Denis Larsimont

• Institut Jules Bordet

While triple-negative breast cancer (TNBC) is known to be heterogeneous at the genomic and transcriptomic levels, spatial information on tumor organization and cell composition is still lacking. Here, we investigate TNBC tumor architecture including its microenvironment using spatial transcriptomics on a series of 92 patients. We perform an in-dept...

Purpose The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). In this study, we combined molecular/metabolic imaging and transcriptomic...

e12576 Background: Triple-negative breast cancer’s (TNBC) dismal prognosis demands more effective therapy selection. Previously described molecular subtypes reveal its heterogeneity but lack spatial insight and are not currently used in clinical practice. Here, we aim to evaluate by immunohistochemistry (IHC) the expression of key biomarkers in TNB...

Background: Invasive lobular carcinoma (ILC) is the second most common histological breast cancer subtype; however, little is known about its tumor microenvironment (TME). Here, we aimed to study ILC TME using spatial transcriptomics (ST). Methods: We performed ST (Visium 10x Genomics) on frozen tumor samples from 43 primary hormone receptor positi...

Background Tertiary lymphoid structures (TLS) are ectopic lymphoid organs playing a role in adaptive antitumor immune response. They were shown to be associated with favorable outcome and appears to be a promising biomarker for response to immune checkpoint inhibitors (ICI). Yet, there is no consensus for their detection and quantification. Here we...

Background Immune checkpoint blockade (ICB) in combination with chemotherapy improves outcome of patients with triple-negative breast cancer (TNBC) in metastatic and early settings. The identification of predictive biomarkers able to guide treatment decisions is challenging and currently limited to programmed death-ligand 1 (PD-L1) expression and h...

Metastatic breast cancer (mBC) remains incurable and liver metastases (LM) are observed in approximately 50% of all patients with mBC. In some cases, surgical resection of breast cancer liver metastases (BCLM) is associated with prolonged survival. However, there are currently no validated marker to identify these patients. The interactions between...

Background: Invasive lobular carcinoma (ILC) is the second most common histological breast cancer subtype; however, little is known about its tumor microenvironment (TME). Here, we aimed to identify and to characterise ILC subgroups based on TME heterogeneity by combining spatial transcriptomics (ST) and single cell RNA-sequencing (scRNA-seq). Meth...

Background: The current binary distinction between HER2-positive and HER2-negative breast cancer (BC) has recently been challenged by the emergence of the HER2-low entity. Antibody-drug conjugates targeting HER2 have shown efficacy in both HER2-positive and HER2-low BC, while some preliminary evidence showed efficacy also in patients with HER2-zero...

Sixty percent of papillary thyroid cancers (PTCs) are driven by BRAFV600E, a mutation associated with high inter- and intra-tumoral heterogeneity. PTCs may become highly aggressive anaplastic thyroid cancers (ATC). While single cell transcriptomics may resolve this heterogeneity, it is potentially confounded by batch effects whose correction may da...

While triple negative breast cancer (TNBC) is known to be heterogeneous at the genomic and transcriptomic levels, spatial information on tumor organization and cell composition is still lacking. Here, we investigated TNBC tumor architecture including its microenvironment using spatial transcriptomics on a series of 92 patients. We performed an in-d...

Recent advances in the field of immuno‐oncology have brought transformative changes in the management of cancer patients. The immune profile of tumours has been found to have key value in predicting disease prognosis and treatment response in various cancers. Multiplex immunohistochemistry and immunofluorescence have emerged as potent tools for the...

Inflammatory breast cancer (IBC) is a rare (1%–5%), aggressive form of breast cancer, accounting for approximately 10% of breast cancer mortality. In the localized setting, standard of care is neoadjuvant chemotherapy (NACT) ± anti-HER2 therapy, followed by surgery. Here we investigated associations between clinicopathologic variables, stromal tumo...

Liver is the third most common organ for breast cancer (BC) metastasis. Two main histopathological growth patterns (HGP) exist in liver metastases (LM): desmoplastic and replacement. Although a reduced immunotherapy efficacy is reported in patients with LM, tumor-infiltrating lymphocytes (TIL) have not yet been investigated in BCLM. Here, we evalua...

Background Luminal B breast cancer (BC) presents a worse prognosis when compared with luminal A BC and exhibits a lower sensitivity to chemotherapy and a lower immunogenicity in contrast to non-luminal BC subtypes. The Neo-CheckRay clinical trial investigates the use of stereotactic body radiation therapy (SBRT) directed to the primary tumor in com...

Metastatic breast cancer (mBC) remains incurable and liver metastases (LM) are observed in approximately 50% of all patients with mBC. In some cases, surgical resection of breast cancer liver metastases (BCLM) could be associated with prolonged survival. However, there are currently no validated marker to identify these patients. The interactions b...

Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherap...

Surgical resection can lead to prolonged survival in patients with isolated liver metastases (LM) from various primary cancers. However, there are currently no validated predictive markers to discriminate between these oligo/argometastatic patients, who will benefit from surgery, and those with diffuse metastatic behavior in whom surgery will be fu...

Quantifying tumor‐infiltrating lymphocytes (TILs) in breast cancer tumors is a challenging task for pathologists. With the advent of whole slide imaging that digitizes glass slides, it is possible to apply computational models to quantify TILs for pathologists. Development of computational models requires significant time, expertise, consensus, and...

Objective:Sentinel lymph node biopsy (SLNB) represents the gold standard for axillary surgical staging. The aim of this study was to assess the proportion of axillary lymph node dissection (ALND) that could be avoided after retrospective application of the ACOSOG Z0011 criteria and to evaluate the shortterm complications associated with axillary su...

Introduction/Background There is no evidence that resection margins after breast conserving surgery (BCS), defined as ’no ink on tumor’ can be applied to patients receiving neoadjuvant systemic treatment (NST). The study aim was to evaluate the impact of the distance of the resection margins on the loco-regional recurrence (LRR) and the survival of...

The clinical significance of the tumor-immune interaction in breast cancer is now established, and tumor-infiltrating lymphocytes (TILs) have emerged as predictive and prognostic biomarkers for patients with triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) breast cancer and HER2-positive breast cancer. How computational...

Modern histologic imaging platforms coupled with machine learning methods have provided new opportunities to map the spatial distribution of immune cells in the tumor microenvironment. However, there exists no standardized method for describing or analyzing spatial immune cell data, and most reported spatial analyses are rudimentary. In this review...

Introduction: The final oncological and aesthetic results of breast-conserving surgery (BCS) are influenced by the precise localization of breast cancer (BC) tumors and by the quality of the intraoperative margin assessment technique. This study aimed to assess the effectiveness of the carbon localization (CL) technique by determining the success...

Introduction: The microarchitecture of liver metastases (LMs), or histopathological growth pattern (HGP), has been demonstrated to be a significant prognostic factor in patients undergoing resection of colorectal liver metastases (CRLMs). Currently, however, HGP can be only determined on the operative specimen. Therefore, the development of new to...

Purpose: Invasive lobular carcinoma (ILC) represents up to 15% of all breast carcinomas. While the proportion of women with overweight and obesity increases globally, the impact of body mass index (BMI) at primary diagnosis on clinicopathological features of ILC and the prognosis of the patients has not been investigated yet. Patients and methods...

The clinical relevance of tumor infiltrating lymphocytes (TIL) in breast cancer (BC) is now widely accepted and being implemented in clinical practice. Our lab previously demonstrated that 60% of BC organize some of their TIL in tertiary lymphoid structures (TLS). TLS have been detected in a wide variety of solid tumors with their prognostic value...

As wider insights are gained on the molecular landscape of triple-negative breast cancer (TNBC), novel targeted therapeutic strategies might become an option in this setting as well. Activating mutations of PIK3CA represent the second most common alteration in TNBC after the TP53 mutation, with a prevalence of about 10-15%. Considering the well-est...

Background: Invasive lobular breast carcinoma (ILC) represents 5 to 15% of all invasive breast cancers. Recent studies showed the importance of tumor microenvironment (TME) heterogeneity on patient outcome. Here, we aim to characterize TME spatial heterogeneity by performing clustering analysis on spatial transcriptomics (ST) data. Methods: Frozen...

Background: Liver metastases (LM) are ultimately present in ~50% of all patients with metastatic breast cancer (BC). Metastatic seeding to the liver relies on the interaction between cancer cells and the host microenvironment, resulting into two main histopathological growth patterns (HGPs): the replacement HGP (metastasis mimics the liver architec...

Background: Invasive lobular carcinoma (ILC) represents up to 15% of all breast carcinomas. The majority of ILC express the estrogen receptor (ER) and have no amplification/overexpression of the human epidermal growth factor receptor 2 (HER2). A high body mass index (BMI) has been associated with an increased risk of developing ILC in postmenopausa...

Background Triple negative breast cancer (TNBC) is a heterogeneous disease characterized by at least five molecular subtypes, namely basal like (BL), immunomodulatory (IM), luminal androgen receptor (LAR), mesenchymal (M) and mesenchymal stem like (MSL), associated with distinct gene expression, genomic and tumor microenvironment (TME) profiles. Re...

Background: Inflammatory breast cancer (IBC) is a rare (1-5%), but aggressive form of breast cancer (BC), accounting for ~10% of BC mortality. In early setting (M0), standard of care is neoadjuvant chemotherapy (NACT), followed by surgery. Nevertheless, outcome is still relatively poor. Pathological complete response (pCR) after NACT is prognostic...

Solitary fibrous tumor (SFT) of the breast is a rare mesenchymal tumor composed of spindle-shaped tumor cells with collagen and large blood vessels in the shape of a "staghorn". It is discovered anywhere in the human body, usually incidentally or through nonspecific symptoms. A combination of clinical, histological, and immunohistochemical features...

Solitary fibrous tumor (SFT) of the breast is a rare mesenchymal tumor composed of spindle-shaped tumor cells with collagen and large blood vessels in the shape of a "staghorn". It is discovered anywhere in the human body, usually incidentally or through nonspecific symptoms. A combination of clinical, histological, and immunohistochemical features...

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,...

PURPOSE Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy in patients with early-stage breast cancer may allow for early detection of relapse. In this study, we analyzed ctDNA using a personalized, tumor-informed multiplex polymerase chain reaction–based next-generation sequencing assay. METHODS Plasma samples (n = 157) fro...

The impact of adiposity on the efficacy of endocrine treatment in patients with estrogen receptor positive breast cancer is poorly investigated. Here, we retrospectively investigated in a cohort of 56 patients whether body mass index and/or mammary adiposity are associated with anti-proliferative response in the neoadjuvant setting. Anti-proliferat...

Background Late distant recurrence is a challenge for the treatment of invasive lobular carcinoma (ILC) of the breast. Despite in-depth characterisation of primary ILC, the molecular landscape of metastatic ILC is still only partially understood. Methods We retrospectively identified 38 ILC patients from the tissue banks of six European institutio...

Invasive lobular carcinoma (ILC) represents the second most common subtype of breast cancer (BC), accounting for up to 15% of all invasive BC. Loss of cell adhesion due to functional inactivation of E-cadherin is the hallmark of ILC. Although the current world health organization (WHO) classification for diagnosing ILC requires the recognition of t...

Introduction The histological growth pattern (HGP) of colorectal liver metastases (CRLMs) reflects tumor biology and local infiltrating behavior. In patients undergoing surgery for CRLMs, we investigated whether HGP and surgical margin status interact when influencing prognosis. Methods Clinicopathological data, margin status, and HGP were reviewe...

Neoadjuvant chemotherapy (NAC) is standard of care for patients with locally advanced breast cancer. TIL scoring is prognostic for response and has additional predictive value to the residual cancer burden after NAC. However, NAC induces various changes in the tumor bed and reliability of TIL scoring in post-NAC samples has not yet been studied. Pr...

Background: The impact of obesity on the efficacy of endocrine treatment (ET) in patients with estrogen receptor positive (ER+) breast cancer (BC) is poorly investigated. Several neoadjuvant trials, using changes in Ki67 as biomarker of anti-proliferative response, have demonstrated that neoadjuvant ET improves surgical and clinical outcomes. A rec...

Background. ILC represents the second most common histological type of breast cancer (BC), accounting for approximately 15% of all invasive BCs. Loss of cell-cell adhesion due to genomic alterations of CDH1,. the gene coding for E-cadherin, is the hallmark of ILC. So far, in the WHO guidelines, it is essential to recognize the dispersed or linear d...

Background: Invasive lobular breast carcinoma (ILC) represents 5 to 15% of all invasive breast cancers (BCs). Here, we aim to investigate inter- and intra-tumor heterogeneity in terms of microenvironment composition, PAM50 molecular classification and proliferation (genomic grade index [GGI]) by combining spatial transcriptomics (ST) and accurate m...

Background: Approximately 30% of patients with early breast cancer present disease relapse after surgery, and technologies that enable the detection of circulating tumor DNA (ctDNA) were shown to identify them earlier than standard imaging. In the present study, we aimed to interrogate the value of the SignateraTM personalized ctDNA assay for early...

Introduction: Invasive lobular breast cancer (ILC) is the most frequent special type of breast cancer. Recent studies showed the impact of intratumor heterogeneity (ITH) on patient outcome. Here, we aimed to better characterize ITH in ILC using spatial transcriptomics (ST) together with high-resolution morphological annotation. Methods: Spatial tra...

Background: Despite therapeutic advancements, a substantial number of patients with treated early-stage invasive lobular carcinoma (ILC) of the breast will still relapse as late as 20 years after the initial tumor diagnosis, thus making follow-up a challenging task. Here, using patient-matched primary and metastatic tumors from patients with ILC, w...

Objective: Nearly 1/5 of women with breast cancer (BC) treated by breast-conserving surgery (BCS) require reoperation due to positive margins on final pathology. In our hospital practice, intraoperative macroscopic pathological margin evaluation (IMPME) of all lumpectomy specimens is routine. The objectives of the study were to assess the accuracy...

Purpose: Validating artificial intelligence algorithms for clinical use in medical images is a challenging endeavor due to a lack of standard reference data (ground truth). This topic typically occupies a small portion of the discussion in research papers since most of the efforts are focused on developing novel algorithms. In this work, we presen...

Introduction/Background* Breast cancer (BC) tumor size (TS) at diagnosis is one of the most important prognostic factors and represent a pivotal key driver of treatment planning for patients with BC. The aim of this study was to evaluate the place of complementary breast magnetic resonance imaging (MRI) for preoperative TS evaluation in patients wi...

Introduction/Background* Digestive tract resection is a common procedure performed in bulky advanced-stage ovarian cancer (AOC) to achieve complete cytoreductive surgery (CRS). Very few data are available on the incidence and the prognostic impact of mesenteric lymph node (MLN) involvement.The aim of this study is to determine the incidence of MLN...

Our expanding knowledge of the interactions between tumor cells and their microenvironment has helped to revolutionize cancer treatments, including the more recent development of immunotherapies. Immune cells are an important component of the tumor microenvironment that influence progression and treatment responses, particularly to the new immunoth...

We previously demonstrated that tumor infiltrating lymphocytes (TIL) in human breast cancer sometimes form organized tertiary lymphoid structures (TLS) characterized by CXCL13-producing T follicular helper (Tfh) cells. The present study found that CD4+ Tfh TIL, CD8+ TIL and TIL-B, co-localizing in TLS, all express the CXCL13 receptor CXCR5. An ex v...

Background Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint b...

Background Current fertility preservation strategies for young breast cancer patients planning a future motherhood include the association of controlled ovarian stimulation with the aromatase inhibitor letrozole (let-COS) to harvest mature oocytes while maintaining low estradiol levels. Despite this is a widely adopted protocol, the safety of let-C...

Introduction Triple negative breast cancer (TNBC) is a heterogeneous disease. Spatial transcriptomics (ST) interrogates gene expression in spatially defined spots. Here, we assessed whether ST expression data could identify specific histomorphologic features from TNBC samples, the ultimate goal being to develop a tool allowing to automatically anno...

p>Introduction Triple negative breast cancer (TNBC) is a heterogeneous disease associated at least with five distinct molecular subtypes namely basal like (BL), immunomodulatory (IM), luminal AR (LAR), mesenchymal (M) and mesenchymal-stem like (MSL). Spatial transcriptomics (ST) interrogates gene expression in spatially defined spots. Here, we aime...

Introduction: Selection for surgery in patients with colorectal liver metastases (CRLM) remains poorly personalized. We evaluated whether the combination of clinico-metabolic characteristics with the histological growth pattern (HGP) of CRLM could improve the prognostication in individual cases. Methods: In a series of 108 patients undergoing re...

Mucinous carcinomas can arise in any organ with epithelial cells that produce mucus. While mucinous tumors from different organs are histologically similar, it remains to be elucidated whether they share molecular alterations. Here we analyzed a total of 902 patients across six cancer types by comparing mucinous and non-mucinous samples, integratin...

Background and Objectives The histological growth pattern (HGP) represents a strong prognostic factor in patients undergoing surgery for colorectal liver metastases (CRLM). We evaluated whether the combination of HGP with clinico‐metabolic parameters could improve its prognostic value. Methods In a series of 108 patients undergoing resection of CR...

Most breast cancers exhibit low immune infiltration and are unresponsive to immunotherapy. We hypothesized that inhibition of the receptor activator of nuclear factor-κB (RANK) signaling pathway may enhance immune activation. Here we report that loss of RANK signaling in mouse tumor cells increases leukocytes, lymphocytes, and CD8⁺ T cells, and red...

Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research comm...

Adipocytes and cancer-associated adipocytes (CAAs) are poorly investigated cells in the tumor microenvironment. Different image analysis software exist for identifying and measuring these cells using scanned hematoxylin and eosin (H&E)-stained slides. It is however unclear which one is the most appropriate for breast cancer (BC) samples. Here, we c...

Currently, there are no markers to identify patients with liver-only or liver-dominant metastases that would benefit from hepatic surgery. Here we characterized histopathological growth patterns (HGPs) of liver metastases in a consecutive series of 36 breast cancer patients who underwent hepatic surgery. Survival analyses showed that the presence o...

Background and Objectives We report, for the first time in the literature, a metastatic lymphatic pathway along the inferior epigastric vessels, through the inferior epigastric lymph nodes (IELNs), in patients with peritoneal carcinomatosis (PC). Interestingly, these lymph nodes (LNs) in the anterior retroperitoneum were not detectable on preoperat...

Purpose: In this work, we present a collaboration to create a validation dataset of pathologist annotations for algorithms that process whole slide images (WSIs). We focus on data collection and evaluation of algorithm performance in the context of estimating the density of stromal tumor infiltrating lymphocytes (sTILs) in breast cancer. Methods: W...

Introduction Positive margins after breast-conserving surgery (BCS) for breast cancer (BC) remain a major concern. In this study we investigate the feasibility and accuracy of indocyanine green (ICG) fluorescence imaging (FI) for the in vivo assessment of surgical margins during BCS. Materials and methods Patients with BC admitted for BCS from Oct...

Background: Nodal staging is a major concern in colorectal cancer as it is an important prognostic factor. Several techniquesthat could potentially improve patient treatment and prognosis have been developed to increase the accuracy of nodal staging.Sentinel lymph node detection has been shown to accurately reflect nodal status in various tumors an...

Background High-throughput sequencing technologies are increasingly used in research but limited data are available on the feasibility and value of these when routinely adopted in clinical practice. Material and methods We analyzed all consecutive cancer patients for whom genomic testing by a 48-gene next-generation sequencing (NGS) panel (Truseq...

There is a growing interest in active immune responses generated by tertiary lymphoid structures (TLS) arising in solid tumors; however, their clinical impact in breast cancer (BC) remains unclear. Several studies show that transcription factors contribute to TLS formation via their regulation of cytokine and chemokine production. The Forkhead box...

Background: The skeleton is the first and most common distant metastatic site for breast cancer. Such metastases complicate cancer management, inducing considerable morbidities and decreasing patient survival. Osteomimetism is part of the complex process of osteotropism of breast cancer cells. Recent data indicate that Farnesoid X Receptor (FXR) i...

Objective Oesophageal cancer (OEC) is an aggressive disease with a poor survival rate. Prognostic markers are thus urgently needed. Due to the demonstrated prognostic value of histopathological growth pattern (HGP) in other cancers, we performed a retrospective assessment of HGP in patients suffering from invasive OEC. Design A first cohort compos...