Trastuzumab deruxtecan in previously treated HER2-positive metastatic or unresectable breast cancer: Real-life data from the temporary use authorization program in France.

BACKGROUND: Early access program (formerly cohort Temporary Authorization for Use) was granted for trastuzumab deruxtecan (T-DXd) in France based on DESTINY-Breast01 trial which demonstrated its efficacy and safety in HER2-positive metastatic/unresectable breast cancer after ≥2 anti-HER2-based regimens received at metastatic stage. METHODS: This multicenter real-world early access program included HER2-positive metastatic/unresectable breast patients pretreated with at least two lines of anti-HER2 regimens who received T-DXd 5.4 mg/kg intravenously in monotherapy every 3 weeks. RESULTS: Four hundred and fifty-nine patients (median age, 58 years; hormone receptor-positive, 67%; brain metastases, 28.1%) received T-DXd. Before inclusion, 81.7% of patients had radiation therapy and 76.5% had undergone surgery. Median number of prior metastatic treatment lines was four (range, 2-22); 99.8% patients had received trastuzumab, 94.8% trastuzumab emtansine and 79.3% pertuzumab. Follow-up was performed from September 30, 2020 to March 30, 2021; when the early access program stopped, the median duration of T-DXd treatment was 3.4 (range, 0-7.8) months. In 160 patients with available tumor assessment, objective response rate was 56.7% and 12.1% had progression. In 57 patients with available brain tumor assessment, complete or partial intracranial response was reported for 35.7% patients and 5.4% had progression. A total of 17 (3.7%) patients with interstitial lung disease (ILD) was reported with no cases of ILD-related death. CONCLUSIONS: In this early access program in patients with heavily pretreated HER2-positive metastatic/unresectable breast cancer, T-DXd had antitumor activity with a similar response to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed.

Red Blood Cell Contribution to Thrombosis in Polycythemia Vera and Essential Thrombocythemia.

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) characterized by clonal erythrocytosis and thrombocytosis, respectively. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. Despite a debated notion that red blood cells (RBCs) play a passive and minor role in thrombosis, there has been increasing evidence over the past decades that RBCs may play a biological and clinical role in PV and ET pathophysiology. This review summarizes the main mechanisms that suggest the involvement of PV and ET RBCs in thrombosis, including quantitative and qualitative RBC abnormalities reported in these pathologies. Among these abnormalities, we discuss increased RBC counts and hematocrit, that modulate blood rheology by increasing viscosity, as well as qualitative changes, such as deformability, aggregation, expression of adhesion proteins and phosphatidylserine and release of extracellular microvesicles. While the direct relationship between a high red cell count and thrombosis is well-known, the intrinsic defects of RBCs from PV and ET patients are new contributors that need to be investigated in depth in order to elucidate their role and pave the way for new therapeutical strategies.

Atezolizumab and paclitaxel as first line therapy in advanced triple-negative breast cancer patients included in the French early access program.

Following the results of the IMpassion130 trial, an early access program (EAP) was opened in France, allowing patients with PD-L1-positive advanced triple negative breast cancer (aTNBC) to receive a combination of paclitaxel and atezolizumab as first line therapy. This EAP was later discontinued when the IMpassion131 trial read out with negative results. We performed a retrospective multicentric analysis in patients who were prospectively enrolled in the French EAP. Efficacy and toxicity data were obtained on 64 patients treated from August 2019 to August 2020 in 10 French cancer centers. Median progression-free survival (PFS) and overall survival (OS) were 4.1 months (95% CI [3.0-5.8]) and 17.9 months (95% CI [12.4-NR]), respectively. The 6-months PFS rate was 28% (95% CI [16-40%]) (N = 18/64), while N = 33/64 patients (52%, 95% CI [38-63%]) experienced a tumor response. Exploratory subgroup analyses retrieved that corticosteroid use at inclusion in the EAP, before treatment initiation, was the only independent unfavorable prognostic factor for PFS (HR 2.7, 95% CI [1.3-5.6]). No new safety signal was observed. This real-life study, unique by its setting (EAP granted by anticipation and later withdrawn), suggests atezolizumab and paclitaxel has a limited efficacy in PD-L1-positive aTNBC, especially in patients receiving corticosteroids as comedication before treatment start.

Pertuzumab Plus Trastuzumab With or Without Chemotherapy Followed by Emtansine in ERBB2-Positive Metastatic Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial.

Importance: In ERBB2 (formerly HER2)-positive metastatic breast cancer (MBC), combining trastuzumab and pertuzumab with taxane-based chemotherapy is the first line of standard care. Given that trastuzumab plus pertuzumab was proven effective in ERBB2-positive MBC, even without chemotherapy, whether the optimal first-line strategy could be trastuzumab plus pertuzumab alone instead of with chemotherapy is unresolved. Objective: To assess overall survival (OS) at 2 years and progression-free survival (PFS) for patients randomly assigned to receive first-line pertuzumab plus trastuzumab alone or with chemotherapy followed by trastuzumab and emtansine at progression; PFS of second-line trastuzumab and emtansine treatment following trastuzumab plus pertuzumab; and OS and PFS in the ERBB2-enriched and ERBB2-nonenriched subtypes. Design, Setting, and Participants: This was a secondary analysis of a multicenter, open-label, phase 2 randomized clinical trial conducted at 27 sites in France, 20 sites in Switzerland, 9 sites in the Netherlands, and 1 site in Germany. Overall, 210 patients with centrally confirmed ERBB2-positive MBC were randomized between May 3, 2013, and January 4, 2016, with termination of the trial May 26, 2020. Data were analyzed from December 18, 2020, to May 10, 2022. Interventions: Patients randomly received pertuzumab (840 mg intravenously [IV], then 420 mg IV every 3 weeks) plus trastuzumab (8 mg/kg IV, then 6 mg/kg IV every 3 weeks) without chemotherapy (group A) or pertuzumab plus trastuzumab (same doses) with either paclitaxel (90 mg/m2 for days 1, 8, and 15, then every 4 weeks for ≥4 months) or vinorelbine tartrate (25 mg/m2 for first administration followed by 30 mg/m2 on days 1 and 8 and every 3 weeks for ≥4 months) followed by pertuzumab plus trastuzumab maintenance after chemotherapy discontinuation (group B). Main Outcomes and Measures: Overall survival at 24 months by treatment group, PFS for first-line treatment, PFS for second-line treatment, and patient-reported quality of life (QOL). Results: A total of 210 patients were included in the analysis, with a median age of 58 (range, 26-85) years. For group A, 24-month OS was 79.0% (90% CI, 71.4%-85.4%); for group B, 78.1% (90% CI, 70.4%-84.5%). Median PFS with first-line treatment was 8.4 (95% CI, 7.9-12.0) months in group A and 23.3 (95% CI, 18.9-33.1) months in group B. Unlike expectations, OS and PFS did not markedly differ between populations with ERBB2-enriched and ERBB2-nonenriched cancer. Adverse events were less common without chemotherapy, with small QOL improvements from baseline in group A and stable QOL in group B. Conclusions and Relevance: The findings of this secondary analysis of a randomized clinical trial suggest that the chemotherapy-free anti-ERBB2 strategy is feasible without being detrimental in terms of OS. The 50-gene prediction analysis of microarray signature could not help to identify the most appropriate patient population for this approach. Trial Registration: ClinicalTrials.gov Identifier: NCT01835236.

[Needs assessment for the establishment of an Oral Therapy Unit]. / Évaluation des besoins pour la mise en place d'une Unité de Thérapie Orale.

INTRODUCTION: Oncological at home-treatment improves patient quality of life and autonomy but requires close watchfulness of adverse events and compliance to treatment. For nearly ten years, pharmaceutical consultations for home-based anticancer oral therapies patients are proposed on medical request in Avignon-Provence Cancer Institute (ICAP). Organizational changes led us to modify this management by integrating dedicated nurses to create an Oral Therapy Unit (OTU). MATERIALS ET METHODS: Needs and expectations assessment questionnaires were proposed to healthcare professionals and patients treated by oral therapies. The analysis of these questionnaires allows to set up an OTU, integrating a dedicated nurse, adapted to the expectations of patients and healthcare professionals. About 8 months later, a new evaluation was carried out to assess the impact of this new support for patient care and health professionals' organization. RESULTS: The results of the studies carried out before OTU implementation highlight the importance of multi-professional support for patients from the start of treatment and during the follow-up. With the new OTU pathway, professionals expect a patient course improvement (94%), a better compliance (88%), a therapeutic accidents reduction (81%) and an improvement in the patient-caregiver relationship (69%). Regarding the organization, 56% of them are expecting to save medical and pharmaceutical time. CONCLUSION: The OTU creation in our institution and these new multi-professionals' teams' management of patients has obtained a favourable opinion from healthcare professionals and patient satisfaction.

Switch to fulvestrant and palbociclib versus no switch in advanced breast cancer with rising ESR1 mutation during aromatase inhibitor and palbociclib therapy (PADA-1): a randomised, open-label, multicentre, phase 3 trial.

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 (bESR1mut), 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 bESR1mut 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 bESR1mut 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 bESR1mut 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 bESR1mut 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 bESR1mut 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.

Everolimus Added to Adjuvant Endocrine Therapy in Patients With High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer.

PURPOSE: Everolimus, an oral inhibitor of the mammalian target of rapamycin, improves progression-free survival in combination with endocrine therapy (ET) in postmenopausal women with aromatase inhibitor-resistant metastatic breast cancer. However, the benefit of adding everolimus to ET in the adjuvant setting in early breast cancer is unknown. PATIENTS AND METHODS: In this randomized double-blind phase III study, women with high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer were randomly assigned to everolimus or placebo for 2 years combined with standard ET. Stratification factors included ET agent, receipt of neoadjuvant versus adjuvant chemotherapy, progesterone receptor status, duration of ET before random assignment, and lymph node involvement. The primary end point was disease-free survival (DFS). The trial is registered with ClinicalTrials.gov (identifier: NCT01805271). RESULTS: Between June 2013 and March 2020, 1,278 patients were randomly allocated to receive everolimus or placebo. At the first interim analysis, the trial was stopped for futility and a full analysis undertaken once data snapshot complete. One hundred forty-seven patients have had a DFS event reported and at 3 years, DFS did not differ between patients who received ET plus everolimus (88% [95% CI, 85 to 91]) or ET plus placebo (89% [95% CI, 86 to 91; hazard ratio, 0.95; 95% CI, 0.69 to 1.32; P = .77]). Grade ≥ 3 adverse events were reported in 22.9% of patients (29.9% with everolimus v 15.9% with placebo, P < .001). 53.4% everolimus-treated patients permanently discontinued experimental treatment early compared with placebo-treated 22.3%. CONCLUSION: Among high-risk patients, everolimus added to adjuvant ET did not improve DFS. Tolerability was a concern, with more than half of patients stopping everolimus before study completion. Everolimus cannot be recommended in the adjuvant setting.

RNA-Seq is not required to determine stable reference genes for qPCR normalization.

Assessment of differential gene expression by qPCR is heavily influenced by the choice of reference genes. Although numerous statistical approaches have been proposed to determine the best reference genes, they can give rise to conflicting results depending on experimental conditions. Hence, recent studies propose the use of RNA-Seq to identify stable genes followed by the application of different statistical approaches to determine the best set of reference genes for qPCR data normalization. In this study, however, we demonstrate that the statistical approach to determine the best reference genes from commonly used conventional candidates is more important than the preselection of 'stable' candidates from RNA-Seq data. Using a qPCR data normalization workflow that we have previously established; we show that qPCR data normalization using conventional reference genes render the same results as stable reference genes selected from RNA-Seq data. We validated these observations in two distinct cross-sectional experimental conditions involving human iPSC derived microglial cells and mouse sciatic nerves. These results taken together show that given a robust statistical approach for reference gene selection, stable genes selected from RNA-Seq data do not offer any significant advantage over commonly used reference genes for normalizing qPCR assays.

Adhesion Molecules Involved in Stem Cell Niche Retention During Normal Haematopoiesis and in Acute Myeloid Leukaemia.

In the bone marrow (BM) of adult mammals, haematopoietic stem cells (HSCs) are retained in micro-anatomical structures by adhesion molecules that regulate HSC quiescence, proliferation and commitment. During decades, researchers have used engraftment to study the function of adhesion molecules in HSC's homeostasis regulation. Since the 90's, progress in genetically engineered mouse models has allowed a better understanding of adhesion molecules involved in HSCs regulation by BM niches and raised questions about the role of adhesion mechanisms in conferring drug resistance to cancer cells nested in the BM. This has been especially studied in acute myeloid leukaemia (AML) which was the first disease in which the concept of cancer stem cell (CSC) or leukemic stem cells (LSCs) was demonstrated. In AML, it has been proposed that LSCs propagate the disease and are able to replenish the leukemic bulk after complete remission suggesting that LSC may be endowed with drug resistance properties. However, whether such properties are due to extrinsic or intrinsic molecular mechanisms, fully or partially supported by molecular crosstalk between LSCs and surrounding BM micro-environment is still matter of debate. In this review, we focus on adhesion molecules that have been involved in HSCs or LSCs anchoring to BM niches and discuss if inhibition of such mechanism may represent new therapeutic avenues to eradicate LSCs.

Immune-Related Genetic Overlap Between Regional Gray Matter Reductions and Psychiatric Symptoms in Adolescents, and Gene-Set Validation in a Translational Model.

Adolescence is a period of vulnerability for the maturation of gray matter (GM) and also for the onset of psychiatric disorders such as major depressive disorder (MDD), bipolar disorder and schizophrenia. Chronic neuroinflammation is considered to play a role in the etiology of these illnesses. However, the involvement of neuroinflammation in the observed link between regional GM volume reductions and psychiatric symptoms is not established yet. Here, we investigated a possible common immune-related genetic link between these two phenomena in european adolescents recruited from the community. Hippocampal and medial prefrontal cortex (mPFC) were defined a priori as regions of interest (ROIs). Their GM volumes were extracted in 1,563 14-year-olds from the IMAGEN database. We found a set of 26 SNPs that correlated with the hippocampal volumes and 29 with the mPFC volumes at age 14. We formed two ROI-Related Immune-gene scores (RRI) with the inflammation SNPs that correlated to hippocampal GM volume and to mPFC GM volume. The predictive ability of both RRIs with regards to the presence of psychiatric symptoms at age 18 was investigated by correlating the RRIs with psychometric questionnaires obtained at age 18. The RRIs (but not control scores constructed with random SNPs) correlated with the presence of depressive symptoms, positive psychotic symptoms, and externalizing symptoms in later adolescence. In addition, the effect of childhood maltreatment, one of the major environmental risk factors for depression and other mental disorders, interacted with the RRI effect. We next sought to validate this finding by investigating our set of inflammatory genes in a translational animal model of early life adversity. Mice were subjected to a protocol of maternal separation at an early post-natal age. We evaluated depressive behaviors in separated and non-separated mice at adolescence and their correlations with the concomitant expression of our genes in whole blood samples. We show that in mice, early life adversity affected the expression of our set of genes in peripheral blood, and that levels of expression correlated with symptoms of negative affect in adolescence. Overall, our translational findings in adolescent mice and humans provide a novel validated gene-set of immune-related genes for further research in the early stages of mood disorders.

Retracing Schwann Cell Developmental Transitions in Embryonic Dissociated DRG/Schwann Cell Cocultures in Mice.

Embryonic Dissociated Dorsal Root Ganglia (DRG) cultures are often used to investigate the role of novel molecular pathways or drugs in Schwann cell development and myelination. These cultures largely recapitulate the order of cellular and molecular events that occur in Schwann cells of embryonic nerves. However, the timing of Schwann cell developmental transitions, notably the transition from Schwann Cell Precursors (SCP) to immature Schwann cells (iSC) and then to myelinating Schwann cells, has not been estimated so far in this culture system. In this study, we determined the expression profiles of Schwann cell developmental genes during the first week of culture and then compared our data to the expression profiles of these genes in developing spinal nerves. This helped in identifying that SCP transition into iSC between the 5th and 7th day in vitro. Furthermore, we also investigated the transition of immature cells into pro-myelinating and myelinating Schwann cells upon the induction of myelination in vitro. Our results suggest that Schwann cell differentiation beyond the immature stage can be observed as early as 4 days post the induction of myelination in cocultures. Finally, we compared the myelinating potential of coculture-derived Schwann cell monocultures to cultures established from neonatal sciatic nerves and found that both these culture systems exhibit similar myelinating phenotypes. In effect, our results allow for a better understanding and interpretation of coculture experiments especially in studies that aim to elucidate the role of a novel actor in Schwann cell development and myelination.

Flow Cytometry Analysis of Mouse Hematopoietic Stem and Multipotent Progenitor Cells.

Flow cytometry has been widely used to detect a single event by means of multiparametric fluorescence measurements. Here we describe a method to analyze subsets of hematopoietic stem and progenitor cells isolated from long bones of mice. We further show that this method allows for comparing JAM-C protein expression between subsets of hematopoietic stem and progenitor cells.

[Patients treated with palbociclib and endocrine therapy for metastatic breast cancer: Can we predict the occurrence of severe early hematological toxicity?] / Patients sous palbociclib et hormonothérapie pour un cancer du sein métastatique : peut-on prédire la survenue d'une hématotoxicité précoce et sévère ?

INTRODUCTION: The addition of palbociclib to endocrine therapy has been shown to improve progression free survival in hormone receptor positive metastatic breast cancer patients. This cyclin CDK4/6 inhibitor could expose patients to a grade 3-4 hematological toxicity, leading to treatment discontinuation or treatment interruption that is potentially associated with a lack of efficiency. The aim of this study was to identify predictive factors of severe early hematotoxicity (ESHT). METHODS: This retrospective cohort study included patients who started palbociclib in the Institut Sainte Catherine between December 1, 2016 and January 1, 2019 for the treatment of metastatic breast cancer. Individual data and hematological toxicity were collected from electronic medical records. ESHT was defined as the occurrence, during the first 3 cycles, of grade 4 or grade 3 hematological toxicity requiring palbociclib dose reduction. RESULTS: In total, 181 patients (180 females) were included; median age was 67 years. Forty-six patients (25.4%) experienced an ESHT. Predictive factors of ESHT in multivariate analysis were a performance status (PS) of 2 or more (P=0.024) and an history of radiotherapy of bone metastasis in the previous year (P=0.003). Before palbociclib initiation, a neutrophil count below 3.37g/L was predictive of ESHT with a sensibility of 76% and a specificity of 71%. CONCLUSIONS: ECOG PS, bone radiotherapy within the year and low baseline neutrophils count are associated with ESHT in palbociclib-treated metastatic breast cancer patients. These elements could be useful for a careful monitoring leading to adapted therapy.

Role of supportive care in improving the quality of life and reducing unscheduled hospital care in patients with metastatic breast cancer.

BACKGROUND: Metastatic breast cancer (MBC) patients experience long survival and report poorer quality of life than localized breast cancer patients. Comprehensive supportive care (CSC) has been shown to improve the quality of life (QoL) of MBC. The respective part of each support care has not been fully examined, and little is known about whether meeting patients' needs is accompanied by decreased unscheduled hospital care (UHC). METHODS: This prospective monocentric study included women who started a new treatment line for MBC between January 2018 and December 2018. The endpoints were factors associated with UHC and QoL (SF36) at month 12. RESULTS: 100 patients were offered CSC, 78 were included (21 refusals, 1 no MBC). CSC was provided to 60 patients: pain (43%), psychological (37%), kinesitherapy (30%), social assistance (22%), esthetic (18%), nutrition (18%), massage (13%), and none (10%). CSC rate was not statistically different among patients with (58%) and without UHD (49%). Factors associated with a decrease of UHC were age > 65 years (p = 0.01), no previous treatment for MBC (p = 0.0001) with a trend for the lack of CSC (p = 0.054). Among the 8 domains of the SF36 scale, only health change perception was improved (p = 0.01) and its predictive factors were treatment carried out as planned (p = 0.0004), pain care (p = 0.003), and lack of MBC progression (p = 0.0035). CONCLUSION: CSC can improve QoL in MBC. Painful patients might benefit more from CSC. UHC did not decrease for patients receiving CSC as expected possibly because of their important needs for clinical care.

PELICAN-IPC 2015-016/Oncodistinct-003: A Prospective, Multicenter, Open-Label, Randomized, Non-Comparative, Phase II Study of Pembrolizumab in Combination With Neo Adjuvant EC-Paclitaxel Regimen in HER2-Negative Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is a highly aggressive entity with a poor outcome and relative resistance to treatment. Despite progresses achieved during the last decades, the survival remains significantly lower than non-IBC. Recent clinical trials assessing PD-1/PD-L1 inhibitors showed promising results in non-IBC. Pembrolizumab, an anti-PD-1 monoclonal antibody, revolutionized the treatment of different cancers. Several recent studies suggested a potential interest of targeting the immune system in IBC by revealing a more frequent PD-L1 expression and an enriched immune microenvironment when compared with non-IBC. Here, we describe the rationale and design of PELICAN-IPC 2015-016/Oncodistinct-003 trial, an open-label, randomized, non-comparative, phase II study assessing efficacy, and safety of pembrolizumab in combination with anthracycline-containing neoadjuvant chemotherapy in HER2-negative IBC. The trial is ongoing. The primary endpoint is the pCR rate (ypT0/Tis, ypN0) in overall population and the co-primary endpoint is safety profile during a run-in phase. Key secondary objectives include tolerability, invasive disease-free, event-free and overall survivals, as well as collection of tumor and blood samples for translational research. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ (NCT03515798).

First-line bevacizumab and eribulin combination therapy for HER2-negative metastatic breast cancer: Efficacy and safety in the GINECO phase II ESMERALDA study.

PURPOSE: Combining bevacizumab with paclitaxel significantly improves progression-free survival (PFS) versus paclitaxel alone in HER2-negative metastatic breast cancer (MBC). Eribulin is active and tolerable in pretreated MBC. To assess whether eribulin may offer a more tolerable yet effective combination partner for bevacizumab, we evaluated a bevacizumab/eribulin combination regimen as first-line therapy for MBC. METHODS: In this single-arm phase II study, patients with histologically confirmed HER2-negative MBC and no prior chemotherapy for MBC received eribulin 1.23 mg/m2 on days 1 and 8 every 3 weeks for ≥6 cycles plus bevacizumab 15 mg/kg on day 1 every 3 weeks until disease progression. The primary endpoint was non-progression rate at 1 year. Secondary endpoints included objective response rate (ORR), PFS, and safety. RESULTS: The median age of the 61 treated female patients was 59 years, 16% had triple-negative MBC, 30% had ≥3 metastatic sites, and 71% had received prior (neo)adjuvant chemotherapy. Patients received a median of six eribulin and nine bevacizumab cycles. The non-progression rate at 1 year was 32% (95% confidence interval [CI]: 20-43%), ORR was 47% (95% CI: 34-60%), and median PFS was 8.3 months (95% CI: 7.0-9.6 months). The only grade ≥3 clinical adverse events in >5% of patients were hypertension (39%), neutropenia (26%), thrombosis (10%), and paresthesia/dysesthesia (7%). CONCLUSION: First-line eribulin/bevacizumab combination therapy showed interesting activity in MBC with an acceptable safety profile, including a particularly low incidence of high-grade neuropathy.

Brief Hospital Supervision of Exercise and Diet During Adjuvant Breast Cancer Therapy Is Not Enough to Relieve Fatigue: A Multicenter Randomized Controlled Trial.

Supervised exercise dietary programs are recommended to relieve cancer-related fatigue and weight increase induced by adjuvant treatment of early breast cancer (EBC). As this recommendation lacks a high level of evidence, we designed a multicenter randomized trial to evaluate the impact of an Adapted Physical Activity Diet (APAD) education program on fatigue. We randomized 360 women with EBC who were receiving adjuvant chemotherapy and radiotherapy to APAD or usual care at eight French cancer institutions. Data were collected at baseline, end of chemotherapy, end of radiotherapy, and 6 months post-treatment. The primary endpoint was the general cancer-related fatigue score using the MFI-20 questionnaire. Fatigue correlated with the level of precariousness, but we found no significant difference between the two groups in terms of general fatigue (p = 0.274). The APAD arm has a smaller proportion of patients with confirmed depression at the end of follow-up (p = 0.052). A transient modification in physical activity levels and dietary intake was reported in the experimental arm. However, a mixed hospital- and home-based APAD education program is not enough to improve fatigue caused by adjuvant treatment of EBC. Cancer care centers should consider integrating more proactive diet-exercise supportive care in this population, focusing on precarious patients.

GPR56/ADGRG1 is associated with response to antidepressant treatment.

It remains unclear why many patients with depression do not respond to antidepressant treatment. In three cohorts of individuals with depression and treated with serotonin-norepinephrine reuptake inhibitor (N = 424) we show that responders, but not non-responders, display an increase of GPR56 mRNA in the blood. In a small group of subjects we also show that GPR56 is downregulated in the PFC of individuals with depression that died by suicide. In mice, we show that chronic stress-induced Gpr56 downregulation in the blood and prefrontal cortex (PFC), which is accompanied by depression-like behavior, and can be reversed by antidepressant treatment. Gpr56 knockdown in mouse PFC is associated with depressive-like behaviors, executive dysfunction and poor response to antidepressant treatment. GPR56 peptide agonists have antidepressant-like effects and upregulated AKT/GSK3/EIF4 pathways. Our findings uncover a potential role of GPR56 in antidepressant response.

GRASP55 Is Dispensable for Normal Hematopoiesis but Necessary for Myc-Dependent Leukemic Growth.

Grasp55 is a ubiquitous Golgi stacking protein involved in autophagy, protein trafficking, and glucose deprivation sensing. The function of Grasp55 in protein trafficking has been attributed to its PDZ-mediated interaction with the C-terminal PDZ-binding motifs of protein cargos. We have recently shown that such an interaction occurs between Grasp55 and the adhesion molecule Jam-C, which plays a central role in stemness maintenance of hematopoietic and spermatogenic cells. Accordingly, we have found that Grasp55-deficient mice suffer from spermatogenesis defects similar to Jam-C knockout mice. However, whether Grasp55 is involved in the maintenance of immunohematopoietic homeostasis through regulation of protein transport and Jam-C expression remains unknown. In this study, we show that Grasp55 deficiency does not affect hematopoietic stem cell differentiation, engraftment, or mobilization, which are known to depend on expression of Grasp55-dependent protein cargos. In contrast, using an Myc-dependent leukemic model addicted to autophagy, we show that knockdown of Grasp55 in leukemic cells reduces spleen and bone marrow tumor burden upon i.v. leukemic engraftment. This is not due to reduced homing of Grasp55-deficient cells to these organs but to increased spontaneous apoptosis of Grasp55-deficient leukemic cells correlated with increased sensitivity of the cells to glucose deprivation. These results show that Grasp55 plays a role in Myc-transformed hematopoietic cells but not in normal hematopoietic cells in vivo.