Assessment of mutation status in patients with non-small cell lung cancer (NSCLC) is often required. The aim of this study was to confirm the feasibility of molecular mutation analysis in cytologic specimens obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA).

Metastatic breast cancer (MBC) is an incurable disease. The goal of treatment is mainly palliative to improve quality of life by the control of disease (in terms of disease free survival [DFS]) as long as possible, and to treat symptoms with fewer side effects. The gene c-erb B2 or neu or HER2 is amplified in 20-25% of breast cancers. This amplification is associated with a more aggressive disease and a poor prognosis. Patients, carrying a HER2-positive MBC, benefit from new therapies targeting the HER2 receptor. These treatments have shown their efficacy as single agent, and have a synergistic effect with chemotherapy. There is a more toxicity profile in comparison with that of chemotherapy. In first line metastatic disease, treatment should include a combination based on trastuzumab and chemotherapy. After disease progression with trastuzumab-based therapy, rechallenging Trastuzumab in combination with chemotherapy is a reasonable option. After a second progression with trastuzumab, a combination based on lapatinib plus Capecitabine (or other chemotherapy if Capecitabine was previously used) should be proposed; the combination based on lapatinib and trastuzumab is reasonable. Inclusion in clinical trials must continue to improve outcomes for our patients.

From the second part of the 20th century, our knowledge of tumor biology widely benefited of tremendous progress in genetics (oncogenes, tumor suppressor genes, chromosomal abnormalities, etc), then in complex epigenetic process that regulates gene expression. Other players have entered the field of oncology and are now considered for their potential therapeutic interest: energetic metabolism, cancer stem cells as sources of tumor recurrence, microenvironment and above all intratumor heterogeneity. A better understanding of these domains of fundamental oncology should not mask the notion that a tumor is a living entity, which obeys the rules of Darwinian evolution.

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.

Soft tissue sarcomas are rare and heterogeneous tumours. Histological diagnosis is often difficult because of the numerous types and subtypes reported and morphological similarities with benign lesions in certain cases. Molecular analyses performed in an appropriate clinical and histological context improve the patients' management in the case of sarcomas with simple genomic profile: the identification of a specific and objective molecular abnormality can confirm a diagnosis, rule out another one, provide prognostic information, and guide the selection of targeted therapy About 15% of sarcomas bear a specific translocation that can be identified by FISH or RT-PCR. The search for a MDM2 amplification, reflecting the presence of an amplicon in the 12q region, is a sensitive and specific tool for the diagnosis of atypical lipomatous tumors/well-differentiated liposarcomas and dedifferentiated iposarcomas. The presence and the type of KITor PDGFRA activating mutation guide the diagnosis and treatment of GIST. Certain molecular abnormalities are found in several tumour types, emphasizing the importance of integrating the results of any molecular study within the morphological and immunohistochemical context: In France, sarcoma diagnosis is structured around a reference network (RRePS) that provides every pathologist an access to these molecular analysis tools.

To review the evidence relating to the epidemiology of endometrial cancer and its diagnostic workups.

Metastatic dissemination represents the true cause of the malignant character of cancers. Its targeting is much more difficult than that of cell proliferation, because metastasis, like angiogenesis, involves a number of complex interactions between tumour and stroma; the contribution of adhesion and motility pathways is added to that of proliferation and survival pathways. Long distance extension, discontinuous in respect to the primitive tumour, is a major feature of cancer and the main cause of patients' death. Cancer cells use two main dissemination pathways: the lymphatic pathway, leading to the invasion of the lymph nodes draining the organs where the tumour evolves; and the blood pathway, leading to the invasion of distant organs such as liver, brain, bone or lung. Metastasis is inscribed within the properties of the primitive tumour, as shown by the comparative molecular analysis of the primitive tumour and its own metastases: their similarity is always more important than what could be expected from the general activation of "metastasis genes" or the inhibition of "metastasis suppressor genes". Among the signalling pathways involved in metastasis, one can mention the integrin pathway, the transforming growth factor beta (TGFβ) pathway, the chemokine pathway, the dependence receptor pathway and many others. These pathways allow the possibility of therapeutic targeting, thanks to therapeutic antibodies or small molecules inhibiting the kinases involved in these signalling pathways, but not a single properly anti-metastatic drug has yet been proposed: the complexity and the diversity of the processes allowing metastasis emergence, as well as the fact that the activation mechanisms are more often epigenetic than genetic and are generally physiological processes misled by the malignant cell, render especially difficult the therapeutic approach of metastasis.

Aero-digestive tract squamous intra-epithelial neoplasia is a disease whose genetic and epigenetic features lead to clinical signs and well codified histologic features. This publication aims to review the molecular alterations which have been identified in these lesions, to clarify the clinical manifestations and to discuss the proposed histological classification.

Endometriosis is considered as a tumor-like lesion under the World Health Organization (WHO) classification of ovarian tumors. Data from large cohort and case-control studies indicate that patients with a history of endometriosis have an increased risk of ovarian cancer. Recent findings suggest an association between endometriosis and the entire type 1 ovarian tumors group including clear-cell, endometrioid and low-grade serous carcinomas. However, current evidence is lacking to draw definitive conclusion whether this association represents causality or the sharing of common risk factors. Nevertheless, assumption that endometriosis could be a precursor of malignancy raises many issues about serial screening, surgical management and surveillance of endometriosis. Beyond these concerns, endometriosis-associated ovarian cancers seem to be a genuine clinical entity as regards clinicopathological features. In view of the high incidence of endometriosis (10 % of women of childbearing age), the low incidence of endometriosis-associated ovarian cancers and the psychological consequences for those women, systematic screening and surgical exploration seem very questionable in this context.

The HER2 gene or c-erb B2 or neu is amplified in 15-25% of breast cancers. This amplification is associated with an aggressive course of disease. The trastuzumab is a monoclonal antibody targeting the extracellular domain of HER2. This is the first targeted molecule designed to treat breast cancer. In the firstline metastatic disease, trastuzumab in combination with chemotherapy significantly improved survival of patients with HER2-positive disease. In the adjuvant setting, trastuzumab has been evaluated in several randomized trials.

Adipose tissue has long been considered as an « organ » of energy storage. Although many works had previously identified the secretory nature of adipocyte, it was only in 1994, when the leptin gene was cloned, that adipose tissue earned the status of endocrine tissue. It was the first demonstration that an adipose tissue-derived hormone was able to communicate with the central nervous system to control satiety and energy balance. In fact, it is almost at the same time that another major adipokine produced by adipocytes, adiponectin, has been discovered. It took several years to identify the insulin-sensitizing, anti-inflammatory and anti-atherogenic properties of this hormone. More recently, several epidemiological, genetic and experimental findings suggest an anti-carcinogenic role for adiponectin. In this brief review we will present the arguments supporting a protective role of adiponectin in tumor progression, particularly in the context of breast cancer. Adiponectin deficiency commonly observed in obesity may contribute to the natural history of several cancers, as well as the elevation of leptin and other hormonal disturbances associated with excessive adiposity.

Multiple familial trichoepithelioma (MFT) is an autosomal dominant disease characterized by the development of numerous skin-coloured papules on the central area of the face. It is associated with various CYLD gene mutations that are also responsible for familial cylindromatosis and Brooke-Spiegler syndrome.

Recent works suggest that Activin A (ActA) and Myostatin (Mstn), two members of the TGFβ superfamily, could contribute to skeletal muscle atrophy observed in some cancers. It is known that several human tumoral cell lines synthesize and secrete ActA and Mstn. In addition, systemic treatment with ActA and Mstn in mice induce muscle atrophy. Likewise, Inhibin-α knock-out mice, which are characterized by elevated circulating levels of ActA, exhibit muscle atrophy and die of cachexia. Finally, administration of ActA and Mstn antagonists prevents muscular atrophy and mortality induced by some animal tumors. Collectively, these findings suggest that ActA or Mstn production by several cancers could contribute to cachexia and thus to mortality associated with some cancers in human. This hypothesis is very interesting since new molecules that are able to inhibit ActA and Mstn, in particularly the sActRIIB, are under development.

Crizotinib is a small orally-administered ALK inhibitor for patients with non-small cell lung cancer with EML4-ALK rearrangement (echinoderm microtubule-associated protein-like 4 and anaplastic lymphoma kinase). This fusion gene is detected with a break apart fluorescence in situ hybridization (FISH) assay. Phase I to III trials have shown an interesting disease control rate and acceptable tolerability. Crizotinib is available in France under temporary use authorization. New potentially effective therapeutics in ALK-positive NSCLC are being developed.

Gastrointestinal stromal tumors (GIST) are the most frequent sarcomas but were underdiagnosed until the beginning of this century. GIST derive from interstitial cells of Cajal and may develop all along the digestive tract. GIST are characterized by the expression of KIT (CD117), and also DOG-1, which was recently discovered by transcriptome analysis. Gain-of-function mutations of the tyrosine kinase receptors KIT and PDGFRA are present in 85% of cases. More than 150 different mutations have been reported, mostly located in exon 11 of the KIT gene. Detection of these mutations may be useful to confirm the diagnosis and to evaluate the prognosis. Mutations also have predictive value. For example, patients with metastatic GIST and a duplication of KIT exon 9 should receive twice the usual dose of imatinib, while GIST with the PDGFRA p. D842 V mutation are resistant to imatinib. This article presents the main pathologic characteristics of GIST and the important insights that GIST research has provided for oncology in general.

Cancer is now the leading cause of mortality in France. It has been clearly demonstrated that mutations in the genetic information is the initiating event of cancer. DNA damage such as DNA double-strand breaks leads to genomic instability and cancer development. Cells can repair DNA double-strand breaks through several mechanisms. Nevertheless, only homologous recombination repair is faithful and repairs DNA without creating mutations. Here, we review the roles of PALB2 and BRCA2 in homologous recombination and genome stability.