The genomic trajectory of ovarian high-grade serous carcinoma can be observed in STIC lesions.

Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinoma (STIC) lesions, which in turn progress into invasive HGSC, which readily spreads to the ovary and disseminates around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole-genome duplication (WGD) observed in late-stage disease were determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded (FFPE) samples from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole-genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next-generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was a strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of WGD, arises early in HGSC and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Challenges for immunotherapy for the treatment of platinum resistant ovarian cancer.

Platinum resistant ovarian cancer, usually defined as progression occurring within 6 months after completing platinum-based therapy, is a heterogeneous disease with poor prognosis and short survival (less than 18 months). It is typically considered as a "cold tumor", characterized by reduced infiltration by immune cells, particularly CD8+ T cells. Response rate to anti-PD1/PD-L1 monotherapy is low, not exceeding 8%. Multiple therapeutic strategies are currently investigated in order to increase response rates to anti-PD1/PD-L1 through adding chemotherapy, anti-angiogenic agents, DNA damage (PARP inhibitors, cyclophosphamide and/or radiotherapy) or other immune checkpoint inhibitors (CTLA-4, etc.). Ovarian clear cell carcinoma, a rare histotype characterized by primary platinum-resistance, recently showed anecdotal but promising response rates to immune checkpoint blockade. Other immunotherapeutic approaches such as adoptive T cell therapy, vaccines and targeting myeloid immune checkpoints like "don't eat me" signal CD47 are currently investigated. Each approach faces distinct challenges that will be reviewed here. Robust immunogenomics studies conducted in parallel of the ongoing trials will help into refining optimal immunotherapy combination for this lethal disease and identify predictive biomarkers.

Treatment Perspectives for Ovarian Cancer in Europe and the United States: Initial Therapy and Platinum-Sensitive Recurrence after PARP Inhibitors or Bevacizumab Therapy.

PURPOSE OF REVIEW: Although the survival rate of patients with ovarian cancer (OC) has significantly improved, OC is still one of the most common causes of gynecologic cancer death in women worldwide. The current advances in primary treatment are based on recent regulatory approvals and recurrency of such treatments, challenging the development of a unified approach to care. Herein, we examine how integration of these new approaches is applied to patient's treatment. RECENT FINDINGS: We and others have recently reported clinical trials using bevacizumab and/or inhibitors of Poly (ADP-ribose) polymerase (PARP), which have greatly affected the change in first-line treatments for OC. As first-line therapy has evolved, therapeutic agents once designated for recurrent disease are increasingly being incorporated, changing our standard of care following previously indexed trials. Here, we provide an overview of the current treatment for OC patients, and we highlight practice patterns in Europe and in the USA with corresponding opinions on current and future treatments for platinum-sensitive recurrent OC.

Poly(ADP-ribose) polymerase inhibitors in combination with anti-angiogenic agents for the treatment of advanced ovarian cancer.

Homologous recombination deficiency and VEGF expression are key pathways in high-grade ovarian cancer. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. The use of PARP inhibitors (PARPi) following chemotherapy has become standard of care in first line. Combination of PARPi with anti-angiogenic agents has demonstrated synergistic activity in preclinical study. This review summarizes the body of evidence supporting the efficacy and safety of the combination of PARPi and anti-angiogenic drugs in first-line homologous recombination deficiency high-grade ovarian cancer leading to US FDA and EMA approvals. This double maintenance is supported by: a large benefit with bevacizumab + olaparib compared with olaparib alone, a rationale for additive effect, and a good safety and cost-effective profile.

Lay abstract Ovarian cancers often present difficulties to repair their DNA and are highly vascularized tumors. Recently, three randomized practice changing trials were published: the PAOLA-1, PRIMA and VELIA trials. They use one type of therapy to target the difficulty of ovarian cancer to repair their DNA which is called poly(ADP-ribose) polymerase inhibitor. This type of therapy has become standard of care after chemotherapy. In this review, we discuss the advantage of combining anti-angiogenic agents to poly(ADP-ribose) polymerase inhibitors to target the fact that tumors are highly vascularized. First, data from laboratory suggest synergistic activity of the combination. Then, clinical data are also in favor of the combination due to additive efficacy, and a good safety and cost-effective profile.

Changes in the Use of Comprehensive Geriatric Assessment in Clinical Trials for Older Patients with Cancer over Time.

BACKGROUND: The objective of this study was to describe the implementation of comprehensive geriatric assessment (CGA) in clinical trials dedicated to older patients before and after the creation of the International Society of Geriatric Oncology in the early 2000s. SUBJECTS, MATERIALS, AND METHODS: All phase I, II, and III trials dedicated to the treatment of cancer among older patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. We considered that a CGA was performed when the authors indicated an intention to do so in the Methods section of the article. We collected each geriatric domain assessed using a validated tool even in the absence of a clear CGA, including nutritional, functional, cognitive, and psychological status, comorbidity, comedication, overmedication, social status and support, and geriatric syndromes. RESULTS: A total of 260 clinical trials dedicated to older patients were identified over the two time periods: 27 phase I, 193 phase II, and 40 phase III trials. CGA was used in 9% and 8% of phase II and III trials, respectively; it was never used in phase I trials. Performance status was reported in 67%, 79%, and 75% of phase I, II, and III trials, respectively. Functional assessment was reported in 4%, 11%, and 13% of phase I, II, and III trials, respectively. Between the two time periods, use of CGA increased from 1% to 11% (p = .0051) and assessment of functional status increased from 3% to 14% (p = .0094). CONCLUSION: The use of CGA in trials dedicated to older patients increased significantly but remained insufficient. IMPLICATIONS FOR PRACTICE: This article identifies the areas in which research efforts should be focused in order to offer physicians well-addressed clinical trials with results that can be extrapolated to daily practice.

Elderly patients with metastatic renal cell carcinoma: position paper from the International Society of Geriatric Oncology.

Therapy for metastatic renal cell carcinoma should be tailored to the circumstances and preferences of the individual patient. Age should not be a barrier to effective treatment. Systematic geriatric screening and assessment contributes to the goal of personalised management, in addition to the involvement of a multidisciplinary team. A task force from the International Society of Geriatric Oncology (SIOG) updated its 2009 consensus statement on the management of elderly patients with metastatic renal cell carcinoma by reviewing data from studies involving recently approved targeted drugs and immunotherapies for this disease. Overall, it seems that age alone does not appreciably affect efficacy. Among the pivotal studies that were included, there is a striking scarcity of analyses that relate toxic effects to patient age. Even if the adverse effects of therapy are no more frequent or severe in elderly patients than in their younger counterparts, the practical, psychological, and functional impact of treatment may be greater, especially if toxic effects are chronic and cumulative.

Is There an Age Threshold for Holding Off on Testing Novel Therapies?

PURPOSE OF REVIEW: We will review the reasons that explain the poor accrual of elderly patients to clinical trials, then we will discuss the relevance of an age threshold for holding off on testing novel therapies. RECENT FINDINGS: Little progress has been made in enrolling elderly patients in clinical trials. Reasons to hold off on testing novel therapies in elderly patients are mainly explained by exclusion criteria and industrials' reluctance to include elderly patients for fear of negative results. No age threshold should exist for testing novel therapies as long as well-designed clinical trials are developed and requested by regulatory authorities. Furthermore, clinical trials assessing novel anticancer therapies such as targeted therapies or immune checkpoint inhibitors should be developed in elderly patients regardless of age as these therapies may present a favorable benefit-risk profile compared to chemotherapy which is often more toxic and at risk of geriatric deconditioning.

Toxicity of Cancer Therapies in Older Patients.

PURPOSE OF THE REVIEW: In clinical practice, older patients are often undertreated due to underrepresentation in clinical trials and fear of toxicity. Our objective was therefore to review toxicities that are specific to older cancer patients, to review risk factors in order to help physicians guide their decisions, and to review interventions that can be implemented in routine clinical practice to prevent toxicity induced by cancer therapies. RECENT FINDINGS: On the whole, reviews report similar number and frequency as well as similar grade 3 or 4 adverse events between subjects older and younger than 65 years. Yet patients included in clinical trials are often not representative of real-life patients and are often fit older cancer patients. Moreover, tolerance to the additive impact of multiple adverse effects is different between older and younger patients. And specific symptoms such as stomatitis may cause a series of consequences such as dehydration, denutrition, renal insufficiency, and adverse events of renally excreted drugs. Older patients are at high risk of toxicity due to many factors but mainly due to the prevalence of frailty in this population that has been estimated to be around 40% increasing the risk of chemotherapy intolerance. As a consequence, interventions must be implemented according to altered domains of comprehensive geriatric assessment in order to improve anticancer tolerance. These interventions are reviewed here.

Long-term survival in patients with epithelial ovarian cancer following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).

OBJECTIVE: Despite a high response rate to first-line therapy, prognosis of epithelial ovarian carcinoma (EOC) remains poor. The objective of the present study was to evaluate the frequency of long-term survivors and to identify the prognostic factors associated with long-term survival in a French cohort of 566 patients. METHODS: Patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for EOC in 13 French centers between 1991 and 2010 were included. Long-term survivors were defined as patients who survived more than 5 years after HIPEC and CRS, irrespective of relapse. RESULTS: Seventy-eight long-term survivors were analyzed. The median follow-up was 74 months. Median age at the time of first HIPEC was 55.4 years (range [22.6-77.6]. Seven patients had advanced EOC and 71 patients had recurrent EOC (37 patients had platinum-resistant EOC and 32 had platinum-sensitive disease). More than half of the long-term survivors had high-grade serous ovarian cancer (HGSOC). In univariate analysis, age ≥50 years (p = .004), peritoneal cancer index (PCI) ≤ 8 (p = .049) and CA-125 < 100 (p = .02) were associated with long-term survival. There was a trend towards an association between higher CC-score and long-term survival (p = .057). CONCLUSION: Age ≥50 years, PCI ≤8 and CA125 < 100 were associated with long-term survival in univariate analysis. There was a trend towards the significance of CC-score. Platinum-status was not associated with long-term survival.

BRCA1/2 alterations and reversion mutations in the area of PARP inhibitors in high grade ovarian cancer: state of the art and forthcoming challenges.

BRCA1/2 genes are part of homologous recombination (HR) DNA repair pathways in charge of error-free double-strand break (DSB) repair. Loss-of-function mutations of BRCA1/2 genes have been associated for a long time with breast and ovarian cancer hereditary syndrome. Recently, polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) have revolutionized the therapeutic landscape of BRCA1/2-mutated tumors, especially of BRCA1/2 high-grade serous ovarian cancer (HGSC), taking advantage of HR deficiency through the synthetic lethality concept. However, PARPi efficiency differs among patients, and most of them will develop resistance, particularly in the relapse setting. In the current proposal, we aim to review primary and secondary resistance to PARPi in HGSC owing to BRCA1/2 alterations. Of note, as several mechanisms of primary or secondary resistance to PARPi have been described, BRCA1/2 reversion mutations that restore HR pathways are by far the most reported. First, the type and location of the BRCA1/2 primary mutation have been associated with PARPi and platinum-salt sensitivity and impact the probability of the occurrence and the type of secondary reversion mutation. Furthermore, the presence of multiple reversion mutations and the variation of allelic frequency under treatment underline the role of intratumor heterogeneity (ITH) in treatment resistance. Of note, circulating tumor DNA might help us to detect and characterize reversion mutations and ITH to finally refine the treatment strategy. Importantly, forthcoming therapeutic strategies, including combination with antiangiogenics or with targeted therapies, may help us delay and overcome PARPi resistance secondary to BRCA1/2 reversion mutations. Also, progression despite PARPi therapy does not preclude PARPi rechallenge in selected patients.

Association of Personality Traits With the Efficacy of Stress Management Interventions for Medical Students Taking Objective Structured Clinical Examinations.

PURPOSE: Personality traits are associated with psychophysiological stress, but few studies focus on medical students. This study aimed to better understand the association of personality traits with the efficacy of stress management interventions for medical students. METHOD: A randomized controlled trial was conducted with fourth-year students who took the objective structured clinical examination at Bernard University Lyon 1 in December 2021. Students were randomized in cardiac biofeedback, mindfulness, and control groups. Each intervention was implemented for 6 minutes before the examination. Physiological stress levels were collected during the intervention. Psychological stress levels were rated by students at baseline and after the intervention. Personality traits were assessed via the Big-Five Inventory. Interactions between personality traits and the efficacy of the interventions were analyzed using multivariable linear regression models. RESULTS: Four hundred eighty-one students participated. Higher baseline psychological stress levels were associated with higher neuroticism and agreeableness ( ß = 10.27 [95% confidence interval {CI}, 7.40-13.13; P < .001] and ß = 3.42 [95% CI, 0.98-5.85; P = .006], respectively) and lower openness ( ß = -4.95; 95% CI, -7.40 to -2.49; P < .001). As compared with the control intervention, both stress management interventions led to lower levels of psychological ( P < .001 for both) and physiological stress levels (biofeedback: P < .001 and mindfulness: P = .009). Biofeedback efficacy varied by extraversion score for psychological ( ß = -5.66; 95% CI, -10.83 to -0.50; P = .03) and physiological stress reduction ( ß = -0.002; 95% CI, -0.003 to -0.00004; P = .045). Mindfulness efficacy varied by agreeableness score for psychological stress reduction ( ß = -7.87; 95% CI, -13.05 to -2.68; P = .003). CONCLUSIONS: Students with a high score in extraversion may benefit more from biofeedback interventions, while students with high scores in agreeableness may benefit more from mindfulness interventions.

Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial.

This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC.

Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.

PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8+PD-1+ T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.93 (95% CI 0.85-1.00) and iii) high CD8B/FOXP3 and high CD8B/ENTPD1 ratios are significantly associated with positive response to NACT + P, while KDR and VEGFR2 expression are associated with resistance. These results indicate that targeting regulatory T cells and endothelial cells, especially VEGFR2+ endothelial cells, could overcome immune resistance of ovarian cancers.

Heterogeneity and Functions of Tumor-Infiltrating Antibody Secreting Cells: Lessons from Breast, Ovarian, and Other Solid Cancers.

Neglected for a long time in cancer, B cells and ASCs have recently emerged as critical actors in the tumor microenvironment, with important roles in shaping the antitumor immune response. ASCs indeed exert a major influence on tumor growth, patient survival, and response to therapies. The mechanisms underlying their pro- vs. anti-tumor roles are beginning to be elucidated, revealing the contributions of their secreted antibodies as well as of their emerging noncanonical functions. Here, concentrating mostly on ovarian and breast cancers, we summarize the current knowledge on the heterogeneity of tumor-infiltrating ASCs, we discuss their possible local or systemic origin in relation to their immunoglobulin repertoire, and we review the different mechanisms by which antibody (Ab) subclasses and isoforms differentially impact tumor cells and anti-tumor immunity. We also discuss the emerging roles of cytokines and other immune modulators produced by ASCs in cancer. Finally, we propose strategies to manipulate the tumor ASC compartment to improve cancer therapies.

Therapeutic Challenges in Patients with Gynecologic Carcinosarcomas: Analysis of a Multicenter National Cohort Study from the French Prospective TMRG Network.

BACKGROUND: Gynecological carcinosarcomas are rare and aggressive diseases, with a poor prognosis. The rarity of these tumors explains the lack of robust and specific data available in the literature. The objective of this study was to investigate the impact of initial adjuvant treatment and recurrent therapeutic strategies. PATIENTS AND METHODS: A multicentric cohort study within the French national prospective Rare Malignant Gynecological Tumors (TMRG) network was conducted. Data from all included carcinosarcomas diagnosed between 2011 and 2018 were retrospectively collected. RESULTS: 425 cases of uterine and ovarian carcinosarcomas (n = 313 and n = 112, respectively) were collected and analyzed from 12 participating centers. At diagnosis, 140 patients (48%) had a FIGO stage III-IV uterine carcinosarcoma (UCS) and 88 patients (83%) had an advanced ovarian carcinosarcoma (OCS) (FIGO stage ≥ III). Two hundred sixty-seven patients (63%) received adjuvant chemotherapy, most preferably carboplatin-paclitaxel regimen (n = 227, 86%). After a median follow-up of 47.4 months, the median progression-free survival (mPFS) was 15.1 months (95% CI 12.3-20.6) and 14.8 months (95% CI 13.1-17.1) for OCS and UCS, respectively. The median overall survival for OCS and UCS was 37.1 months (95% CI 22.2-49.2) and 30.6 months (95% CI 24.1-40.9), respectively. With adjuvant chemotherapy followed by radiotherapy, mPFS was 41.0 months (95% CI 17.0-NR) and 18.9 months (95% CI 14.0-45.6) for UCS stages I-II and stages III-IV, respectively. In the early stage UCS subgroup (i.e., stage IA, n = 86, 30%), mPFS for patients treated with adjuvant chemotherapy (n = 24) was not reached (95% CI 22.2-NR), while mPFS for untreated patients (n = 62) was 19.9 months (95% IC 13.9-72.9) (HR 0.44 (0.20-0.95) p = 0.03). At the first relapse, median PFS for all patients was 4.2 months (95% CI 3.5-5.3). In the first relapse, mPFS was 6.7 months (95% CI 5.1-8.5) and 2.2 months (95% CI 1.9-2.9) with a combination of chemotherapy or monotherapy, respectively (p < 0.001). CONCLUSIONS: Interestingly, this vast prospective cohort of gynecological carcinosarcoma patients from the French national Rare Malignant Gynecological Tumors network (i) highlights the positive impact of adjuvant CT on survival in all localized stages (including FIGO IA uterine carcinosarcomas), (ii) confirms the importance of platinum-based combination as an option for relapse setting, and (iii) reports median PFS for various therapeutic strategies in the relapse setting.

Genomic Instability Is Defined by Specific Tumor Microenvironment in Ovarian Cancer: A Subgroup Analysis of AGO OVAR 12 Trial.

BACKGROUND: Following disappointing results with PD-1/PD-L1 inhibitors in ovarian cancer, it is essential to explore other immune targets. The aim of this study is to describe the tumor immune microenvironment (TME) according to genomic instability in high grade serous ovarian carcinoma (HGSOC) patients receiving primary debulking surgery followed by carboplatin-paclitaxel chemotherapy +/- nintedanib. METHODS: 103 HGSOC patients' tumor samples from phase III AGO-OVAR-12 were analyzed. A comprehensive analysis of the TME was performed by immunohistochemistry on tissue microarray. Comparative genomic hybridization was carried out to evaluate genomic instability signatures through homologous recombination deficiency (HRD) score, genomic index, and somatic copy number alterations. The relationship between genomic instability and TME was explored. RESULTS: Patients with high intratumoral CD3+ T lymphocytes had longer progression-free survival (32 vs. 19.6 months, p = 0.009) and overall survival (OS) (median not reached). High HLA-E expression on tumor cells was associated with a longer OS (median OS not reached vs. 52.9 months, p = 0.002). HRD profile was associated with high HLA-E expression on tumor cells and an improved OS. In the multivariate analysis, residual tumor, intratumoral CD3, and HLA-E on tumor cells were more predictive than other parameters. CONCLUSIONS: Our results suggest HLA-E/CD94-NKG2A/2C is a potential immune target particularly in the HRD positive ovarian carcinoma subgroup.

Neoadjuvant immune checkpoint inhibitors in cancer, current state of the art.

Immunotherapy has been a revolution in cancer management in the metastatic setting. This has led to a prompt evaluation of such therapies in earlier stages. This article discusses the still limited amount of data finding the rationale to assess such therapy in this setting and reviews preclinical and clinical data available. Overall, neoadjuvant immunotherapy is a promising approach for the treatment of cancers and the rationale supporting its use is strong. Neoadjuvant immunotherapy resulted, in the majority of clinical trials, in improved pathologic complete response rates with a favorable toxicity profile and no delay in surgery. Various regimens were effective: inhibitory immune check-point blockers (IICPB) alone, combination of PD-1 and CTLA-4 inhibitors, combination of chemotherapy (CT) and IICPB, phased CT and IICPB (either IICPB before CT or IICPB after CT). Yet the question whether neoadjuvant immunotherapy will benefit to patients in terms of disease-free and, ultimately, overall survival remains unknown.

Feasibility of a prehabilitation programme dedicated to older patients with cancer before complex medical-surgical procedures: the PROADAPT pilot study protocol.

BACKGROUND: Ageing is associated with an increased prevalence of comorbidities and sarcopenia as well as a decline of functional reserve of multiple organ systems, which may lead, in the context of the disease-related and/or treatment-related stress, to functional deconditioning. The multicomponent 'Prehabilitation & Rehabilitation in Oncogeriatrics: Adaptation to Deconditioning risk and Accompaniment of Patients' Trajectories (PROADAPT)' intervention was developed multiprofessionally to implement prehabilitation in older patients with cancer. METHODS: The PROADAPT pilot study is an interventional, non-comparative, prospective, multicentre study. It will include 122 patients oriented to complex medical-surgical curative procedures (major surgery or radiation therapy with or without chemotherapy). After informed consent, patients will undergo a comprehensive geriatric assessment and will be offered a prehabilitation kit that includes an advice booklet with personalised objectives and respiratory rehabilitation devices. Patients will then be called weekly and monitored for physical and respiratory rehabilitation, preoperative renutrition, motivational counselling and iatrogenic prevention. Six outpatient visits will be planned: at inclusion, a few days before the procedure and at 1, 3, 6 and 12 months after the end of the procedure. The main outcome of the study is the feasibility of the intervention, defined as the ability to perform at least one of the components of the programme. Clinical data collected will include patient-specific and cancer-specific characteristics. ETHICS AND DISSEMINATION: The study protocol was approved by the Ile de France 8 ethics committee on 5 June 2018. The results of the primary and secondary objectives will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03659123. Pre-results of the trial.

Rapalog-Mediated Repression of Tribbles Pseudokinase 3 Regulates Pre-mRNA Splicing.

Rapalogs have become standard-of-care in patients with metastatic breast, kidney, and neuroendocrine cancers. Nevertheless, tumor escape occurs after several months in most patients, highlighting the need to understand mechanisms of resistance. Using a panel of cancer cell lines, we show that rapalogs downregulate the putative protein kinase TRIB3 (tribbles pseudokinase 3). Blood samples of a small cohort of patients with cancer treated with rapalogs confirmed downregulation of TRIB3. Downregulation of TRIB3 was mediated by LRRFIP1 independently of mTOR and disrupted its interaction with the spliceosome, where it participated in rapalog-induced deregulation of RNA splicing. Conversely, overexpression of TRIB3 in a panel of cancer cell lines abolished the cytotoxic effects of rapalogs. These findings identify TRIB3 as a key component of the spliceosome, whose repression contributes significantly to the mechanism of resistance to rapalog therapy. SIGNIFICANCE: Independent of mTOR signaling, rapalogs induce cytoxicity by dysregulating spliceosome function via repression of TRIB3, the loss of which may, in the long term, contribute to therapeutic resistance.

[Current advances in immunotherapy in ovarian cancer]. / Les avancées actuelles de l'immunothérapie dans le cancer de l'ovaire.

Ovarian cancers express highly immunogenic tissue-specific antigens. The resulting immune infiltration is a major prognostic factor. There is therefore a strong biological rationale for the development of immunotherapy in ovarian cancer. However, based on Phase I and II clinical trials data, the efficacy of anti-PD-1 and anti-PD-L1 immune checkpoint inhibitors (ICPIs) remains limited in monotherapy in heavily pre-treated patients. Currently, the identification of predictive biomarkers of response and resistance is one of the major areas of research. Identifying effective combination of anti-PD-1 or anti-PD-L1 with other anticancer agents is another clinical need. Several combinations were evaluated. The association of ICPIs with chemotherapy (anthracyclines or carboplatin+paclitaxel) is disappointing (JAVELIN studies). The association with PARP inhibitors, anti-angiogenic agents and CTLA-4 inhibitors seems promising. Other immune therapies such as cell therapies (adoptive transfer of intra-tumor lymphocytes, CAR T cells or vaccines from dendritic cells) could be the future of immunotherapy in ovarian cancer but only early phase studies clinical data is available at this time.