Molecular Characterization and Immunity of Triple-Negative Breast Carcinomas

Le cancer du sein triple négatif (CSTN) est le sous-type de cancer du sein le plus hétérogène et le plus défavorable. La pierre angulaire du traitement de ces tumeurs repose sur la chimiothérapie systémique, de plus en plus fréquemment administrée en néoadjuvant, puisqu’aucune thérapie ciblée n’est à ce jour validée. L'obtention d'une réponse complète histologique (RCH) constitue un marqueur pronostique favorable majeur ainsi qu'un test in vivo de la sensibilité aux médicaments anti-tumoraux. L’objectif de notre travail de thèse a donc été d’apporter des éléments de compréhension de cette hétérogénéité grâce à la dissection clinique, biologique et moléculaire de ces tumeurs. Nous avons analysé les profils d'expression géniques de ces CSTN et ainsi identifié 6 sous-types moléculaires distincts avec des biologies et des pronostics différents. Cette classification s’appuie sur une méthodologie originale basée à la fois sur des outils bioinformatiques classiques associée à l’utilisation de réseaux biologiques. L’enrichissement en gènes de l'immunité issus du compartiment stromal de la tumeur représente un déterminant majeur du pronostic de ces tumeurs : une forte expression des gènes de l'immunité est associée un pronostic significativement plus favorable. Notre principale contribution repose sur une meilleure compréhension de l’immunité et de l’infiltrat lymphocytaire (TILS) de ces CSTN. Il s’agit probablement du sous-groupe de cancers du sein le plus immunogène avec des taux de TILS pré-CNA parmi les plus élevés avec les tumeurs HER2-positives. Cet infiltrat lymphocytaire est d'ailleurs très corrélé aux gènes de notre module immunitaire pronostique dans les CSTN. La valeur prédictive et pronostique des TILS du stroma tumoral est différente selon le sous-type moléculaire de cancer du sein, suggérant une immunité complètement différente de ces tumeurs. Le taux de TILS varie également différentiellement au sein de chaque sous-groupe sous l'influence de la CNA, témoignant d'une interaction complexe entre les TILS et les traitements. Nous montrons que la cinétique des TILS sous l'effet de la CNA est un indicateur pertinent de réponse à la CNA avec une réponse d'autant plus importante qu'une décroissance du taux de TILS sera importante. Les tumeurs les plus immunogènes avec une activité immunitaire importante sont donc les tumeurs triple-négatives les plus favorables. L'un des challenge des années à venir sera donc d'identifier le plus tôt possible les CSTN les moins immunogènes susceptibles de bénéficier au mieux des immunothérapies seules ou combinées au traitement chimiothérapique afin d'activer ou de rétablir précocement une immunité déficiente. Sous une même dénomination de TILS se trouve très certainement des populations phénotypiques de lymphocytes différentes. En effet, après CNA, leur valeur pronostique est opposée entre les CSTN et les tumeurs HER2-positives: des taux élevés de TILS sont associés à un pronostic défavorable dans les tumeurs HER2-positives alors qu’ils ont une tendance à être associés à des CSTN de meilleur pronostic. Les interactions sont complexes entre les agents cytotoxiques et la tumeur et/ou son microenvironnement. L'analyse du résidu tumoral mammaire ou ganglionnaire représente un matériel sous-exploité qui pourrait permettre de mieux comprendre les mécanismes de sensibilité ou de résistance aux traitements. Au delà de la pierre angulaire que constitue l'immunité pour ces tumeurs, nos travaux identifient certains CSTN pour lesquels l'environnement hormonal, au travers de l'indice de masse corporel ou du statut ménopausique, pourrait jouer un rôle. Ainsi l'exploration du métabolome, des particularités immunitaires chez les patientes en surpoids/obèses ou l'analyse de la voie androgène-récepteur (et ses connexions avec les voies oestrogène et progestérone-récepteur) des CSTN doit aussi être explorée de manière détaillée. Ceci ouvre des perspectives de traitement possibles pour certaines patientes.Triple negative breast cancer (TNBC) is the most heterogeneous and pejorative subtype of breast cancer. The cornerstone of the treatment of such tumors is based on systemic chemotherapy, more and more frequently administered before surgery, since no targeted therapy has been validated to date. Obtaining a pathological complete response (PCR) is a major favorable prognostic marker as well as an in vivo test of anti-tumor drug susceptibility. The objective of our thesis work was therefore to provide elements of understanding of this heterogeneity through the clinical, biological and molecular dissection of these tumors.We analyzed gene expression profiles of TNBCs and identified 6 distinct molecular subtypes with different biologies and prognoses. This classification used an original methodology based on both classical bioinformatic tools and biological networks. The enrichment of immunity genes from the stromal compartment of the tumor represents a major determinant of the prognosis of these tumors: a strong expression of the immunity genes is associated with a significantly more favorable prognosis.Our main contribution is based on a better understanding of immunity and tumor infiltrated lymphocytes (TILS) of these TNBCs. It is probably the most immunogenic subgroup of breast cancers with the highest TILs levels pre-NAC with HER2-positive tumors. TILS levels are also highly correlated with genes of our immune prognosis module. The predictive and prognostic value of stromal TILS is different according to the molecular subtype of breast cancer, suggesting a completely different immunity of these tumors. The rate of TILS also varies differentially within each subgroup under the influence of the NAC, indicating a complex interaction between TILS and treatments. We show that the kinetics of TILS levels with NAC is a relevant indicator of response to NAC with a response that is all the more important that a decrease in the TILS rate will be important. The most immunogenic tumors with an important immune activity are therefore the most favorable triple-negative tumors. One of the challenges of the coming years will therefore be to identify, as soon as possible, the least immunogenic TNBC that can best benefit from immunotherapies alone or in combination with chemotherapeutic treatment in order to activate or restore early a deficient immunity.Under the same denomination of TILS there are probably different phenotypic populations of lymphocytes. Indeed, after CNA, their prognostic value is opposite between the TNBC and the HER2-positive tumors: high levels of TILS are associated with an unfavorable prognosis in HER2-positive tumors whereas they have a tendency to be associated with a better prognosis for TNBC tumors. The interactions are complex between cytotoxic agents and the tumor and / or its microenvironment. The analysis of the breast or axillary lymph node residual disease represents an underutilized material that could lead to a better understanding of the mechanisms of sensitivity or resistance to treatment.Beyond the key role immunity for these tumors, our work identifies some TNBCs for which the hormonal environment, through the body mass index or the menopausal status, could play a role. Thus, the exploration of the metabolome, immune features in overweight / obese patients or the analysis of the androgen-receptor pathway (and its connections with the estrogen and progesterone-receptor pathways) of the TNBC must also be explored. This opens up possible treatment perspectives for some patients

Influence of geographic access and socioeconomic characteristics on breast cancer outcomes: A systematic review

Socio-economic and geographical inequalities in breast cancer mortality have been widely described in European countries and the United States. To investigate the combined effects of geographic access and socio-economic characteristics on breast cancer outcomes, a systematic review was conducted exploring the relationships between: (i) geographic access to healthcare facilities (oncology services, mammography screening), defined as travel time and/or travel distance; (ii) breast cancer-related outcomes (mammography screening, stage of cancer at diagnosis, type of treatment and rate of mortality); (iii) socioeconomic status (SES) at individuals and residential context levels. In total, n = 25 studies (29 relationships tested) were included in our systematic review. The four main results are: The statistical significance of the relationship between geographic access and breast cancer-related outcomes is heterogeneous: 15 were identified as significant and 14 as non-significant. Women with better geographic access to healthcare facilities had a statistically significant fewer mastectomy (n = 4/6) than women with poorer geographic access. The relationship with the stage of the cancer is more balanced (n = 8/17) and the relationship with cancer screening rate is not observed (n = 1/4). The type of measures of geographic access (distance, time or geographical capacity) does not seem to have any influence on the results. For example, studies which compared two different measures (travel distance and travel time) of geographic access obtained similar results. The relationship between SES characteristics and breast cancer-related outcomes is significant for several variables: at individual level, age and health insurance status; at contextual level, poverty rate and deprivation index. Of the 25 papers included in the review, the large majority (n = 24) tested the independent effect of geographic access. Only one study explored the combined effect of geographic access to breast cancer facilities and SES characteristics by developing stratified models

Influence of geographic access and socioeconomic characteristics on breast cancer outcomes: A systematic review

International audienceSocioeconomic and geographical inequalities in breast cancer mortality have been widely described in European countries and the United States. To investigate the combined effects of geographic access and socioeconomic characteristics on breast cancer outcomes, a systematic review was conducted exploring the relationships between: (i) geographic access to healthcare facilities (oncology services, mammography screening), defined as travel time and/or travel distance; (ii) breast cancer-related outcomes (mammography screening, stage of cancer at diagnosis, type of treatment and rate of mortality); (iii) socioeconomic status (SES) at individuals and residential context levels. In total, n = 25 studies (29 relationships tested) were included in our systematic review. The four main results are: The statistical significance of the relationship between geographic access and breast cancer-related outcomes is heterogeneous: 15 were identified as significant and 14 as non-significant. Women with better geographic access to healthcare facilities had a statistically significant fewer mastectomy (n = 4/6) than women with poorer geographic access. The relationship with the stage of the cancer is more balanced (n = 8/17) and the relationship with cancer screening rate is not observed (n = 1/4). The type of measures of geographic access (distance, time or geographical capacity) does not seem to have any influence on the results. For example, studies which compared two different measures (travel distance and travel time) of geographic access obtained similar results. The relationship between SES characteristics and breast cancer-related outcomes is significant for several variables: at individual level, age and health insurance status; at contextual level, poverty rate and deprivation index. Of the 25 papers included in the review, the large majority (n = 24) tested the independent effect of geographic access. Only one study explored the combined effect of geographic access to breast cancer facilities and SES characteristics by developing stratified models

Impact de la précarité sur la prise en charge du cancer du sein en Île-de-France : résultats de l’étude DESSEIN

International audienceINTRODUCTION: Precariousness has been associated with an increase in breast cancer mortality, but the links between precariousness, stage at diagnosis and care pathways are little explored. The objective of the DESSEIN study was to assess the impact of precariousness on disease and care pathways.METHODS: Prospective observational study in Île-de-France comparing precarious and non-precarious patients consulting for breast cancer and followed for 1 year. RESULTS: In total, 875 patients were included between 2016 and 2019 in 19 institutions: 543 non-precarious patients and 332 precarious patients. Precarious patients had a more advanced stage at diagnosis (55% T1 vs. 63%, 30% N+ vs 19%, P = 0.0006), had a higher risk of not receiving initially planned treatment (4 vs. 1%, P = 0.004), and participated less in clinical trials (5 vs. 9%, P = 0.03). Non-use of supportive oncology care was 2 times more frequent among patients in precarious situations (P < 0.001). During treatment, 33% of deprived patients reported a loss of income, compared with 24% of non-deprived patients (P < 0.001). At 12 months from diagnosis, lay-offs were 2 times more frequent in precarious patients (P = 0.0001).DISCUSSION: Precariousness affects all stages of the cancer history and care pathway. Particular attention needs to be paid to vulnerable populations, considering issues of accessibility and affordability of care, health literacy and possible implicit bias from the care providers.INTRODUCTION : La précarité a été associée à une augmentation de la mortalité liée au cancer du sein mais les liens entre précarité, stade au diagnostic et parcours de soins sont peu explorés. L'objectif de l'étude DESSEIN était d'évaluer l'impact de la précarité sur la maladie et les parcours de soins. METHODES : Étude prospective observationnelle en Île-de-France comparant des patientes précaires et non précaires consultant pour un cancer du sein et suivies pendant un an.RESULTATS : Au total, 875 patientes ont été incluses entre 2016 et 2019 dans dix-neuf établissements : 543 patientes non précaires et 332 patientes précaires. Les patientes précaires avaient un stade au diagnostic plus avancé (55 % de T1 versus 63 %, 30 % de N+ versus 19 %, p = 0,0006), avaient un risque plus élevé de ne pas recevoir le traitement initialement prévu (4 versus 1 %, p = 0,004), et participaient moins à des essais cliniques (5 versus 9 %, p = 0,03). Le non-recours aux soins oncologiques de support était deux fois plus fréquent chez les patientes précaires (p < 0,001). En cours de traitement, 33 % des patientes précaires déclaraient subir une perte de revenus contre 24 % des patientes non précaires (p < 0,001). À douze mois du diagnostic, les licenciements étaient deux fois plus nombreux chez les patientes précaires (p = 0,0001).DISCUSSION : La précarité affecte toutes les étapes de l'histoire du cancer et du parcours de soins. Une attention particulière doit être portée aux populations vulnérables, prenant en compte les questions d'accessibilité géographique et financière, la littératie en santé et les biais implicites des soignants

New insight for pharmacogenomics studies from the transcriptional analysis of two large-scale cancer cell line panels (vol 7, 15126, 2016)

Author Correction: New insight for pharmacogenomics studies from the transcriptional analysis of two large-scale cancer cell line panelsInternational audienc

Validation of the 2018 FIGO Classification for Cervical Cancer: Lymphovascular Space Invasion Should Be Considered in IB1 Stage

Background: The aim of this study was to assess the prognostic impact of Lymphovascular space invasion (LVSI) in IB1 stage of the revised 2018 International Federation of Gynecology and Obstetrics (FIGO) classification for cervical cancer. Methods: A secondary analysis of two French prospective multicentric trials on Sentinel Lymph node biopsy for cervical cancer was performed. Patients with 2009 FIGO IB1 stage who underwent radical surgery between January 2005 and July 2012 from 28 French expert centers were included. The stage was modified retrospectively according to the new 2018 FIGO staging system. Results: According to the 2009 FIGO classification, 246 patients had IB1 disease stage and fulfilled the inclusion criteria. The median follow-up was 48 months (4–127). Twenty patients (8.1%) experienced a recurrence, and the 5-year Disease Free Survival (DFS) was 90.0%. Compared to 2018 IB1 staged patients, new IB2 had significantly decreased 5-year DFS, 78.6% vs. 92.9%, p = 0.006 whereas IIIC patients had similar 5-year DFS (91.7%, p = 0.95). In the subgroup of patients with FIGO 2018 IB1 stage, the presence of LVSI was associated with a significant decrease in DFS (82.5% vs. 95.8%, p = 0.04). Conclusions: LVSI is associated with decreased 5-year DFS in IB1 2018 FIGO stage and LVSI status should be considered in early-stage cervical cancer for a more precise risk assessment

A Stromal Immune Module Correlated with the Response to Neoadjuvant Chemotherapy, Prognosis and Lymphocyte Infiltration in <i>HER2</i>-Positive Breast Carcinoma Is Inversely Correlated with Hormonal Pathways

<div><p>Introduction</p><p><i>HER2</i>-positive breast cancer (BC) is a heterogeneous group of aggressive breast cancers, the prognosis of which has greatly improved since the introduction of treatments targeting <i>HER2</i>. However, these tumors may display intrinsic or acquired resistance to treatment, and classifiers of <i>HER2</i>-positive tumors are required to improve the prediction of prognosis and to develop novel therapeutic interventions.</p><p>Methods</p><p>We analyzed 2893 primary human breast cancer samples from 21 publicly available datasets and developed a six-metagene signature on a training set of 448 <i>HER2</i>-positive BC. We then used external public datasets to assess the ability of these metagenes to predict the response to chemotherapy (Ignatiadis dataset), and prognosis (METABRIC dataset).</p><p>Results</p><p>We identified a six-metagene signature (138 genes) containing metagenes enriched in different gene ontologies. The gene clusters were named as follows: Immunity, Tumor suppressors/proliferation, Interferon, Signal transduction, Hormone/survival and Matrix clusters. In all datasets, the Immunity metagene was less strongly expressed in ER-positive than in ER-negative tumors, and was inversely correlated with the Hormonal/survival metagene. Within the signature, multivariate analyses showed that strong expression of the “Immunity” metagene was associated with higher pCR rates after NAC (OR = 3.71[1.28–11.91], <i>p</i> = 0.019) than weak expression, and with a better prognosis in <i>HER2</i>-positive/ER-negative breast cancers (HR = 0.58 [0.36–0.94], <i>p</i> = 0.026). Immunity metagene expression was associated with the presence of tumor-infiltrating lymphocytes (TILs).</p><p>Conclusion</p><p>The identification of a predictive and prognostic immune module in <i>HER2</i>-positive BC confirms the need for clinical testing for immune checkpoint modulators and vaccines for this specific subtype. The inverse correlation between Immunity and hormone pathways opens research perspectives and deserves further investigation.</p></div