Renaud Sabatier

Claudin-low breast cancers: clinical, pathological, molecular and prognostic characterization

BackgroundThe lastly identified claudin-low (CL) subtype of breast cancer (BC) remains poorly described as compared to the other molecular subtypes. We provide a comprehensive characterization of the largest series of CL samples reported so far.MethodsFrom a data set of 5447 invasive BC profiled using DNA microarrays, we identified 673 CL samples (12,4%) that we describe comparatively to the other molecular subtypes at several levels: clinicopathological, genomic, transcriptional, survival, and response to chemotherapy.ResultsCL samples display profiles different from other subtypes. For example, they differ from basal tumors regarding the hormone receptor status, with a lower frequency of triple negative (TN) tumors (52% vs 76% for basal cases). Like basal tumors, they show high genomic instability with many gains and losses. At the transcriptional level, CL tumors are the most undifferentiated tumors along the mammary epithelial hierarchy. Compared to basal tumors, they show enrichment for epithelial-to-mesenchymal transition markers, immune response genes, and cancer stem cell–like features, and higher activity of estrogen receptor (ER), progesterone receptor (PR), EGFR, SRC and TGFβ pathways, but lower activity of MYC and PI3K pathways. The 5-year disease-free survival of CL cases (67%) and the rate of pathological complete response (pCR) to primary chemotherapy (32%) are close to those of poor-prognosis and good responder subtypes (basal and ERBB2-enriched). However, the prognostic features of CL tumors are closer to those observed in the whole BC series and in the luminal A subtype, including proliferation-related gene expression signatures (GES). Immunity-related GES valuable in basal breast cancers are not significant in CL tumors. By contrast, the GES predictive for pCR in CL tumors resemble more to those of basal and HER2-enriched tumors than to those of luminal A tumors.ConclusionsMany differences exist between CL and the other subtypes, notably basal. An unexpected finding concerns the relatively high numbers of ER-positive and non-TN tumors within CL subtype, suggesting a larger heterogeneity than in basal and luminal A subtypes.

Personalized medicine: Present and future of breast cancer management

Breast cancer is the first cause of cancer in women worldwide. Recent molecular analyses have shown that it is not a single disease but a mixture of several diseases with different biological behaviors, which should lead to treatment customization for each patient. Personalized medicine is based on tumor and/or patient molecular profiles. This new way to think oncology is currently applied at different stages of breast cancer management, including prognosis, prediction of treatment efficacy, and development of new therapies via new kinds of clinical trials. These trials are not only based on tumor site but also on tumor genetic characterization using genomic tools such as gene expression profiling, array-CGH or next-generation sequencing technologies. The aim of personalized medicine is to tailor treatment according to the specificities of a single disease in a given patient. In this review, we present the advances in treatment personalization which are currently used in daily practice as well as the technologies and therapies under investigation in various clinical trials.

Cancer du sein triple-négatif : caractéristiques histocliniques et moléculaires, prise en charge et perspectives thérapeutiques

Triple-negative breast cancer (TNBC), as defined by the absence of estrogen and progesterone receptor expression, as well as the lack of HER2 overexpression/amplification, corresponds to 15% of breast cancer and represents an aggressive form of the disease. TNBC are frequently confounded with basal subtype in the molecular classification of breast cancer and also share some similarities with BRCA1-mutated tumors. Epidemiological and clinical characteristics are distinct from other subtypes, including a younger age at diagnosis, a higher risk of relapse in spite of increased chemosensitivity, and a higher incidence of lung and brain metastatic relapses. Conventional cytotoxics remain the mainstay of current systemic management but recent evaluation of more targeted therapeutics, including specific cytotoxics (such as the use of platinum salts), PARP and EGFR inhibition, and antiangiogenics have been performed, providing contrasted but rather disappointing results. Recent data indicate that TNBC represent a heterogeneous entity composed of multiple and distinct molecular subtypes, which should deserve specific targeted therapeutics.

“Stealth” tumors: Breast cancer cells shun NK-cells anti-tumor immunity

Breast cancers (BCs) comprise heterogeneous subtypes of various prognoses. An active anti-tumor immune profile usually correlated with a better survival. Two current major challenges of BC research are to understand the inter-relations between BC and anti-tumor immunity, and to identify candidates whose targeting would contribute to enhance anti-tumor efficiency.

Autorisation de mise sur le marché du trastuzumab emtansine (Kadcyla®) dans les cancers du sein métastatiques HER2-positifs

HER2 (human epidermal growth factor receptor 2) is overexpressed in 15 to 20% of breast cancer. Anti-HER2 targeted therapies, notably trastuzumab, have transformed the natural history of this disease. Trastuzumab emtansine, consisting of trastuzumab coupled to a cytotoxic agent, emtansine (DM1), by a stable linker, has been approved in November 2013 by the European Medicine Agency. Trastuzumab emtansine targets and inhibits HER2 signaling, but also allows emtansine to be directly delivered inside HER2-positive cancer cells. It is indicated as single-agent in taxane and trastuzumab-pretreated HER2-positive breast cancer patients with metastatic and locally recurrent unresecable disease or relapsing within 6 months of the end of adjuvant therapy. This indication is based on the results of the EMILIA study, an open label phase III randomized trial comparing trastuzumab emtansine to lapatinib-capecitabine. The two primary endpoints were reached. The progression-free survival was 6.4 months in the lapatinib-capecitabine arm versus 9.6 months for the trastuzumab emtansine arm (HR=0.65; 95% CI=0.55-0.77, P<0.001). Overall survival at the second interim analysis was 25.1 months in the lapatinib-capecitabine arm versus 30.9 months in the trastuzumab emtansine arm (HR=0.68; 95% CI=0.55-0.85, P<0.001). Moreover, adverse events were more frequent in the lapatinib-capecitabine arm.

[Pertuzumab (Perjeta®) approval in HER2-positive metastatic breast cancers].

Fifteen to 20% of breast cancers display HER2 amplification. Many therapeutic successes have been obtained for this subtype in the last decade since trastuzumab approval for metastatic and localized diseases. Pertuzumab, a new anti-HER2 antibody, has been approved in 2013 by the European Medicine Agency. This drug can be used in combination with trastuzumab and docetaxel for the first line treatment of metastatic or locally recurrent non resecable HER2-positive breast cancers not previously treated by chemotherapy or HER2-inhibitors in the metastatic setting. This approval has been done after the CLEOPATRA trial results. This was a randomized, double-blind, multicentre, phase III trial evaluating the standard treatment (trastuzumab plus docetaxel) associated to pertuzumab or placebo. The authors have reported a statistically significant and clinically relevant benefit for the pertuzumab-based treatment. Median progression-free survival was 18.4 for the pertuzumab arm versus 12.5 months for the control group (p<0.001). They also observed benefits concerning the secondary endpoints: overall response rate and overall survival. Patients receiving pertuzumab presented more frequent diarrhea and febrile neutropenia but no increase in cardiac events. This drug has already been evaluated in the neoadjuvant setting with a FDA approval recently obtained. Its use in the adjuvant setting is under evaluation.

Immunohistochemical subtypes predict survival in metastatic breast cancer receiving high-dose chemotherapy with autologous haematopoietic stem cell transplantation

INTRODUCTION The objective of this study was to evaluate the outcome of patients affected with different subtypes of metastatic breast cancer (MBC) following treatment with high-dose chemotherapy (HDC) and autologous haematopoietic progenitor cell transplantation (AHSCT). METHODS All consecutive female patients treated for MBC with HDC and AHSCT at the Institut Paoli-Calmettes between 2003 and 2012 were included. Patient, tumour and treatment characteristics were collected. Patients were categorised in three subtypes based on hormonal receptor (HR) and human epidermal growth factor receptor 2 (HER2) status of the primary tumour: luminal (L), (HR+/HER2-), HER2 (HER2+, any HR), and triple negative (TN) (HER2- and HR-). The main objective was the analysis of overall survival (OS) according to the immunohistochemical (IHC) subtypes. RESULTS A total of 235 patients were included, median age was 46 (range 21-62). Median follow up was 53.28 months (95% confidence interval [CI] 45.12-57.6). The TN subtype appeared to have the worst prognosis with a median OS of 19.68 months (95% CI 11.76-44.4) compared to 44.64 months (95% CI 40.32-67.56) for the luminal subtype and a median OS not reached for the HER2 subtype (p < 0.01). In the multivariate analysis, the TN subtype retained an independent poor prognosis value compared to the luminal subtype, with a hazard ratio of 2.03 (95% CI 1.26-3.29, p = 0.037). CONCLUSION HDC-AHSCT does not change the prognostic value of IHC subtypes in MBC patients. OS favourably compares with data available in the literature on similar groups of patients. These findings provide additional information and options for patients with MBC and who could potentially benefit of HDC-AHSCT.