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Background: Patients with HER2-positive breast cancer (HER2 + BC) develop central nervous system metastases twice as often as patients with luminal HER2-negative breast cancer. Leptomeningeal progression results in a drastically altered prognosis with limited therapeutic options. This phase II study was conducted to assess the efficacy of intrathecal (IT) trastuzumab in HER2 + BC patients with leptomeningeal metastasis (LM), based on a phase I dose-escalation study that had determined the recommended weekly dose of 150 mg for phase II., Methods: Eligible patients received weekly administrations of 150 mg of IT trastuzumab. The primary endpoint was clinical neurologic progression-free survival (LM-related-PFS) after 8 weeks. Overall survival (OS), toxicities, and quality of life (QoL) were secondary endpoints., Results: Among the 19 enrolled patients, 16 (84%) had concomitant brain metastases, 15 of them had received prior radiotherapy to the brain. All patients had received at least one line of systemic anti-HER2 therapy. After 8 weeks, 14 patients (74%) were free of neurological progression. The median LM-related-PFS was 5.9 months and the median OS was 7.9 months. According to the QLQ-C30 and BN20 scales, the global health-related QoL status seemed preserved and no toxicity above grade 3 was observed., Conclusions: Conducting studies on patients with LM poses significant challenges and ethical dilemmas inherent to this population. Despite some limits, this phase II study's findings in terms of clinical neurologic response and QoL's control confirms weekly administration of 150 mg of IT trastuzumab as a valuable option for HER + BC patients with LM and support the interest for further investigations., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In advanced oestrogen receptor-positive, HER2-negative breast cancer, acquired resistance to aromatase inhibitors frequently stems from ESR1-mutated subclones, which might be sensitive to fulvestrant. The PADA-1 trial aimed to show the efficacy of an early change in therapy on the basis of a rising ESR1 mutation in blood (bESR1 mut ), while assessing the global safety of combination fulvestrant and palbociclib., Methods: We did a randomised, open-label, phase 3 trial in 83 hospitals in France. Women aged at least 18 years with oestrogen receptor-positive, HER2-negative advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited and monitored for rising bESR1 mut during first-line aromatase inhibitor (2·5 mg letrozole, 1 mg anastrozole, or 25 mg exemestane, orally once per day, taken continuously) and palbociclib (125 mg orally once per day on days 1-21 of a 28-day cycle) therapy. Patients with newly present or increased bESR1 mut in circulating tumour DNA and no synchronous disease progression were randomly assigned (1:1) to continue with the same therapy or to switch to fulvestrant (500 mg intramuscularly on day 1 of each 28-day cycle and on day 15 of cycle 1) and palbociclib (dosing unchanged). The randomisation sequence was generated within an interactive web response system using a minimisation method (with an 80% random factor); patients were stratified according to visceral involvement (present or absent) and the time from inclusion to bESR1 mut detection (<12 months or ≥12 months). The co-primary endpoints were investigator-assessed progression-free survival from random assignment, analysed in the intention-to-treat population (ie, all randomly assigned patients), and grade 3 or worse haematological adverse events in all patients. The trial is registered with Clinicaltrials.gov (NCT03079011), and is now complete., Findings: From March 22, 2017, to Jan 31, 2019, 1017 patients were included, of whom 279 (27%) developed a rising bESR1 mut and 172 (17%) were randomly assigned to treatment: 88 to switching to fulvestrant and palbociclib and 84 patients to continuing aromatase inhibitor and palbociclib. At database lock on July 31, 2021, randomly assigned patients had a median follow-up of 35·3 months (IQR 29·2-41·4) from inclusion and 26·0 months (13·8-34·3) from random assignment. Median progression-free survival from random assignment was 11·9 months (95% CI 9·1-13·6) in the fulvestrant and palbociclib group versus 5·7 months (3·9-7·5) in the aromatase inhibitor and palbociclib group (stratified HR 0·61, 0·43-0·86; p=0·0040). The most frequent grade 3 or worse haematological adverse events were neutropenia (715 [70·3%] of 1017 patients), lymphopenia (66 [6·5%]), and thrombocytopenia (20 [2·0%]). The most common grade 3 or worse adverse events in step 2 were neutropenia (35 [41·7%] of 84 patients in the aromatase inhibitor and palbociclib group vs 39 [44·3%] of 88 patients in the fulvestrant and palbociclib group) and lymphopenia (three [3·6%] vs four [4·5%]). 31 (3·1%) patients had grade 3 or worse serious adverse events related to treatment in the overall population. Three (1·7%) of 172 patients randomly assigned had one serious adverse event in step 2: one (1·2%) grade 4 neutropenia and one (1·2%) grade 3 fatigue among 84 patients in the aromatase inhibitor and palbociclib group, and one (1·1%) grade 4 neutropenia among 88 patients in the fulvestrant and palbociclib group. One death by pulmonary embolism in step 1 was declared as being treatment related., Interpretation: PADA-1 is the first prospective randomised trial showing that the early therapeutic targeting of bESR1 mut results in significant clinical benefit. Additionally, the original design explored in PADA-1 might help with tackling acquired resistance with new drugs in future trials., Funding: Pfizer., Competing Interests: Declaration of interests F-CB reports, outside the submitted work, grants or contracts from Novartis, Lilly, Amgen, Sanofi, Radius, Seagen, AstraZeneca, General Electric, Menarini/Stemline, Menarini Silicon Biosystems, Merck, Pfizer, Prolynx, Rain Therapeutics, and Roche; consulting fees from AstraZeneca, Exact Sciences, General Electric, GlaxoSmithKline, Lilly, Menarini/Stemline, Novartis, Pfizer, Rain Therapeutics, and Sanofi; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, Lilly, Menarini/Stemline, Pfizer, Rain Therapeutics, and Sanofi; support for attending meetings or travel from AstraZeneca, Pfizer, Novartis, and Roche; and applied for an international patent (application number PCT/EP2019/056445), filed on March 14, 2019, named: method for identifying one or more mutations in a hotspot mutation sequence. A-CH-B reports, outside the submitted work, consulting fees from AstraZeneca and Merck Sharpe & Dohme; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from MSD, AstraZeneca, Daiichi, GSK, Seagen, and Gilead; support for attending meetings or travel from Novartis, Pfizer, and Daiichi; and participation on a data safety monitoring board or advisory board for MSD, AstraZeneca, Daiichi, Pfizer, Novartis, GSK, Seagen, Gilead, and Eisai. TB reports, outside the submitted work, grants or contracts from Roche, AstraZeneca, Pfizer, and SeaGen; and consulting fees from AstraZeneca, Daiichi, Lilly, SeaGen, Roche, Novartis, and Pfizer. J-YP reports, outside the submitted work, grants or contracts from Servier and Menarini; consulting fees from Pfizer, Daiichi Sankyo, AstraZeneca, and MSD; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Daiichi Sankyo, Gilead, MSD, Seagen, Novartis, Lilly, Pierre Fabre, and Amgen; support for attending meetings or travel from Roche and AstraZeneca; and participation on a data safety monitoring board or advisory board for Sanofi and Novartis. TdlMR reports, outside the submitted work, grants or contracts from Novartis, Pfizer, AstraZeneca, MSD, Roche, Pfizer, and Seagen; consulting fees from AstraZeneca, Clovis Oncology, Eisai, MSD, Novartis, Pfizer, Roche, Sanofi, Tesaro, GSK, and Seagen; and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from GSK. RS reports, outside the submitted work, grants or contracts from AstraZeneca; consulting fees from GSK; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis, GSK, Clovis, and AstraZeneca; and support for attending meetings or travel from Pfizer, Roche, GSK, and Bristol Myers Squibb. J-SF reports, outside the submitted work, consulting fees from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, and Seagen; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lilly, Novartis, AstraZeneca, Gilead, Daiichi Sankyo, and Seagen; and support for attending meetings or travel from Pfizer, Lilly, Novartis, AstraZeneca, Clovis Oncology, GSK, Gilead, Daiichi Sankyo, and Seagen. SL reports, outside the submitted work, grants or contracts from Novartis, Eisai, and BMS; consulting fees from Pfizer, Novartis, Lilly, AstraZeneca, Sanofi, Astellas, Janssen, Ipsen, Roche, BMS, Daiichi, Seagen, and Pierre Fabre; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Pfizer, Novartis, Lilly, AstraZeneca, Sanofi, Astellas, Janssen, Ipsen, Roche, BMS, Daiichi, Seagen, and Pierre Fabre; payment for expert testimony from Pfizer, Novartis, Lilly, AstraZeneca, Sanofi, Astellas, Janssen, Ipsen, Roche, BMS, Daiichi, and Seagen; support for attending meetings or travel from Pfizer, Novartis, AstraZeneca, Janssen, BMS, Daiichi, and Seagen; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from BMS. CL reports, outside the submitted work, consulting fees from MSD, Daiichi, Roche, and AstraZeneca; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Lilly; support for attending meetings or travel from Roche, Pfizer, Sandoz, Lilly, and AstraZeneca; and participation on a data safety monitoring board or advisory board for Roche, AstraZeneca, and Lilly. AL reports, outside the submitted work, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca, MSD, and Clovis; participation on a data safety monitoring board or advisory board for AstraZeneca, MSD, and Clovis; and leadership or fiduciary role in other board for GINECO group. JG reports, outside the submitted work, support for attending meetings or travel from Lilly and Daiichi; and participation on a data safety monitoring board or advisory board for Daiichi and Pfizer. HV reports, outside the submitted work, grants or contracts from Eisai, Novartis, AstraZeneca, Daiichi, and Pfizer; and support for attending meetings or travel from Eisai, GSK, MSD, and Novartis. CG-T reports, outside the submitted work, grants or contracts from Pfizer; consulting fees from Pfizer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astrazeneca, Pfizer and Novartis; and support for attending meetings or travel from MSD, Mylan, and Pfizer. BP reports, outside the submitted work, consulting fees from AstraZeneca, Myriad, Pierre Fabre, and Pfizer; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Daiichi Sankyo, Novartis, and Puma; support for attending meetings or travel from AstraZeneca, Pierre Fabre, and MSD; and participation on a data safety monitoring board or advisory board for Novartis, AstraZeneca, and Daiichi Sankyo. FA reports, outside the submitted work, reports grants or contracts from Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Novartis, and Lilly; and consulting fees from Gilead, Guardant Health, MedImmune, and Relay Therapeutics. LA reports, outside the submitted work, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Roche, MSD, AstraZeneca, and BMS; and support for attending meetings or travel from Roche. JL reports a Pfizer grant to his institution for carrying out this study. SD reports, outside the submitted work, grants or contracts from AstraZeneca, Pfizer, Novartis, Roche Genentech, Lilly, Puma, Myriad, Orion, Amgen, Sanofi, MSD, BMS, Seagen, and Taiho; consulting fees from Isis/Servier, Cellectis, Pierre Fabre, and General Electric; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Seagen, AstraZeneca, Pfizer, Exact Sciences, Daiichi, and Lilly; support for attending meetings or travel from Pfizer, AstraZeneca, and Roche Genentech; and participation on a data safety monitoring board or advisory board for AstraZeneca, Sanofi, Orion, and Rappta. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Following the PALOMA-3 study results, the combination of palbociclib, a CDK4/6 inhibitor, with fulvestrant, a selective estrogen receptor degrader, has become a standard therapy in women with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). Palbociclib has been shown to increase the progression-free survival (PFS) overall but no predictive biomarker of palbociclib efficacy has been validated so far. We thus evaluated whether early changes of circulating tumor DNA (ctDNA) levels are associated with palbociclib plus fulvestrant efficiency., Methods: ER+ HER2- MBC patients were included in a prospective observational cohort before treatment initiation. Tumor response was assessed by radiological evaluation (RECIST v1.1) every 3 months. Plasma samples were collected before treatment (baseline), at day 15 (D15), at day 30 (D30), and at disease progression. We searched for somatic mutations from archived tumor tissues by targeted deep sequencing. For patients with somatic mutations identified, circulating tumor DNA (ctDNA) was tracked using digital droplet PCR. Ratios of ctDNA levels ([D15/baseline] and [D30/baseline]) were then correlated with prospectively registered patient characteristics and outcomes., Results: Twenty-five of the 61 patients enrolled had a somatic mutation testable in plasma (N PIK3CA  = 21, N TP53  = 2, N AKT1  = 2). At baseline, 84% of patients had detectable ctDNA levels but ctDNA levels had no prognostic impact on PFS (p = 0.10). Among those patients, ctDNA was still detected in 82% at D15 and 68% at D30. ctDNA clearance observed at day 30 was associated with longer PFS (HR = 7.2, 95% CI = 1.5-32.6, p = 0.004). On the contrary, a [D30/baseline] ctDNA ratio > 1 was associated with a shorter PFS (HR = 5.1, 95% CI = 1.4-18.3, p = 0.02) and all 5 patients with increased ctDNA levels at D30 showed disease progression after 3 months under palbociclib-fulvestrant. Finally, at the time of radiological tumor progression, ctDNA was detected in all patients tested., Conclusion: Our study demonstrates that the efficiency of palbociclib and fulvestrant can be monitored by serial analyses of ctDNA before radiological evaluation and that early ctDNA variation is a prognostic factor of PFS.

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 < 8.0 g/dL (OR = 3.7 [0.9; 16.7]) and prothrombin time < 50% (OR = 9.1 [1.2; 50.0]). A score to predict early death displayed a sensitivity of 86% (95% CI [0.67; 0.96]), a specificity of 73% (95% CI [0.52; 0.88]) and an area under the curve of 0.90 (95% CI [0.83; 0.97])., 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.

Background: Young age is a poor prognostic factor in early stage breast cancer (BC) but its value is less established in metastatic BC (MBC). We evaluated the impact of age at MBC diagnosis on overall survival (OS) across three age groups (<40, 40 to 60 and > 60 years(y))., Methods: ESME MBC database is a national cohort, collecting retrospective data from 18 participating French cancer centers between January 01, 2008 and December 31, 2014., Results: Among 14 403 women included, 1077 (7.5%), 6436 (44.7%) and 6890 (47.8%) pts were <40, 40-60 and > 60 y respectively. Pts <40 had significantly more aggressive presentations than other age groups: more frequent HER2+ (25.7 vs 15.3% in >60y) and triple negative subtypes (27.4 vs 14.6% in >60y), and more frequent visceral involvement (36.3 vs 29.8% in >60y). At a median follow-up of 48 months, median OS differed across age groups: 38.8, 38.4 and 35.6 months for pts <40, 40-60 and > 60y, respectively (p < 0.0001). Compared to pts <40y, older pts had a statistically significant higher risk of death (all causes of death included), although of limited clinical value (HR = 1.1, IC 95%:1.01-1.20). There was a significant trend for better OS in pts <40y with HER2+ and luminal diseases. A possible explanation is a greater use of anti-Her2 therapies as first-line treatments: 86.6, 81.9 and 74.9% for pts <40, 40-60 and > 60y, respectively (p < 0.0001)., Conclusion: Although young age seems associated with more aggressive presentations at diagnosis of MBC, it has no deleterious effect on OS in this large series., Competing Interests: Declaration of competing interest Co-authors having declared no conflict of interests: Sophie Frank, Matthieu Carton, Coraline Dubot, Barbara Pistilli (GR), Audrey Mailliez (COL), Christelle Levy (CFB), Véronique D’Hondt (ICM), Marc Debled (IB), Thomas Vermeulin (CHB), Bruno Coudert (CGFL), Christophe Perrin (CEM), Anthony Gonçalves (IPC), Lionel Uwer (ICL), Jean-Marc Ferrero (CAL), Jean-Christophe Eymard (IJG), Thierry Petit (CPS), Marie-Ange Mouret-Reynier (CJP), Anne Patsouris (ICO PP), Tahar Guesmia (R&D Unicancer), Thomas Bachelot (CLB), Mathieu Robain (R&D Unicancer), Paul Cottu. Mario campone: Advisory Board: Consulting fees to my Institut:Astra ZENECA, Novartis, Abbvie, Sanofi, Pfizer, Sandoz, ACCORD. Personal fees to Lilly, G1 Therapeutic Consultant: Fees to my Institute: Pierre Fabre Oncology; Sanofi; Novartis; Servier. Speaker bureau: Personnal fees Novartis, Lilly Travel: Pfizer, Novartis, Roche, Astra Zeneca. Barbara Pistilli:P ersonal fees from AstraZeneca, Pfizer, Myriad, Pierre Fabre and non-financial support from Pfizer, Puma and Merus, Novartis outside the submitted work Florence Dalenc: Advisory Board: Novartis, Pfizer, Lilly Travel: Pfizer, Novartis, Roche, Astra Zeneca Paul Cottu: Advisory Board: Novartis, Pfizer, Lilly, Roche Travel: Pfizer, Novartis, Roche, Astra Zeneca., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: 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)., Methods: 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)., Results: 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 < 0.001; dichotomized: HR 1.52, 95% CI [1.15-2.02], p = 0.004). CEC counts at 4 weeks had no prognostic impact., Conclusion: This study confirms that CEC count may be associated with the outcome of mBC patients treated with chemotherapy and bevacizumab. However, discrepancies with previous reports in terms of both the timing of CEC count and the direction of the prognostic impact warrant further clinical investigation.

Background: Outcome of HER2-positive metastatic breast cancer (MBC) patients has improved since the use of trastuzumab. However, most HER2-positive MBC patients will progress within 1 year of trastuzumab-based therapy. Only limited data are available concerning long-term responders., Methods: The primary objective of this study was to compare overall survival (OS) of HER2+ MBC patients with long-term response to first-line trastuzumab with overall survival of those with non-long-term response, based on two institutional databases: the French Epidemiological Strategy and Medical Economics program and the Breast Database. Long-term responders (LTR) were defined as patients with non-progressive disease for ≥ 2 years on first-line trastuzumab. Secondary objectives included progression-free survival (PFS), and predictive factors for LTR status., Results: From 2004 to 2014, 422 HER2-positive MBC patients received first-line trastuzumab. With a median follow-up of 48 months, median OS and PFS were 63 months (CI95%, 50-71), and 18 months (CI95%, 15-21) respectively. In 111 patients (26.3%) classified as LTR, median OS was 110 months (CI95%, 95-not reached) versus 56 months in non-LTR patients (CI95%, 47-68). In multivariate logistic regressions, the following factors were independently associated with LTR status: number of metastatic sites (≤ 2 versus > 2, p = 0.01); endocrine therapy for metastatic disease (p = 0.001) and taxane-based first-line chemotherapy (p = 0.003)., Conclusion: Several features are associated with long-term response to trastuzumab: few metastatic sites, taxane-based chemotherapy and maintenance endocrine therapy in HR+ patients. Further studies are needed to identify patients in whom trastuzumab can be stopped after several years of sustained response.

Background: In this prospective phase 2 trial, we assessed the efficacy of trastuzumab-emtansine (T-DM1) in HER2-negative metastatic breast cancer (MBC) patients with HER2-positive CTC., Methods: Main inclusion criteria for screening were as follows: women with HER2-negative MBC treated with ≥ 2 prior lines of chemotherapy and measurable disease. CTC with a HER2/CEP17 ratio of ≥ 2.2 by fluorescent in situ hybridization (CellSearch) were considered to be HER2-amplified (HER2 amp ). Patients with ≥ 1 HER2 amp CTC were eligible for the treatment phase (T-DM1 monotherapy). The primary endpoint was the overall response rate., Results: In 154 screened patients, ≥ 1 and ≥ 5 CTC/7.5 ml of blood were detected in N = 118 (78.7%) and N = 86 (57.3%) patients, respectively. ≥1 HER2 amp CTC was found in 14 patients (9.1% of patients with ≥ 1 CTC/7.5 ml). Among 11 patients treated with T-DM1, one achieved a confirmed partial response. Four patients had a stable disease as best response. Median PFS was 4.8 months while median OS was 9.5 months., Conclusions: CTC with HER2 amplification can be detected in a limited subset of HER2-negative MBC patients. Treatment with T-DM1 achieved a partial response in only one patient., Trial Registration: NCT01975142, Registered 03 November 2013.

Background: Febrile neutropenia (FN) is one of the most common and most critical adverse effects of chemotherapy. Despite many existing guidelines based on the use of granulocyte-colony stimulating factor (G-CSF), FN continues to impair the quality of life and interfere with the treatment of many patients. The purpose of this study was to assess the incidence and management of FN associated with chemotherapy for early breast cancer in routine clinical practice., Methods: All patients with early-stage breast cancer (ESBC) treated by chemotherapy at Institut Curie, Hôpital René Huguenin, in 2014 were retrospectively included. The incidence and management of FN were reported. Risk factors associated with FN were studied by robust-error-variance Poisson regression., Results: A total of 524 patients received either neoadjuvant (N = 130) or adjuvant chemotherapy (N = 394). Most patients (80%) were treated with a combination of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC100; 3 cycles) followed by docetaxel 100 mg/m 2 (D; 3 cycles). The overall incidence of FN was 17%. Eighteen percent of patients received primary prophylaxis (PP) for FN with G-CSF, using pegfilgrastim in 64% of cases and 74% of patients over the age of 70 received PP. Less than 5% of patients who received PP experienced FN. Recurrent FN after secondary prophylaxis was observed in 9% of patients. Forty-seven percent of cases of FN occurred after the first cycle and 30% occurred after the fourth cycle, corresponding to D ± trastuzumab (T). The FEC100 regimen was associated with a relative risk of FN of 1.98 (p = 0.09). Autoimmune (AI) and inflammatory diseases were associated with a higher risk of FN (RR 3.08; p < 0.01). No significant difference in the incidence of FN was observed between adjuvant and neoadjuvant chemotherapy. FN was managed on an outpatient basis in 72% of cases. Outpatients with FN were mainly treated by a combination of amoxicillin-clavulanic acid and ciprofloxacin. Dose reduction or chemotherapy regimen modification were necessary in 25% of patients after FN. No toxic death was reported., Conclusion: The incidence of FN induced by adjuvant/neoadjuvant chemotherapy in ESBC is higher in routine clinical practice than in clinical trials. AI or inflammatory diseases were significant independent risk factors for FN. Primary prophylaxis in patients at risk (elderly, comorbid patients), especially treated with the FEC regimen, is the keystone of management of this adverse effect. Prevention and management of FN to ensure the patient's safety and quality of life are a major issue for both medical oncologists and supportive care physicians.

Study the epidemiological, diagnostic, and treatment features and outcomes of necrotic breast cancer in women. This observational, longitudinal, and descriptive study covered the period from January, 2011, to the end of May, 2016 at the Surgery and Gynecology Departments of Yalgado Ouedraogo University Hospital and Schiphra Medical Center. The study included all women with necrotic breast cancers. Survival was calculated by the Kaplan Meier method and survival comparison was possible with the log-rank method. À risk of error of 0.05 was allowed. Necrotic cancer accounted for 9.1% of all breast cancers. The median age of the patients was 46 years old. The median interval before consultation was 12.4 months. The histological type was invasive ductal carcinoma in 90.8% of cases. Surgery was performed in 51 patients (52%). It was a palliative (cleaning) procedure in 92.2% of cases. Chemotherapy was performed in 28 patients. Overall survival was 61.8% at 6 months, 39.5% at 1 year, and 9.2% at 3 years. Median survival was 10 months: 13 months for women with surgery and 6 months for those without it (p<0.001). Necrotic breast cancer is still common in Ouagadougou. Surgery is the mainstay of the treatment. Survival is mediocre. It therefore seems urgent to focus on raising population awareness and organizing screening campaigns.

Purpose: Leptomeningeal carcinomatosis (MC) is commonly associated with HER2-positive breast cancer (HER2-BC), with a poor prognosis and no standardised treatment. We conducted a phase I dose-escalation study of intrathecal (IT) administration of trastuzumab in HER2-BC patients with MC to determine the maximum tolerated dose (MTD), which was based on both the achievement of a trastuzumab intra-cerebrospinal fluid concentration close to a conventional therapeutic plasma concentration (30 mg/L) and/or dose-limiting toxicity (DLT)., Methods: The protocol planned IT administration of trastuzumab (30 mg, 60 mg, 100 mg or 150 mg dose levels) once a week, over the course of at least 4 weeks. Sixteen patients with MC from HER2-BC received IT trastuzumab. Intra-cerebrospinal fluid samples were obtained before each injection for pharmacokinetics., Results: We did not observe DLT of IT trastuzumab. Eleven patients had no toxicity attributed to IT trastuzumab. For 60 mg or higher dose levels, minor toxicities attributed to IT trastuzumab included headache (2 patients), nausea (2 patients), vomiting (1 patient), cervical pain (1 patient) and peripheral neuropathy (1 patient). Two patients experienced immediate toxicity including headache or vomiting. The mean residual intra-cerebrospinal fluid concentration of trastuzumab was 27.9 mg/L for the 150 mg dose level. Three patients achieved a clinical response, seven patients had stable disease and four patients had progressive disease., Conclusions: The MTD and recommended phase II weekly dose of IT trastuzumab in patients with HER2-BC and MC is 150 mg. A phase II trial using this dose regimen in MC from HER2-BC is ongoing., Registration Identification: ClinicalTrials.gov Identifier: NCT01373710 (https://clinicaltrials.gov/ct2/show/NCT01373710?term=trastuzumab+intrathecal&rank=1)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

International guidelines have set the frame and methods of patients' surveillance after early breast cancer (BC) treatment. Since 1998, delegation of low-risk BC patients follow-up to nonhospital practitioners has been developed within a care network in the Paris region. We used the Gynecomed care network digital database to describe the characteristics of oncological events which occurred in the cohort, and to assess the quality of BC follow-up in relapsing patients. Events were defined as any local, contralateral, or metastatic recurrence, as well as second cancer or death due to any cause. We developed a ranked evaluation method of our surveillance program. Among the 3019 patients followed in the network, 116 (4.3%) patients had 116 events. Median follow-up was 7.1 years (0-51). First events were local-regional relapses, contralateral BCs, metastatic events, second primaries in respectively 52, 26, 14, 24 cases. During the first 5 years, 68.4% of surveillance visits were performed on time, 13.5% were behind schedule and 18.1% were not performed, while 79.1% of mammographies were performed on time, 7.7% behind schedule, and 13.2% were not performed. On schedule examinations allowed diagnosis of 77% of the local-regional, ipsilateral relapses or contralateral BCs, including 38 (69%) discovered by mammographies and 17 (31%) by clinical examination. A nonhospital practitioner care network is able to comply with good surveillance practices and deliver high quality surveillance, in accordance with international guidelines. Delegation of low-risk BC surveillance to nonhospital practitioners is reliable., (© 2017 Wiley Periodicals, Inc.)

Purpose: The Prosigna® breast cancer prognostic gene signature assay identifies a gene-expression profile that permits the classification of tumors into subtypes and gives a score for the risk of recurrence (ROR) at 10 years. The primary objective of this multicenter study was to evaluate the impact of Prosigna's assay information on physicians' adjuvant treatment decisions in patients with early-stage breast cancer. Secondary objectives were to assess confidence of practitioners in their therapeutic recommendations before and after the added information provided by the Prosigna assay; and to evaluate the emotional state of patients before and after the Prosigna test results., Methods: Consecutive patients with invasive early-stage breast cancer were enrolled in a prospective, observational, multicenter study carried out in 8 hospitals in France. The Prosigna test was carried out on surgical specimens using the nCounter® Analysis System located at the Institut Curie. Both before and after receiving the Prosigna test results, physicians completed treatment confidence questionnaires and patients completed questionnaires concerning their state of anxiety, the difficulties felt in face of the therapy and quality of life. Information was also collected at 6 months regarding the physicians' opinion on the test results and the patients' degree of anxiety, difficulties with therapy and quality of life., Results: Between March 2015 and January 2016, 8 study centers in France consecutively enrolled 210 postmenopausal women with estrogen receptor (ER) positive, human epidermal growth hormone-2 (HER-2) negative, and node negative tumors, either stage 1 or stage 2. Intrinsic tumor subtypes as assessed by the Prosigna test were 114 (58.2%) Luminal A, 79 (40.3%) Luminal B, 1 (0.5%) HER-2 enriched (HER-2E), and 2 (1.0%) basal-like. Before receiving the Prosigna test results, physicians categorized tumor subtypes based on immunohistochemistry (IHC) as Luminal A in 126 (64%) patients and Luminal B in 70 (36%) patients, an overall discordance rate of 25%. The availability of Prosigna assay results was significantly associated with the likelihood of change in treatment recommendations, with 34 patients (18%) having their treatment plan changed from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa (p<0.001, Fisher's exact test). Prosigna test results also decreased patients' anxiety about the chosen adjuvant therapy, and improved emotional well-being and measures of personal perceptions of uncertainty., Conclusions: The results of this prospective decision impact study are consistent with 2 previous, identically designed studies carried out in Spain and Germany. The availability of Prosigna test results increased the confidence of treating physicians in their adjuvant treatment decisions, and led to an 18% change in chemotherapy treatment plan (from Adjuvant Chemotherapy to No Adjuvant Chemotherapy or vice versa). Prosigna testing decreased anxiety and improved measures of health-related quality of life in patients facing adjuvant therapy. The 25% discordance between Prosigna test and IHC subtyping underlines the importance of molecular testing for optimal systemic therapy indications in early breast cancer.

The objective of this literature review is to describe the types of tumor heterogeneity in breast cancer and their clinical implication. Two kinds of tumor heterogeneity are described: intertumor heterogeneity and intra-tumor heterogeneity. In breast cancer, inter-tumor heterogeneity was best characterized in the 2000s thanks to high throughput analyses. These analyzes resulted in a molecular classification of breast cancers distinguishing four subtypes: Luminal A, Luminal B, HER 2+ and basal like. This variability may be observed between the primary tumor and metastases, namely the temporal intratumor heterogeneity. The average discrepancy for the progesterone receptor, estrogen, and between HER2 status appears to be 33%, 20% and 8%, respectively. It is then interesting to study the heterogeneity within the primary tumor: this spatial intra-tumor heterogeneity is poorly known. Physiopathology of intra-tumor heterogeneity light be deciphered by studies on cancer stem cells and clonal evolution model. In addition, the tumor microenvironment seems to actively contribute to this heterogeneity. The major interest to study this heterogeneity is the clinical implication that could result. While precision medicine is emerging, it is important to capture the heterogeneity of each specific tumor type. These new biological knowledge will allow us to anticipate such heterogeneity and individualize the management of breast cancer.

The delegation of low-risk breast cancer patients' follow-up to non-hospital practitionners (NHP), including gynaecologists and general practitioners, has been assessed prospectively within a care network in the Paris region. Patients with early stage breast cancer were eligible. The follow-up protocol was built according to international guidelines. By 2012, 289 NHPs were following 2266 patients treated in 11 centres. Median follow-up time was 7.4 years. The mean intervals between two consecutive consultations were 9.5 [9.2-9.8] months for women supposed to be monitored every 6 months and 12.5 [12.2-12.8] for those requiring annual monitoring. The relapse rate was 3.2% [2.1-4.3] at 5 years and 7.8% [5.9-9.7] at 10 years. Seventy one percent of relapses were diagnosed on a scheduled assessment. Only 6% were lost-to-follow-up. Delegating follow-up after low risk breast cancer to NHPs in a care network is feasible, well accepted and provides an alternative to follow-up in specialized centres., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Because of increasing breast cancer incidence and improvement in long-term prognosis, follow-up of patients cannot be carried out entirely in specialized cancer centres. The Réseau Gynécomed was created to transfer the follow-up of patients to primary care physicians (PCP). In 2009, to evaluate the quality of PCP follow-up, a satisfaction study was performed for the 1,245 women followed after breast cancer. Sixty-four percent of the women participate in the study. Before starting follow-up, 87% were informed about its purpose and 93% about its schedule. The satisfaction score was excellent (91%). Old age, perception of a good health status, a high quality of information about and a confident relationship with their PCP were associated with a better satisfaction level. Forty-eight percent of patients thought easy to accept the PCP follow-up. Considering this data, PCP monitoring seems to provide a good follow-up and may be developed. Nonetheless, conditions of patients' choice should be improved and particularly exclude patients with financial difficulties. It would facilitate the growing transfer of follow-up to the PCP.