (GnRH) agonist (GA) for ovarian suppression may be indicated in high-risk or in metastatic cancer. AIs are effective in premenopausal women only when ovarian estrogen production is suppressed, a state achievable through the use of GAs. However, a complete suppression sometimes proves elusive. We report here three cases of ovarian suppression failure in premenopausal breast cancer patients who received adjuvant AI+GA. Frequency of GA administration, BMI, and young age could affect gonadotropin suppression and may be implied in these failures. Clinical monitoring of these patients is advisable, and hormone assays and pelvic ultrasound should be performed in case of symptoms of estrogen activity.

This abstract was withdrawn by the authors.

Objective To investigate clinical factors associated with prolonged progression-free survival (PFS) and overall survival (OS) in relapsing epithelial ovarian cancer (EOC) patients with BRCA mutations and receiving olaparib as maintenance therapy in daily practice. Methods Multicenter (8 hospitals) European retrospective study of relapsing EOC patients having germline or somatic mutations of BRCA1/BRCA2 genes and treated with olaparib as maintenance therapy after platinum-based chemotherapy. Results One hundred and fifteen patients were included. Median age was 54 years. There were 90 BRCA1 carriers, 24 BRCA2 carriers and one patient had germline mutation of BRCA1 and BRCA2. Six patients had somatic mutations (all BRCA1) and 109 had germline mutations. Ninety percent had serous carcinomas and were platinum-sensitive. Following ultimate platinum-based chemotherapy, 69% of the patients had normalization of CA-125 levels and 87% had RECIST objective responses, either partial (53%) or complete (34%). After a median follow-up of 21 months, median PFS was 12.7 months and median OS was 35.4 months. In multivariate analysis, factors associated with prolonged PFS under olaparib were: platinum-free interval (PFI) ≥ 12 months, RECIST complete response (CR) or partial response (PR) and normalization of CA-125 upon ultimate platinum-based chemotherapy. Factors associated with prolonged OS were PFI ≥ 12 months, CR and normalization of CA-125. Conclusions Platinum-free interval ≥ 12 months, complete response and normalized CA-125 levels after ultimate platinum-based chemotherapy are associated with prolonged PFS and OS in relapsing BRCA1/BRCA2 mutated ovarian cancer patients who received olaparib as maintenance therapy.

5507 Background: Endometrial carcinoma is generally hormone dependent and aromatase inhibitors are used in routine practice before or after 1st line chemotherapy (CT) for HR positive patients. Deregulation of the Pi3K-Akt-mTOR signaling pathway is observed in many tumor types including endometroid carcinoma driven oncogenesis and hormonal resistance. Vistusertib (V) is a small-molecule ATP competitive inhibitor of both mTORC1 and mTORC2 complexes. Methods: Adult patients (pts) with recurrent oestrogen or progesterone (ER and/or PR) positive advanced/metastatic endometrial carcinoma, one previous line of chemotherapy (CT) allowed, with ECOG PS 0/1, were randomised (2:1, stratification according to prior CT line: 0 vs 1) to receive V (125 mg bid/2 days/week, orally) + Anastrozole (A, 1 mg/d, orally) or A alone. Treatments were given until progression, intolerable toxicity or patient willingness. Following a safety run in phase, a Simon’s 2-stage design was employed to explore the 8-week progression free rate (PFR-8W) according to central review (p1: 60%, p0: 40%, type I error rate of 5%, power of 80%). At the end of Stage II, if ≥24/46 evaluable pts are progression free at 8w in Arm A+V, the combination will be considered of interest for further investigation. Overall response rate (ORR) by RECIST v1.1, safety and progression-free survival (PFS) were key secondary endpoints. Results: Out of 75 patients (pts) enrolled, 73 were randomised and treated (Arm V+A: 49; Arm A: 24; median age: 69.5 y [36.8; 87.8]), BMI ≥30 kg/m²: 45%). PS ECOG was 0 (48%) and 44% of randomised pts were chemotherapy naïve; 12% previously received hormonal therapy. At the end of the safety run-in, no major safety concerns were reported. At the end of Simon’ Stage II, centrally assessed PFR-8W was 67.3% (33/49 [95% CI unilateral: 54.7; -]) for A + V arm and 39.1% (9/23 [[95% CI unilateral: 22.2; -[) for arm A. Median PFS was 5.2 months (95% CI: 3.4-8.9) and 1.9 months (95% CI: 1.6-8.9) for A+V and A arms, respectively. One complete response and 11 partial responses (PR) were observed (ORR: 24.5 % (CI 95% [13.3 – 38/9%]) in the combination arm and 4 PR in arm A (ORR: 17.4% [CI 95%: 5-38.8%]). Fatigue, lymphopenia, hyperglycaemia and diarrhoea were the main (≥10%) Grade ≥2 adverse events related to V. Overall survival and translational research are ongoing. Conclusions: The A+V combination demonstrated clinically and meaningful improvement in 8w-PFR and median PFS with manageable toxicity. PI3K pathway remains a key target for new therapies in endometrial cancer and translational research must help to better select pts benefiting from these targeted therapies. Clinical trial information: NCT02730923.

Background: The COVID-19 pandemic has dramatically changed the Health Care System organization in many European countries Many Oncology departments have rapidly implemented telehealth in their clinical practice For breast cancer (BC) patients (pts), up to 80% of all in-person visits have been transformed in TV Methods: 18 centers from France and Italy invited all BC pts who have had at least one TV (Visio conference or telephone) during the COVID-19 pandemic to answer an online, anonym questionnaire (Q) ontheir experience with TV Q included 42 questions: demographic data, BC medical situation, TSQ scale (telehealth specific Q), physician’s module of EORTC OUTPATSAT35 (11 SAT35), and HADS anxiety scale The primary objective was to evaluate satisfaction with TV Secondary objectives: anxiety, factors associated with satisfaction and description of satisfaction in pts’ subgroups Results: Between 6/4/2020 and 15/05/2020, 1244 pts (out of 3762 invited) filled in the Q and were included in the analysis Main characteristics and results are shown in the Table Mean 11 SAT35: 85 21 and 77 41 for pts who had visio versus telephone TVs respectively 11 SAT35 was highly correlated to HADS score (p < 0 001) Multivariate analyses will be presented [Formula presented] Conclusions: TV during the COVID-pandemic appeared feasible and well accepted by BC pts regardless of their medical situation and mode of TV Anxiety was high during this period, and correlated with satisfaction These findings help identifying BC pts who may be proposed TV beyond the pandemic crisis Legal entity responsible for the study: The authors Funding: Has not received any funding Disclosure: C Levy: Honoraria (self): Pfizer;Honoraria (self), Travel/Accommodation/Expenses: Roche;Honoraria (self): MSD;Honoraria (self), Travel/Accommodation/Expenses: Lilly;Travel/Accommodation/Expenses: Daiichi C Uzan: Honoraria (self), Advisory/Consultancy: Roche D Genet: Advisory/Consultancy: AstraZeneca;Travel/Accommodation/Expenses: Roche;Amgen;Pfizer;Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis A Patsouris: Travel/Accommodation/Expenses: Roche;Travel/Accommodation/Expenses: ESAI;Travel/Accommodation/Expenses: Pfizer;Honoraria (institution): Lily;Research grant/Funding (institution): ESAI V C Dieras: Advisory/Consultancy, Travel/Accommodation/Expenses, and travel expenses and speaker: Roche;Novartis;Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses, and travel expenses and speaker: Pfizer;Advisory/Consultancy, Travel/Accommodation/Expenses, and travel expenses and speaker: Lilly;AstraZeneca;Daiichi Sankyo;Advisory/Consultancy: Abbvie;MSD;Eisai Speaker Bureau/Expert testimony: Seattle Genetics J-Y Pierga:Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Research grant/Funding (institution): Roche;Honoraria (self), Speaker Bureau/Expert testimony: Ipsen;Novartis;AstraZeneca;Amgen S Ladoire: Speaker Bureau/Expert testimony: Lilly;Speaker Bureau/Expert testimony, and Travel/Accommodation expense: Pfizer;BMS;Ipsen;Janssen Oncology;Sanofi;Speaker Bureau/Expert testimony: Roche;Speaker Bureau/Expert testimony, Research grant/Funding (institution): Novartis;Travel/Accommodation/Expenses: AstraZeneca;Travel/Accommodation/Expenses: Astellas Pharma W Jacot: Honoraria (self), Honoraria (institution), Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca;Honoraria (self), Travel/Accommodation/Expenses: Eisai;Lilly France;Pfizer;Roche;Honoraria (self): MSD;Travel/Accommodation/Expenses: Novartis;Sanofi Aventis;GSK;Fabre;Chugai Pharma S Delaloge: Honoraria (institution), Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca;Roche;Pfizer;Honoraria (institution), Research grant/Funding (institution): Sanofi;BMS;Honoraria (institution): Pierre Fabre;Puma;Lilly;Servier;Research grant/Funding (institution): Orion;MSD;Daichy M Lambertini: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche;Spe ker Bureau/Expert testimony: Takeda;Lilly;Theramex B Pistilli: Advisory/Consultancy: PUMA biotechnologies;Speaker Bureau/Expert testimony: Fabre;Novartis;Myriad genetics;Travel/Accommodation/Expenses: MSD oncology;Astra Zeneca;Novartis;Pfizer All other authors have declared no conflicts of interest

BACKGROUND There is limited knowledge regarding the potential benefits of physical activity in patients with metastatic breast cancer. OBJECTIVE The Advanced stage Breast cancer and Lifestyle Exercise (ABLE) Trial aimed to assess the feasibility of a physical activity intervention in women with metastatic breast cancer and to explore the effects of physical activity on functional, psychological, and clinical parameters. METHODS The ABLE Trial was a single-arm, 6-month intervention study with a home-based, unsupervised, and personalized walking program using an activity tracker. At baseline and 6 months, we assessed anthropometrics, functional fitness, physical activity level, sedentary behavior, quality of life, fatigue, and tumor progression. Paired proportions were compared using the McNemar test and changes of parameters during the intervention were analyzed using the Wilcoxon signed-rank test, the Mann-Whitney test, and Spearman rank correlations. RESULTS Overall, 49 participants (mean age 55 years; recruitment rate 94%) were enrolled and 96% adhered to the exercise prescription (attrition rate 2%). Statistically significant improvements in the 6-minute walking distance test (+7%, PPP=.03) and hip circumference (-4.0%, PP=.07) in fatigue was observed. CONCLUSIONS The high recruitment and adherence rates suggest the willingness of patients with metastatic breast cancer to participate in a physical activity program. The beneficial outcomes regarding physical fitness and anthropometry of this unsupervised physical activity program may encourage these patients to maintain a physically active lifestyle. Future randomized controlled trials with larger sample sizes are warranted. CLINICALTRIAL ClinicalTrials.gov NCT03148886; https://clinicaltrials.gov/ct2/show/NCT03148886 INTERNATIONAL REGISTERED REPORT RR2-10.2196/10487