Mutations in the epidermal growth factor receptor (EGFR) gene are commonly observed in non-small-cell lung cancer (NSCLC). Over the past decade, the management of NSCLC-carrying EGFR mutation has evolved considerably with the use of tyrosine kinase inhibitors (TKIs). The main objective of this retrospective study was to analyze the evolution of therapeutic strategies in a cohort of patients with metastatic or locally advanced EGFR- mutated NSCLC.

Waldenström's disease is a B-cell neoplasm characterized by the accumulation of lymphoplasmacytic cells (LPCs) in the bone marrow, and more rarely in the lymph nodes and the spleen, which produce a monoclonal immunoglobulin M (IgM) protein. The diagnosis requires the identification of LPCs in the bone marrow, using specific markers in flow cytometry. The MYD88L265P mutation is found in 95% of cases and the CXCR4 mutation in 30-40% of cases. These markers must be sought because they have a diagnostic and prognostic role, and they might become predictive in the future. The clinical presentation is very variable, and includes anomalies related to the bone marrow infiltration of the LPCs (such as anemia), but also anomalies of the physico-chemical and/or immunological activity of the overproduced IgM (hyperviscosity, AL amyloidosis, cryoglobulinemia, anti-MAG neuropathies, etc.). Prognostic scores (IPSSWM) now make it possible to understand the prognosis of symptomatic WM requiring appropriate treatment. The therapeutic management depends on many parameters, such as the specific clinical presentation, the speed of evolution and of course the age and comorbidities. Immuno-chemotherapy is often the 1st line treatment (rituximab-cyclophosphamide-dexamethasone (RCD) or bendamustine-rituximab (BR)) but the role of targeted therapies is becoming preponderant. Bruton tyrosine kinase inhibitors (BTKi) are used today in first relapse. Other therapeutic perspectives will certainly allow us tomorrow to better understand this incurable chronic disease, such as new generations of BTKi, BCL2 inhibitors, anti-CXCR4, bi-specific antibodies, and CAR-T cells.

Heterozygous germline mutations of GATA2 gene (guanine-adenine-thymine-adenine binding protein 2) are hereditary mutations that can be pathogenic, sometimes occurring sporadically, responsible for a florid clinical-biological picture, sometimes serious and quickly leading to the death.

In Europe, endometrial cancer is the fourth most common cancer among women. The majority of patients are diagnosed at a localized stage. For these patients, the standard of care is based on an hysterectomy with salpingo oophorectomy±lymph node staging. Through the assessment of histopathologic features, risk groups are determined: low, intermediate, high-intermediate, and high risk. Adjuvant strategies are guided by these risk groups. While the prognosis of low-risk and high-risk is well known, that of intermediate and high-intermediate risk is more heterogeneous, and the therapeutic index of adjuvant treatments is more questionable. Several trials (PORTEC [Post Operative Radiation Therapy in Endometrial Carcinoma] I, GOG [Gynecologic Oncology Group] 99, ASTEC [A Study in the Treatment of Endometrial Cancer] EN.5, PORTEC II, Sorbe et al trial) have assessed observation, vaginal cuff brachytherapy and/or pelvic external beam radiotherapy in this population. Vaginal cuff brachytherapy reduces the local recurrence rate, and pelvic external beam radiotherapy the pelvic recurrence rate. However, no benefit in terms of overall survival or occurrence of distant metastases is highlighted. Compared to observation, brachytherapy and above all external beam radiotherapy are associated with an increased morbidity, and with a decreased quality of life. In order to improve the therapeutic ratio and to optimize medico-economic decisions, therapeutic de-escalation strategies, based on the molecular profiles, are emerging in clinical trials, and in the recommendations for the management of intermediate and high-intermediate risk endometrial cancers. The four main molecular profiles highlighted by the genomic analyzes of The Cancer Genome Atlas (TCGA) - POLE (polymerase epsilon) mutation, non-specific molecular profile, MMR (MisMatch repair) deficiency, and p53 mutation - but also the quantification of lymphovascular space invasion (absent, focal or substantial), and the assessment of L1CAM (L1 cell adhesion molecule) overexpression represent growing concerns. Thus, the use of molecular-integrated risk profile to determine the best adjuvant treatment represent a major way to personalize adjuvant treatment of endometrial cancers, with therapeutic de-escalation opportunity for around half of the high-intermediate risks. However, in the absence of prospective data, inclusion in clinical trials assessing molecular profile-based treatment remains the best therapeutic opportunity.

About 5% of gastric cancers are associated with hereditary cancer syndromes. Histology is paramount in this context, as major susceptibility genes are associated with specific subtypes. Germline pathogenic variants in CDH1 and CTNNA1 cause Hereditary Diffuse Gastric Cancer (HDGC). Major advances have been made in the past ten years regarding HDGC. Penetrance estimates for diffuse cancer are now lower than previously thought, at 30-40%. Surveillance upper gastrointestinal endoscopy is now an acceptable alternative to prophylactic total gastrectomy. Indeed, its sensitivity in detecting advanced disease is satisfactory assuming it is performed by an expert and according to a specific protocol. The risk of intestinal-type gastric cancer is increased in patients with Lynch syndrome, although it is much lower than the risk of colorectal and endometrial cancer. Intestinal-type gastric cancers are also observed in excess in patients with hereditary polyposis, the main one being APC-associated familial adenomatous polyposis. The main and most clinically relevant manifestations in patients with polyposes remain colorectal and duodenal polyps and carcinomas, well ahead of gastric cancer. Finally, recent data point towards increased gastric cancer risk in hereditary breast and ovarian cancer.

Gastrointestinal stromal tumors (GIST) are rare digestive tumors. Activating KIT mutations are the most common molecular alteration in these patients, identified in approximately 70 % of cases, followed by PDGFRA mutations (10-15 %), of which the D842V mutation accounts for most cases. Succinate dehydrogenase (SDH) deficiency and alterations involving NF1, BRAFV600E, RAS or NTRK genes are rare molecular subgroups. In advanced GIST, treatment is based on tyrosine kinase inhibitors, including imatinib, which has been the standard first-line treatment since the early 2000s, with sunitinib and regorafenib as second- and third-line standards, respectively. Two new compounds have recently been evaluated in patients with advanced GIST. Ripretinib has become the validated fourth-line therapy for patients with KIT or PDGFRA non-D842V mutations, and avapritinib has been shown to be effective in patients with D842V mutations who were previously resistant to validated treatments. Avapritinib is now the recommended first-line treatment in this subgroup and may represent an additional option, whose place remains to be clarified, in pre-treated patients without D842V mutations. Specific treatments are available or under evaluation for some rare subgroups, and new therapeutic strategies are likely to further improve the management of advanced GIST in the coming years. This overview summarizes the results of recent trials and the place of these new molecules, as well as the main strategies under development for advanced GIST.

GENETIC SUSCEPTIBILITY TO OVARIAN CANCERS About 15% of ovarian cancers are hereditary. Hereditary ovarian cancers are caused by a germline pathogenic variant in a susceptibility gene, mainly BRCA1 and BRCA2. Cumulative risks before age of 80 years are 44% and 17%, respectively, and are high enough to warrant risk-reducing salpingo-annexectomy in asymptomatic carriers before the menopause. Risk of breast cancer is also increased, with an associated recommendation of intensive breast screening with MRI at its core, and a possibility of risk-reducing mastectomy for well-informed patients who might request it. Ovarian and breast cancers associated with a BRCA1/BRCA2 pathogenic variant, can be, under certain conditions, treated with a new class of drugs called poly-(ADP-ribose)-polymerase (PARP) inhibors in addition to surgery and/or chemotherapy. The other ovarian cancer susceptibility genes are RAD51C, RAD51D, PALB2 and the mismatch repair genes (Mismatch repair [MMR] of Lynch syndrome). Cumulative risks are however in general smaller than for BRCA1/BRCA2.

EVOLUTION IN ADJUVANT TREATMENT OF OVARIAN CARCINOMA High grade cancer of the ovary is a poor prognosis disease most often diagnosed at an advanced stage. Main prognostic factors include stage of disease, possibility of complete surgery and chemosensitivity. New maintenance targeted therapy deeply changed the prognosis of some ovarian cancers. In early stages, adjuvant treatment after surgery remains based on a platinum-based association for 6 cycles. In initially inoperable advanced stages, neoadjuvant chemotherapy must be discussed on a case-by-case basis during a multidisciplinary meeting. Standard of care remains first-line chemotherapy -with the 3 weekly association carboplatin- paclitaxel-, with or without bevacizumab after surgery. Poly-(ADP-ribose) polymerase inhibitors (PARPi) are indicated as maintenance treatment from the first line of advanced forms (FIGO stages III and IV) with BRCA1 or BRCA2 mutation following partial or complete response to chemotherapy (olaparib ou niraparib), when there is no indication for bevacizumab; they are also indicated as maintenance treatment with olaparib associated to bevacizumab in patients whose HRD test (homologous recombination deficiency : DNA repair defect by homologous recombination) is positive (with or without BRCA mutation) and have an indication for bevacizumab. In case of contraindication or no indication for bevacizumab, niraparib can also be used alone for 3 years after response to chemotherapy, whatever the HR status.

Castration resistant prostate cancers are highly heterogenous at the molecular level. With the use of new generation sequencing technologies, a series of alterations were identified, opening the way for potential alternative treatments that could be more efficient for specific molecular subtypes. In this brief update, we summarize the new targetable pathways that are currently investigated. In this era of liquid biopsy and of precision medicine, it seems pertinent to be able to screen for these alterations on a more systematic basis before initiating any treatment.

Patients with very high risk of cancer mutation may decide to undergo prophylactic surgery in order to avoid heavy clinical and radiological monitoring. This is a promising and nonetheless risky surgery because it is a complicated procedure and highly mutilating. Our goal was to improve the practice of this prophylactic surgery, to do so we assessed a postoperative satisfaction survey to cancer-free patients who have undergone this procedure.

The MAPK/ERK pathway is an essential intracellular signaling pathway. Its deregulation is involved in tumor transformation and progression. The discovery of activating mutations of BRAF in various cancers has opened new therapeutic avenues with BRAF protein kinase inhibitors. Depending on the type of cancers, these inhibitors have shown either insufficient efficacy due to primary resistance of tumor cells or transient efficacy due to the development of acquired resistance. In this review, we revisit the discoveries that led to the development of BRAF inhibitors and detail the molecular and cellular mechanisms of resistance in cancers treated with these inhibitors. Understanding these mechanisms is crucial for developing more efficient therapeutic strategies.

Tyrosine kinase inhibitors targeting the BCR-ABL1 oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 3rd generation tyrosine kinase inhibitor ponatinib is licensed for the treatment of chronic, accelerated or blast phase chronic myeloid leukaemia patients who are resistant to dasatinib or nilotinib; intolerant of dasatinib or nilotinib and for whom further treatment with imatinib is not clinically appropriate; or who express the T315I mutation. Ponatinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucémies Myéloïdes Chroniques is to provide an overview of ponatinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in ponatinib-treated patients.

Although some genetic alterations in glioblastoma (GBM) have been characterized, the prognostic value of these gene mutations is not yet established in patients treated with standard therapy.

Congenital aniridia is a rare panocular disease defined by a national diagnostic and care protocol (PNDS) validated by the HAS. In most cases, it is due to an abnormality in the PAX6 gene, located at 11p13. Aniridia is a potentially blinding autosomal dominant disease with high penetrance. The prevalence varies from 1/40,000 births to 1/96,000 births. Approximately one third of cases are sporadic. Ocular involvement includes complete or partial absence of iris tissue, corneal opacification with neovascularization, glaucoma, cataract, foveal hypoplasia, optic disc hypoplasia and ptosis. These ocular disorders coexist to varying degrees and progress with age. Congenital aniridia manifests in the first months of life as nystagmus, visual impairment and photophobia. A syndromic form such as WAGR syndrome, WAGRO syndrome (due to the risk of renal Wilms tumor) or Gillespie syndrome (cerebellar ataxia) must be ruled out. Systemic associations may include diabetes, due to expression of the PAX6 gene in the pancreas, as well as other extraocular manifestations. Initial assessment is best carried out in a referral center specialized in rare ophthalmologic diseases, with annual follow-up. The management of progressive ocular involvement must be both proactive and responsive, with medical and surgical management. Visual impairment and photophobia result in disability, leading to difficulties in mobility, movement, communication, learning, fine motor skills, and autonomy, with consequences in personal, school, professional, socio-cultural and athletic life. Medico-socio-educational care involves a multidisciplinary team. Disability rehabilitation must be implemented to prevent and limit situations of handicap in activities of daily living, relying on the Commission for the Rights and Autonomy of People with Disabilities (CDAPH) within the Departmental House of People with Disabilities (MDPH). The general practitioner coordinates multidisciplinary medical and paramedical care.