Over the past 30 years, since the identification of the BRCA1 and BRCA2 genes, the panorama of breast cancer predisposition tests has continued to evolve: today, ultra-high-throughput sequencing enables the study of eight predisposition genes, and indications are constantly expanding, with the new entry point being the identification of BRCA1/2 alterations in tumors, 75% of which are of constitutional origin. While these tests can be used to provide appropriate preventive treatment in cases where risk factors have been identified, many challenges remain to be met: identification of new predisposition genes, or rather validation of candidate genes such as ATM, detection of new modes of inactivation of genes already included in the diagnosis (remote deletions, epigenetic modifications), classification of variants of unknown significance as pathogenic or benign, and identification and inclusion of modifying factors, whether genetic or not, in multifactorial risk models. Patients and their relatives have played, and continue to play, a major role in the development of oncogenetics. We owe them quality tests, information, support and protection.

Histopathological examination is a cornerstone in the diagnosis, prognostic stratification, and therapeutic planning of breast cancer. It combines morphological, immunophenotypic, and molecular data to guide clinical decision-making. This article provides a comprehensive overview of the main histological types, technical modalities, and conventional and emerging biomarkers in breast cancer pathology. Breast carcinomas are categorized into in situ (DCIS, LCIS) and invasive forms. The most frequent invasive types are invasive carcinoma of no special type (NST) and invasive lobular carcinoma (ILC). Rare histologic variants (e.g., mucinous, micropapillary, metaplastic) exhibit distinct biological and prognostic features. The diagnostic workflow includes standardized steps: sampling, formalin fixation, paraffin embedding, H&E staining, immunohistochemistry (ER, PR, HER2, Ki-67), and molecular testing when needed (FISH, PCR, NGS). Routine biomarkers help define surrogate molecular subtypes (luminal A/B, HER2-positive, triple-negative) and guide systemic therapies. The emergence of the HER2-low category exemplifies how biomarker refinement impacts clinical practice. Additional markers such as PIK3CA and ESR1 mutations, BRCA/HRD status, PD-L1 expression, and tumor-infiltrating lymphocytes (TILs), along with multigene signatures (e.g., Oncotype DX, MammaPrint), further individualize prognostic assessment and treatment selection. Innovative approaches such as liquid biopsy and next-generation sequencing (NGS) enable minimally invasive monitoring and personalized care, especially in advanced disease. Breast cancer pathology is thus a dynamic, integrative discipline central to precision oncology, driven by ongoing technological and molecular advances, and essential to multidisciplinary cancer care.

Molecular analyses performed on cell and tissue samples play a major diagnostic, prognostic, and theragnostic role. Their complexity and diversity, as well as that of the biological matrix involved (formalin-fixed paraffin-embedded tissue, frozen tissue, cytological sample, liquid biopsy), are increasing. The tumor cell content of the sample is an important limiting factor as well as the quality and quantity of nucleic acids extracted from the initial matrix. Therefore, it is crucial to understand and manage the conditions of sample preparation and storage, as those will directly impact the quality of the extracted material and constrain the types of analyses that will be performed. This article highlights the key pre-analytical steps as well as the limitations and interpretative biases that may result from mishandling of the samples.

This review aims to describe the role of poly-ADP-ribose polymerase inhibitors (PARPi) in the treatment of metastatic castration-resistant prostate cancer (mCRPC), an aggressive and lethal form of the disease. The introduction of PARPi has led to improved prognosis, particularly in patients with at least one somatic or germline mutation in DNA damage repair genes such as BRCA1 or BRCA2. Several recent studies have shown that PARPi, used alone or in combination with abiraterone or enzalutamide, improve progression-free survival and overall survival in patients with mCRPC. However, whether the three PARPi evaluated in phase 3 trials are therapeutically equivalent, and whether combination therapies should be recommended as first-line treatment for all mCRPC patients or reserved for those carrying mutations, particularly BRCA1/2, remain to be determined.

The national investigators group for ovarian and breast cancer studies (GINECO) is an academic clinical research group specialized in gynecological oncology. Within the translational research group, the pathologists have several roles, including qualifying samples from patients included in clinical trials (tumor surface and cellularity). Since 2015, several clinical trials have required the qualification of tissue material, leading to a substantial database gathering tumor surface and cellularity associated with the concentration and quantity of DNA/RNA extracted. The main objective of this study was to investigate variations in nucleic acid concentration and quantity depending on the tumor cellularity and surface, using 1734 formalin-fixed, paraffin-embedded (FFPE) specimens from several GINECO clinical trials. The quantities of DNA and RNA extracted appeared to correlate well with tumor surface. The amount of RNA extracted also appeared to correlate with tumor cellularity. An optimal DNA concentration (>50ng/μL) was achieved with a tumor surface of at least 51-100mm2 and a tumor cellularity of at least 20%. An optimal RNA concentration (>100ng/μL) was obtained with a tumor surface of at least 26-50mm2 and a tumor cellularity of at least 51%. These data underline the importance of sending FFPE material with the highest tumor surface and cellularity when including patients in clinical trials. Inclusion in clinical trials enables patients to benefit from innovative therapeutic management.

The most common cancer in women is breast cancer (BC). MicroRNA-21 was one of the first oncomiRs to be found at elevated levels in a number of malignancies, including gliomas, BC, and colorectal cancer (miR-21). MiRNA is associated with processes such as apoptosis, invasion, metastasis, and proliferation, which are known features of cancer. This study aimed to investigate the molecular basis and clinical significance of miR-21 in BC, as microRNAs play a critical role in this disease.

Over the past decade, targeted therapies have significantly improved the prognosis of metastatic breast cancer. CDK4/6 and PARP inhibitors are now gaining traction in the adjuvant setting, and their potential use in the neoadjuvant context is also being explored. This review presents an analysis of the current scientific evidence and associated clinical perspectives. CDK4/6 inhibitors act on cell cycle dysregulation, commonly observed in hormone receptor-positive breast cancers. In the adjuvant setting, abemaciclib and ribociclib have shown improvements in progression-free survival (PFS) in the monarchE and NATALEE trials, respectively, leading to their approval by the European Medicines Agency. In the neoadjuvant context, although these agents have demonstrated a reduction in proliferation markers such as Ki67, their impact on clinical practice remains limited to date. PARP inhibitors are based on the concept of synthetic lethality, specifically targeting cancers with germline BRCA1 or BRCA2 mutations. In the adjuvant setting, the OlympiA trial demonstrated a significant improvement in both PFS and overall survival (OS). In the neoadjuvant setting, these agents have also shown effects on pathological markers, though the clinical relevance of these findings has yet to be clearly established. Overall, these results underscore the growing role of targeted therapies in the adjuvant management of breast cancer. The identification and validation of predictive biomarkers will be crucial in optimizing their use, both in adjuvant and neoadjuvant settings.

Diagnosis of central nervous system tumors is based on the histopathologic features and molecular alterations. For certain entities, this histomolecular diagnosis now includes DNA methylation profiles. Methylation profiles reflect the cell of origin and epigenetic modifications that occur during tumorigenesis and may help classify central nervous system tumors via artificial intelligence algorithms. This powerful approach to tumor classification has revolutionized the field of neuro-oncology, allowing more reliable diagnosis and prognostic assessment, particularly for pediatric neoplasms. The analysis of methylation profiles currently requires data to be shared with the developer of the AI algorithms. As DNA methylation profiling may be useful in a growing number of cancers, local alternatives, such as those based on the nanopore technology, need to be developed.

Antibodies-drugs conjugate (ADC) are revolutionizing breast cancer treatment thanks to their specific targeting and cytotoxic efficacy. Despite significant advances with agents such as trastuzumab emtansine, sacituzumab govitecan and trastuzumab deruxtecan, resistance mechanisms limit their efficacy. These include reduced or heterogeneous expression of the antigenic target on the surface of tumour cells (HER2, TROP2), mutations in genes encoding the targets of cytotoxic agents, increased efflux of these agents out of the cell, and alterations in intracellular trafficking. These resistances are associated with reduced efficacy of ADCs, underlining the need for new strategies, such as the development of next-generation ADCs by optimizing conjugation systems, for example. Therapeutic prospects also include the development of bispecific antibodies, the targeting of new proteins such as HER3, and the combination of ADCs with other treatments, notably immune checkpoint inhibitors or other ADCs. Despite these advances, challenges remain, notably in identifying biomarkers of response and defining the optimal therapeutic sequence to avoid cross-resistance. Ongoing research is aimed at refining the use of ADCs to maximize their efficacy and prolong the survival of breast cancer patients.

In France breast cancer is the most common cancer among women and the leading cause of cancer deaths. Identifying women with a "high" or "very high" breast cancer risk, according to the terminology of the Haute Autorité de santé 2014 guidelines, is essential to offer them special cares in term of screening and prevention. Women genetically predisposed have a very high risk of breast cancer. During the oncogenetic specialist consultation, familial and personal history of cancer is considered to evaluate the risk of hereditary Breast/Ovarian syndrome and thus the need of a genetic screening. In 2017 a list of 13 genes involved in hereditary ovarian or breast cancer has been established in France (Genetic and Cancer Group - Unicancer). Women carrying a BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN mutation have a higher risk of breast cancer and are considered as "high risk". Therefore medical breast surveillance similar to carriers of BRCA1/BRCA2 mutation is recommended for these patients (INCa guidelines 2017). However a mutation in one of those genes is only identified in approximatively 10% of the screened families. The oncogenetic specialist's assessment distinguishes families in which women remain at a "high" risk of breast cancer (HAS 2014 for screening) from those where women have a "very high" risk (INCa guidelines 2017 for screening and prevention).

Breast cancer affects 5% of women of childbearing age, accounting for 30% of cancer cases in this population. These cancers are often more aggressive with a less favorable prognosis in younger women. Hormonal exposure plays a key role in the development of this cancer, although the specific impact of certain exposures, such as hormonal contraception or ovarian stimulation treatments, remains debated. Studies on the link between hormonal contraception and breast cancer risk present contradictory results. Some suggest a slight increase in risk, particularly after prolonged use, while others find no significant association. Regarding assisted reproductive technology, data show no increased risk of breast cancer after ovarian stimulation. For women with breast cancer, fertility preservation is possible before the implementation of gonadotoxic treatments without significantly impacting the risk of recurrence. Pregnancy after breast cancer, including hormone-dependent cancer, is not associated with a higher risk of recurrence. Lastly, women with BRCA mutations would face an increased risk of reduced ovarian reserve, but fertility preservation, as well as the use of contraception or hormone replacement therapy, can be considered in this high-risk population.

Breast cancer in adolescents and young adults (AYAs) is a rare event but requires a well-structured and tailored approach for this specific population. Oncogenetic and oncofertility consultations are essential at the time of breast cancer diagnosis in an AYA. Therapeutic management follows breast cancer guidelines, with particular attention to the risks of long-term side effects, potential constitutional genetic mutations, and specific considerations regarding hormone therapy. The number of adults who have survived cancer during childhood or adolescence/young adulthood increases each year. The morbidity associated with prior treatments and the risk of secondary cancers create needs for care and follow-up, which must be organized, anticipated, and adapted.

Past decade was marked by development of several new drug for HR+/HER2- metastatic breast cancer leading to several major question in terms of strategy. We propose here to review state of art in terms of targeted therapy for advanced luminal breast cancer and how treatment strategy will be more and more personalized in a near future.

Cysts, common and ubiquitous pathological anomalies, are defined as cavities lined by a distinct wall and filled with fluid or semi-solid material. They result from complex mechanisms involving genetic alterations, biophysical forces, and tissue microenvironment interactions. Recent advances in genomics have identified key mutations that disrupt cell polarity, intracellular signaling, and fluid dynamics. Concurrently, biophysical models elucidate the impact of mechanical and osmotic forces on cyst growth and rupture. Multiscale models, integrating these approaches, connect molecular mechanisms to tissue dynamics, providing powerful tools to unravel the complex interactions driving cyst formation. These advances offer promising perspectives in terms of diagnosis, through genetic and biophysical biomarkers and therapeutics. This article provides an integrative update on the genetic and biophysical mechanisms of cysts and explores their clinical applications within a multidisciplinary framework.

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.