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International audience; Objective > Despite an increasing number of therapeutic indications, there are no specific recommendations regarding the management of PARP inhibitors other than what is specified in the SmPC of each substance. A Delphi French consensus was conducted to establish practical guidelines to meet the needs identified by healthcare professionals and patients. Method > Following the Delphi method, statements to optimize PARP inhibitor management were drafted by a multidisciplinary Steering Committee made up of 17 experts. These statements were submitted to the independent and anonymous vote of clinicians involved in treating patients on PARP inhibitors. Results > This article presents 52 statements on the following topics: initiation and treatment; management of adverse events (hematological effects, gastrointestinal effects, renal effects, pulmonary effects, cutaneous effects, hypertension, insomnia, fatigue, dizziness); special popu-lations and situations; communication with the patient; adherence. Forty-nine statements obtained voter consensus after 3 voting rounds. A hematologist and a nephrologist supplemented this task by drafting an expert opinion on the risk of occurrence of secondary leukemia and nephrological toxicity. Conclusions > This paper is the first Delphi consensus on the practical management of PARP inhibitors. The pragmatic recommendations resulting from this paper should make it possible to manage the side effects of PARP inhibitors better and thus prevent early treatment discontinua-tion and improve patient adherence by preserving quality of life.

Background Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UT) are aggressive neoplasms. Data linking BAF alterations with tumor microenvironment (TME) and efficacy of immune checkpoint inhibitors (ICI) are contradictory. The TME of SMARCA4-UT and their response to ICI are unknown. Materials and Methods Patients diagnosed with SMARCA4-UT in our institution were included. Immunostainings for tertiary lymphoid structures (TLS), immune cell markers, and checkpoints were assessed. Validation was performed using an independent transcriptome dataset including SMARCA4-UT, non–small cell lung cancers (NSCLC) with/without SMARCA4 mutations, and unclassified thoracic sarcomas (UTS). CXCL9 and PD-L1 expressions were assessed in NSCLC and thoracic fibroblast cell lines, with/without SMARCA4 knockdown, treated with/without interferon gamma. Results Nine patients were identified. All samples but one showed no TLS, consistent with an immune desert TME phenotype. Four patients received ICI as part of their treatment, but the only one who responded, had a tumor with a TLS and immune-rich TME. Unsupervised clustering of the validation cohort using immune cell scores identified 2 clusters associated with cell ontogeny and immunity (cluster 1 enriched for NSCLC independently of SMARCA4 status (n = 9/10; P = .001); cluster 2 enriched for SMARCA4-UT (n = 11/12; P = .005) and UTS (n = 5/5; P = .0005). SMARCA4 loss-of-function experiments revealed interferon-induced upregulation of CXCL9 and PD-L1 expression in the NSCLC cell line with no effect on the thoracic fibroblast cell line. Conclusion SMARCA4-UT mainly have an immune desert TME with limited efficacy to ICI. TME of SMARCA4-driven tumors varies according to the cell of origin questioning the interplay between BAF alterations, cell ontogeny and immunity.

Purpose:In patients with ovarian cancer receiving neoadjuvant chemotherapy, the first-line treatment success will depend on both the tumor-primary chemosensitivity and the completeness of interval debulking surgery (IDS). The modeled CA-125 ELIMination rate constant K (KELIM), calculated with the CA-125 longitudinal kinetics during the first 100 chemotherapy days, is a validated early marker of tumor chemosensitivity. The objective was to investigate the role of the chemosensitivity relative to the success of first-line medical–surgical treatment.Experimental Design:The CA-125 concentrations were prospectively measured in the randomized phase II trial CHIVA (NCT01583322, carboplatin–paclitaxel regimen ± nintedanib, and IDS, n = 188 patients). The KELIM predictive value regarding the tumor response rate, likelihood of complete IDS, risk of subsequent platinum-resistant relapse (PtRR), progression-free survival (PFS), and overall survival (OS) was assessed using univariate and multivariate tests.Results:The data from 134 patients were analyzed. KELIM was an independent and major predictor of subsequent PtRR risk, and of survivals. The final logistic regression model, including KELIM [OR = 0.13; 95% confidence interval (CI), 0.03–0.49] and complete IDS (no vs. yes, OR = 0.30; 95% CI, 0.11–0.76) highlights the preponderant role of chemosensitivity on the success of the first-line treatment. In patients with highly chemosensitive diseases, the patient prognosis was driven more by the chemotherapy-induced antitumor effects than by the surgery.Conclusions:The tumor-primary chemosensitivity, assessed by the modeled CA-125 KELIM calculated during neoadjuvant chemotherapy (http://www.biomarker-kinetics.org/CA-125-neo), may be a major parameter to consider for decision-making regarding IDS attempt, and selecting patients for treatments meant to reverse the primary chemoresistance.See related commentary by May and Oza, p. 4432

A. Completeness of interval debulking surgery (IDS) according to standardized (std) KELIM value. Wilcoxon P < 0.01. B. Logistic regression curve regarding the probability of complete surgery according to continuous std KELIM values.

Supplementary Table 4

Explorative analyses of overall survival according to standardized KELIM terciles (upper vs intermediate + lower) and completeness of interval debulking surgery. Med.: Median; IDS: interval debulking surgery; std: standardized; NR: not reached; 95% CI: 95% confidence interval; P: Log-rank test.

Purpose:This prospective nationwide cohort study aimed to investigate desmoid-type fibromatosis (DF) outcomes, focusing on the prognostic value of CTNNB1 mutations.Experimental Design:ALTITUDES (NCT02867033) was a nationwide prospective cohort study of DF diagnosed between January 2016 and December 2020. At diagnosis, CTNNB1 molecular alterations were identified using next-generation sequencing or Sanger sequencing. The primary endpoint was event-free survival (EFS; progression, relapse, or death). We enrolled 628 patients managed by active surveillance, surgical resection, or systemic treatment as first-line therapy.Results:Overall, 516 (82.2%) patients [368 females (71.3%), median age 40.3 years (range, 1–89)] were eligible for analysis. In 435 (84.3%) cases, there was one CTNNB1 molecular alteration: p.T41A, p.S45F, or p.S45P. The first-line management was active surveillance in 352 (68.2%), surgical resection in 120 (23.3%), and systemic treatments in 44 (8.5%) patients. CTNNB1 mutation distribution was similar across the three therapeutic groups. The median follow-up period was 24.7 (range, 0.4–59.7) months. The estimated 3-year EFS rate was 66.2% [95% confidence interval (CI), 60.5%–71.2%]. DF harboring p.S45F was significantly associated with male sex (P = 0.03), non-abdominal wall sites (P = 0.05), pain (P = 0.007), and large tumor size (P = 0.025). CTNNB1 p.S45F mutation was not significantly associated with EFS, either in univariate (HR, 1.06; 95% CI, 0.65–1.73; P = 0.81) or in multivariate analysis (HR, 0.91; 95% CI, 0.55–1.49; P = 0.71).Conclusions:We found that CTNNB1 mutation profile was associated with unfavorable prognostic factors but was not a prognostic factor for EFS.See related commentary by Greene and Van Tine, p. 3911

Flowchart of the study. IDS: Interval debulking surgery; PFS: progression-free survival; OS: overall survival.

Explorative analyses of progression-free survival according to standardized KELIM terciles (upper vs intermediate + lower) and completeness of interval debulking surgery. Med.: Median; std: standardized; IDS: interval debulking surgery; NR: not reached; 95% CI: 95% confidence interval; P: Log-rank test.

Supplementary Table 5

Suppl Table 3

Goodness-of-fit plots. Predicted versus observed CA-125 concentrations are shown for the population (left panel) and for individuals (right panel). Black line: identity line.

Supplementary Data from Lack of Prognostic Value of CTNNB1 Mutation Profile in Desmoid-Type Fibromatosis

Receiver Operating Characteristics curve regarding Complete interval debulking surgery (Yes vs No) according to KELIM. Selection of the best predictive KELIM cut-off using Youden index.

Supplementary Figure from Lack of Prognostic Value of CTNNB1 Mutation Profile in Desmoid-Type Fibromatosis

Explorative analyses of overall survival according to standardized KELIM terciles (upper vs intermediate + lower) and disease risk-group adjusted from Oza et al. Med.: Median; std: standardized; NR: not reached; 95% CI: 95% confidence interval; P: Log-rank test.

Explorative analyses of progression-free survival according to standardized KELIM terciles (upper vs intermediate + lower) and disease-risk groups, adjusted from Oza et al. Med.: Median; std: standardized; NR: not reached; 95% CI: 95% confidence interval; P: Log-rank test.

Supplementary Table 1

Supplementary Table 2

Visual predictive checks. Purple areas represent the 95% confidence intervals of the 10th, 50th, and 90th percentiles of simulated data. Red lines represent the median (solid line), and the 10th and 90th percentiles (dashed lines) of the observations.

Contains fulltext : 283536.pdf (Publisher’s version ) (Closed access) The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.

PURPOSE To compare standard versus extended duration of bevacizumab treatment in combination with front-line chemotherapy in women with newly diagnosed stage IIB-IV ovarian cancer. METHODS In this multicenter, open-label, randomized phase III trial (ClinicalTrials.gov identifier: NCT01462890 ), patients with newly diagnosed International Federation of Gynecology and Obstetrics stage IIB-IV epithelial ovarian, fallopian tube, or peritoneal cancer underwent primary cytoreductive surgery followed by six cycles of chemotherapy (paclitaxel 175 mg/m2 plus carboplatin area under the curve 5 once every 3 weeks) and bevacizumab (15 mg/kg once every 3 weeks). Patients were randomly assigned 1:1 to receive bevacizumab for either 15 or 30 months, stratified by International Federation of Gynecology and Obstetrics stage/residual tumor. The primary end point was investigator-assessed progression-free survival (PFS) according to RECIST version 1.1. Secondary end points included overall survival (OS), safety, and tolerability. RESULTS Between November 11, 2011, and August 6, 2013, 927 women were randomly assigned. There was no difference in PFS between treatment arms (hazard ratio, 0.99; 95% CI, 0.85 to 1.15; unstratified log-rank P = .90). Median PFS was 24.2 versus 26.0 months with standard versus extended duration of bevacizumab, respectively; restricted mean PFS was 39.5 versus 39.3 months, respectively. There was no OS difference between treatment arms (hazard ratio, 1.04; 95% CI, 0.87 to 1.23; P = .68). Serious/nonserious adverse events of special interest occurred in 29% versus 34% of patients in the standard versus experimental arms, respectively, and were consistent with the known safety profile of standard bevacizumab. CONCLUSION Longer treatment duration with bevacizumab for up to 30 months did not improve PFS or OS in patients with primary epithelial ovarian, fallopian tube, or peritoneal cancer. A bevacizumab treatment duration of 15 months remains the standard of care.

International audience; The aim of this study is to evaluate the prevalence, determinants and prognostic value of pain at diagnosis in patients with desmoid-type fibromatosis (DF). We selected patients from the ALTITUDES cohort (NCT02867033), managed by surgery, active surveillance or systemic treatments, with pain assessment at diagnosis. Patients were invited to fill QLQ-C30 questionnaire and Hospital Anxiety Depression Scale. Determinants were identified using logistic models. Prognostic value on event-free survival (EFS) was evaluated using the Cox model. Overall, 382 patients were included in the current study (median age: 40.2 years; 117 men). The prevalence of pain was 36%, without significant difference according to first-line treatment (P =.18). In the multivariate analysis, pain was significantly associated with tumor size >50 mm (P =.013) and tumor site (P

Purpose: This prospective nationwide cohort study aimed to investigate desmoid-type fibromatosis (DF) outcomes, focusing on the prognostic value of CTNNB1 mutations. Experimental Design: ALTITUDES (NCT02867033) was a nationwide prospective cohort study of DF diagnosed between January 2016 and December 2020. At diagnosis, CTNNB1 molecular alterations were identified using next-generation sequencing or Sanger sequencing. The primary endpoint was event-free survival (EFS; progression, relapse, or death). We enrolled 628 patients managed by active surveillance, surgical resection, or systemic treatment as first-line therapy. Results: Overall, 516 (82.2%) patients [368 females (71.3%), median age 40.3 years (range, 1–89)] were eligible for analysis. In 435 (84.3%) cases, there was one CTNNB1 molecular alteration: p.T41A, p.S45F, or p.S45P. The first-line management was active surveillance in 352 (68.2%), surgical resection in 120 (23.3%), and systemic treatments in 44 (8.5%) patients. CTNNB1 mutation distribution was similar across the three therapeutic groups. The median follow-up period was 24.7 (range, 0.4–59.7) months. The estimated 3-year EFS rate was 66.2% [95% confidence interval (CI), 60.5%–71.2%]. DF harboring p.S45F was significantly associated with male sex (P = 0.03), non-abdominal wall sites (P = 0.05), pain (P = 0.007), and large tumor size (P = 0.025). CTNNB1 p.S45F mutation was not significantly associated with EFS, either in univariate (HR, 1.06; 95% CI, 0.65–1.73; P = 0.81) or in multivariate analysis (HR, 0.91; 95% CI, 0.55–1.49; P = 0.71). Conclusions: We found that CTNNB1 mutation profile was associated with unfavorable prognostic factors but was not a prognostic factor for EFS. See related commentary by Greene and Van Tine, p. 3911

We describe a large series of patients with solid tumors in an early COVID‐19 cluster in the eastern part of France. From February to May 2020, this multicenter retrospective study enrolled 212 patients with cancer under treatment or on follow‐up for any type of malignant solid tumor and positive for SARS‐CoV‐2. The mortality rate was 30%. Patients with gastrointestinal cancers were identified as a subset of more vulnerable patients; immunotherapy and radiotherapy within 3 months from COVID‐19 diagnosis were risk factors for death. The reported data support the essential need to be proactive and weigh the risks of morbidity from COVID‐19 against the magnitude of benefits of intended cancer therapies during this pandemic. Implications for Practice This article supports the essential need to be proactive (treatment delay or modification) in oncology in the setting of pandemic. This study identified patients with gastrointestinal cancers as a more vulnerable subset of patients with cancer and found that immunotherapy and radiotherapy within 3 months from COVID‐19 diagnosis to be risk factors for death. The reported data indicate the necessity of weighing the risks of morbidity from COVID‐19 against the magnitude of benefits of intended cancer therapies in any future wave of COVID‐19., In the light of a local experience in an area of France, this article describes disease characteristics, management, and outcomes in patients with cancer and confirmed or highly suspected COVID‐19.

Recently, ovarian cancer research has evolved considerably because of the emerging recognition that rather than a single disease, ovarian carcinomas comprise several different histotypes that vary by etiologic origin, risk factors, molecular profiles, therapeutic approaches and clinical outcome. Despite significant progress in our understanding of the etiologic heterogeneity of ovarian cancer, as well as important clinical advances, it remains the eighth most frequently diagnosed cancer in women worldwide and the most fatal gynecologic cancer. The International Agency for Research on Cancer and the United States National Cancer Institute jointly convened an expert panel on ovarian carcinoma to develop consensus research priorities based on evolving scientific discoveries. Expertise ranged from etiology, prevention, early detection, pathology, model systems, molecular characterization and treatment/clinical management. This report summarizes the current state of knowledge and highlights expert consensus on future directions to continue advancing etiologic, epidemiologic and prognostic research on ovarian carcinoma.

To assess efficacy and safety of percutaneous cryoablation (CA) for advanced and refractory extra-abdominal desmoid tumors. This retrospective study reviewed 30 consecutive patients with symptomatic desmoid tumors evolving after “wait and watch” periods, and despite medical treatment, treated by CA between 2007 and 2019. Progression free survival (PFS), objective response rate, pain reduction (decreased of visual analogic scale pain (VAS) $$\ge$$ 3 or disappearance of pain), total volume lesion (TVL) and complications were documented. Kaplan Meier method was used to outline PFS. Paired sample t test was used to compare volume of tumors before treatment and at 1 and 3 year. With a median follow-up of 18.5 months (range 6–93 months, interquartile range (IQR): 12–55), the PFS was 85.1% at 1 year and 77.3% at 3 years. Objective response was obtained for 80% of patients with a complete response for 43% patients. Pain reduction was obtained for 96.7% (95% confidence interval (95% CI): 90.3, 100) of patients. Median volume of desmoid tumor before treatment was 124.1cm3 (range 2–1727cm3, IQR: 54–338cm3). Median change of TLV after ablation was 66.6% (95% CI: 37.2, 72.3; p = 0.002) at 1 year and 76.4% (95% CI: 59.1, 89.8; p = 0.002) at 3 year. Adverse events rate was 36.6%, the most common was edema and temporary increase of pain in the days following CA. Four patients experienced a major complication (13.3%): 2 skin necrosis, 1 infection and 1 brachial plexopathy. CA is an effective treatment for advanced and refractory extra-abdominal desmoid tumor, that induces durable responses.

BACKGROUND According to guidelines, all sarcoma patients must be managed from initial diagnosis at expert sarcoma centers. However, in everyday practice, the time interval to an expert center visit can be long, which delays presentation to an expert multidisciplinary tumor board (MTB) and increases the risk of inappropriate management, negatively affecting local tumor control and prognosis. The advent of mobile health (mHealth) offers an easy way to facilitate communication and cooperation between general health care providers (e.g., general practitioners and radiologists) and sarcomas experts. We developed a mobile application (Sar’Connect) based on the algorithm designed by radiologists from French Sarcoma Group. Through a small number of easy-to-answer questions, Sar’Connect provides personalized advice for management of patients and contact information on the closest expert center. OBJECTIVE This retrospective study is the first to assess this mobile application’s benefits in reducing the time interval for patient referral to an expert center according to the initial clinical characteristics of the soft tissue tumor. METHODS We extracted tumor mass data for 78 patients discussed by MTBs of three centers of French Sarcoma Group. We applied the Sar’Connect algorithm to these data and estimated the time interval to expert center referral; then, we compared this estimated time interval with the observed time interval. RESULTS We found that the use of Sar’Connect shortened the time interval to a referral center by approximately 7.5 months. Moreover, for half of patients with a malignant soft tissue tumor, Sar’Connect avoided inappropriate management outside of the reference center. We did not identify a significant determinant for shortening the time interval for referral. CONCLUSIONS Overall, promoting the use of a simple mobile application is an innovative and straightforward means to accelerating both the referral and management of soft tissue sarcoma patients in expert centers.

Background. The initial management of patients with sarcoma is critical. We used the French National Cancer Institute-funded nationwide sarcoma database NETSARC to report the management and oncologic outcomes in children, adolescents and young adults (AYAs) patients with sarcoma at the national level. Patients and methods. Data from patients with sarcoma are collected, regularly monitored and updated using NETSARC. NETSARC was searched for pediatric (Results. We collected data from 3,972 pediatric and AYA patients with sarcoma diagnosed between 2010 and 2017, including 714 children, 1,290 AYAs treated in RSC, and 937 AYAs in non-RSC. Significant differences in compliance to guidelines were observed regarding pre-treatment biopsy (Children: 83.5%; AYA in RSC: 85.9%; AYA in non-RSC 48.1%), pre-treatment imaging (Children: 81.2%; AYA in RSC: 86.8%; AYA in non-RSC: 56.5%) and R0 margins (Children: 52%; AYA in RSC 57.6%; AYA in non-RSC: 20.2%) (pConclusions. This study highlights the importance for AYA patients with sarcoma to be managed in national sarcoma reference centers involving multidisciplinary medical teams with paediatric and adult oncologists.

Purpose: In patients with ovarian cancer receiving neoadjuvant chemotherapy, the first-line treatment success will depend on both the tumor-primary chemosensitivity and the completeness of interval debulking surgery (IDS). The modeled CA-125 ELIMination rate constant K (KELIM), calculated with the CA-125 longitudinal kinetics during the first 100 chemotherapy days, is a validated early marker of tumor chemosensitivity. The objective was to investigate the role of the chemosensitivity relative to the success of first-line medical–surgical treatment. Experimental Design: The CA-125 concentrations were prospectively measured in the randomized phase II trial CHIVA (NCT01583322, carboplatin–paclitaxel regimen ± nintedanib, and IDS, n = 188 patients). The KELIM predictive value regarding the tumor response rate, likelihood of complete IDS, risk of subsequent platinum-resistant relapse (PtRR), progression-free survival (PFS), and overall survival (OS) was assessed using univariate and multivariate tests. Results: The data from 134 patients were analyzed. KELIM was an independent and major predictor of subsequent PtRR risk, and of survivals. The final logistic regression model, including KELIM [OR = 0.13; 95% confidence interval (CI), 0.03–0.49] and complete IDS (no vs. yes, OR = 0.30; 95% CI, 0.11–0.76) highlights the preponderant role of chemosensitivity on the success of the first-line treatment. In patients with highly chemosensitive diseases, the patient prognosis was driven more by the chemotherapy-induced antitumor effects than by the surgery. Conclusions: The tumor-primary chemosensitivity, assessed by the modeled CA-125 KELIM calculated during neoadjuvant chemotherapy (http://www.biomarker-kinetics.org/CA-125-neo), may be a major parameter to consider for decision-making regarding IDS attempt, and selecting patients for treatments meant to reverse the primary chemoresistance. See related commentary by May and Oza, p. 4432

Several interventional treatments have recently been integrated into the therapeutic armamentarium available for the treatment of bone tumors. In some scenarios (e.g., osteoid osteoma), interventional treatments represent the sole and definitive applied treatment. Due to the absence of widely shared protocols and the complex multivariate scenarios underlying the clinical presentation of the remaining bone tumors including metastases, therapeutic strategies derived from a multidisciplinary tumor board are essential to provide effective treatments tailored to each patient. In the present review, we present the multidisciplinary therapeutic strategies commonly adopted for the most frequent bone tumors.

Locoregional therapy for advanced or recurrent desmoid tumor is part of our therapeutic armamentarium. Radiation therapy at a dose of 56Gy is feasible and has led to favorable results despite limited prospective data available. Cryoablation is a novel, very promising technique that may be applied in the same clinical picture of advanced, progressing or recurrent disease, in the hands of trained teams. All these options have to be discussed in sarcoma tumor boards due to the rarity of the disease and the expertise needed.

Cutaneous angiosarcoma is a rare type of tumor that represents approximately 2% of all soft tissue sarcoma [1]. This tumor grows mainly on the scalp or the face of elderly males [2]. The prognosis is very poor with a 5-year survival rate from 12% to 31% and a median overall survival (OS) about 15 months [3], [4]. The optimal treatment is considered to be surgery with wide excision margin followed by adjuvant radiotherapy. Chemotherapy is usually used for metastatic disease. We want to present a successful strategy of treatment with chemotherapy and radiation therapy.

Despite an increasing number of therapeutic indications, there are no specific recommendations regarding the management of PARP inhibitors other than what is specified in the SmPC of each substance. A Delphi French consensus was conducted to establish practical guidelines to meet the needs identified by healthcare professionals and patients.Following the Delphi method, statements to optimize PARP inhibitor management were drafted by a multidisciplinary Steering Committee made up of 17 experts. These statements were submitted to the independent and anonymous vote of clinicians involved in treating patients on PARP inhibitors.This article presents 52 statements on the following topics: initiation and treatment; management of adverse events (hematological effects, gastrointestinal effects, renal effects, pulmonary effects, cutaneous effects, hypertension, insomnia, fatigue, dizziness); special populations and situations; communication with the patient; adherence. Forty-nine statements obtained voter consensus after 3 voting rounds. A hematologist and a nephrologist supplemented this task by drafting an expert opinion on the risk of occurrence of secondary leukemia and nephrological toxicity.This paper is the first Delphi consensus on the practical management of PARP inhibitors. The pragmatic recommendations resulting from this paper should make it possible to manage the side effects of PARP inhibitors better and thus prevent early treatment discontinuation and improve patient adherence by preserving quality of life.

Anti-angiogenic rechallenge with bevacizumab plus chemotherapy is effective in recurrent ovarian cancer (rOC); however, data are limited on tyrosine kinase inhibitors after progression on maintenance bevacizumab.In the randomized phase II TAPAZ trial, patients with rOC during the first year of bevacizumab maintenance therapy were assigned 2:1 to either weekly paclitaxel 65 mg/mOverall, 116 patients were randomized and treated: 79 with combination therapy and 37 with single-agent paclitaxel. Median follow-up was 13.1 months. There was no difference between treatment arms in 4-month PFS rate (61% [95% CI, 51-73%] with the combination versus 68% [95% CI, 54-85%] with paclitaxel alone), median PFS (4.9 [95% CI, 4.1-6.1] versus 5.8 [95% CI, 4.8-7.4] months, respectively) or median overall survival (13.6 versus 12.9 months, respectively). The combination was associated with more grade 3/4 toxicities (87% versus 70%, respectively) and toxicity-related paclitaxel discontinuations (22% versus 11%). Pazopanib was discontinued for toxicity in 44% of patients, most commonly for gastrointestinal and vascular events. There were two treatment-related deaths, both in the combination arm (pulmonary embolism and gastrointestinal perforation). At month 4, patient-reported outcomes deteriorated from baseline in the combination arm, particularly for abdominal/gastrointestinal symptoms, which showed a clinically important difference versus paclitaxel alone.In rOC progressing during maintenance bevacizumab, adding pazopanib to paclitaxel did not improve efficacy, increased toxicity, and compromised chemotherapy delivery.govregistration:NCT02383251.

MBD4 mutations have been reported in uveal melanomas, acute myeloid leukemias, colorectal adenocarcinomas, gliomas, and spiradenocarcinomas and cause a hypermutated phenotype. Although metastatic uveal melanomas (mUM) are usually resistant to immune checkpoint inhibitors (ICI), the first reported MBD4-mutated (MBD4m) patient responded to ICI, suggesting that MBD4 mutation may predict response to ICI.Retrospective cohort of mUM patients treated with ICI. MBD4 was sequenced in a subset of these patients.Three hundred mUM patients were included. Median follow-up was 17.3 months. Ten patients with an objective response and 20 cases with stable disease forgt;12 months were observed, corresponding to an objective response rate of 3.3% and a clinical benefit (i.e., responder patients and stable disease) rate of 10%. Of the 131 tumors sequenced for MBD4, five (3.8%) were mutated. MBD4 mutation was associated with a better objective response rate as three out of five MBD4m versus 4% of MBD4 wild-type patients responded (p lt; 0.001). Of these five responders, three presented progressive disease at 2.8, 13.9, and 22.3 months. Median PFS was 4.0 months in MBD4 wild-type and 22.3 months in MBD4m patients (HR = 0.22; p = 0.01). Median OS in MBD4def patients was unreached as compared to 16.6 months in MBD4pro (HR = 0.11; 95% CI: 0.02-0.86; log-rank p-test = 0.04; Fig. 2e).In mUM patients, MBD4 mutation is highly predictive for the response, PFS, and overall survival benefit to ICI. MBD4 could be a tissue-agnostic biomarker and should be sequenced in mUM, and other tumor types where MBD4 mutations are reported.

Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into three RMC cell states along an epithelial-mesenchymal gradient by loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic cell death. Ferroptosis resistance links TAL cell survival with the high extracellular medullar iron concentrations associated with sickle cell trait, an environment propitious to the mutagenic events associated with RMC development. This unique environment may explain why RMC is the only SMARCB1-deficient tumour arising from epithelial cells, differentiating RMC from rhabdoid tumours arising from neural crest cells.