Stefan Michiels

Institut de Cancérologie Gustave Roussy | IGR · Biostatistical and Epidemiological Division

Background The research of biomarker-treatment interactions is commonly investigated in randomized clinical trials (RCT) for improving medicine precision. The hierarchical interaction constraint states that an interaction should only be in a model if its main effects are also in the model. However, this constraint is not guaranteed in the standard...

The availability of patient cohorts with several types of omics data opens new perspectives for exploring the disease's underlying biological processes and developing predictive models. It also comes with new challenges in computational biology in terms of integrating high-dimensional and heterogeneous data in a fashion that captures the interrelat...

Metastatic relapse after treatment is the leading cause of cancer mortality, and known resistance mechanisms are missing for most treatments administered to patients. To bridge this gap, we analyze a pan-cancer cohort (META-PRISM) of 1,031 refractory metastatic tumors profiled via whole-exome and transcriptome sequencing. META-PRISM tumors, particu...

Background: The prognostic value of stromal tumor-infiltrating lymphocytes (TILs) as a biomarker for triple-negative breast cancer (TNBC) has been extensively demonstrated in patients (pts) receiving (neo)adjuvant systemic therapy. In addition, several small studies suggest that a subset of pts with early-stage TNBC and high TILs have excellent lon...

Metastatic relapse after treatment is the primary cause of cancer morbidity and mortality. While genetic mechanisms of primary tumors and, to a lesser extent, metastatic cancers have been studied in large cohorts, refractory metastatic tumors are not yet sufficiently characterized. Markers of aggressiveness and resistance that molecular profiling c...

The discovery of molecular subtypes has corroborated the heterogeneity of breast cancers. But in clinical routine, treatment selection relies on measuring the aggressiveness of the tumor via histopathology, which is routinely based on grading, a prognostic yet laborious, poorly reproducible, and subjective procedure defined more than 30 years ago,...

Importance Suboptimal adherence to endocrine therapy (ET) among patients with hormone-receptor–positive breast cancer significantly affects survival outcomes and is associated with higher hospitalization rates and health care costs. Weak adherence to long-term treatments has multiple determinants, including disease characteristics, treatment advers...

The importance of integrating biomarkers into the TNM staging has been emphasized in the 8 th Edition of the American Joint Committee on Cancer (AJCC) Staging system. In a pooled analysis of 2148 TNBC-patients in the adjuvant setting, TILs are found to strongly up and downstage traditional pathological-staging in the Pathological and Clinical Progn...

Nine drugs have been marketed for 10 years for the treatment of advanced melanoma (AM). With half of patients reaching a second line, the optimal sequence of treatments remains unclear. To inform policy-makers about their efficiency, we performed a cost-effectiveness analysis of sequential strategies in clinical practice in France, for BRAF-mutated...

Metastatic relapse after treatment is the leading cause of cancer mortality, and known resistance mechanisms are missing for most treatments administered to patients. To bridge this gap, we analyze a pan-cancer cohort (META-PRISM) of 1,031 refractory metastatic tumors profiled via whole-exome and transcriptome sequencing. META-PRISM tumors, particu...

Background For patients with metastatic rare cancers, treatments are limited. How systematic tumor sequencing can improve therapeutic possibilities in this population? Patients and methods Patients with rare cancer were identified in the MOSCATO-01 trial. Patients’ outcome was measured by progression-free survival (PFS) and overall survival (OS)....

Recent advances in high-throughput sequencing technologies have enabled the extraction of multiple features that depict patient samples at diverse and complementary molecular levels. The generation of such data has led to new challenges in computational biology regarding the integration of high-dimensional and heterogeneous datasets that capture th...

The development of prognostic molecular signatures considering the inter-patient heterogeneity is a key challenge for the precision medicine. We propose a joint model of this heterogeneity and the patient survival, assuming that tumor expression results from a mixture of a subset of independent signatures. We deconvolute the omics data using a non-...

CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated...

Background Variable selection for regression models plays a key role in the analysis of biomedical data. However, inference after selection is not covered by classical statistical frequentist theory, which assumes a fixed set of covariates in the model. This leads to over-optimistic selection and replicability issues. Methods We compared proposals...

Supplement to: Prognostic value of stromal tumor infiltrating lymphocytes in young, node-negative, triple-negative breast cancer patients who did not receive (neo)adjuvant systemic therapy. DOI: 10.1200/JCO.21.01536 Journal of Clinical Oncology 40, no. 21 (July 20, 2022) 2361-2374. Creative Commons Attribution Non-Commercial No Derivatives 4.0 Li...

Purpose: Return to work (RTW) after breast cancer (BC) can be a major challenge for patients. Multidisciplinary interventions seem to be effective but the role of digital solutions is under-developed and therefore not evaluated. We explored the preferences, needs, and barriers regarding RTW interventions, including opinions about the use of digita...

Purpose: Targeted therapies (TT) and immune checkpoint blockers (ICB) have revolutionized the approach to non-small cell lung cancer (NSCLC) treatment in the era of precision medicine. Their impact as switch maintenance therapy based on molecular characterization is unknown. Experimental design: SAFIR02-Lung was an open-label, randomized, phase...

Background Despite huge efforts to identify biomarkers associated with long-term clinical outcomes in patients with early-stage Human Epidermal growth factor Receptor 2 (HER2)-positive Breast Cancer (HER2+ BC) treated with (neo)adjuvant anti-HER2 therapy, no reliable predictors have been identified so far. Fatty Acid uptake, a process mediated by t...

Background Axillary lymph node dissection (ALND) in patients with breast cancer has potential side effects, including upper-limb lymphedema. Axillary reverse mapping (ARM) is a technique that enables discrimination of the lymphatic drainage of the upper limb in the axillary lymph node basin from that of the breast. We aimed to evaluate ARM node ide...

Identifying individual mechanisms involved in complex diseases, such as cancer, is essential for precision medicine. Their characterization is particularly challenging due to the unknown relationships of high-dimensional omics data and their inter-patient heterogeneity. We propose to model individual gene expression as a combination of unobserved m...

There has been increased interest in the use of clinical risk prediction models for decision-making in medicine for patient care. This has been accelerated through the focus on precision medicine, the revolution in omics data, and increasing use of randomized controlled trial and electronic health record databases. These models are expected to assi...

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 a...

Background: The research of biomarker-treatment interactions is commonly investigated in randomized clinical trials (RCT) for improving medicine precision. The hierarchical interaction constraint states that an interaction should only be in a model if its main effects are also in the model. However, this constraint is not guaranteed in the differen...

The near-infrared (NIR) fluorescence axillary reverse mapping (ARM) procedure is a promising tool to identify and preserve arm lymphatic drainage during axillary lymph node dissection (ALND). The ARMONIC clinical trial was conducted to validate the technique on a large cohort of patients and to analyze the predictive clinical factors for ARM lymph...

Background A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated. Methods H...

Introduction Avec l'essor de l'apprentissage profond, de nouveaux outils à base de réseaux de neurones ont vu le jour pour intégrer de manière plus efficace les données multi-omiques en introduisant des moyens plus flexibles de capturer les interactions non linéaires entre les sources et créer des représentations plus informatives des données multi...

Introduction L'identification de signatures moléculaires pronostiques en oncologie constitue un défi important pour développer une médecine stratifiée. L'identification de signatures moléculaires individuelles est une tâche complexe, car les mécanismes biologiques du cancer impliquent plusieurs milliers de gènes présentant une grande hétérogénéité...

Introduction Plusieurs essais cliniques randomisés ont démontré l'efficacité de l'utilisation prolongée du tamoxifène (TAM) comme traitement adjuvant pour améliorer la survie sans maladie invasive (iDFS) et la survie globale (OS) dans le cancer du sein précoce. Cependant, la non-adhérence au traitement à long terme peut être importante et l'effet t...

Introduction Dans le domaine de la santé, les réseaux de neurones sont de plus en plus souvent appliqués aux donnée de survie pour effectuer des prédictions. Cependant, peu de méthodes proposent une estimation de l'incertitude associée à ces prédictions. Nous comparons ici différentes méthodes de mesure d'incertitude appliquées aux perceptrons mult...

Introduction Apparier deux bases de données se définit par un ensemble de processus permettant de retrouver les individus d'une base dans une autre base. Dans le cadre des données hospitalières, retrouver le statut vital des patients est un enjeu très important, qui permettra à la fois de mener les études épidémiologiques sur ce type de données et...

Introduction Lung cancer remains the most frequent cause of brain metastases (BMs) and is responsible for high morbidity and mortality. Intracranial response to systemic treatments is inconsistent due to several mechanisms: genomic heterogeneity, blood–tumor barrier, and the brain-specific microenvironment. We conducted a study using data from the...

Purpose: We aimed to characterize long-term quality of life (QOL) trajectories among patients with breast cancer treated with adjuvant chemotherapy and to identify related patterns of health behaviors. Methods: Female stage I-III breast cancer patients receiving chemotherapy in CANTO (CANcer TOxicity; ClinicalTrials.gov identifier: NCT01993498)...

Introduction: Near-infrared (NIR) fluorescence axillary reverse mapping (ARM) procedure is a promising tool to identify and preserve arm lymphatic drainage during axillary lymph node dissection (ALND). The ARMONIC clinical trial was conducted to validate the technique on a large cohort of patients and to analyse predictive clinical factors for ARM...

Importance: Breast cancer (BC) diagnosis and treatment expose patients to a 5-fold higher risk of depression compared with the general population, with an estimated prevalence of 10% to 25%. A depressive episode in patients with BC has implications for the tolerance of and adherence to treatment, impairing quality of life and reducing life expecta...

PURPOSE Triple-negative breast cancer (TNBC) is considered aggressive, and therefore, virtually all young patients with TNBC receive (neo)adjuvant chemotherapy. Increased stromal tumor-infiltrating lymphocytes (sTILs) have been associated with a favorable prognosis in TNBC. However, whether this association holds for patients who are node-negative...

MAPPYACTS (NCT02613962) is an international prospective precision medicine trial aiming to define tumor molecular profiles in pediatric patients with recurrent/refractory malignancies in order to suggest the most adapted salvage treatment. From February 2016 to July 2020, 787 patients were included in France, Italy, Ireland, and Spain. At least one...

PURPOSE Fatigue is recognized as one of the most burdensome and long-lasting adverse effects of cancer and cancer treatment. We aimed to characterize long-term fatigue trajectories among breast cancer survivors. METHODS We performed a detailed longitudinal analysis of fatigue using a large ongoing national prospective clinical study (CANcer TOxici...

Background Recent advances in biotechnology enable the acquisition of high-dimensional data on individuals, posing challenges for prediction models which traditionally use covariates such as clinical patient characteristics. Alternative forms of covariate representations for the features derived from these modern data modalities should be considere...

Background 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 ai...

Background Currently, mammographic-based breast cancer screening (BCS) using age as the single criterion for population selection, apart from rare high-risk indications, is being questioned for its imperfect sensitivity (interval cancers) and specificity (false positive recalls), as well as the risk of over-diagnoses. BC risk scores incorporating p...

Background: The definition of breast cancer (BC) prognosis has historically relied on clinico-pathological factors. Novel omics markers including proteomic analyses could improve our understanding of the biological host drivers of breast cancer recurrence and survival. We aimed at identifying patients (pts) at high risk of recurrence based on prote...

Background: We previously developed a clinico-behavioral model of CRF and reported an increased risk of severe CRF among survivors of breast cancer (BC) receiving adjuvant hormonal therapy (HT) (Di Meglio A, ASCO 2021). We now aim to comprehensively explore the contribution of relevant serum proteins in explaining CRF. We adopted a multimodal appro...

Background: Weight management is an integral part of survivorship care. Excess weight in BCS is associated with worse clinical outcomes and quality of life. Early identification of BCS at risk of gaining substantial weight could lead to prompt and tailored interventions. We aimed at developing a predictive model of weight gain that integrates clini...

Background: Up to 35% BC survivors who receive adjuvant treatment (tx) experience severe CRCI, which has a significant impact on quality of life, disrupting daily functioning as well as self-esteem, self-confidence, and work ability. However, limited tools exist to predict the risk of CRCI. We aimed to develop a comprehensive model of severe CRCI,...

Background: Reduction in response rates is common in longitudinal studies, generating significant attrition bias. ATTITUDE is a comprehensive project built on the CANcer TOxicity (CANTO) cohort, using a mixed-methodology, multi-step approach aimed at reducing attrition: Step 1- understand patterns of attrition; Step 2- understand patients’ experien...

Purpose: Return to work (RTW) after breast cancer (BC) can be a major challenge for patients. Existing interventions often suffer from methodological weaknesses that hamper their implementation. In this study, we aimed to explore 1) use, as well as 2) preferences, needs and barriers regarding RTW interventions and their deployment, including 3) pre...

Background: Physical activity (PA) and psychosocial interventions are recommended management strategies for cancer-related fatigue (CRF). Randomized trials support the use of mind-body techniques, whereas no data show benefit for homeopathy or naturopathy. Methods: We used data from CANTO (ClinicalTrials.gov identifier: NCT01993498), a multicent...

Background The development of targeted agents, such as osimertinib for EGFR-mutated NSCLC, has drastically improved patient outcome, but tumor resistance eventually always occurs. In osimertinib resistant NSCLC, the emergence of a second molecular driver alteration (such as ALK, RET, FGFR3 fusions or BRAF, KRAS mutations) has been described. Whethe...

PURPOSE Fatigue is common and troublesome among breast cancer survivors; however, limited tools exist to predict its risk. PATIENTS AND METHODS Participants with stage I-III breast cancer were prospectively included from CANTO (ClinicalTrials.gov identifier: NCT01993498 ), collecting longitudinal data at diagnosis (before the initiation of any can...

Introduction Le cancer bronchique reste le premier pourvoyeur de métastases cérébrales (MC), responsables d’une importante morbidité et mortalité. De plus, la réponse cérébrale aux traitements systémiques est inconstante et imprévisible. Ceci peut être lié à l’hétérogénéité moléculaire connue entre MC et tumeur primitive, mais également aux spécifi...

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 in...

The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed dea...

Introduction: Which neoadjuvant treatment for locally advanced thoracic oesophagus (TE) or gastro-oesophageal junction carcinoma is best remains an open question. Randomised controlled trials variously accrued patients with adenocarcinoma and squamous cell carcinoma, making strong conclusions hard to obtain. The primary objective of this individua...

Introduction Individual patient data (IPD) present particular advantages in network meta-analysis (NMA) because interactions may lead an aggregated data (AD)-based model to wrong a treatment effect (TE) estimation. However, fewer works have been conducted for IPD with time-to-event contrary to binary outcomes. We aimed to develop a general frequent...

Network meta-analysis (NMA) allows the combination of direct and indirect evidence from a set of randomized clinical trials. Performing NMA using individual patient data (IPD) is considered as a “gold standard” approach as it provides several advantages over NMA based on aggregate data. For example, it allows to perform advanced modeling of covaria...

We compared accuracy for breast cancer (BC) risk stratification of a new fully automated system (DenSeeMammo—DSM) for breast density (BD) assessment to a non-inferiority threshold based on radiologists’ visual assessment. Pooled analysis was performed on 14,267 2D mammograms collected from women aged 48–55 years who underwent BC screening within th...

Patients with advanced triple-negative breast cancer (TNBC) benefit from treatment with atezolizumab, provided that the tumor contains ≥1% of PD-L1/SP142-positive immune cells. Numbers of tumor-infiltrating lymphocytes (TILs) vary strongly according to the anatomic localization of TNBC metastases. We investigated inter-pathologist agreement in the...

Phase II immuno-oncology clinical trials screen for efficacy an increasing number of treatments. In rare cancers, using historical control data is a pragmatic approach for speeding up clinical trials. The drop-the-losers design allows dropping off ineffective arms at interim analyses. We extended the original drop-the-losers design for a time-to-ev...

Introduction: Organized and individual breast screening have been accompanied by an increase in the detection of "atypical breast lesions "(ABL). Recently, the NOMAT multicenter study proposed a predictive model of the risk of developing breast cancer after detection of an ABL in order to avoid surgical removal of "low-risk" lesions. It also aimed...

Poster for the ISCB42, Lyon, France, 2021

p>Metastatic cancer refractory to treatment has a dismal prognosis. While genetic mechanisms of primary tumors and to a lesser extent of metastatic cancers have been studied on large cohorts, it is still not well understood if metastatic tumors refractory to systemic treatment contain specific signatures at genomic or transcriptional levels. Molecu...