Update on new treatments for rare ovarian tumours.

PURPOSE OF REVIEW: In spite of their rarity when considered individually, the sum of all rare ovarian tumours (ROT) represent almost half of all ovarian malignancies. As such, their appropriate inclusion within dedicated clinical trials is essential for enhanced management. RECENT FINDINGS: Supported by institutional expert national (e.g. TMRG) and international (e.g. ESGO) networks and owing to national (e.g. ARCAGY-GINECO) and international (e.g. ENGOT) collaborations dedicated to clinical research, the last few years have shown increased number of clinical trials dedicated to ROT. These either were based on specific molecular features of ROT (e.g. expression of oestrogen receptors for low-grade serous ovarian carcinomas and anastrazole evaluation in the PARAGON trial) or on the evaluation of innovative therapies (e.g. pembrolizumab within the ROT cohort from the AcSé Pembrolizumab multicentric basket trial). Furthermore, recent years have also shown the advent of randomized clinical trials. For instance, the ALIENOR trial positioned weekly paclitaxel as a new option for relapsed sex cord-stromal tumours, while the GOG281/LOGS trial raised trametinib as a new standard-of-care option for recurrent low-grade serous carcinomas. SUMMARY: The last few years have exhibited a paradigm shift towards the possibility to develop dedicated trials for ROT, owing to international collaborations supported by institutional networks. Current trials, molecular-driven and based on innovative designs, are highly promising, as they may bring ROT management towards more personalized medicine.

[Homologous recombination deficiency in epithelial ovarian cancers: from molecular characterization to patient journey]. / Déficit de la recombinaison homologue dans les cancers épithéliaux de l'ovaire : de la caractérisation moléculaire au parcours des patientes.

High-grade serous ovarian carcinoma (HGSOC), the most frequent and aggressive form of epithelial ovarian cancer is characterized in half of cases by homologous recombination deficiency (HRD). This molecular alteration is defined by distinct causes and consequences. The main and most characterized cause is the presence of an alteration affecting BRCA1 and BRCA2 genes. Regarding consequences, a specific genomic instability leads to increased sensitivity to platinum salts and poly (ADP-ribose) polymerase (PARPi) inhibitors. This latter point enabled the advent of PARPi in first and second line maintenance. As such, the initial and rapid evaluation of HRD status with molecular tests is a key step in the management of HGSOC. Until recently, the range of tests offered proved to be very limited and suffered from technical and medical limitations. This has recently led to the development and validation of alternatives, including academic ones. This "state of the art" review will bring a synthesis concerning the assessment of HRD status in HGSOCs. After a brief introduction of HRD (including main causes and consequences) and of its predictive value regarding PARPi, we will discuss the limitations of current molecular tests and the existing alternatives. Finally, we will contextualize this to the situation in France, with special consideration concerning the positioning and the financial coverage of these tests, with the perspective of optimizing patient management .

Optimal First-Line Medico-Surgical Strategy in Ovarian Cancers: Are We There Yet?

In spite of tremendous advances in advanced ovarian cancer management through the past decade, notably owing to surgical expertise and novel combination molecules (including bevacizumab and PARP inhibitors), the optimal initial sequential strategy remains a major concern. Indeed, following seminal clinical trials, primary cytoreductive surgery (PCS) followed by adjuvant systemic therapy and interval cytoreductive surgery (ICS) following neoadjuvant chemotherapy (NACT) have been positioned as validated alternatives with distinct pros and cons, although a definite response is still unassessed. In clinical practice, decisions between PCS and ICS rely on multilayer parameters: the tumor itself, the patient, and the health structure. In this state-of-the-art review, we will discuss the current evidence based on clinical trials and real-world data and highlight the remaining questions, including the fittest positioning of PCS vs. ICS and the optimal number of NACT cycles; subsequently, we will discuss current axes of research such as dedicated clinical trials and more global perspectives. These ongoing strategies and perspectives could contribute to improving the patient journey through personalized medicine.

[Tertiary lymphoid structures in cancer: From biology to therapeutic guides]. / Structures lymphoïdes tertiaires : de la biogenèse à l'impact thérapeutique en cancérologie.

Tertiary lymphoid structures (TLS) are inducible ectopic lymphoid aggregates, which form in response to various inflammatory situations, including cancer. TLS are notably composed of B lymphocytes, T lymphocytes, mature dendritic cells and other key players such as high endothelial venules. Furthermore, TLS can present different levels of organization and maturation, from simple T/B lymphocyte aggregates to authentic mature B cell follicles with germinal centers adjacent to T cell rich areas. While over the past decade, TLS may have been associated with a favorable prognosis in various cancers, the year 2022 was marked by the first prospective trial (PEMBROSARC) that reported the interest of TLS as predictive biomarkers of pembrolizumab efficacy for the treatment of soft-tissue sarcomas. All along this review, we will first address the molecular and cellular bases of TLS as well as the different strategies for identifying them in clinical practice, then discuss the prognostic/predictive impact of their presence and finally, we will elaborate on the current limitations and perspectives in translational research.

[Combination strategies for checkpoint inhibition: Current practices and perspectives]. / Combinaisons d'inhibiteurs de points de contrôle immunitaires en oncologie : état de l'art et perspectives.

T-cell checkpoint blockade therapies have revolutionized treatment protocols and prognosis in patients with cancer. Pointed out by the success of PD-1 (programmed cell death-1) plus CTLA-4 (cytotoxic-T-lymphocyte associated antigen 4) blockade in patients with melanoma, the perspective of new synergistic immunotherapy combinations seems to be an important opportunity to improve outcomes for patients. In this article, we first focus on immunotherapy combinations that have shown their efficiency and that are currently approved in solid tumors. Then, we present a summary of emerging targets with reported pre-clinical efficacy and currently evaluated through ongoing clinical trials and other immunomodulatory molecules in the tumor microenvironment.

[Treatments for rare ovarian tumors: What's new?] / Avancées thérapeutiques dans la prise en charge des tumeurs rares malignes ovariennes.

Even if each rare ovarian tumor (ROT) has a low incidence, the sum of all these entities represents almost the half of all ovarian neoplasms. Thus, development of dedicated clinical trial emerged as a prerequisite to improve their managements. Owing to the spreading of dedicated institutional networks and (supra)national collaborations, the number of clinical trials has increased the past few years, with different types of trials; while some focused on specific molecular features, others assessed innovative molecules. Furthermore, relevant randomized clinical trials were designed as a mean to position new treatment options. Currently, innovative molecular-driven trials, based on master protocol trials are emerging and may shed light towards the improvement of personalized medicine regarding ROT.

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer Part 2: Medical Perspectives.

High-grade serous ovarian cancer (HGSOC) is the most frequent and aggressive form of ovarian cancer, representing an important challenge for clinicians. Half of HGSOC cases have homologous recombination deficiency (HRD), which has specific causes (mainly alterations in BRCA1/2, but also other alterations encompassed by the BRCAness concept) and consequences, both at molecular (e.g., genomic instability) and clinical (e.g., sensitivity to PARP inhibitor) levels. Based on its prevalence and clinical impact, HRD status merits investigation. To date, three PARP inhibitors have received FDA/EMA approval. For some approvals, the presence of specific molecular alterations is required. Three companion diagnostic (CDx) assays based on distinct technical and medical considerations have received FDA approval to date. However, their use remains controversial due to their technical and medical limitations. In this companion and integrated review, we take a "bench-to-bedside" perspective on HRD definition and evaluation in the context of HGSOC. Part 1 of the review adopts a molecular perspective regarding technical considerations and the development of CDx. Part 2 focuses on the clinical impact of HRD evaluation, primarily through currently validated CDx and prescription of PARP inhibitors, outlining achievements, limitations and medical perspectives.

Toward More Comprehensive Homologous Recombination Deficiency Assays in Ovarian Cancer, Part 1: Technical Considerations.

High-grade serous ovarian cancer (HGSOC), the most frequent and lethal form of ovarian cancer, exhibits homologous recombination deficiency (HRD) in 50% of cases. In addition to mutations in BRCA1 and BRCA2, which are the best known thus far, defects can also be caused by diverse alterations to homologous recombination-related genes or epigenetic patterns. HRD leads to genomic instability (genomic scars) and is associated with PARP inhibitor (PARPi) sensitivity. HRD is currently assessed through BRCA1/2 analysis, which produces a genomic instability score (GIS). However, despite substantial clinical achievements, FDA-approved companion diagnostics (CDx) based on GISs have important limitations. Indeed, despite the use of GIS in clinical practice, the relevance of such assays remains controversial. Although international guidelines include companion diagnostics as part of HGSOC frontline management, they also underscore the need for more powerful and alternative approaches for assessing patient eligibility to PARP inhibitors. In these companion reviews, we review and present evidence to date regarding HRD definitions, achievements and limitations in HGSOC. Part 1 is dedicated to technical considerations and proposed perspectives that could lead to a more comprehensive and dynamic assessment of HR, while Part 2 provides a more integrated approach for clinicians.

Perioperative FOLFOX in Patients With Locally Advanced Oesogastric Adenocarcinoma.

BACKGROUND: We hypothesized that perioperative FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) might be used as an alternative to standard FLOT (docetaxel, 5-fluorouracil, leucovorin, and oxaliplatin) in patients with locally advanced oesogastric adenocarcinomas (OGA), particularly those with frailties. PATIENTS AND METHODS: We reviewed the charts of 61 consecutives patients treated with FOLFOX for resectable OGA to estimate overall survival, recurrence-free survival, and safety. RESULTS: The median follow-up was 69.7 (range=3.6-97.9) months. Few patients experienced grade 3 adverse events during the preoperative (n=6; 10%) and postoperative (n=6; 16%) phases. One patient experienced a fatal grade 5 adverse events (cardiogenic shock). Median overall survival was 51.7 months [95% confidence interval (CI)=31.6-93.2 months] and the 5-year survival rate was 44.4% (95% CI=30.3%-57.5%). CONCLUSION: Regarding its comparable efficacy and its favourable toxicity profile, perioperative FOLFOX is a reasonable alternative to FLOT for frail patients with resectable OGA.

[Combining surgery and medical treatments for ovarian cancer: Is there an optimal strategy?] / Combinaison de la chirurgie et du traitement médical du cancer de l'ovaire : y a-t-il une stratégie optimale ?

The objective of this review is to evaluate the optimal positioning of cytoreduction surgery and perioperative medical treatments in the initial management and relapse of advanced-stage epithelial ovarian carcinoma. In the initial management, primary surgery should be proposed if the absence of tumor residue is feasible with reasonable surgery (extensive surgical resections to be considered and their complications, but also the general condition of the patient). Guidelines recommend 3 to 4 cycles of neoadjuvant chemotherapy before interval surgery for patients not eligible for primary surgery. Late interval surgery (i.e. after≥5-6 cycles of chemotherapy) is not a standard of care and should only be proposed in case of poor tumor response after 3-4 cycles and when complete interval surgery seems feasible. At first tumor recurrence in platinum-sensitive patients, a primary cytoreduction surgery can be considered if complete surgery can be managed. Predictive scores (AGO score; i-model score) can be used to select eligible patients. Given the lack of strong evidence, performing cytoreduction surgery at first recurrence in platinum-resistant patients or in the event of subsequent recurrence cannot be recommended. Nevertheless, obtaining a complete surgery in these clinical situations seems to provide a benefit in terms of overall survival and its application should be based on the expertise of specialized teams.

Efficacy, safety, and feasibility of volumetric modulated arc therapy for synchronous bilateral breast cancer management.

Purpose: Volumetric Modulated Arc Therapy (VMAT) exhibits potent advantages regarding target volume coverage and protection of organs at risk, notably in the context of anatomical constraints. Nevertheless, reports concerning VMAT for the treatment of synchronous bilateral breast cancers (SBBC) have been scarce to date. As such, we conducted this observational study to assess efficacy, safety and feasibility of VMAT in SBBC. Materials and Methods: From August 2011 to December 2017, 54 consecutive patients with SBBC with or without axillary nodes involvement underwent a treatment protocol containing radiotherapy using VMAT. A total dose (TD) of 52.2Gy in 29 fractions was delivered to breast and internal mammary chain (IMC) nodes Planning Target Volume (PTV) plus, if applicable, a TD of 49.3Gy in 29 fractions to the supra- and infra-clavicular nodes PTV and a TD of 63.22Gy in 29 fractions to tumor boost PTV. Lungs, heart, esophagus, trachea, liver, thyroid and spinal cord were considered as organs at risk. VMAT feasibility and organ at risk sparing were evaluated by treatments planning of the 20 first enrolled patients. Tolerance and patients' outcome were prospectively monitored by acute/late toxicities records and by the analysis of overall survival (OS), locoregional recurrence-free survival (LRFS) and recurrence-free survival (RFS). Results: Breast, supraclavicular nodes and boost PTV coverage was adequate with at least 98% of PTV encompassed by more than 95% of the prescribed dose. Less than 90% of IMC PTV was encompassed by 95% of the prescribed dose. Mean lung dose was 12.3Gy (range: 7.7 - 18.7); mean heart dose was 10.7Gy (range: 6.2 - 22.3). Concerning acute toxicities, only 2 patients experienced grade 3 skin toxicity (3.7%) and only 1 patient developed grade 1 pneumonitis. After a median follow-up of 5.3 years, grade 2 fibrosis and/or shrinking was observed in 5 patients (10%), and grade 3 fibrosis in 1 patients (2%). The 5-year LRFS-rate, RFS-rate and OS were 98% [95% CI= 86.12-99.70%], 96% [95% CI= 84.63-98.96%] and 100%, respectively.

Real-World Data on Newly Diagnosed BRCA-Mutated High-Grade Epithelial Ovarian Cancers: The French National Multicenter ESME Database.

BACKGROUND: In spite of the frequency and clinical impact of BRCA1/2 alterations in high-grade epithelial ovarian cancer (HGEOC), real-world information based on robust data warehouse has been scarce to date. METHODS: Consecutive patients with BRCA-mutated HGEOC treated between 2011 and 2016 within French comprehensive cancer centers from the Unicancer network were extracted from the ESME database. The main objective of the study was the assessment of clinicopathological and treatments parameters. RESULTS: Out of the 8021 patients included in the ESME database, 266 patients matching the selection criteria were included. BRCA1 mutation was found in 191 (71.8%) patients, while 75 (28.2%) had a BRCA2 mutation only; 95.5% of patients received a cytoreductive surgery. All patients received a taxane/platinum-based chemotherapy (median = six cycles). Complete and partial response were obtained in 53.3% and 20.4% of the cases, respectively. Maintenance therapy was administered in 55.3% of the cases, bevacizumab being the most common agent. After a median follow up of 51.7 months, a median progression-free survival of 28.6 months (95% confidence interval (CI) [26.5; 32.7]) and an estimated 5-year median overall survival of 69.2% (95% CI [61.6; 70.3]) were reported. Notably, BRCA1- and BRCA2-mutated cases exhibited a trend towards different median progression-free survivals, with 28.0 (95% CI [24.4; 32.3]) and 33.3 months (95% CI [26.7; 46.1]), respectively (p-value = 0.053). Furthermore, five-year OS for BRCA1-mutated patients was 64.5% (95% CI [59.7; 69.2]), while it was 82.5% (95% CI [76.6; 88.5]) for BRCA2-mutated ones (p-value = 0.029). CONCLUSIONS: This study reports the largest French multicenter cohort of BRCA-mutated HGEOCs based on robust data from the ESME, exhibiting relevant real-world data regarding this specific population.

Alterations in Homologous Recombination-Related Genes and Distinct Platinum Response in Metastatic Triple-Negative Breast Cancers: A Subgroup Analysis of the ProfiLER-01 Trial.

BACKGROUND: a specific subset of metastatic triple-negative breast cancers (mTNBC) is characterized by homologous recombination deficiency (HRD), leading to enhanced sensitivity to platinum-based chemotherapy. Apart from mutations in BRCA1/2 genes, the evaluation of other HRD-related alterations has been limited to date. As such, we analyzed data from mTNBC patients enrolled in the ProfiLER-01 study to determine the prevalence of alterations in homologous recombination-related (HRR) genes and their association with platinum sensitivity. METHODS: next-generation sequencing and promoter methylation of BRCA1 and RAD51C were performed on tumors from patients with mTNBC, using a panel of 19 HRR genes. Tumors were separated into three groups based on their molecular status: mutations in BRCA1/2, mutations in other HRR genes (BRCA1/2 excluded) or BRCA1/RAD51C promoter methylation and the absence of molecular alterations in HRR genes (groups A, B and C, respectively). Sensitivity to platinum-based chemotherapy was evaluated through the radiological response. RESULTS: mutations in BRCA1/2 were detected in seven (13.5%) patients, while alterations in other HRR genes or hypermethylation in BRCA1 or RAD51C were reported in 16 (30.7%) patients; furthermore, no alteration was found in the majority of patients (n = 29; 55.8%). Among 27 patients who received platinum-based chemotherapy, the disease control rate was 80%, 55% and 18% (groups A, B and C, respectively; p = 0.049). Regarding group B, patients with disease control exhibited mutations in FANCL, FANCA and the RAD51D genes or RAD51C methylation; Conclusion: mutations in HRR genes and epimutations in RAD51C were associated with disease control through platinum-based chemotherapy. As such, apart from well-characterized alterations in BRCA1/2, a more comprehensive evaluation of HRD should be considered in order to enlarge the selection of patients with mTNBC that could benefit from platinum-based chemotherapy.

Cancer-Related Alopecia: From Etiologies to Global Management.

Alopecia represents a multifaceted challenge with distinct etiologies and consequences. Transposed to the world of oncology, different types of alopecia and molecular pathways have been characterized, allowing a better understanding of the underlying mechanisms. In patients with cancer, alopecia can be iatrogenic (i.e., due to conventional chemotherapies, endocrine therapies, targeted therapies, immunotherapies, radiotherapy and surgery) or a direct consequence of the disease itself (e.g., malnutrition, scalp metastases and paraneoplastic syndromes). Identification of the actual incriminated mechanism(s) is therefore essential in order to deliver appropriate supportive care, whether preventive or curative. On the preventive side, the last few years have seen the advent of the automated cooling cap, a prophylactic approach supported by several randomized clinical trials. On the curative side, although the treatments currently available are limited, several promising therapeutic approaches are under development. Appropriate alopecia management is essential, particularly regarding its psychological repercussions with significant consequences on the quality of life of patients and their family and with a potential impact on treatment compliance.

[Alopecia and cancers: From basics to clinical practice]. / Alopécie et cancers : de la physiopathologie à la pratique clinique.

Alopecia, although long considered an unavoidable consequence of cancer therapy, currently presents a multifaceted challenge. The knowledge of the physiology of the hair and consequently of the pathophysiology of alopecia has led to show that there is not one but several types of alopecia. Transposed to the world of oncology, different types of alopecia and subsequently molecular pathways have been characterized, allowing a better understanding of the underlying mechanisms. Thus, in patients with cancer, alopecia can be iatrogenic (chemotherapies, endocrine therapies, targeted therapies, immunotherapies, radiotherapy, surgery) or directly the consequence of the disease itself (malnutrition, scalp metastases, paraneoplastic syndromes). Knowledge of the incriminated mechanism(s) could thus make it possible to deploy an appropriate care component, whether on the preventive or curative sides or in terms of supportive care. These are particularly essential regarding the psychological repercussions caused by alopecia, with significant consequences on the quality of life of patients and with a potential impact on treatment compliance. On the preventive side, the last few years have seen the advent of the automated scalp cooling therapy, supported by several randomized clinical trials. On the curative side, several therapeutic proposals are currently deployed or under development in order to provide relevant treatments.

Loss of Apc Rapidly Impairs DNA Methylation Programs and Cell Fate Decisions in Lgr5+ Intestinal Stem Cells.

Colorectal cancer initiation and progression result from the accumulation of genetic and epigenetic alterations. Although aberrant gene expression and DNA methylation profiles are considered hallmarks of colorectal cancer development, the precise timing at which these are produced during tumor establishment remains elusive. Here we investigated the early transcriptional and epigenetic changes induced by adenomatous polyposis coli (Apc) inactivation in intestinal crypts. Hyperactivation of the Wnt pathway via Apc inactivation in crypt base columnar intestinal stem cells (ISC) led to their rapid accumulation driven by an impaired molecular commitment to differentiation, which was associated with discrete alterations in DNA methylation. Importantly, inhibiting the enzymes responsible for de novo DNA methylation restored the responsiveness of Apc-deficient intestinal organoids to stimuli regulating the proliferation-to-differentiation transition in ISC. This work reveals that early DNA methylation changes play critical roles in the establishment of the impaired fate decision program consecutive to Apc loss of function. SIGNIFICANCE: This study demonstrates the functional impact of changes in DNA methylation to determine the colorectal cancer cell phenotype following loss of Apc function.