Detection of genetic alterations in the EGFR tyrosine kinase domain is a major concern in the management of non-small cell lung cancer because it conditions access to tyrosine kinase inhibitors. In practice, it is possible to characterize only well-documented mutations or to sequence all relevant EGFR exons and also other targets of theranostic interest. This prospective study compares the targeted EGFR characterization on Idylla platform (Biocartis) and a more extensive one by next generation sequencing using Ion Torrent technology.

The advent of molecular biology resulted in the discovery of new oncogenes that have led to the development of targeted therapies for the management of cancer patients. The development of these therapies has improved the prognosis of patients in various tumour localizations. The TRK receptor (tropomyosin receptor kinase) is a transmembrane receptor with a tyrosine kinase activity that plays a role in both cell proliferation and the physiology of the nervous system. Fusions involving the NTRK gene, which codes for this receptor, have been found in different types of solid tumours and lead to its constitutional activation. These fusions, however uncommon, are mainly found in rare pediatric tumours but can also be encountered in digestive cancers with high prevalence (such as colorectal cancer, especially in case of microsatellite instability, with a frequency of 2.5 to 38.5 %) or in aggressive cancers (such as pancreatic cancer). Therapies targeting TRK, such as larotrectinib or entrectinib, have shown significant response rates, usually greater than 6 months, for tumours from various primary sites presenting NTRK fusions and refractory to standard therapies. These fusions can be detected by different methods: immunohistochemistry, FISH (fluorescence in situ hybridization) as well as NGS (next generation sequencing). The intent of this review is to report on current knowledge on NTRK fusions in oncology and to discuss the role of these fusions in digestive cancers and potential therapeutic implications.

Gastrointestinal stromal tumors (GIST) are the most common non-epithelial tumors of the gastrointestinal tract. Wild-type GISTs (WT-GIST) consist of a rare heterogeneous group characterized by the lack of activating mutations in the tyrosine kinase receptor (Kit) and/or platelet derived growth factor receptor A (PDGFRA). However, WT-GIST is characterized by other genomic alterations, including dehydrogenase succinate (SDH) deficiency or mutations in the Ras pathway. Recent studies have reported many mutations in others genes that may be incriminated in the development of WT-GISTs. Moreover, WT-GIST is frequently associated with hereditary cancer syndromes such as the Carney Triad and Type 1 Neurofibromatosis (NF1). WT-GIST affects usually young and pediatric patients. Most WT-GIST subtypes are insensitive to imatinib; therefore, their therapeutic management is somewhat different from usual GISTs. This review resumes the molecular and therapeutic features of this rare entity.

Perioperative chemotherapy is the standard strategy for localized gastric cancers. Nevertheless, this strategy seems to be inefficient, if not deleterious, for patients with tumors harboring microsatellite instability (MSI) and/or mismatch repair deficiency (dMMR), a tumor phenotype predictive for the efficacy of immune checkpoint inhibitors (ICKi).

Patients who carry the BReast Cancer 1 or 2 (BRCA) gene mutations have an underlying hereditary predisposition for breast and ovarian cancers. These deleterious genetic mutations are the most common ones implicated in hereditary breast and ovarian cancers. Oncogenetic counselling plays a key role in identifying patient for BRCA testing and for mutation identification. BRCA1/2 carriers have to be followed up regularly and may justify breast and/or adnexal prophylactic surgery, according to the French National Cancer Institute guidelines (INCa). Poly- (DNA-riboses) polymerases inhibitors, notably olaparib, have a major role in the management of epithelial ovarian cancer in patients with BRCA mutation and many studies are ongoing to expand their indications in a near future.

It is paramount to identify patients whose cancer is associated with genetic susceptibility to the disease, since their long-term management depends on it. Anatomical and molecular pathologists play a key role in the process. Indeed, their diagnosis supports or even sometimes warrants germline genetic testing. For example, a colorectal cancer with mismatch repair protein expression loss suggests Lynch syndrome, while a rare type of renal cell carcinoma with fumarate hydrate expression loss is highly evocative of hereditary leiomyomatosis and renal cell carcinoma syndrome. Similarly, the presence of the T790M EGFR variant before treatment in a non-small-cell lung carcinoma warrants further testing as the variant is likely of germline origin. Patients with suspected genetic susceptibility to cancer are referred to the nearest clinical cancer genetics clinic. The cancer geneticist, assisted by a genetic counsellor, then collects detailed personal and familial information, sometimes feeds them into bioinformatics tools or clinico-pathological scores, decides whether germline genetic analysis is justified, determines which genes should be analysed and prescribes testing. Germline testing is carried out on a blood sample by expert laboratories using next generation sequencing on panels of cancer susceptibility genes. The cancer geneticists then return the result to the patient. When a pathogenic variant is identified, the patient's management is modified, with recommendations ranging from intensified surveillance to risk-reducing surgery. Treatment is sometimes adapted to the pathogenic variant. In addition, relatives can undergo genetic testing, should they wish to know whether they carry the familial variant. In the near future, we expect clinical cancer genetics to move towards strengthened partnerships with molecular pathologists and medical oncologists. Somatic genetic analyses are now routine, at least in metastatic cancer, and a proportion of the tumoral variants identified are actually of germline origin. As for the oncologists, the development of mainstreaming programs where they are allowed to prescribe germline testing under the supervision of a cancer genetics team is unavoidable.

MiT family translocation renal cell carcinomas (tRCC) represent a rare subtype of renal cell carcinomas. These tumors have been introduced for the first time in the World Health Classification (WHO) classification of kidney cancers in 2004. tRCC are characterized by reccurent translocations involving members of the MiT family transcription factors, mainly TFE3 and TFEB. The estimated incidence of these tumors is ∼1-5 % among all renal cell carcinomas, with female prodominance. tRCC were initially described in children, and the spectrum has been expanded over time to encompass adolescents and adults. TFE3- and TFEB-rearranged RCC harbor characteristic clinicopathological and immunohistochemical features and fluorescent hybridization in situ is considered the gold standard for their diagnosis, although it has some limitations especially when the partners are located in the vicinity of TFE3. Nephron-sparing surgery is an efficient treatment of localized cases when achievable. In metastatic setting, targeted agents and immunotherapy showed modest efficacy, with response rates and median overall survival inferior to those observed in clear-cell renal cell carcinomas. Management of tRCC necessite a multidisciplinary team and accrual in clinical trials have to be encouraged when possible. Novel biological insights are urgently awaited to better understand the mechanisms associated with kidney oncogenesis in this setting, and ultimately help to identify therapeutic targets.

About 5% of gastroenteropancreatic and thoracic neuroendocrine neoplasms (NENs) arise in the context of an inherited tumour syndrome. The two most frequent syndromes are: multiple endocrine neoplasia type 1 (MEN1), associated with a large spectrum of endocrine and non endocrine tumours, including duodenopancreatic, thymic and bronchial NENs, and the von Hippel-Lindau syndrome VHL, associated with pancreatic NENs. Two inherited syndromes have a low incidence of NENs: neurofibromatosis type 1 (NF1), associated with duodenal somatostatinomas, and tuberous sclerosis (TSC), associated with pancreatic NENs. Two rare syndromes have a high incidence of NENs: multiple endocrine neoplasia type 4 (MEN4), with a tumour spectrum similar to that of MEN1, and glucagon cell hyperplasia neoplasia (GCHN), involving only the pancreas. It is likely that other syndromes remain to be characterized, especially in familial small-intestinal NENs. The diagnosis is usually raised because of the suggestive clinical setting: young age at diagnosis, multiple tumours in multiple organs, familial history. Except in VHL and NF1, tumours themselves do not show specific pathological features; they usually are well differentiated and of low histological grade; their prognosis is good, except for MEN1-associated thymic NENs. The most suggestive pathological feature is their combination with various endocrine and/or non endocrine lesions in the adjacent tissue. Pathological examination is important, for a correct diagnosis and for an accurate management of the patients and their families, who must be referred to expert centers.

Pancreatic ductal adenocarcinoma (PDAC) is a rapidly evolving and most frequently fatal disease. Despite the enormous progress in understanding the mechanisms related to PDAC pathogenesis, the impact on patient management has not yet been possible. Pancreatic organoids can be generated from small amounts of tissue. One of the most promising applications of organoids is that they can serve as a platform for selecting the right drugs for each patient. This approach has the potential to identify individual therapeutic vulnerabilities by allowing the personalization of treatments. However, these analyzes require several weeks before obtaining enough organoids from the same individual, to carry out the tests with several drugs, and to analyze the results, which limits its use in current clinical practice for the patients with a PDAC, whose it must be remembered that half die within 6 months of diagnosis. To overcome this obstacle, we assessed the ability of transcriptomic molecular signatures to identify patients with a particular sensitivity profile to a given treatment. The approaches based on transcriptomic profiling have the enormous advantage of using very little biological material and thus significantly reducing the time to arrive at the selection of more effective drugs to each patient.

Breast cancer affects about 3,000 new women of childbearing age each year. The desire for pregnancy is therefore a frequent issue in the management of breast cancer. We reviewed the current state of knowledge and recommendations in high-risk women, on the consideration of this desire for pregnancy in therapeutic management, the way to approach it, the preservation of fertility in the care process and finally on the outcomes of pregnancy after breast cancer. We evaluated the desire for pregnancy, qualitatively and quantitatively, after breast cancer through a literature review.

Over the past decades, progresses in oncology have improved the recovery rates after numerous malignant diseases, including breast cancer, that strike young adults in childbearing age. Quality of life of young cancer survivors has become a major issue. However, anticancer therapies can have a detrimental impact on fertility. It is now well-established that all patients should receive information about the fertility risks associated with their cancer treatment and the fertility preservation options available. These techniques aim to limit the negative impact of chemotherapy on the ovaries or to preserve gametes before treatment. Currently, oocyte or embryo freezing after controlled ovarian hyperstimulation represents the most effective method for preserving female fertility. Over the past years innovative protocols of ovarian stimulation have been developed to enable breast cancer patients to undergo oocyte or embryo cryopreservation irrespective of the phase of the cycle or without exogenous follicle-stimulating hormone related increase in serum estradiol levels. When controlled ovarian hyperstimualtion cannot be implemented, other techniques such as cryopreservation of ovarian cortex, in vitro maturation or the use of GnRH agonists may be proposed. However, it is important to inform patients that all these fertility preservation techniques do not represent a guarantee of pregnancy.

Breast cancer in young women requires special vigilance because of the unique condition and complex management that is involved. The indication for chemotherapy should not be based on age alone but in association with the biological characteristics of the tumour. In addition, age is not considered as demonstrated predictor of chemosensitivity. The choice of adjuvant or neoadjuvant chemotherapy should be guided by the histological type of the tumour, the stage of the tumour and the patient's comorbidities. In this subgroup of patients, the recommendations for the use of molecular signatures follow those of the general population. This manuscript summarizes the main data and recommendations on the management of breast cancer in young women in term of chemotherapy.

Early-onset of breast cancer (under the age of 40) represents only 7% of all breast cancers, but is the most common cancer in this age group in women. It is also known to be of worse prognosis, with a more aggressive tumoral behavior. The interaction of different prognostic factors contributes to the complexity of this population: tumor burden and biological features (using classical histopronostic features and genomic data) show differences from older women. Nevertheless, the prognostic impact of age varies according to the histological subtypes and seems pejorative mainly for the luminal subtype, probably with a crucial role of the hormonal environment and the treatments targeting the endocrine sensitivity of these tumors. In other subtypes, the influence of young age appears to be less significant, especially in HER2+ breast cancers.

Desmoid tumors (TDs) are derived from mesenchymal stem cells and their pathogenesis is strongly linked to the Wingless/Wnt cascade where the deregulation of β-catenin plays a major role. A mutation of the CTNNB1 encoding β-catenin is found in the majority of sporadic TD cases and constitutional mutations of APC have been described in heritable forms in patients with familial adenomatous polyposis (FAP). Estrogens could also play a role in pathogenesis and this is the basis for the use of hormone therapy. Other signaling pathways have been involved in the development of TDs such as Notch, Hedgehog, JAK/STAT, PI3 Kinase/AKT and mTOR. Metalloproteases are expressed in TDs and play a role in invasiveness. TGF-ß, as a growth factor, stimulates the transcriptional activity of β-catenin. Future studies will need to focus on better describing and understanding the immune environment of TDs. One of the major difficulties for the experimental study of TDs is the virtual absence of a preclinical model, either in vitro or in vivo. This is partly why the interactions between the different signaling pathways presented here and their consequences for the development of TDs are still poorly understood.

A growing number of studies suggest a tumor suppressor role for the SWI/SNF complex involved in the remodeling of chromatin. Alterations of this complex have been found in many tumors of different origins, with topographic, morphologic and phenotypic diversity. Notably, they define 2 types of thoracic tumors: SMARCA4-deficient non-small cell lung carcinoma and SMARCA4-deficient sarcoma. Some clinical features appear to be common to both, such as intrathoracic localization, smoking exposure, male predominance and poor prognosis. However, the histological distinction between these two entities is sometimes difficult and it is not excluded that these entities belong to the same tumor spectrum with different degrees of differentiation. The therapy of these tumors is not yet codified. These tumors do not seem associated with oncogenic driver mutations allowing the prescription of targeted therapy, but immunotherapy has been shown to be effective in rare reported cases. More specific treatments using EZH2 inhibitors also seem promising in SMARCA4 deficient sarcomas.

About 15 % of patients with familial adenomatous polyposis "PAF" develop one or more desmoid tumors in their lifetime. These are benign mesenchymal tumors with local aggressivity but with no potential for metastases. Most of the desmoids tumors result from a sporadic genetic anomaly in the β catenin gene. When related to familial adenomatous polyposis or "PAF", this mutation is not present, and the patients must be sent in genetic counselling. The PAF is a dominant autosomic illness related to a germinal mutation in the APC gene. Sometimes, these tumors can be the first manifestation of the illness. The diagnosis in a context of PAF can be easily done by imaging, but a pathological confirmation is needed. These tumors raise a therapeutic problem because of their heterogeneity and the absence of predictive biomarkers along illness evolution. The identification of prognostic biological and clinical factors would make easier the selection of patients requiring first-line treatment, as spontaneous remissions have also been observed in patients with FAP whom which an active surveillance could also be a valid therapeutic option. The particularity of desmoids tumors associated to PAF lies in their predominantly intra-abdominal location and the risk of complication. In the last ten years, surgery has largely given way to conservative treatments such as chemotherapy and more recently to tyrosine kinase inhibitors that have shown their efficacy with a significant improvement in progression-free survival of patients.

Chordomas are rare malignant tumours, which typically occur in the axial skeleton and skull base. They arise from embryonic remnants of the notochord. They constitute less than 5 % of primary bone tumours. They are characterised by their locally aggressive potential with high frequency of recurrences and a median overall survival of 6 years. The initial therapeutic strategy must be discussed in an expert centre and may involve surgery, preoperative radiotherapy, exclusive radiotherapy or therapeutic abstention. Despite this, more than 50 % of patients will be facing recurrences with few therapeutic options available at this advanced stage. This review aims to outline current treatment options available in chordomas, as well as discussing potentiality of new therapeutic approaches through their molecular characterization and the comprehension of their immunological environment.