BRCA1 and BRCA2 gene pathogenic variants account for most hereditary breast cancer and are increasingly used to determine eligibility for PARP inhibitor (PARPi) therapy of BRCA-related cancer. Because issues of BRCA testing in clinical practice now overlap with both preventive and therapeutic management, updated and comprehensive practice guidelines for BRCA genotyping are needed. The integrative recommendations for BRCA testing presented here aim to (1) identify individuals who may benefit from genetic counselling and risk-reducing strategies; (2) update germline and tumour-testing indications for PARPi-approved therapies; (3) provide testing recommendations for personalised management of early and metastatic breast cancer; and (4) address the issues of rapid process and tumour analysis. An international group of experts, including geneticists, medical and surgical oncologists, pathologists, ethicists and patient representatives, was commissioned by the French Society of Predictive and Personalised Medicine (SFMPP). The group followed a methodology based on specific formal guidelines development, including (1) evaluating the likelihood of BRCAm from a combined systematic review of the literature, risk assessment models and expert quotations, and (2) therapeutic values of BRCAm status for PARPi therapy in BRCA-related cancer and for management of early and advanced breast cancer. These international guidelines may help clinicians comprehensively update and standardise BRCA testing practices.

Circulating tumoral DNA (ctDNA), commonly named “liquid biopsy”, has emerged as a new promising noninvasive tool to detect biomarker in several cancers including lung cancer. Applications involving molecular analysis of ctDNA in lung cancer have increased and encompass diagnosis, response to treatment, acquired resistance and prognosis prediction, while bypassing the problem of tumor heterogeneity. ctDNA may then help perform dynamic genetic surveillance in the era of precision medicine through indirect tumoral genomic information determination. The aims of this review were to examine the recent technical developments that allowed the detection of genetic alterations of ctDNA in lung cancer. Furthermore, we explored clinical applications in patients with lung cancer including treatment efficiency monitoring, acquired therapy resistance mechanisms and prognosis value.

Objective: High-grade serous ovarian cancers (HGSOC) are heterogeneous, often diagnosed at an advanced stage, and associated with poor overall survival (OS, 39% at five years). There are few data about the prognostic factors of late relapses in HGSOC patients who survived ≥five years, long-term survivors (LTS). The aim of our study is to assess the probability of survival according to the already survived time from diagnosis. Methods: Data from HGSOC patients treated between 1995 and 2016 were retrospectively collected to estimate the conditional probability of survival (CPS), probability of surviving Y years after diagnosis when the patient had already survived X years, and to determine the LTS prognostic factors. The primary endpoint was OS. Results: 404 patients were included; 120 of them were LTS. Patients were aged 61 years (range: 20–89), WHO performance status 0–1 in 86.9% and 2 in 13.1%, and Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) staging III and IV in 82.7% and 17.3% patients. Breast cancer (BRCA) status was available in 116 patients (33% mutated), including 58 LTS (36% mutated). No macroscopic residual disease was observed in 58.4% patients. First-line platinum-based chemotherapy plus paclitaxel was administered in 80.4% of patients (median: six cycles (range: 1–14)). After a 9 point 3-year follow-up, median OS was four years (95% CI: 3.6–4.5). The CPS at five years after surviving one year was 42.8% (95% CI: 35.3–48.3); it increased to 81.7% (95% CI: 75.5–87.8) after four survived years. Progression-free interval>18 months was the only LTS prognostic factor in the multivariable analysis (hazard ratio (HR) = 0.23; 95% CI: 0.13–0.40; p < 0.001). Conclusion: The CPS provided relevant and encouraging clinical information on the life expectancy of HGSOC patients who already survived a period of time after diagnosis. LTS prognostic factors are useful for clinicians and patients.

Although the development of mitogen-activated protein kinase (MAPK) inhibitors has greatly improved the prognosis of BRAF^V600 cutaneous melanomas, the identification of molecular indicators for mutated patients at risk of early progression remains a major issue. Using an amplicon-based next-generation-sequencing (NGS) assay that targets cancer-related genes, we investigated co-occurring alterations in 89 melanoma samples. We analyzed both their association with clinicopathological variables and clinical significance in terms of progression-free survival (PFS) and overall survival (OS) according to BRAF genotyping. Among co-occurring mutations, TERT promoter was the most frequently mutated gene. Although no significant difference in PFS was observed in the presence or absence of co-occurring alterations to BRAF^V600, there was a trend of longer PFS for patients harboring TERT c.-124C>T mutation. Of most interest, this mutation is an independent marker of good prognosis in subgroups of patients with poor prognosis (presence of brain metastasis and elevated level of lactate dehydrogenase, LDH). Moreover, combination of elevated LDH level, presence of brain metastasis, and TERT c.-124C>T mutation was identified as the best fit model for predicting clinical outcome. Our work revealed the potential interest of c.-124C>T status determination in order to refine the prognosis of BRAF^V600 melanoma under mitogen-activated protein kinase (MAPK) inhibitors.

Endocrine therapies targeting oestrogen signalling have significantly improved breast cancer management. However, their efficacy is limited by intrinsic and acquired resistance to treatment, which remains a major challenge for oestrogen receptor α (ERα)-positive tumours. Though many studies using in vitro models of endocrine resistance have identified putative actors of resistance, no consensus has been reached. We demonstrated previously that oestrogen non-genomic signalling, characterized by the formation of the ERα/Src/PI3K complex, is activated in aggressive breast cancers (BC). We wondered herein whether the activation of this pathway is also involved in resistance to endocrine therapies. We studied the interactions between ERα and Src or PI3K by proximity ligation assay (PLA) in in-vitro and in-vivo endocrine therapy-resistant breast cancer models. We reveal an increase in ERα/Src and ERα/PI3K interactions in patient-derived xenografts (PDXs) with acquired resistance to tamoxifen, as well as in tamoxifen-resistant MCF-7 cells compared to parental counterparts. Moreover, no interactions were observed in breast cancer cells resistant to other endocrine therapies. Finally, the use of a peptide inhibiting the ERα–Src interaction partially restored tamoxifen sensitivity in resistant cells, suggesting that such components could constitute promising targets to circumvent resistance to tamoxifen in BC.

Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) represents a minimally invasive alternative to conventional tissue biopsies, providing real-time genomic snapshots of heterogeneous tumors from blood draws. This liquid biopsy approach has demonstrated significant utility for early detection, molecular profiling, and monitoring treatment response in cancer patients. However, significant barriers to widespread clinical implementation still remain, such as a lack of standardized methods for ctDNA content quantification and limited variant detection sensitivity at ultra-low frequencies. Herein, we discuss three key improvements: (i) reducing the limit of detection (LoD) from 0.5% to 0.1%, which would increase alteration detection from 50% to approximately 80%; (ii) developing a dynamic LoD approach calibrated to sequencing depth, thereby enhancing result reliability and confidence in clinical interpretation; and (iii) utilizing strategic bioinformatics pipelines with “allowed” and “blocked” lists to enhance accuracy while minimizing false positives. While ctDNA analysis remains approximately 30% less sensitive than tissue-based testing, addressing these limitations through technological advancement and standardization protocols could accelerate integration into routine clinical practice, potentially transforming cancer management while reducing healthcare costs.