Isocitrate dehydrogenase IDH1 and IDH2, key enzymes in central and energy metabolism, are frequently mutated in acute myeloid leukemia (AML). They catalyze the production of the oncometabolite R-2-hydroxyglurate, which plays a key role in leukemogenesis and relapse of patients after standard AML treatments. Although the recent introduction of selective inhibitors of IDH1 (ivosidenib) and IDH2 (enasidenib) has improved the prognosis of patients with IDH1- and IDH2-mutant AML, several mechanisms of resistance to these treatments have already been identified, including metabolic reprogramming. The study of these mechanisms has opened up new therapeutic opportunities for the monitoring and treatment of patients with this subtype of AML.

The discovery of ALK gene rearrangement in 3 to 5% of non-small cell lung carcinomas has revolutionized our understanding and therapeutic approach of these cancers. This oncogenic driver is associated with specific clinical and biological features is associated with specific clinical and biological features, mainly affecting young and never-smoker patients, with a particular tropism for brain metastases. The development of ALK tyrosine kinase inhibitors has transformed patient outcomes, with remarkable efficacy of latest-generation molecules, particularly in controlling brain metastases. However, the emergence of complex resistance mechanisms, whether ALK-dependent or ALK-independent, remains a major challenge. The comprehensive understanding of these resistance mechanisms now guides the development of next-generation inhibitors and innovative therapeutic strategies, paving the way for increasingly personalized precision medicine.

Among the oncogenic alterations of non-small cell lung cancer (NSCLC), the EGFR gene mutation is observed in 15% of patients in France, particularly among non-smokers and women. Treatment mainly relies on tyrosine kinase inhibitors (TKIs) targeting EGFR. In first-line metastatic treatment, osimertinib, a third-generation TKI, has become the standard, improving progression-free survival (PFS) and overall survival (OS) compared to first- or second-generation TKIs. The combination of TKI/chemotherapy (osimertinib/carboplatine-pemetrexed) and TKI/bispecific antibodies (e.g., amivantamab/lazertinib) are alternatives under evaluation, with benefits in PFS but increased toxicity. In case of progression under first- or second-generation TKIs, the most common resistance is the T790M mutation, which can be targeted by osimertinib. For other resistances, platinum-based chemotherapy remains an option. Amivantamab combined with chemotherapy has shown an improvement in PFS in the second line and has early access in France. Other emerging approaches include conjugated antibodies (patritumab deruxtecan, datopotamab deruxtecan) and next-generation TKIs. In the future, personalized treatment based on the molecular profile and early response to TKIs could optimize management, particularly by integrating predictive markers such as EGFR clearance under treatment.

EGFR-mutant and ALK-positive non-small-cell lung cancer derive benefit from adjuvant treatment with tyrosine kinase inhibitors after complete resection. Testing of these alterations is therefore recommended on surgical specimens and, where appropriate, on pre-treatment biopsies. Many questions remain with regards to the implementation of these strategies: duration of treatment, treatment in case of recurrence, impact on molecular evolution.

Molecular testing of non-small cell lung cancers has become mandatory at all stages of the disease. National and international recommendations for molecular testing are up-dated regularly. In this review, we will summarize diagnostic approaches focusing on targetable oncogenic alterations (mutations, gene rearrangements) and we will indicate the limits currently associated with sample types and sequencing technologies. Biomarkers that have not showed routine clinical utility will not be presented here.

In non-small cell lung cancer, the presence of an oncogenic driver is frequently documented. Advances in molecular biology have enabled the identification of so-called rare oncogenic addictions, with an incidence of less than 5%, such as ROS-1 and RET rearrangements, and MET, BRAF and HER2 mutations. Targeted therapies have shown strong tumor responses with a better tolerance profile compared to chemotherapy. Consequently, targeted therapies have revolutionized the therapeutic landscape, particularly as immune checkpoint inhibitors are often ineffective in the presence of an oncogenic driver. To ensure optimal management in the era of personalized medicine, it is recommended to screen for oncogenic addictions, including rare ones, at diagnosis. In this review, we discuss the targeted therapies available in France and the promising future molecules for managing rare oncogenic drivers. Targeted therapies have already proven their efficacy as first-line treatments for ROS-1 and RET alterations, and as second-line treatments for MET and BRAF mutations.

In Europe, a rare cancer is defined as having an incidence rate of less than 6/100,000. Rare lung cancers encompass many entities defined by the 2021 WHO classification of thoracic tumors, and represent around 10% of all lung cancers. Rare lung cancers involve several histological types (carcinoma, sarcoma and lymphoma), each of which comprises several entities. The management of these patients with rare cancers requires specific medical expertise at every level (diagnosis, treatment and follow-up). These patients should therefore be referred to expert centers affiliated with national networks, giving them appropriate care and better access to innovative treatments. The deployment of systematic molecular characterization of these tumors has allowed for the identification and better characterization of specific entities. Some entities are specific to the lung, while others are more commonly found in other organs. In this review, we will only consider malignant lung tumors with an incidence of less than 1%.

Small cell lung cancer (SCLC) remains one of the most aggressive cancers, with an overall survival of approximately one year for patients with extensive stage SCLC, and we still have very few effective therapies, especially after the first line of treatment. A better understanding of SCLC and their mechanisms, especially molecular mechanisms, has led to the exploration of new therapeutic strategies. For example, transcriptomic analyses have identified 4 subtypes of CBPC, which could be predictive of response to treatments. Immune checkpoint inhibitors have shown limited benefit in extensive stage SCLC, but appear to have a clear benefit for limited stage SCLC, in association with radio-chemotherapy. Anti- PARP molecules, involved in DNA repair and aberrantly expressed in CBPC, have been studied. New molecules have been developed, to bypass antigen presentation, which is defective in SCLC; such as bispecific T-cell engager molecules, that binds to SCLC cells and patient's cytotoxic T-cell, leading to T-cell activation and tumor lysis. These molecules target tumor cell's surface proteins, such as delta-like ligand 3 (DLL3), aberrantly expressed on the surface of most SCLC cells. Tarlamab, a DLL3-targeted immune therapy, has shown very promising durable responses in patients with previously treated SCLC. These new molecules lead to new side effects we will have to manage, such as the Cytokine Relargage Syndrome. Other molecules, targeting DLL3 or other pathways are still ungoing clinical evaluation, we should see further advances in the treatment of SCLC over the coming years.

A better understanding of the molecular mechanisms associated with the aggressiveness and high recurrence rate of non-small cell lung cancers is needed to identify new biomarkers and therapeutic targets to improve patient management. In this context, this review provides a non-exhaustive update on the emerging family of long non-coding RNAs, important regulators of gene expression, frequently deregulated in cancers and in response to hypoxia - an environmental factor that plays an important role in the development, aggressiveness and treatment resistance of these tumors.

Endometrial cancer is the 4th most common cancer in women in France, with an increasing incidence partly due to the increase in diabetes and obesity. A genetic predisposition is found in approximately 5% of cases, notably Lynch syndrome, Peutz-Jeghers syndrome, hamartomatous tumor syndrome (Cowden syndrome), and BRCA1/2 mutations. Although no organized screening is in place for endometrial cancer in the general population, individual screening is recommended for most of these at-risk populations. Prophylactic surgery is a key strategy to reduce the risk of endometrial cancer in high-risk women. For patients with Lynch syndrome, recommendations favor a total hysterectomy with bilateral salpingo-oophorectomy starting at age 40, after childbearing is complete. Hormonal supplementation with natural estrogens is important until the physiological age of menopause to reduce bone and cardiovascular risks and to improve the quality of life, including sexual health, for these women. In Cowden syndrome and Peutz-Jeghers syndrome, the lack of data limits surgical recommendations, although prophylactic hysterectomy may be considered starting at age 40, once childbearing is complete. For patients with BRCA1/2 mutations, while risk-reducing adnexal surgery is recommended, hysterectomy remains debated. It requires a personalized assessment with patients based on the benefit/risk balance.

Risk reducing salpingo-oophorectomy has long been the gold standard for preventing the development of tubo-ovarian cancers in high-risk population such as BRCA1/2 mutation carriers. Although a clear survival benefit has been demonstrated of these prophylactic procedures, important side effect from the associated surgical menopause have been described. Given that recent evidence suggests that most high-grade serous carcinomas (HGSC), the majority of all ovarian carcinomas, and especially for patients with a genetic predisposition originate in the fallopian tube, where also precursor lesions such as STIC can be found, an alternative risk reduction strategy has emerged, the prophylactic fimbriectomy with delayed oophorectomy. Multiple studies have already investigated the acceptability, side effects and safety of this procedure, with promising results. And currently multiple studies are ongoing to investigate the long-term effects on sexuality and the risk of developing subsequent tubo-ovarian carcinomas. A long-term follow-up in a large population is essential given the latency of 4-5 years between precursor lesions and HGSC. In this review, we provide an overview of the current knowledge on the origin, screening, and risk-reducing surgery for the prevention of tubo-ovarian cancers in high-risk women.

Currently, the main means of diagnosing ovarian cancer at an early stage involve risk prediction, prevention and screening in patients identified as being at genetic risk. Our aim is to identify patients who may benefit from bilateral salpingo-oophorectomy for risk reduction purposes, as well as the modalities for its realization. We list the genes associated with ovarian cancer predisposition, their frequency in the general population, the risk of patients carrying these genes developing ovarian cancer, and the risk-reducing surgical procedures associated with each gene.

In France, breast cancer is the most common cancer among women, with 5 to 10% of cases being genetic. Frequently involved genes include BRCA1 and BRCA2, PALB2, TP53, CDH1, and PTEN, among others. Approximately, two in 1000 women carry a BRCA1 or BRCA2 gene mutation. The National Cancer Institute (INCa) provides guidelines for screening and risk-reduction treatments. Prophylactic surgery, including bilateral mastectomy, is a preventive option for high-risk women. Immediate breast reconstruction (IBR), particularly using the DIEP flap technique, helps mitigate the psychological impact of mastectomy, and is part of the gold standard to be offered to patients. This technique uses excess of skin and fat from the lower abdomen and requires micro-surgical skills. Despite logistical challenges, this method is favored for its durability and natural outcome. INCa and other organizations are working to improve access and information for these treatments.

In the area of cancer predisposition, certain situations may lead to the discussion of prophylactic surgery. This is rarely strictly recommended and depends on the patient's choice. The advantages and disadvantages must be weighed up. The main advantage of prophylactic surgery is obviously risk reduction. At present, this risk is assessed on an individual basis using "classical" instruments. Artificial intelligence is expected to improve the selection of useful genetic information, the classification of variants of unknown significance, the combination of more comprehensive analysis results and the ability to associate them with non-genetic features. Artificial intelligence could also help to make genetic testing more accessible to people, or even contribute to direct patient information. This last point is likely to require considerable vigilance.

Coloproctectomy for familial adenomatous polyposis (FAP) is a surgical procedure often required to prevent the development of colorectal cancer in patients with this condition. FAP is an inherited disease characterized by the development of hundreds, or even thousands, of adenomatous polyps in the colon and rectum. The standard treatment to prevent progression to cancer is often coloproctectomy, which involves surgical removal of the colon and rectum. Other hereditary polyposis, such as Peutz-Jeghers syndrome or hyperplastic polyposis, may also require similar surgical approaches.

Breast cancer associated with pathogenic variants of BRCA1 and BRCA2 genes requires specific management. This review examines the prognostic benefits, prophylactic surgical strategies, and impact on quality of life of patients at very high risk of breast cancer. Breast surgical prophylaxis concerns women at high risk of breast cancer with a risk assessment based on their personal and family history, or by diagnosis of pathogenic variants in high-risk genes. Personalized management is based on enhanced clinical and radiological monitoring, the use of predictive tools such as BOADICEA, and surgical options such as prophylactic bilateral mastectomy, which can reduce the risk of cancer by over 90 %. Although its impact on overall survival is still debated, advances in surgical techniques have significantly improved aesthetic results and patient satisfaction, thanks to modern reconstruction methods. The surgical strategy, whether primary or secondary, must be individualized, considering the patient's history, therapeutic needs, and preferences. Mastectomy with preservation of the skin envelope, often performed in one or two stages, offers significant psychosocial benefits, although radiotherapy may increase the risk of complications. Options include immediate reconstruction, by implant or autologous technique, adapted to the patient's morphology and any adjuvant treatments.

Mutations in the BRCA1/2 genes increase the risk of breast and ovarian cancer, leading to complex medical decisions (surveillance, risk-reducing surgery) and major psychological consequences. A support group for BRCA1/2 mutation carriers has been conducted at the CHUV since 2016 by a psychologist-psychotherapist, a genetic counselor, and a geneticist. This article presents the context and then develops some of the psychological issues raised by the participants, focusing in particular on the notions of risk, uncertainty, and guilt. The processes at work in the group, between identification and differentiation, allow for a valuable work of appropriation and subjectivation around the presence of this genetic mutation.

Breast cancer is a complex disease influenced by genetic and environmental factors. Molecular profiling research has revealed significant diversity within the disease, including among tumours with similar morphological features. This diversity can lead to significant differences in tumour behaviour. Scientists have turned their attention to molecular biomarkers to predict cancer behaviour and/or response to treatment, and to ensure personalised, optimal management of breast cancer patients. This article presents four examples of molecular biomarkers and genetic tests used in the field of breast cancer, highlighting their latest advances and their clinical use as predictive and/or prognostic markers.

Hairy cell proliferations represent very different entities. They include hairy cell leukemia in its classic form (HCL), a well-defined entity, but also the variant form of HCL (LT-V ou HCL-V), whose presentation is far from HCL and whose prognosis is poorer. Other hairy cell proliferations include splenic red pulp lymphoma (SDRPL) and splenic marginal zone lymphomas (SMZL) with circulating villous cells. In this article, we emphasize the novelties concerning the different recent biological aspects of HCL, including the unusual clinical presentations but also the importance for the diagnosis of the detection of the BRAFV600E mutation, a molecular marker of the disease, and the presence of other non-canonical mutations that should be identified because of the contraindication to the use of BRAF inhibitors. Finally, the presence of a non-mutated profile of immunoglobulin heavy chains (IGHV), observed in 20% of cases, is associated with a poor prognosis. We also provide guidance in characterizing other hairy cell proliferations when examining the blood smear. The first-line treatment of HCL has recently changed and immunochemotherapy combining cladribine plus rituximab has become the gold standard. In relapsed or refractory forms, other treatments should be discussed in a multidisciplinary consultation meeting and combine BRAF inhibitors with anti-CD20 antibodies, BTK inhibitors or Bcl-2 inhibitors. The choices should be discussed according to the patient's profile but also their biological profile.

Alterations in DNA methylation profiles are typically found in cancer cells, combining genome-wide hypomethylation with hypermethylation of specific regions, such as CpG islands, which are normally unmethylated. Driving effects in cancer development have been associated with alteration of DNA methylation in certain regions, inducing, for example, the repression of tumor suppressor genes or the activation of oncogenes and retrotransposons. These alterations represent prime candidates for the development of specific markers for the detection, diagnosis and prognosis of cancer. In particular, these markers, distributed along the genome, provide a wealth of information that offers potential for innovation in the field of liquid biopsy, in particular thanks to the emergence of artificial intelligence for diagnostic purposes. This could overcome the limitations related to sensitivities and specificities, which remain too low for the most difficult applications in oncology: the detection of cancers at an early stage, the monitoring of residual disease and the analysis of brain tumors. In addition, targeting the enzymatic processes that control the epigenome offers new therapeutic strategies that could reverse the regulatory anomalies of these altered epigenomes.