Epigenetic gene regulation contributes, together with genetic alterations, to cancer development and progression. In contrast to genetic disorders, the possibility of reversing epigenetic alterations has provided original targets for therapeutic application. In the last years, work has been focused on the pharmacological restoration of epigenetic regulation balance using epidrugs which yield hopes for novel strategy in cancer therapy. Histone acetylation and DNA methylation are epigenetic modifications which have been closely linked to the pathology of human cancers, and inhibitors of both enzyme classes for clinical use are at hands. Novel findings accumulated during the last years both in chemistry and biomedical applications give rise to new targeted treatments against cancer. Since their links with pathogenesis and progression of cancer were recognized, histone methyltransferases emerge as promising therapeutic targets in cancer treatment.

Histone deacetylases inhibitors (HDACi) represent a new epigenetic targeting therapy class, which is widely investigated in fundamental research and clinical trials. They are able to restore and increase tumor suppressor genes expression and to play an anti-tumoral activity through numerous targets, which are distributed all over the main differentiation, proliferation and survival cellular pathways. Their use in hematology led to vorinostat (SAHA) and romidepsin approval by FDA for the treatment of refractory cutaneous T-cell lymphomas. Preclinical and preliminary clinical results show a promising antineoplasic activity in most hematologic malignancies. This review will focus on the HDACi recent developments and current investigations, highlighted by recent communications.

Triple negative breast cancers are defined by the lack of expression of estrogen, progesterone and HER2 receptors. They represent an heterogeneous population with poor prognosis. The treatment of these tumors is a challenge because there is no known specific target. A huge number of studies try to better characterise these tumors at the molecular level with the aim to identify new therapeutic targets. The finding of new specific biomarkers like intracellular and extracellular microRNAs is also an important field of research. This article reviews some recent data in this field and the research on different pathways for the development of new therapies.

Bilateral prophylactic mastectomy is the most efficient risk management strategy for women at very high risk for breast cancer. Different methods can be used. The implementation of such a strategy must respond to the request of a well informed patient.

Many factors determine a woman's risk of breast cancer; some genetic are related to family history, others are based on personal factors such reproductive and medical history. A high-risk woman must benefit of a specific screening regimen including breast examination, mammography, ultrasonography and contrast material-enhanced magnetic resonance. But she can also benefit of chemo prevention or/and risk-reducing surgery such bilateral prophylactic salpingo-oophorectomy and bilateral prophylactic mastectomy.

Various subgroups of breast tumours have been identified during the last 10 years according to the risk of local relapse. Prognostic factors for local relapse are age, surgical margins, tumour size, Her2 expression and hormonal receptors status. For tumours with a high risk of local relapse, an increased in boost dose or the addition of new drugs (trastuzumab, antiangiogenics, PARP inhibitors) could be considered. For low risk tumours, hypofractionated, accelerated partial breast and intraoperative radiotherapy are being evaluated. The classical schedule (45-50 Gy to the whole gland followed by a boost dose of 16 Gy) is no longer the universal rule. Treatment individualization, according to clinical and biological characteristics of the tumour and - possibly - to the radiobiological profile of the patient, is likely to be the future of breast cancer radiotherapy.

Since the IPASS study, that has shown a benefit in term of progression-free survival in first line of treatment in non-small cell lung cancer (NSCLC) with activating EGFR mutations, and the restricted prescription of this treatment to the presence of these mutations, the determination of the mutational status has became necessary at the diagnosis. This research study of these mutations, present in about 10% of non-selected NSCLC, has to be preferred in case of clinical factors predictive of mutations (sex, race, tobacco status, adenocarcinoma), but don't have to be exclusive, the correlation between these clinical factors and the presence of the mutations being imperfect. Also, the research study of the EGFR mutations should be performed for patients non eligible for chemotherapy (PS>2). Molecular testing could be performed on biopsies, and also on cytology, knowing that there is a mismatch between the tumor and the metastasis for EGFR status. Samples should be prepared according to standardized protocols, avoiding fixation with Bouin. The gold-standard for molecular testing is still sequencing, but alternative targeted tests (allele-specific PCR...) seem to be more sensitive. Some immunohistochemistry tests are in development for EGFR mutations, but have to be validated on large prospective cohorts. At last, new tumoral sampling have to be performed in case of progression under gefitinib in first line, to look for acquired resistance EGFR mutations, or for other resistance molecular markers (Met amplification).

Screening of EGFR mutations in the 28 molecular biology centers that responded to a questionnaire obtained a mutation rate of 13% during the first semester of 2010. 87% of tested tumors were adenocarcinomas, but 79% of the centers test also other histological types. The main EGFR mutations sites (exons 19 and 21) were tested in all the centers. The most used technique is sequencing, whereas it is considered as the low sensitive test by most of the centers. Therefore many platforms are in the process of improving their technique and for some of them to choose alternative targeted techniques, with also stronger intra- and inter-center quality controls.

Since several years, the perception of lung cancer has considerably evolved. Indeed, we have proceeded from a simple classification based on histology to a molecular dismemberment, with a lot of subtypes of tumors according to there molecular alteration profile. Mutations of the EGFR receptor define so a group of cancers particularly sensitive to EGFR tyrosine kinase inhibitors (TKI). Gefitinib has shown its efficacy in term of response and survival in first line treatment of NSCLC arboring EGFR mutations. Recently, the ALK-AML4 translocation has been found in approximately 5% of NSCLC, accessible to a specified targeted therapy (crizotinib) with response rate around 60%. NSCLC with HER2 mutation or amplification could be treated with trastuzumab, whereas treatments targeting Met pathway are currently in development. At last, several drugs active in case of DNA repair dysfunction, like PARP inhibitors, have already shown there efficacy in particular types of NSCLC. In a very near future, molecular screening of these molecular alterations should be systematic from the diagnostic, to allow a personalized treatment according to the mutation profile.

Patients presenting with non-small cell lung cancer (NSCLC) and active EGFR mutation have a high response rate (60-70%) to EGFR tyrosine kinase inhibitors (TKI) with little immediate progression (primary resistance). However, progression on this treatment (secondary resistance) is inevitable even for those who responded initially. These two situations are distinct in terms of management. In case of primary resistance, screening for other associated molecular abnormalities (tumour heterogeneity) should be done, even resulting in a false positive in the initial screening of EGFR mutation. In case of secondary resistance, a new pathology sample should be taken insofar as is possible to determine the presence of an acquired mutation of EGFR resistance (T790M in 60% of cases) or c-Met amplification (20% of cases). The presence of a T790M mutation could respond to irreversible EGFR-TKI, while a c-Met amplification could be managed with a targeted anti-Met therapy. However, the gold standard is still cytotoxic chemotherapy at present if a clinical trial based on a targeted therapy is not possible.

The arrival of tyrosine kinase inhibitors (TKI) in first line of treatment for advanced non-small cell lung cancer with EGFR mutations has changed the strategy of treatment of theses patients. Indeed, response rates in these cases reach around 60 to 70%, with a progression-free survival greatly prolonged, up to 10 months. It seems that these patients with mutated tumor benefit from TKI whatever the treatment line, with the same efficacy. So, the best sequence of treatment (TKI in first line then chemotherapy in second line, or the opposite) needs still to be defined in this sub-group of NSCLC. The choice has to take in account the data of efficacy of TKIs and chemotherapy in the EGFR mutated tumors, with an anticipation of subsequent lines from the first line. Besides, data of toxicity and quality of life have also to be considered.

Treatment of advanced non-small cell lung cancer has evolved last years, until an individualized approach, notably according to patient characteristics, histology, and molecular profile of the tumor. So, the presence of EGFR mutations allows the administration of gefitinib in first line, with response rate around 70% and a progression-free survival around 12 months. If there is no EGFR mutation, the treatment consists in cytotoxic chemotherapy, according to histology. Indeed, non squamous carcinomas are accessible to a platin-pemetrexed doublet, and squamous carcinomas to another platin-based doublet. Besides, new molecular targets are identified, with corresponding targeted treatment. So, the EML4 - ALK translocation is accessible to a treatment by crizotinib, with response rate around 60-70%.

Tyrosine kinase inhibitors (TKI) of EGFR are used in advanced non-small cell lung cancer (NSCLC) in 2(nd) and 3(rd) line, and for gefitinib in first line in case of EGFR mutations. These drugs are particularly active in presence of these mutations, with response rate around 60-70%. Pharmacological data suggest an equivalent effect of erlotinib and gefitinib. One phase II study has directly compared the two drugs in 2(nd) line, with a non significant advantage for gefitinib in term of response and progression-free survival. However, skin tolerance profile was statistically better with gefitinib. Indirect comparisons between erlotinib and gefitinib in the phase III trials vs chemotherapy 1(st) line have to be interpreted, with caution and take under consideration the impact of the chemotherapy arm on the Hazard Ratio for Progression-free and overall survival. However, response rates seem to be equivalent. Cohort and phase IV studies have shown no significant difference for response and survival, and a similar tolerance profile.