The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics ...was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.
Elevated body mass index (BMI) represents a risk factor for cancer-related fatigue (CRF). Weight loss interventions are feasible and safe in cancer survivors, leading to improved cardio-metabolic and ...quality of life (QOL) outcomes and modulating inflammatory biomarkers. Randomized data are lacking showing that a lifestyle intervention aimed at weight loss, combining improved diet, exercise, and motivational counseling, reduces CRF. Motivating to Exercise and Diet, and Educating to healthy behaviors After breast cancer (MEDEA) is a multi-center, randomized controlled trial evaluating the impact of weight loss on CRF in overweight or obese survivors of breast cancer. Herein, we described the MEDEA methodology.
Patients (N = 220) with stage I-III breast cancer and BMI ≥ 25 kg/m
, within 12 months of primary treatment, and able to walk ≥ 400 m are eligible to enroll. Participants are randomized 1:1 to health education alone vs. a personalized telephone-based weight loss intervention plus health education. Both arms receive a health education program focusing on healthy living. Patients in the intervention arm are paired with an individual lifestyle coach, who delivers the intervention through 24 semi-structured telephone calls over 1 year. Intervention goals include weight loss ≥ 10% of baseline, caloric restriction of 500-1000 Kcal/day, and increased physical activity (PA) to 150 (initial phase) and 225-300 min/week (maintenance phase). The intervention is based on the social cognitive theory and is adapted from the Breast Cancer Weight Loss trial (BWEL, A011401). The primary endpoint is the difference in self-reported CRF (EORTC QLQ-C30) between arms. Secondary endpoints include the following: QOL (EORTC QLQ-C30, -BR45, -FA12), anxiety, and depression (HADS); weight and BMI, dietary habits and quality, PA, and sleep; health care costs (hospital-admissions, all-drug consumption, sick leaves) and cost-effectiveness (cost per quality-adjusted life-year); and patient motivation and satisfaction. The primary analysis of MEDEA will compare self-reported CRF at 12 months post-randomization between arms, with 80.0% power (two-sided α = 0.05) to detect a standardized effect size of 0.40.
MEDEA will test the impact of a weight loss intervention on CRF among overweight or obese BC survivors, potentially providing additional management strategies and contributing to establish weight loss support as a new standard of clinical care.
ClinicalTrials.gov NCT04304924.
Patient and public involvement (PPI) has become an essential part of health research. There is a need for genuine involvement in order to ensure that research is relevant to patients. This can then ...improve the quality, relevance, and impact of health research, while at the same time reducing wasted research and in doing so bringing science and society closer together. Despite the increasing attention for this involvement, it is not yet common practice to report on proposed activities. An article reporting planned PPI could provide guidance and inspiration for the wider academic community in future activities. Therefore, this current article aims to describe the way in which PPI principles are incorporated in the research project called "Quality of Life in Oncology: measuring what matters for cancer patients and survivors in Europe (EUonQoL)." This project aims to develop a new set of questionnaires to enable cancer patients to assess their quality of life, entitled the EUonQoL-Kit. The first step is to recruit cancer patients and their informal caregivers as co-researchers in order to train them to collaborate with the researchers. Based on their skills and preferences, they are then assigned to several of the project's work packages. Their individual roles, tasks, and responsibilities regarding the work packages, to which they have been assigned, are evaluated and adapted when necessary. The impact of their involvement is evaluated by both the researchers and co-researchers. PPI is a complex and dynamic process. As such, the overall structure of the research may be defined while at the same time leaving room for certain aspects to be filled in later. Our research is, we believe, relevant as co-researcher involvement in such a large European project as EUonQoL is a new development.
Gene transfer in human hematopoietic stem cells (HSCs) has great potential for both gene therapy and the understanding of hematopoiesis. As HSCs have extensive proliferative capacities, stable gene ...transfer should include genomic integration of the transgene. Lentiviral vectors are now preferred to oncoretroviral vectors especially because they integrate in nondividing cells such as HSCs, thereby avoiding the use of prolonged cytokine stimulation. Human immunodeficiency virus type-1 (HIV-1) has evolved a complex reverse transcription strategy including a central strand displacement event controlled in cis by the central polypurine tract (cPPT) and the central termination sequence (CTS). This creates, at the center of HIV-1 linear DNA molecules, a 99-nucleotide-long plus-strand overlap, the DNA flap, which acts as a cis-determinant of HIV-1 genome nuclear import. The reinsertion of the DNA flap sequence in an HIV-derived lentiviral vector promotes a striking increase of gene transduction efficiency in human CD34+ hematopoietic cells, and the complementation of the nuclear import defect present in the parental vector accounts for this result. In a short ex vivo protocol, the flap-containing vector allows efficient transduction of the whole hierarchy of human HSCs including both slow-dividing or nondividing HSCs that have multiple lymphoid and myeloid potentials and primitive cells with long-term engraftment ability in nonobese diabetic/severe combined immunodeficiency mice (NOD/SCID).
Abstract
Rationale: Overweight and obesity are highly prevalent among BC patients and are linked to poorer prognosis and worse patient-reported outcomes (PROs). Weight loss interventions, based on ...caloric restriction, increased physical activity (PA) and behavioral counselling, are safe and feasible among BC survivors and hold the promise to improve BC-specific outcomes. MEDEA: Motivating to Exercise and Diet, and Educating to healthy behaviors After breast cancer (ClinicalTrials.gov NCT04304924) will evaluate the impact of weight loss on CRF.
Trial design: French multi-center 1:1 randomized controlled trial comparing a 12-month personalized, telephone-based weight loss program + health education intervention vs health education alone in overweight or obese BC patients.
Endpoints and measures: Primary endpoint: difference in self-reported CRF 12 months post-randomization between arms, measured using the EORTC QLQ-C30 CRF subscale. Secondary endpoints: 1) PROs (EORTC QLQ-C30, -B45, -FA12), anxiety and depression (Hospital Anxiety and Depression Scale); 2) weight and body mass index (BMI), diet habits and quality, PA, sleep; 3) cost-effectiveness (number and length of hospital-admissions, all-drug consumption, number and duration of sick leaves). Accelerometer data will be collected to track PA and sleep measures. Qualitative analyses will evaluate patient motivation and satisfaction.
Main eligibility criteria: stage I-II-III BC, primary BC treatment completed within the prior 12 months (definitive surgery, adjuvant chemo-, and/or radio-therapy, if administered), BMI ≥25 kg/m2, ability to walk at least 400 meters at any pace, ECOG PS 0-1, not participating in another weight loss, dietary or PA intervention clinical trial.
Intervention and Control arms: The intervention and health education program are adapted from the BWEL: Breast Cancer WEight Loss study (ClinicalTrials.gov NCT02750826; PI Ligibel JA). The behavior change program is based on the Social Cognitive Theory. Patients in the intervention arm are paired with an individual lifestyle coach, who delivers the intervention through 24 semi-structured telephone calls of 30-60 minutes, supplemented by a detailed participant workbook and scheduled as follows: 1) intensive phase (weeks 1-12), 12 weekly calls; 2) consolidation phase (weeks 13-24), 6 bi-weekly calls; 3) maintenance phase (weeks 25-52), 1 monthly call. Coaches were hired and trained specifically for MEDEA, they are located at a centralized call center and receive support from coordinating nutrition, PA, and behavioral experts. Regular meetings with study team and investigators assure standardized delivery of the intervention and troubleshooting. Intervention goals include weight loss ≥10% of baseline weight, caloric restriction of 500-1000 Kcal/day, increased PA to 150 minutes/week in the initial phase and 225-300 minutes/week in the maintenance phase. Toolbox solutions are offered to tailor the intervention and meet the needs of specific ethnic, socioeconomic or other patient populations with difficulties in achieving intervention goals. All participants in both arms receive a health education program focusing on healthy living.
Accrual: MEDEA will enroll 220 patients overall. Recruitment started in June 2020.
Statistical considerations: The primary analysis of MEDEA will compare the primary endpoint of CRF scores at the 12-month post-randomization time point between arms. The study has 90.0% power at two-sided α=0.05 to detect a standardized effect size of 0.40 (sample size inflated for drop outs). For interpreting the clinical significance of effects, 0.2, 0.5 and 0.8 standard deviation effects will be considered as small, moderate, and large (Cohen, 1988). All other measures, time points and analyses will be considered secondary or exploratory.
Citation Format: Antonio Di Meglio, Elise Martin, Stefan Michiels, Cecile Charles, Tracy E. Crane, Aude Barbier, Bruno Raynard, Anthony Mangin, Olivier Tredan, Paul H. Cottu, Laurence Vanlemmens, Carine Segura-Djezzar, Anne Lesur, Barbara Pistilli, Florence Joly, Thomas Ginsbourger, Bernadette Coquet, Guillemette Jacob, Aude Sirven, Julia Bonastre, Jennifer A. Ligibel, Ines Vaz-Luis. MEDEA: A randomized trial of weight loss to reduce cancer-related fatigue (CRF) among overweight and obese breast cancer (BC) patients abstract. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-38-01.
The recent development of lentivirus-derived vectors is an important breakthrough in gene transfer technology because these vectors allow transduction of nondividing cells such as hematopoietic stem ...cells (HSC), due to an active nuclear import of reverse-transcribed vector DNA. We recently demonstrated that addition of the central DNA flap of HIV-1 to an HIV-derived lentiviral vector strikingly increases transduction of CD34+ cells. We now describe improvements of the transduction protocol designed to preserve HSC properties and two modifications of the previously described TRIP-CMV vector. First, deletion of the enhancer/promoter of the 3′ LTR in the TRIP-CMV vector resulted in a safer vector (TRIPΔU3-CMV) with conserved transduction efficiency and increased EGFP transgene expression. Second, the original internal CMV promoter was replaced with the promoter for the ubiquitously expressed elongation factor 1α (EF1α). This promoter substitution resulted in a significantly more homogeneous expression of the EGFP transgene in all hematopoietic cell types, including CD34+-derived T lymphocytes, in which the CMV promoter was inactive, and NOD/SCID mouse repopulating cells. We thus present here an HIV-derived lentiviral vector, TRIPΔU3-EF1α, which can very efficiently transduce human cord blood HSC and results in high long-term transgene expression in CD34+-derived T, B, NK, and myeloid hematopoietic cells.
Gene transfer in human hematopoietic stem cells (HSCs) has great potential for both gene therapy and the understanding of hematopoiesis. As HSCs have extensive proliferative capacities, stable gene ...transfer should include genomic integration of the transgene. Lentiviral vectors are now preferred to oncoretroviral vectors especially because they integrate in nondividing cells such as HSCs, thereby avoiding the use of prolonged cytokine stimulation. Human immunodeficiency virus type-1 (HIV-1) has evolved a complex reverse transcription strategy including a central strand displacement event controlled in cis by the central polypurine tract (cPPT) and the central termination sequence (CTS). This creates, at the center of HIV-1 linear DNA molecules, a 99-nucleotide-long plus-strand overlap, the DNA flap, which acts as a cis-determinant of HIV-1 genome nuclear import. The reinsertion of the DNA flap sequence in an HIV-derived lentiviral vector promotes a striking increase of gene transduction efficiency in human CD34+ hematopoietic cells, and the complementation of the nuclear import defect present in the parental vector accounts for this result. In a short ex vivo protocol, the flap-containing vector allows efficient transduction of the whole hierarchy of human HSCs including both slow-dividing or nondividing HSCs that have multiple lymphoid and myeloid potentials and primitive cells with long-term engraftment ability in nonobese diabetic/severe combined immunodeficiency mice (NOD/SCID).
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