Bevacizumab, olaparib, and durvalumab in patients with relapsed ovarian cancer: a phase II clinical trial from the GINECO group.

Most patients with advanced ovarian cancer (AOC) ultimately relapse after platinum-based chemotherapy. Combining bevacizumab, olaparib, and durvalumab likely drives synergistic activity. This open-label phase 2 study (NCT04015739) aimed to assess activity and safety of this triple combination in female patients with relapsed high-grade AOC following prior platinum-based therapy. Patients were treated with olaparib (300 mg orally, twice daily), the bevacizumab biosimilar FKB238 (15 mg/kg intravenously, once-every-3-weeks), and durvalumab (1.12 g intravenously, once-every-3-weeks) in nine French centers. The primary endpoint was the non-progression rate at 3 months for platinum-resistant relapse or 6 months for platinum-sensitive relapse per RECIST 1.1 and irRECIST. Secondary endpoints were CA-125 decline with CA-125 ELIMination rate constant K (KELIM-B) per CA-125 longitudinal kinetics over 100 days, progression free survival and overall survival, tumor response, and safety. Non-progression rates were 69.8% (90%CI 55.9%-80.0%) at 3 months for platinum-resistant relapse patients (N = 41), meeting the prespecified endpoint, and 43.8% (90%CI 29.0%-57.4%) at 6 months for platinum-sensitive relapse (N = 33), not meeting the prespecified endpoint. Median progression-free survival was 4.1 months (95%CI 3.5-5.9) and 4.9 months (95%CI 2.9-7.0) respectively. Favorable KELIM-B was associated with better survival. No toxic deaths or major safety signals were observed. Here we show that further investigation of this triple combination may be considered in AOC patients with platinum-resistant relapse.

Added value of whole-exome and RNA sequencing in advanced and refractory cancer patients with no molecular-based treatment recommendation based on a 90-gene panel.

INTRODUCTION: The objective was to determine the added value of comprehensive molecular profile by whole-exome and RNA sequencing (WES/RNA-Seq) in advanced and refractory cancer patients who had no molecular-based treatment recommendation (MBTR) based on a more limited targeted gene panel (TGP) plus array-based comparative genomic hybridization (aCGH). MATERIALS AND METHODS: In this retrospective analysis, we selected 50 patients previously included in the PROFILER trial (NCT01774409) for which no MBT could be recommended based on a targeted 90-gene panel and aCGH. For each patient, the frozen tumor sample mirroring the FFPE sample used for TGP/aCGH analysis were processed for WES and RNA-Seq. Data from TGP/aCGH were reanalyzed, and together with WES/RNA-Seq, findings were simultaneously discussed at a new molecular tumor board (MTB). RESULTS: After exclusion of variants of unknown significance, a total of 167 somatic molecular alterations were identified in 50 patients (median: 3 [1-10]). Out of these 167 relevant molecular alterations, 51 (31%) were common to both TGP/aCGH and WES/RNA-Seq, 19 (11%) were identified by the TGP/aCGH only and 97 (58%) were identified by WES/RNA-Seq only, including two fusion transcripts in two patients. A MBTR was provided in 4/50 (8%) patients using the information from TGP/aCGH versus 9/50 (18%) patients using WES/RNA-Seq findings. Three patients had similar recommendations based on TGP/aCGH and WES/RNA-Seq. CONCLUSIONS: In advanced and refractory cancer patients in whom no MBTR was recommended from TGP/aCGH, WES/RNA-Seq allowed to identify more alterations which may in turn, in a limited fraction of patients, lead to new MBTR.

MDR1-EXPRESSING CD4+ T CELLS WITH TH1.17 FEATURES RESIST TO NEOADJUVANT CHEMOTHERAPY AND ARE ASSOCIATED WITH BREAST CANCER CLINICAL RESPONSE.

BACKGROUND: Multidrug resistance-1 (MDR1) transporter limits the intracellular accumulation of chemotherapies (paclitaxel, anthracyclines) used in breast cancer (BC) treatment. In addition to tumor cells, MDR1 is expressed on immune cell subsets in which it confers chemoresistance. Among human T cells, MDR1 is expressed by most CD8+ T cells, and a subset of CD4+ T helper (Th) cells. Here we explored the expression, function and regulation of MDR1 on CD4+ T cells and investigated the role of this population in response to neoadjuvant chemotherapy (NAC) in BC. METHODS: Phenotypic and functional characteristics of MDR1+ CD4 Th cells were assessed on blood from healthy donors and patients with BC by flow cytometry. These features were extended to CD4+ Th cells from untreated breast tumor by flow cytometry and RNA-sequencing (RNA-seq). We performed in vitro polarization assays to decipher MDR1 regulation on CD4 Th cells. We evaluated in vitro the impact of chemotherapy agents on MDR1+ CD4+ Th cells. We analyzed the impact of NAC treatment on MDR1+ CD4+ Th cells from blood and tumors and their association with treatment efficacy in two independent BC cohorts and in a public RNA-seq data set of BC tumor biopsies before and after NAC. Finally, we performed single cell (sc) RNAseq of blood CD4+ memory T cells from NAC-treated patients and combined them with an scRNAseq public data set. RESULTS: MDR1+ CD4 Th cells were strongly enriched in Th1.17 polyfunctional cells but also in Th17 cells, both in blood and untreated breast tumor tissues. Mechanistically, Tumor growth factor (TGF)-ß1 was required for MDR1 induction during in vitro Th17 or Th1.17 polarization. MDR1 expression conferred a selective advantage to Th1.17 and Th17 cells following paclitaxel treatment in vitro and in vivo in NAC-treated patients. scRNAseq demonstrated MDR1 association with tumor Th1.17 and Th with features of cytotoxic cells. Enrichment in MDR1+ CD4+ Th1.17 and Th17 cells, in blood and tumors positively correlated with pathological response. Absence of early modulation of Th1.17 and Th17 in NAC-resistant patients, argue for its use as a biomarker for chemotherapy regimen adjustment. CONCLUSION: MDR1 favored the enrichment of Th1.17 and Th17 in blood and tumor after NAC that correlated to clinical response.

Chemotherapy-Related Amenorrhea and Quality of Life Among Premenopausal Women With Breast Cancer.

Importance: Younger survivors of breast cancer frequently report more treatment-related symptoms, mostly related to the menopausal transition. Objective: To assess factors associated with chemotherapy-related amenorrhea (CRA) and to evaluate its association with long-term quality of life (QOL). Design, Setting, and Participants: The prospective, longitudinal Cancer Toxicities Study, a multicenter French cohort study, includes women with a diagnosis of stage I to III breast cancer and collects data approximately yearly after diagnosis. The current study reports outcomes up to 4 years after diagnosis for participants enrolled from 2012 to 2017. Participants included premenopausal women younger than 50 years treated with chemotherapy and not receiving adjuvant ovarian function suppression. Data analysis was performed from September 2021 to June 2023. Exposures: Clinical, socioeconomic, tumor, and treatment characteristics assessed at diagnosis (for the analysis of factors associated with CRA) and persistent CRA (for the QOL analysis). Main Outcomes and Measures: The main outcome of interest was CRA at year 1 (Y1), year 2 (Y2), and year 4 (Y4) after diagnosis. Generalized estimating equations assessed associations of exposure variables with CRA. In the QOL analysis, QOL at Y4 (assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 and BR23) was the outcome of interest. Multivariable random-effect mixed models assessed the association of persistent CRA (ie, never recovering menses after treatment) with QOL. Results: Among 1636 women, the mean (SD) age at diagnosis was 42.2 (5.6) years. Overall, 1242 of 1497 women (83.0%) reported CRA at Y1, 959 of 1323 women (72.5%) reported it at Y2, and 599 of 906 women (66.1%) reported it at Y4. Older age vs 18 to 34 years (adjusted odds ratio [OR] for 35 to 39 years, 1.84 [95% CI, 1.32 to 2.56]; adjusted OR for 40 to 44 years, 5.90 [95% CI, 4.23 to 8.24]; and adjusted OR for ≥45 years, 21.29 [95% CI, 14.34 to 31.61]) and receipt of adjuvant tamoxifen (adjusted OR, 1.97 [95% CI, 1.53 to 2.53]) were associated with higher likelihood of CRA. In the QOL analysis, 416 of 729 women (57.1%) had persistent CRA. However, late menses recovery among women aged 18 to 34 years with no menses at Y2 were reported by 11 of 21 women (52.4%) between Y2 and Y4. Persistent CRA was associated with worse insomnia (mean difference vs recovery at any time, 9.9 points [95% CI, 3.2 to 16.5 points]; P = .004), systemic therapy-related adverse effects (mean difference, 3.0 points [95% CI, 0.2 to 5.8 points]; P = .04), and sexual functioning (mean difference, -9.2 points [95% CI, -14.3 to -4.1 points]; P < .001) at Y4. Conclusions and Relevance: In this cohort study of premenopausal women with breast cancer, persistent CRA was common, although some women recovered menses late, and was associated with worse long-term QOL. This study can help inform risk communication, personalized counseling, and early supportive care referrals for such patients.

Sustainable return to work among breast cancer survivors.

PURPOSE: This study assessed sustainable return to work (SRTW) of breast cancer survivors (BCS). METHODS: We used data from the prospective French cohort, CANTO. We included 1811 stage I-III BCS who were <57 years old and employed at the moment of diagnosis and working 2 years after diagnosis. Using logistic regression, we investigated the role of clinical, health and socio-economic factors, and the work environment on SRTW 3 years after diagnosis. We compared having any sick leave with having worked continuously and being unemployed to having worked continuously between 2 and 3 years after diagnosis. RESULTS: Overall, 77% (n = 1395) worked continuously after return to work (RTW). Out of the other 416 BCS, 66% had any sick leave period, 33% had been unemployed, 4% had an early retirement, 2% a disability and 1% another status (multiple situations possible). Being on sick leave was associated with age > 50 (OR = 0.59; 95%CI = 0.43-0.82), stage III (2.56; 1.70-3.85), tumour subtype HR+/HER2+ (0.61; 0.39-0.95), severe fatigue (1.45; 1.06-1.98), workplace accommodations (1.63; 1.14-2.33) and life priorities (0.71; 0.53-0.95). Unemployment was associated with age > 50 (0.45; 0.29-0.72), working in the public sector (0.31; 0.19-0.51), for a small company (3.00; 1.74-5.20) and having a fixed-term contract (7.50; 4.74-11.86). CONCLUSIONS: A high number of BCS have periods of sick leave or unemployment after RTW. The determinants differ between sick leave and unemployment. IMPLICATIONS FOR CANCER SURVIVORS: BCS need to be supported even after RTW, which should be regarded as a process.

Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Sacituzumab govitecan demonstrated significant progression-free survival benefit over chemotherapy in the phase 3 TROPiCS-02 trial in patients with pretreated, endocrine-resistant hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ and HER2-) metastatic breast cancer with limited treatment options. Here, we report the protocol-specified final analysis of overall survival and endpoints by trophoblast cell-surface antigen 2 (Trop-2) expression and other variables. METHODS: In this randomised, open-label, multicentre, phase 3 trial, which took place in 91 centres across North America (the USA and Canada) and Europe (Belgium, France, Germany, Italy, the Netherlands, Spain, and the UK), patients were randomly assigned (1:1) to receive sacituzumab govitecan or chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine). Patients had confirmed HR+ and HER2- locally recurrent inoperable or metastatic breast cancer and had received at least one previous endocrine therapy, a taxane, and a CDK4/6 inhibitor in any setting and two to four previous chemotherapy regimens for metastatic disease. The primary endpoint was progression-free survival (previously reported and not included in this analysis), and secondary endpoints included overall survival, objective response rate (ORR), and patient-reported outcomes. Overall survival was assessed using stratified log-rank tests and Cox regression. Trop-2 expression was assessed in tumour tissue by immunohistochemistry. In the statistical testing hierarchy, ORR and patient-reported outcomes were tested sequentially if overall survival was significant. This study is registered with ClinicalTrials.gov, NCT03901339. FINDINGS: At the data cutoff date of July 1, 2022, 543 of 776 screened patients were randomly assigned between May 30, 2019, and April 5, 2021, with 272 patients in the sacituzumab govitecan group and 271 patients in the chemotherapy group. With a 12·5-month (IQR 6·4-18·8) median follow-up, 390 deaths occurred among 543 patients. Overall survival was significantly improved with sacituzumab govitecan versus chemotherapy (median 14·4 months [95% CI 13·0-15·7] vs 11·2 months [10·1-12·7]; hazard ratio [HR] 0·79, 95% CI 0·65-0·96; p=0·020); survival benefit was consistent across Trop-2 expression-level subgroups. ORR was significantly improved with sacituzumab govitecan compared with chemotherapy (57 [21%] patients vs 38 [14%]; odds ratio 1·63 [95% CI 1·03-2·56]; p=0·035), as was time to deterioration of global health status and quality of life (median 4·3 months vs 3·0 months; HR 0·75 [0·61-0·92]; p=0·0059) and fatigue (median 2·2 months vs 1·4 months; HR 0·73 [0·60-0·89]; p=0·0021). The safety profile of sacituzumab govitecan was consistent with previous studies (including the TROPiCS-02 primary analysis and the ASCENT trial). One fatal adverse event (septic shock caused by neutropenic colitis) was determined to be related to sacituzumab govitecan treatment. INTERPRETATION: Sacituzumab govitecan demonstrated statistically significant and clinically meaningful benefit over chemotherapy, with a 3·2-month median overall survival improvement and a manageable safety profile. These data support sacituzumab govitecan as a new treatment option for patients with pretreated, endocrine-resistant HR+ and HER2- metastatic breast cancer. FUNDING: Gilead Sciences.

PRMT5 triggers glucocorticoid-induced cell migration in triple-negative breast cancer.

Triple-negative breast cancers (TNBCs) are the most aggressive breast cancers, and therapeutic options mainly rely on chemotherapy and immunotherapy. Although synthetic glucocorticoids (GCs) are given to alleviate the side effects of these treatments, GCs and their receptor, the glucocorticoid receptor (GR), were recently associated with detrimental effects, albeit the mechanisms involved remain elusive. Here, we identified the arginine methyltransferase PRMT5 as a master coregulator of GR, serving as a scaffold protein to recruit phospho-HP1γ and subsequently RNA polymerase II, independently of its methyltransferase activity. Moreover, the GR/PRMT5/HP1γ complex regulated the transcription of GC-target genes involved in cell motility and triggering cell migration of human TNBC cells in vitro and in a zebrafish model. Of note, we observed that GR/PRMT5 interaction was low in primary tumors but significantly increased in residual tumors treated with chemotherapy and GCs in neoadjuvant setting. These data suggest that the routine premedication prescription of GCs for early TNBC patients should be further assessed and that this complex could potentially be modulated to specifically target deleterious GR effects.

Do surgeons overestimate diaphragmatic peritoneal disease in interval debulking surgery of ovarian cancer?

INTRODUCTION: Cytoreductive surgery is a key point in ovarian cancer treatment. Substantial morbidity may be consecutive to this major radical surgery. However, the objective of no residual tumor (CC-0) had demonstrated its clear improvement of prognosis. Could macroscopically-driven interval debulking surgery (IDS) overestimate active cancer cells and be unnecessarily morbid? MATERIALS AND METHODS: This retrospective cohort study was conducted in Center Leon Berard Cancer Center between 2000 and 2018. We included women with advanced epithelial ovarian cancer who received neoadjuvant chemotherapy and underwent an IDS including resection of peritoneal metastases on the diaphragmatic domes. The primary endpoint was the pathological outcome of peritoneal resections of diaphragmatic domes. RESULTS: Peritoneal resections of diaphragmatic domes consisted of 117 patients. 75 patients required resection of nodules from the right cupola only, 2 patients from the left cupola only, and 40 patients bilaterally. Pathological analysis of the diaphragmatic domes found that 84.6% of samples demonstrated the presence of malignant cells, and only 12.8% found no tumor involvement. Pathology analysis could not be performed for 3 patients (2.6%) (vaporization). CONCLUSION: Surgical evaluation after neoadjuvant chemotherapy in ovarian cancer does not often overestimate peritoneal involvement by active carcinomatosis. Potential surgical morbidity due to peritoneal resection in IDS is admissible.

Sorafenib in Molecularly Selected Cancer Patients: Final Analysis of the MOST-Plus Sorafenib Cohort.

BACKGROUND: MOST-plus is a multicenter, randomized, open-label, adaptive Phase II trial evaluating the clinical benefit of targeted treatments matched to molecular alteration in advanced/metastatic solid tumors. Sorafenib was tested on patients with tumors harboring sorafenib-targeted genes. METHODS: The MOST-plus trial used a randomized discontinuation design. After 12 weeks of sorafenib (400 mg, po BID), patients with progressive disease discontinued study, patients with objective response were proposed to continue sorafenib, whereas patients with stable disease (SD) were randomly assigned (1:1) to the maintenance or interruption of treatment. The primary endpoint was RECIST version 1.1 progression-free rate at 16 weeks after randomization (PFR-16w). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Statistical analyses used a sequential Bayesian approach with interim efficacy analyses. The enrolment could be stopped in the case of a 95% probability for the estimated PFR-16w to be higher in the maintenance than in the interruption arm (NCT02029001). RESULTS: 151 patients were included, of whom 35 had SD at 12 weeks of Sorafenib. For the 35 patients with SD on sorafenib, the PFR-16w was 65% [95% credibility interval 43.4-83.7] in the continuation arm and 25% [7.8-48.1] in the interruption arm. Median PFS and OS were improved in the maintenance versus the interruption arm (mPFS: 5.6 [95%CI 1.97-6.77] months versus 2.0 [95%CI 1.61-3.91] months (p = 0.0231) and mOS: 14.3 [95%CI 8.9-23.8] versus 8.0 months [95%CI 3.5-15.2] (p = 0.0857)). CONCLUSION: Sorafenib showed activity in progressive patients with solid tumors harboring somatic genomic alterations in sorafenib-targeted genes. Continuing sorafenib when SD is achieved improves PFR compared to interruption.

Adjuvant endocrine therapy uptake, toxicity, quality of life, and prediction of early discontinuation.

BACKGROUND: Many patients receiving adjuvant endocrine therapy (ET) for breast cancer experience side effects and reduced quality of life (QoL) and discontinue ET. We sought to describe these issues and develop a prediction model of early discontinuation of ET. METHODS: Among patients with hormone receptor-positive and HER2-negative stage I-III breast cancer of the Cancer Toxicities cohort (NCT01993498) who were prescribed adjuvant ET between 2012 and 2017, upon stratification by menopausal status, we evaluated adjuvant ET patterns including treatment change and patient-reported discontinuation and ET-associated toxicities and impact on QoL. Independent variables included clinical and demographic features, toxicities, and patient-reported outcomes. A machine-learning model to predict time to early discontinuation was trained and evaluated on a held-out validation set. RESULTS: Patient-reported discontinuation rate of the first prescribed ET at 4 years was 30% and 35% in 4122 postmenopausal and 2087 premenopausal patients, respectively. Switching to a new ET was associated with higher symptom burden, poorer QoL, and higher discontinuation rate. Early discontinuation rate of adjuvant ET before treatment completion was 13% in postmenopausal and 15% in premenopausal patients. The early discontinuation model obtained a C index of 0.62 in the held-out validation set. Many aspects of QoL, most importantly fatigue and insomnia (European Organization for Research and Treatment of Cancer QoL questionnaire 30), were associated with early discontinuation. CONCLUSION: Tolerability and adherence to ET remains a challenge for patients who switch to a second ET. An early discontinuation model using patient-reported outcomes identifies patients likely to discontinue their adjuvant ET. Improved management of toxicities and novel more tolerable adjuvant ETs are needed for maintaining patients on treatment.

Nuclear PRMT5 is a biomarker of sensitivity to tamoxifen in ERα+ breast cancer.

Endocrine therapies targeting estrogen signaling, such as tamoxifen, have significantly improved management of estrogen receptor alpha (ERα)-positive breast cancers. However, their efficacy is limited by intrinsic and acquired resistance to treatment, and there is currently no predictive marker of response to these anti-estrogens to guide treatment decision. Here, using two independent cohorts of breast cancer patients, we identified nuclear PRMT5 expression as an independent predictive marker of sensitivity to tamoxifen. Mechanistically, we discovered that tamoxifen stimulates ERα methylation by PRMT5, a key event for its binding to corepressors such as SMRT and HDAC1, participating in the inhibition of the transcriptional activity of ERα. Although PRMT5 is mainly localized in the cytoplasm of tumor cells, our analyses show that tamoxifen triggers its nuclear translocation in tamoxifen-sensitive tumors but not in resistant ones. Hence, we unveil a biomarker of sensitivity to tamoxifen in ERα-positive breast tumors that could be used to enhance the response of breast cancer patients to endocrine therapy, by fostering its nuclear expression.

Real-world clinical and survival outcomes of patients with early relapsed triple-negative breast cancer from the ESME national cohort.

BACKGROUND: Early metastatic relapse of triple-negative breast cancer (mTNBC) after anthracyclins and/or taxanes based (A/T) primary treatment represents a highly aggressive cancer situation requiring urgent characterisation and handling. Epidemio-Strategy-Medico-Economical-Metastatic Breast Cancer (ESME-MBC) database, a multicenter, national, observational cohort (NCT03275311) provides recent data on this entity. METHODS: All ESME patients diagnosed between 2008 and 2020 with mTNBC occurring as a relapse after a systemic neoadjuvant/adjuvant taxane and/or anthracycline-based chemotherapy were included. Early relapses were defined by a metastatic diagnosis up to 12 months of the end of neo/adjuvant A/T chemotherapy. We assessed overall survival (OS) and progression-free-survival under first-line treatment (PFS1) by early versus late relapse (≥12 months). RESULTS: Patients with early relapse (N = 881, 46%) were younger and had a larger tumour burden at primary diagnosis than those with late relapses (N = 1045). Early relapse rates appeared stable over time. Median OS was 10.1 months (95% CI 9.3-10.9) in patients with early relapse versus 17.1 months (95% CI 15.7-18.2) in those with late relapse (adjusted hazard-ratio (aHR): 1.92 (95% CI 1.73-2.13); p < 0.001). The median PFS1 was respectively 3.1 months (95% CI 2.9-3.4) and 5.3 months (95% CI 5.1-5.8); (aHR: 1.66; [95% CI 1.50-1.83]; p < 0.001). Among early relapsed patients, a higher number of metastatic sites, visceral disease but not treatment types, were independently associated with a poorer OS. CONCLUSION: These real-world data provide strong evidence on the dismal prognosis, higher treatment resistance and major unmet medical need associated with early relapsed mTNBC. Database registration: clinicaltrials.gov Identifier NCT032753.

A Digital Solution for an Advanced Breast Tumor Board: Pilot Application Cocreation and Implementation Study.

BACKGROUND: Cancer treatment is constantly evolving toward a more personalized approach based on clinical features, imaging, and genomic pathology information. To ensure the best care for patients, multidisciplinary teams (MDTs) meet regularly to review cases. Notwithstanding, the conduction of MDT meetings is challenged by medical time restrictions, the unavailability of critical MDT members, and the additional administrative work required. These issues may result in members missing information during MDT meetings and postponed treatment. To explore and facilitate improved approaches for MDT meetings in France, using advanced breast cancers (ABCs) as a model, Centre Léon Bérard (CLB) and ROCHE Diagnostics cocreated an MDT application prototype based on structured data. OBJECTIVE: In this paper, we want to describe how an application prototype was implemented for ABC MDT meetings at CLB to support clinical decisions. METHODS: Prior to the initiation of cocreation activities, an organizational audit of ABC MDT meetings identified the following four key phases for the MDT: the instigation, preparation, execution, and follow-up phases. For each phase, challenges and opportunities were identified that informed the new cocreation activities. The MDT application prototype became software that integrated structured data from medical files for the visualization of the neoplastic history of a patient. The digital solution was assessed via a before-and-after audit and a survey questionnaire that was administered to health care professionals involved in the MDT. RESULTS: The ABC MDT meeting audit was carried out during 3 MDT meetings, including 70 discussions of clinical cases before and 58 such discussions after the implementation of the MDT application prototype. We identified 33 pain points related to the preparation, execution, and follow-up phases. No issues were identified related to the instigation phase. Difficulties were grouped as follows: process challenges (n=18), technological limitations (n=9), and the lack of available resources (n=6). The preparation of MDT meetings was the phase in which the most issues (n=16) were seen. A repeat audit, which was undertaken after the implementation of the MDT application, demonstrated that (1) the discussion times per case remained comparable (2 min and 22 s vs 2 min and 14 s), (2) the capture of MDT decisions improved (all cases included a therapeutic proposal), (3) there was no postponement of treatment decisions, and (4) the mean confidence of medical oncologists in decision-making increased. CONCLUSIONS: The introduction of the MDT application prototype at CLB to support the ABC MDT seemed to improve the quality of and confidence in clinical decisions. The integration of an MDT application with the local electronic medical record and the utilization of structured data conforming to international terminologies could enable a national network of MDTs to support sustained improvements to patient care.

Pembrolizumab in Lymphopenic Metastatic Breast Cancer Patients Treated with Metronomic Cyclophosphamide: A Clinical and Translational Prospective Study.

Purpose: Metastatic endocrine-resistant breast cancer (MBC) is a disease with poor prognosis and few treatment options. Low lymphocyte count is associated with limited overall survival. In a prospective cohort of lymphopenic patients with HER-2 negative MBC, we assessed the clinical and biological impact of pembrolizumab combined with metronomic cyclophosphamide. Experimental Design: This multicenter Phase II study evaluated the safety and clinical activity of pembrolizumab (intravenous (IV), 200mg, every 3 weeks) combined with metronomic cyclophosphamide (50mg/day, per os) in lymphopenic adult patients with HER2-negative MBC previously treated by at least one line of chemotherapy in this setting according to a Simon's minimax two-stage design. Blood and tumor samples were collected to assess the impact of the combined treatment on circulating immune cells and the tumor immune microenvironment through multiparametric flow cytometry and multiplex immunofluorescence analyses. Primary endpoint was the clinical benefit rate at 6 months of treatment (CBR-6M). Secondary endpoints were objective response rate (ORR), duration of response, progression free survival (PFS), and overall survival (OS). Results: Two out of the twenty treated patients presented clinical benefit (one Tumor Mutational Burden (TMB)-high patient with complete response (CR) and one patient with objective response (OR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1) associated with a strong increase of cytokine-producing and proliferating CD4+ T cells and higher CD8+ T cells to macrophage ratios in the tumor. This impact on CD4+ and CD8+ T cell polyfunctionality was still observed more than one year for the patient with CR. A decreased in their absolute number of CD4+ and CD8+ memory T cells was observed in other patients. Conclusion: Pembrolizumab combined with metronomic cyclophosphamide was well tolerated, and displayed limited anti-tumoral activity in lymphopenic MBC. Correlative translational data of our trial advocates for additional studies with other chemotherapy combinations.

[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.

Splenectomy in epithelial ovarian cancer surgery.

OBJECTIVE: Splenectomy is performed in 4-32% of cytoreductive surgeries for ovarian cancer. The objective of our study was to assess splenectomy and evaluate its impact on overall and disease-free survival. METHODS: We conducted a retrospective single-center study between January 2000 and December 2016. Patients who underwent a cytoreduction for epithelial ovarian cancer, regardless of stage and surgical approach, were eligible for the study. Patients deemed not operable were excluded from the study. Patients were stratified into two groups, splenectomy or no splenectomy. A univariate analysis followed by a multivariate analysis was conducted to evaluate the postoperative complications after splenectomy and the overall and disease-free survival. RESULTS: This cohort included 464 patients. Disease stages, peritoneal carcinomatosis scores, and the rate of radical surgery (Pomel classification) were significantly higher in the splenectomy group, p=0.04, p<0.0001, and p<0.001, respectively. However, no significant difference was found in the rate of complete cytoreduction between the two groups (p=0.26) after multivariate analysis. In univariate analysis, splenectomy was significantly associated with extensive surgical procedures. In multivariate analysis, the two more prevalent complications in the splenectomy group were the risk of abdominopelvic lymphocele (overall response (OR) =4.2; p=0.01) and blood transfusion (OR=2.4; p=0.008). The average length of hospital stay was significantly longer in the splenectomy group, 17.4 vs 14.6 days (p<0.0001). The delay in adjuvant chemotherapy was longer in the splenectomy group (p=0.001). There was no significant difference in overall and disease-free survival (p=0.09) and (p=0.79), respectively. CONCLUSION: Splenectomy may be considered an acceptable and safe procedure; however, with no impact on overall or disease-free survival. In addition, it is associated with longer hospital stay and longer time to chemotherapy.

G-CSF filgrastim biosimilar-Sandoz reduces the incidence of febrile neutropenia in patients receiving chemotherapy regimens with rest periods not exceeding 14 days: A French, multicenter, prospective, non-interventional study.

PURPOSE: The objective of this study was to describe filgrastim biosimilar-Sandoz modalities of use in patients receiving cytotoxic chemotherapy regimens with a rest period of ≤14 days and to investigate the incidence of febrile neutropenia (FN) in routine clinical practice. METHODS: This was a French, multicenter, prospective and descriptive, non-interventional study including patients with breast, lung, gastrointestinal cancer or a lymphoma initiating filgrastim biosimilar-Sandoz treatment and in the context of cytotoxic chemotherapy with a rest period not exceeding 14 days. Data were collected during two routine clinical visits on the modalities of use of filgrastim biosimilar-Sandoz, on the incidence of neutropenia events and on adverse events. RESULTS: Between November 2015 and June 2018, 1080 patients were enrolled in the study in 129 centers. Overall, 941 patients were evaluable for efficacy and 937 for safety. Of the 941 patients, 84.8% had a solid tumor and 15.2% had a lymphoid hemopathy. Filgrastim biosimilar-Sandoz was prescribed as primary prophylaxis in 74.0% of the patients and as secondary prophylaxis in 22.4% of the patients. FN was reported in 1.5% of patients with a solid tumor and 12.6% of patients with a lymphoma. A chemotherapy relative dose intensity of over 85% with regard to the reference dose was achieved by more than 80% of the patients in all tumor localizations. CONCLUSIONS: The study showed that filgrastim biosimilar-Sandoz is safe to use and effective in preventing FN and in allowing to maintain the dose intensity of chemotherapy.

Association of chemotherapy and comorbidities with overall survival in elderly patients with early breast cancer: a French population-based propensity score-matched analysis.

BACKGROUND: Additional systemic treatment for early breast cancer in elderly is challenged by increasing comorbidities with age. We aimed to examine the effect of additional chemotherapy on overall survival in patients aged 70 years or older and the impact of comorbidities on chemotherapy benefit. METHODS: This retrospective monocentric cohort study includes data from all patients aged 70 years and older who underwent surgery for an early breast cancer from 1997 to 2016. A propensity score analysis allowed adjustment for chemotherapy prescription preferences based on tumour characteristics. RESULTS: Of 15,599 patients who had surgery for an early breast cancer, 1743 (11.2%) over 70 years old were included, of whom 269 (15.4%) had received additional chemotherapy. Median follow-up was 5.3 years. Multivariate analyses on the propensity-score weighted cohort (n = 1 354) identified improved overall survival in patients with chemotherapy versus without (HR 0.54, 95% CI 0.31-0.92). Chronic obstructive pulmonary disease (HR, 2.16, 95% CI 1.40-3.34) and polypharmacy (HR 1.40, 95%CI 1.07-1.84) were associated with worse overall survival. No statistically significant interactions were identified between these comorbidities and chemotherapy prescription. CONCLUSION: Additional chemotherapy in elderly with early breast cancer is feasible and associated with overall survival benefit, supporting the importance of chemotherapy considerations in this population, and of avoiding undertreatment based on chronological age considerations alone.

Baseline quality of life and chemotherapy toxicities in patients with early breast cancer.

BACKGROUND: The authors used the French breast cancer Cancer and Toxicities (CANTO) cohort to study the associations between baseline quality of life and chemotherapy dose-reductions (CDRs) or postchemotherapy-toxicities (PCTs). METHODS: In total, 3079 patients with breast cancer who received chemotherapy were included in this analysis. The associations between baseline physical functioning (PF) and fatigue measured using the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire Core 30, and two endpoints-CDRs during adjuvant or neoadjuvant chemotherapy; and selected PCTs were estimated with odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) using logistic regression models. RESULTS: Among the 3079 patients from the CANTO cohort who were included, 718 (33.0%) received chemotherapy in the neoadjuvant setting, and 2361 (67.0%) received chemotherapy as adjuvant treatment. The chemotherapy included taxanes in 94.2% of patients and anthracyclines in 90.5% of patients. Overall, 15.5% of patients experienced CDRs and, 31.0% developed PCTs. Women with low baseline PF scores (<83) had higher multivariate odds of developing CDRs compared with those who had PF scores ≥83 (OR, 1.54; 95% CI, 1.13-2.09). The corresponding OR for PCTs was 1.50 (95% CI, 1.13-2.00). Women with high baseline fatigue scores had higher odds of CDRs (OR, 1.43; 95% CI, 1.13-1.76) and PCTs (OR, 1.32; 95% CI, 1.10-1.59). CONCLUSIONS: By using the national CANTO cohort, baseline PF and fatigue were independently associated with CDRs and PCTs.

[Use of genome-wide testing in oncology: French expert opinion based on the Delphi methodology]. / Utilisation des tests génomiques en oncologie : avis d'experts Français selon la méthode Delphi.

In oncology, genome-wide testing is a major element in facilitating the implementation of precision medicine. However, current recommendations do not always specify the indication and utility of these tests according to the type of cancer. A national consensus approach based on a modified Delphi methodology was set up to provide expert opinion on the use of genome-wide testing in clinical practice in France. Four groups of experts - 4 each representing the following topics of interest - were defined: non-small cell lung cancer (NSCLC), breast cancer, melanoma, and cancer of unknown primary (CUP). In each group, assertions were formulated by a lead expert (8, 5, 7 and 6, respectively) and rated by five panellists involved in the management of these cancers, on a scale from 1 (strongly disagree) to 9 (strongly agree). Consensus was reached when 75% of the scores were above 7. In case of disagreement, the panellists were asked to justify their rate. In total, 24 statements reached consensus after two to four rounds of rating, depending on the group. While the experts advocated the routine use of genome-wide testing in the diagnostic management of NSCLC and CUP, they did not recommend the systematisation of these tests for breast cancer and melanoma. Nevertheless, access to innovation in France could soon remove certain barriers and allow greater standardisation of broad molecular screening in oncology.