Whole-genome/exome analysis of circulating tumor DNA and comparison to tumor genomics from patients with heavily pre-treated ovarian cancer: subset analysis of the PERMED-01 trial

IntroductionThe poor prognosis of ovarian carcinoma (OvC) is due to the advanced stage at diagnosis, a high risk of relapse after first-line therapies, and the lack of efficient treatments in the recurrence setting. Circulating tumor DNA (ctDNA) analysis is a promising tool to assess treatment-resistant OvC and may avoid iterative tissue biopsies. We aimed to evaluate the genomic profile of recurrent heavily pre-treated OvC.MethodsWe performed tumor panel-based sequencing as well as low-coverage whole-genome sequencing (LC-WGS) of tumor and plasma collected in patients with ovarian cancer included in the PERMED-01 trial. Whole-exome sequencing (WES) data of plasma samples were also analyzed and compared to mutation and copy number alteration (CNA) tumor profiles. The prognostic value [progression-free survival (PFS)] of these alterations was assessed in an exploratory analysis.ResultsTumor and plasma genomic analyses were done for 24 patients with heavily pretreated OvC [67% high-grade serous carcinoma (HGSC)]. Tumor mutation burden was low (median 2.04 mutations/Mb) and the most frequent mutated gene was TP53 (94% of HGSC). Tumor CNAs were frequent with a median of 50% of genome altered fraction. Plasma LC-WGS and WES detected ctDNA in 21/24 cases (88%) with a median tumor fraction of 12.7%. We observed a low correlation between plasma and tumor CNA profiles. However, this correlation was significant in cases with the highest circulating tumor fraction. Plasma genome altered fraction and plasma mutation burden (p = 0.011 and p = 0.041, respectively, log-rank tests) were associated with PFS.ConclusionsCombination of LC-WGS and WES can detect ctDNA in most pre-treated OvCs. Some ctDNA characteristics, such as genome altered fraction and plasma mutation burden, showed prognostic value. ctDNA assessment with LC-WGS may be a promising and non-expansive tool to evaluate disease evolution in this disease with high genomic instability.Clinical Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT02342158, identifier NCT02342158

NOV/CCN3, une protéine d'intérêt dans les pathologies tumorales et dans les facteurs de risque des maladies cardiovasculaires?

NOV/CCN3 (Nephroblastoma overexpressed), est un membre fondateur de la famille des CCN. Il code une protéine sécrétée intervenant dans des situations physiologiques (développement, angiogenèse et cicatrisation) et pathologiques (fibrose, tumorigenèse). Ce projet de thèse en CIFRE vise à mettre en évidence les propriétés anti-tumorales et anti-angiogéniques de NOV et de son fragment C-terminal (NOV C-ter) dans des modèles tumoraux. Nous avons évalué les effets thérapeutiques de NOV et NOV C-ter dans trois modèles de tumeurs angiogéniques et avons démontré l efficacité de NOV C-ter dans le glioblastome. Ces résultats constituent les premières preuves d une action thérapeutique de NOV C-ter dans le cancer. Nous avons parallèlement développé une thématique portant sur le rôle de NOV dans les facteurs de risque de maladies cardiovasculaires (MCV). Nous avons mis en évidence une augmentation de l expression de NOV in vitro et in vivo dans un contexte de surexpression d angiotensine II et de TNFa, deux acteurs essentiels de la composante inflammatoire de l hypertension. NOV induit par ailleurs l expression de deux chimiokines CCL2 et CCL5 impliquées dans la physiopathologie hypertensive. Une étude réalisée sur une cohorte de patients présentant des facteurs de risque de MCV nous a permis de déterminer les facteurs responsables de 40% de la variabilité de la concentration plasmatique de NOV et de mettre en évidence une corrélation entre l expression locale et systémique de NOV et les paramètres de l obésité. L ensemble de ces résultats suggère que NOV est impliquée dans la physiopathologie de l hypertension et de l obésité et serait un nouvel acteur des facteurs de risque des MCVPARIS-BIUSJ-Biologie recherche (751052107) / SudocSudocFranceF

The Psychological Distress of Cancer Patients following the COVID-19 Pandemic First Lockdown: Results from a Large French Survey

Cancer patients commonly experience psychological distress that may increase with the current COVID-19 pandemic. This prospective study aimed to measure post-traumatic stress disorder (PTSD) and anxiety in cancer patients following France’s first COVID-19-related lockdown, together with associated factors. Cancer patients receiving outpatient treatment or post-treatment follow-up completed a questionnaire which measured, among other things, PTSD (IES-R), anxiety (State-Trait Anxiety Inventory), and fear of cancer recurrence (FCR). Of the 1097 patients included in the study, 14.7% and 30.5% suffered from PTSD and anxiety, respectively. Patients afraid to come to hospital due to the risk of COVID-19 transmission (OR = 3.49, p < 0.001), those with a negative lockdown experience (OR = 0.98, p < 0.001), women (OR = 1.97; p = 0.009), and patients living alone (OR = 1.63, p = 0.045) were all more likely to have PTSD. Older patients (OR = 1.65, p = 0.020), women (OR = 1.62, p = 0.018), those with a higher FCR score (OR = 5.02, p < 0.001), patients unsatisfied with their cancer management (OR = 2.36, p < 0.001), and those afraid to come to hospital due to COVID-19 (OR = 2.43, p < 0.001) all had a higher risk of anxiety. These results provide a greater understanding of the psychological consequences of the COVID-19 pandemic in cancer patients and highlight the need to better integrate psychosocial support in pandemic response measures in order to guide health systems

The Psychological Distress of Cancer Patients following the COVID-19 Pandemic First Lockdown: Results from a Large French Survey

Cancer patients commonly experience psychological distress that may increase with the current COVID-19 pandemic. This prospective study aimed to measure post-traumatic stress disorder (PTSD) and anxiety in cancer patients following France’s first COVID-19-related lockdown, together with associated factors. Cancer patients receiving outpatient treatment or post-treatment follow-up completed a questionnaire which measured, among other things, PTSD (IES-R), anxiety (State-Trait Anxiety Inventory), and fear of cancer recurrence (FCR). Of the 1097 patients included in the study, 14.7% and 30.5% suffered from PTSD and anxiety, respectively. Patients afraid to come to hospital due to the risk of COVID-19 transmission (OR = 3.49, p < 0.001), those with a negative lockdown experience (OR = 0.98, p < 0.001), women (OR = 1.97; p = 0.009), and patients living alone (OR = 1.63, p = 0.045) were all more likely to have PTSD. Older patients (OR = 1.65, p = 0.020), women (OR = 1.62, p = 0.018), those with a higher FCR score (OR = 5.02, p < 0.001), patients unsatisfied with their cancer management (OR = 2.36, p < 0.001), and those afraid to come to hospital due to COVID-19 (OR = 2.43, p < 0.001) all had a higher risk of anxiety. These results provide a greater understanding of the psychological consequences of the COVID-19 pandemic in cancer patients and highlight the need to better integrate psychosocial support in pandemic response measures in order to guide health systems

A study of elite sport-inspired coaching for patients after allogeneic hematopoietic stem cell transplantation

International audienceA need for social support is often expressed after hospitalization post HSCT. Emotional support and positive psychological constructs play an important role in post-HSCT recovery. Interventions generating positive affect can influence the health and well-being of transplant patients. It has been established that coaching in elite sport area leads to performance by playing a decisive role in maintaining the athlete's feelings of hope and autonomy in order to enable him or her to achieve their goals. In this single-center, prospective, one-arm study, we evaluated, in 32 post-HSCT patients, the acceptability of a coaching program inspired by elite sport coaching. Benefits were evaluated by questionnaires and semi-structured interviews. The coaching program was accepted by 97% of the patients. Analysis of the scores on the "Means" sub-dimension of Hope showed a significant increase over time (p = 0.0249 < 0.05) for every patient. Qualitative analysis of patient's satisfaction pointed out that this support facilitated the transition to a life without illness in particular in the non-hospital context of coaching sessions. Our results show that a "sport-inspired coaching" may offer an innovative approach supporting psychological and social recovery after HSCT and helping to start and/or maintain the processes leading to psychological well-being

Major Response to Carboplatin in a Patient With Metastatic Triple-Negative Breast Cancer With Somatic Mutation of BRCA1 and Loss of RAD51B

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TRAINING-Ovary 01 (connecTed pRehabiliAtIoN pelvIc caNcer surGery): multicenter randomized study comparing neoadjuvant chemotherapy for patients managed for ovarian cancer with or without a connected pre-habilitation program

International audienceBackground Patients undergoing neoadjuvant chemotherapy before surgery for advanced ovarian cancer may have impaired functional capacity, nutritional status, and emotional well-being. Primary objective(s) TRAINING-01 aims to determine if a connected pre-habilitation program during neoadjuvant chemotherapy for patients treated for an advanced ovarian cancer will improve physical capacity before major abdomino-pelvic surgery. Study hypothesis A pre-habilitation program during neoadjuvant chemotherapy will bring a fitter patient to surgery and will decrease treatment morbidity and improve oncological outcomes. Trial design This study is a prospective, multi-center, phase III study. The pre-habilitation program consists of providing multi-dimensional support during neoadjuvant chemotherapy using connected devices. The control group will receive usual care. Major inclusion/exclusion criteria Eligible patients will be women with International Federation of Gynecology and Obstetrics stage III–IV advanced ovarian cancer undergoing neoadjuvant chemotherapy. Patients must be able to perform a cardiopulmonary exercise test. Primary endpoint(s) The primary endpoint will be the comparison of the variation in maximum oxygen uptake (VO 2 max) between baseline and surgery in the pre-habilitation group and control groups. Sample size 136 patients (68 per arm) will be recruited to demonstrate a medium standardized effect d=0.5 in the variations of VO 2 max between baseline and surgery. Estimated dates for completing accrual and presenting results The duration of the study includes 24 months of recruitment and 5 years of follow up. We anticipate reporting primary endpoint results in 2024. Trial registration TRAINING-01-IPC 2018-039 ( NCT04451369 )

Circulating tumor DNA predicts efficacy of a dual AKT/p70S6K inhibitor (LY2780301) plus paclitaxel in metastatic breast cancer: plasma analysis of the TAKTIC phase IB/II study

International audienceThe phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently activated in HER2-negative breast cancer and may play a role in taxane resistance. The phase IB/II TAKTIC trial (NCT01980277) has shown that combining a dual AKT and p70 ribosomal protein S6 kinase (p70S6K) inhibitor (LY2780301) taken orally with weekly paclitaxel in HER2-negative advanced breast cancer is feasible, with preliminary evidence of efficacy. We wanted to explore whether circulating tumor DNA (ctDNA) may be a surrogate marker of treatment efficacy in this setting. Serial plasma samples were collected and cell-free DNA was sequenced using low-coverage whole-genome sequencing, and analysis was completed with droplet digital PCR for some patients with driver mutations. Baseline tumor fraction (TF) and TF after 7 weeks on treatment were compared to progression-free survival (PFS) and overall response rate. We also explored circulating copy number alterations associated with treatment failure. Of the 51 patients enrolled in the TAKTIC trial, at least one plasma sample was available for 44 cases (96 time points). All patients with tumor TP53, PI3KCA or AKT1 mutations harbored at least one of these alterations in plasma. TF at inclusion was correlated to PFS (6m-PFS was 92% for ctDNAneg patients vs 68% for ctDNApos cases; HR=3.45, 95%CI [1.34-8.90], p=0.007). ctDNA status at week 7 was not correlated to prognosis. Even though most circulating copy number alterations were conserved at disease progression, some genomic regions of interest were altered in post-progression samples. In conclusions, ctDNA detection at baseline was associated with shorter PFS in patients included in the TAKTIC trial. Plasma-based copy number analysis may help to identify alterations involved in resistance to treatment

High Response to Cetuximab in a Patient With EGFR -Amplified Heavily Pretreated Metastatic Triple-Negative Breast Cancer

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Plasma NOV/CCN3 levels are closely associated with obesity in patients with metabolic disorders.

OBJECTIVE: Evidence points to a founder of the multifunctional CCN family, NOV/CCN3, as a circulating molecule involved in cardiac development, vascular homeostasis and inflammation. No data are available on the relationship between plasma NOV/CCN3 levels and cardiovascular risk factors in humans. This study investigated the possible relationship between plasma NOV levels and cardiovascular risk factors in humans. METHODS: NOV levels were measured in the plasma from 594 adults with a hyperlipidemia history and/or with lipid-lowering therapy and/or a body mass index (BMI) >30 kg/m(2). Correlations were measured between NOV plasma levels and various parameters, including BMI, fat mass, and plasma triglycerides, cholesterol, glucose, and C-reactive protein. NOV expression was also evaluated in adipose tissue from obese patients and rodents and in primary cultures of adipocytes and macrophages. RESULTS: After full multivariate adjustment, we detected a strong positive correlation between plasma NOV and BMI (r = 0.36 p<0.0001) and fat mass (r = 0.33 p<0.0005). According to quintiles, this relationship appeared to be linear. NOV levels were also positively correlated with C-reactive protein but not with total cholesterol, LDL-C or blood glucose. In patients with drastic weight loss induced by Roux-en-Y bariatric surgery, circulating NOV levels decreased by 28% (p<0.02) and 48% (p<0.0001) after 3 and 6 months, respectively, following surgery. In adipose tissue from obese patients, and in human primary cultures NOV protein was detected in adipocytes and macrophages. In mice fed a high fat diet NOV plasma levels and its expression in adipose tissue were also significantly increased compared to controls fed a standard diet. CONCLUSION: Our results strongly suggest that in obese humans and mice plasma NOV levels positively correlated with NOV expression in adipose tissue, and support a possible contribution of NOV to obesity-related inflammation