Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment.

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

Caractérisation des altérations épigénétiques au sein des gliomes

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocSudocFranceF

A prospective matched study on symptomatic dengue in pregnancy.

Dengue fever is an increasing problem worldwide, but consequences during pregnancy remain unclear. Much of the available literature suffers from methodological biases that compromise the validity of clinical recommendations. We conducted a matched cohort study during an epidemic in French Guiana to compare events and pregnancy outcomes between two paired groups of pregnant women: women having presented with symptomatic dengue during pregnancy (n = 73) and women having had neither fever nor dengue during pregnancy (n = 219). Women in each arm were matched by place of follow up, gestation weeks at inclusion, and place of residence. Dengue infection was considered to be confirmed if viral RNA, N S1 antigen, the seroconversion of IgM antibodies or the presence of IgM was detected in collected samples. According to the 2009 WHO classification, 27% of the women with symptomatic dengue had at least one clinical or biological warning sign. These complications occurred after the 28th week of gestation in 55% of cases. The medical history, socioeconomic status and demographic characteristics were included in multivariate analysis. Exposure to dengue during pregnancy was not significantly associated with prematurity, small for gestational age infants, hypertension or emergency caesarian section. Maternal dengue with warning signs was a risk factor for peripartum hemorrhage with adjusted relative risk = 8.6(95% CI = 1.2-62). There was a near significant association between dengue and in utero death (p = 0.09). This prospective comparative study underlined the importance of taking into account potential confounders between exposure to dengue and the occurrence of obstetrical events. It also confirms the need for increased vigilance for pregnant women with dengue, particularly for women who present with severe dengue

Estimating the Risk of Vertical Transmission of Dengue: A Prospective Study

International audienceThe incidence of dengue worldwide is increasing rapidly. A better understanding of dengue transmission may help improve interventions against this major public health problem. The virus is mostly transmitted by vectors. There are, however, other modes of transmission, notably mother-to-child transmission or vertical transmission. We studied a prospective cohort of 54 women who had dengue while pregnant during the 2012–2013 epidemic in French Guiana to estimate the mother-to-child transmission rate and assess the clinical and biological presentation of neonatal dengue. The rate of vertical transmission was between 18.5% (95% confidence interval [CI]: 9.25–31.4) and 22.7% (95% CI: 11.5–37.8), depending on the calculation method used. Mother-to-child transmission occurred both in early and late pregnancy. There were 52 births, including three newborns who presented neonatal dengue with warning signs requiring platelet transfusion. This quantification of the mother-to-child transmission of dengue highlights three points: first, vertical transmission of dengue is not negligible; second, it is more frequent when maternal dengue occurs late during pregnancy near delivery; and third, reliable diagnostic tests must be used to allow the diagnosis of vertical transmission. Our findings indicate that if there is a known history of maternal dengue during pregnancy, or if there is fever during the 15 days before term, cord blood and placenta should be sampled after delivery and tested for the virus, and the newborn should be closely monitored during the postpartum period

Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas

The O6-methylguanine-DNA methyltransferase gene (MGMT) is methylated in several cancers, including gliomas. However, the functional role of cysteine-phosphate-guanine (CpG) island (CGI) methylation in MGMT silencing is still controversial. The aim of this study was to investigate whether MGMT CGI methylation correlates inversely with RNA expression of MGMT in glioblastomas and to determine the CpG region whose methylation best reflects the level of expression. The methylation level of CpG sites that are potentially related to expression was investigated in 54 glioblastomas by pyrosequencing, a highly quantitative method, and analyzed with respect to their MGMT mRNA expression status. Three groups of patients were identified according to the methylation pattern of all 52 analyzed CpG sites. Overall, an 85% rate of concordance was observed between methylation and expression (p < 0.0001). When analyzing each CpG separately, six CpG sites were highly correlated with expression (p < 0.0001), and two CpG regions could be used as surrogate markers for RNA expression in 81.5% of the patients. This study indicates that there is good statistical agreement between MGMT methylation and expression, and that some CpG regions better reflect MGMT expression than do others. However, if transcriptional repression is the key mechanism in explaining the higher chemosensitivity of MGMT-methylated tumors, a substantial rate of discordance should lead clinicians to be cautious when deciding on a therapeutic strategy based on MGMT methylation status alone

The Challenge of Return to Work after Breast Cancer: The Role of Family Situation, CANTO Cohort

International audienceReturn to work (RTW) after breast cancer is associated with improved quality of life. The link between household characteristics and RTW remains largely unknown. The aim of this study was to examine the effect of the family situation on women’s RTW two years after breast cancer. We used data of a French prospective cohort of women diagnosed with stage I-III, primary breast cancer (CANTO, NCT01993498). Among women employed at diagnosis and under 57 years old, we assessed the association between household characteristics (living with a partner, marital status, number and age of economically dependent children, support by the partner) and RTW. Logistic regression models were adjusted for age, household income, stage, comorbidities, treatments and their side effects. Analyzes stratified by age and household income were performed to assess the association between household characteristics and RTW in specific subgroups. Among the 3004 patients included, women living with a partner returned less to work (OR = 0.63 [0.47–0.86]) and decreased their working time after RTW. Among the 2305 women living with a partner, being married was associated with decreased RTW among women aged over 50 (OR = 0.57 [0.34–0.95]). Having three or more children (vs. none) was associated with lower RTW among women with low household income (OR = 0.28 [0.10–0.80]). Household characteristics should be considered in addition to clinical information to identify vulnerable women, reduce the social consequence of cancer and improve their quality of life

Determinants of use of oral complementary-alternative medicine among women with early breast cancer: a focus on cancer-related fatigue

BACKGROUND: Despite the questionable effectiveness of oral complementary and alternative medicine (OCAM) in relieving cancer-related symptoms, including fatigue (CRF), many patients use it aiming to improve their quality of life. We assessed factors associated with OCAM use, focusing on CRF. METHODS: Women with stage I-III breast cancer (BC) were included from CANTO (NCT01993498). OCAM use was defined as taking homeopathy, vitamins/minerals, or herbal/dietary supplements. Multivariable multinomial logistic regressions evaluated associations of CRF (EORTC QLQ-C30), patient, and treatment characteristics with OCAM use. RESULTS: Among 5237 women, 23.0% reported OCAM use overall (49.3% at diagnosis, 50.7% starting post-diagnosis), mostly homeopathy (65.4%). Mean (SD) CRF score was 27.6 (24.0) at diagnosis and 35.1 (25.3) at post-diagnosis. More intense CRF was consistently associated with OCAM use at diagnosis and post-diagnosis [adjusted odds ratio (aOR) for 10-point increase 1.05 (95% Confidence interval 1.01-1.09) and 1.04 (1.01-1.09) vs. never use, respectively]. Odds of using OCAM at diagnosis were higher among older [for 5-year increase, 1.09 (1.04-1.14)] and more educated patients [college vs. primary 1.80 (1.27-2.55)]. Women with income > 3000 [vs. < 1500 euros/month, 1.44 (1.02-2.03)], anxiety [vs. not, 1.25 (1.01-1.54)], and those receiving chemotherapy [vs. not, 1.32 (1.04-1.68)] had higher odds of using OCAM post-diagnosis. CONCLUSION: One-in-four patients reported use of OCAM. More severe CRF was consistently associated with its use. Moreover, older, better educated, wealthier, more anxious women, and those receiving chemotherapy seemed more prone to use OCAM. Characterizing profiles of BC patients more frequently resorting to OCAM may help deliver targeted information about its benefits and potential risks.Etude des toxicités chroniques des traitements anticancéreux chez les patientes porteuses cance

Perceived Discrimination at Work: examining social, health and work-related factors as determinants among breast cancer survivors. Evidence from the prospective CANTO cohort

International audienceBackground We assessed the prevalence of self-reported perceived discrimination in the workplace after the end of treatment among breast cancer (BC) survivors and studied its association with social, health-related and work-related factors. Methods We used data from a French prospective cohort (CANcer TOxicities) including women diagnosed with stage I–III BC. Our analysis included 2130 women who were employed, <57 years old at BC diagnosis and were working 2 years afterwards. We assessed the association between social, health-related and work-related factors and perceived discrimination in the workplace using logistic regression models. Results Overall, 26% of women reported perceived discrimination in the workplace after the end of treatment. Women working for a small company, in the public sector or with better overall health status were less likely to report perceived discrimination. Women who benefited from easing dispositions at their workplace, who did not feel supported by their colleagues and those who returned to work because of fear of job loss were more likely to report perceived discrimination. Conclusions One in four BC survivors perceives discrimination in the workplace. Health and work-related factors are associated with increased likelihood of reporting perceived discrimination. Trial registration number NCT01993498

Association between physical activity and neoadjuvant chemotherapy completion and pathologic complete response in primary breast cancer: the CANTO study.

BACKGROUND: Regular physical activity is associated with improved symptom control in patients with breast cancer but its association with chemotherapy completion or response is unclear. METHODS: Using a prospective design, 1075 breast cancer patients receiving neoadjuvant chemotherapy between March 2012 and February 2017 were studied. Physical activity was assessed using the Global Physical Activity Questionnaire [GPAQ-16], quantified in standardised MET-h/wk. Chemotherapy completion was defined as the proportion of patients completing planned treatment course, requiring dose reduction, or requiring dose delay. Response was evaluated by pathologic complete response (pCR). Associations between physical activity and primary outcomes were assessed using multivariable logistic regression models. RESULTS: There was no differences between any chemotherapy completion outcome on the basis of physical activity classification. The percent of patients not completing planned treatment was 5.7% for ≦0.33 MET-h/wk, compared with 6.8% for 0.34-16.65 MET-h/wk, and 4.6% for ≥16.6 MET-h/wk (p = 0.52). No significant relationships were observed between physical activity dose classification and pCR for the overall cohort or upon stratification by clinical subtype. CONCLUSION: Future studies are required to further investigate the relationship between pre-treatment levels of physical activity and function on treatment completion and response in breast and other cancer populations. CLINICAL TRIAL REGISTRATION: NCT01993498

Radiation-induced lung injury after breast cancer treatment: incidence in the CANTO-RT cohort and associated clinical and dosimetric risk factors

International audiencePurpose: Radiation-induced lung injury (RILI) is strongly associated with various clinical conditions and dosimetric parameters. Former studies have led to reducing radiotherapy (RT) doses to the lung and have favored the discontinuation of tamoxifen during RT. However, the monocentric design and variability of dosimetric parameters chosen have limited further improvement. The aim of our study was to assess the incidence of RILI in current practice and to determine clinical and dosimetric risk factors associated with RILI occurrence. Material and methods: Data from 3 out of the 10 top recruiting centers in CANTO-RT, a subset of the CANTO prospective longitudinal cohort (NCT01993498), were retrospectively analyzed for RILI occurrence. This cohort, which recruited invasive cT0-3 cN0-3 M0 breast cancer patients from 2012 to 2018, prospectively recorded the occurrence of adverse events by questionnaires and medical visits at the end of, and up to 60 months after treatment. RILI adverse events were defined in all patients by the association of clinical symptoms and compatible medical imaging. Results: RILI was found in 38/1565 (2.4%) patients. Grade II RILI represented 15/38 events (39%) and grade III or IV 2/38 events (6%). There were no grade V events. The most frequently used technique for treatment was 3D conformational RT (96%). In univariable analyses, we confirmed the association of RILI occurrence with pulmonary medical history, absence of cardiovascular disease medical history, high pT and pN, chemotherapy use, nodal RT. All dosimetric parameters were highly correlated and had close predictive value. In the multivariable analysis adjusted for chemotherapy use and nodal involvement, pulmonary medical history (OR=3.05, p15% was significantly associated with RILI occurrence in a multivariable analysis (OR=3.07, p=0.03). Conclusion: Our study confirms the pulmonary safety of breast 3D RT in CANTO-RT. Further analyses with modern radiation therapy techniques such as IMRT are needed. Our results argue in favor of a dose constraint to the ipsilateral lung using V30 Gy not exceeding 15%, especially in patients presenting pulmonary medical history. Pulmonary disease records should be taken into account for RT planning. Copyrigh