Netrin-1 blockade inhibits tumour growth and EMT features in endometrial cancer.

Netrin-1 is upregulated in cancers as a protumoural mechanism1. Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC. As best response we observed 8 stable disease (8 out of 14, 57.1%) and 1 objective response as RECIST v.1.1 (partial response, 1 out of 14 (7.1%), 51.16% reduction in target lesions at 6 weeks and up to 54.65% reduction during the following 6 months). To evaluate the NP137 mechanism of action, mouse tumour gene profiling was performed, and we observed, in addition to cell death induction, that NP137 inhibited epithelial-to-mesenchymal transition (EMT). By performing bulk RNA sequencing (RNA-seq), spatial transcriptomics and single-cell RNA-seq on paired pre- and on-treatment biopsies from patients with EC from the NP137 trial, we noted a net reduction in tumour EMT. This was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. Given the importance of EMT in resistance to current standards of care2, we show in the EC mouse model that a combination of NP137 with carboplatin-paclitaxel outperformed carboplatin-paclitaxel alone. Our results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments.

Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. METHODS: BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. FINDINGS: Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. FUNDING: Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.

A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR).

BACKGROUND: Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. METHODS: This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). DISCUSSION: Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06059014.

The French multicentric molecular analysis platforms and personalized medicine trials MOST, MOST Plus and MEGAMOST.

BACKGROUND AND PURPOSE: In this manuscript we describe the academic French multicentric molecular analysis platforms including PROFILER, promoted by Centre Léon Berard, and the multicentric personalized medicine trials MOST, MOST Plus and MEGAMOST. PATIENTS/MATERIAL AND METHODS: MOST, MOST Plus and MEGAMOST comprise 14 cohorts with different targeted agents and immunotherapies. RESULTS AND INTERPRETATION: PROFILER has recruited 5,991 patients in 10 years, MOST and MOST Plus 875 patients since 2014 and MEGAMOST 172 patients since 2020, and are still ongoing. We provide a description of the local, national and international implications of these initiatives, and we review the results of the sorafenib and olaparib cohorts.

Association between progression-free survival and overall survival in women receiving first-line treatment for metastatic breast cancer: evidence from the ESME real-world database.

BACKGROUND: Overall survival (OS) is the gold standard endpoint to assess treatment efficacy in cancer clinical trials. In metastatic breast cancer (mBC), progression-free survival (PFS) is commonly used as an intermediate endpoint. Evidence remains scarce regarding the degree of association between PFS and OS. Our study aimed to describe the individual-level association between real-world PFS (rwPFS) and OS according to first-line treatment in female patients with mBC managed in real-world setting for each BC subtype (defined by status for both hormone-receptor [HR] expression and HER2 protein expression/gene amplification). METHODS: We extracted data from the ESME mBC database (NCT03275311) which gathers deidentified data from consecutive patients managed in 18 French Comprehensive Cancer Centers. Adult women diagnosed with mBC between 2008 and 2017 were included. Endpoints (PFS, OS) were described using the Kaplan-Meier method. Individual-level associations between rwPFS and OS were estimated using the Spearman's correlation coefficient. Analyses were conducted by tumor subtype. RESULTS: 20,033 women were eligible. Median age was 60.0 years. Median follow-up duration was 62.3 months. Median rwPFS ranged from 6.0 months (95% CI 5.8-6.2) for HR-/HER2 - subtype to 13.3 months (36% CI 12.7-14.3) for HR + /HER2 + subtype. Correlation coefficients were highly variable across subtypes and first-line (L1) treatments. Among patients with HR - /HER2 - mBC, correlation coefficients ranged from 0.73 to 0.81, suggesting a strong rwPFS/OS association. For HR + /HER2 + mBC patients, the individual-level associations were weak to strong with coefficients ranging from 0.33 to 0.43 for monotherapy and from 0.67 to 0.78 for combined therapies. CONCLUSIONS: Our study provides comprehensive information on individual-level association between rwPFS and OS for L1 treatments in mBC women managed in real-life practice. Our results could be used as a basis for future research dedicated to surrogate endpoint candidates.

Cutting Edge: mTORC1 Inhibition in Metastatic Breast Cancer Patients Negatively Affects Peripheral NK Cell Maturation and Number.

NK cells are cytotoxic lymphocytes displaying strong antimetastatic activity. Mouse models and in vitro studies suggest a prominent role of the mechanistic target of rapamycin (mTOR) kinase in the control of NK cell homeostasis and antitumor functions. However, mTOR inhibitors are used as chemotherapies in several cancer settings. The impact of such treatments on patients' NK cells is unknown. We thus performed immunophenotyping of circulating NK cells from metastatic breast cancer patients treated with the mTOR inhibitor everolimus over a three-month period. Everolimus treatment resulted in inhibition of mTORC1 activity in peripheral NK cells, whereas mTORC2 activity was preserved. NK cell homeostasis was profoundly altered with a contraction of the NK cell pool and an overall decrease in their maturation. Phenotype and function of the remaining NK cell population was less affected. This is, to our knowledge, the first in vivo characterization of the role of mTOR in human NK cells.

Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer.

BACKGROUND: Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown. METHODS: We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or BRCA mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death. RESULTS: Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. CONCLUSIONS: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).

Low level of Fibrillarin, a ribosome biogenesis factor, is a new independent marker of poor outcome in breast cancer.

BACKGROUND: A current critical need remains in the identification of prognostic and predictive markers in early breast cancer. It appears that a distinctive trait of cancer cells is their addiction to hyperactivation of ribosome biogenesis. Thus, ribosome biogenesis might be an innovative source of biomarkers that remains to be evaluated. METHODS: Here, fibrillarin (FBL) was used as a surrogate marker of ribosome biogenesis due to its essential role in the early steps of ribosome biogenesis and its association with poor prognosis in breast cancer when overexpressed. Using 3,275 non-metastatic primary breast tumors, we analysed FBL mRNA expression levels and protein nucleolar organisation. Usage of TCGA dataset allowed transcriptomic comparison between the different FBL expression levels-related breast tumours. RESULTS: We unexpectedly discovered that in addition to breast tumours expressing high level of FBL, about 10% of the breast tumors express low level of FBL. A correlation between low FBL mRNA level and lack of FBL detection at protein level using immunohistochemistry was observed. Interestingly, multivariate analyses revealed that these low FBL tumors displayed poor outcome compared to current clinical gold standards. Transcriptomic data revealed that FBL expression is proportionally associated with distinct amount of ribosomes, low FBL level being associated with low amount of ribosomes. Moreover, the molecular programs supported by low and high FBL expressing tumors were distinct. CONCLUSION: Altogether, we identified FBL as a powerful ribosome biogenesis-related independent marker of breast cancer outcome. Surprisingly we unveil a dual association of the ribosome biogenesis FBL factor with prognosis. These data suggest that hyper- but also hypo-activation of ribosome biogenesis are molecular traits of distinct tumors.

CaboPoint: a phase II study of cabozantinib as second-line treatment in patients with metastatic renal cell carcinoma.

Cabozantinib is an inhibitor of multiple tyrosine kinases, including AXL, MET and VEGF receptors. Here, we describe the rationale and design for the phase II CaboPoint trial (ClinicalTrials.gov identifier: NCT03945773), which will evaluate the efficacy and safety of cabozantinib as a second-line treatment in patients with unresectable, locally advanced or metastatic renal cell carcinoma whose disease has progressed despite checkpoint inhibitor therapy. Patients will be recruited into two cohorts: prior ipilimumab plus nivolumab (cohort A) or prior checkpoint inhibitor-VEGF-targeted therapy (cohort B). All patients will receive once-daily oral cabozantinib 60 mg for up to 18 months. The primary end point is objective response rate. Secondary end points include overall survival, progression-free survival and safety.

Most patients diagnosed with kidney cancer have a type of tumor called renal cell carcinoma (RCC). Most cases of RCC are described as 'clear cell' because the tumor cells appear clear when viewed under a microscope. Cabozantinib is an oral treatment approved for use in some patients with advanced RCC, including those with clear cell disease. Cabozantinib slows RCC progression by targeting pathways that help tumors grow, including inhibition of VEGF. The ongoing CaboPoint study will assess the efficacy and safety of cabozantinib in patients with clear cell RCC that has progressed despite previous anticancer treatment involving an immune checkpoint inhibitor (CPI). CPI therapy helps the body to detect tumors and to launch its own anticancer response. Patients included in CaboPoint must be adults with clear cell RCC that is not suitable for surgery and has either spread within the kidney or to other organs, despite previous CPI-based therapy. In total, 250 patients will be recruited: 125 who received previous combination CPI treatment (ipilimumab plus nivolumab; group A) and 125 who received previous CPI treatment plus anti-VEGF therapy (group B). Patients will start cabozantinib at a dose of 60 mg/day and continue treatment for up to 18 months. The main outcome to be studied will be the number of patients with a reduction in tumor size (objective response rate). The length of time patients live with their disease, the effect of treatment on symptoms and patient safety will also be evaluated. Clinical trial registration: NCT03945773 (ClinicalTrials.gov).

Impact of early palliative care on additional line of chemotherapy in metastatic breast cancer patients: results from the randomized study OSS.

PURPOSE: The most appropriate criteria and timing for palliative care referral remain a critical issue, especially in patients with metastatic breast cancer for whom long-term chemosensibility and survival are observed. We aimed to compare the impact of early palliative care including formal concertation with oncologists on decision for an additional line of chemotherapy compared with usual oncology care. METHODS: This randomized prospective study enrolled adult women with metastatic breast cancer and visceral metastases with a 3rd- or 4th-line chemotherapy (CT). Patients received usual oncology care with a palliative care consultation only upon patient or oncologist request (standard group, S) or were referred to systematic palliative care consultation including a regular concertation between palliative care team and oncologists (early palliative care group, EPC). The primary endpoint was the rate of an additional CT (4th or 5th line) decision. Quality of life, symptoms, social support and satisfaction were self-evaluated at 6 and 12 months, at treatment discontinuation or 3 months after discontinuation. RESULTS: From January 2009 to November 2012, two authorized cancer centers included 98 women (EPC: 50; S: 48). Thirty-seven (77.1%, 95%CI 62.7-88%) patients in the EPC group had a subsequent chemotherapy prescribed and 36 (72.0%, 95%CI 57.5-83.8%) in the S group (p = 0.646). No differences in symptom control and global quality of life were observed, but less deterioration in physical functioning was reported in EPC (EPC: 0 [- 53-40]; S: - 6; 7 [- 60 to - 20]; p = 0.027). Information exchange and communication were significant improved in EPC (exchange, EPC: - 8.3 [- 30 to + 7]; S: 0.0 [- 17 to + 23]; p = 0.024; communication, EPC: 12.5 [- 8 to - 37]; S: 0.0 [- 21 to + 17]; p = 0.004). CONCLUSION: EPC in metastatic breast cancer patients did not impact the prescription rate of additional chemotherapy in patients a 3rd- or 4th-line chemotherapy for metastatic breast cancer; however, EPC may contribute to alleviate deterioration in physical functioning, while facilitating communication. TRIAL REGISTRATION: ClinicalTrial.gov identifier: NCT00905281, May 20, 2009.

Second primary cancers: a retrospective analysis of real world data using the enhanced medical research engine ConSoRe in a French comprehensive cancer center.

BACKGROUND: Second primary cancers (SPC) account for 18% of all cancers. We used the enhanced medical/health data mining tool ConSoRe to search aggregated data, analyze electronic patient records (EPR), and better characterize patients with SPC. METHODS: This retrospective cohort study used ConSoRe to identify EPRs from patients with SPC referred to the regional cancer center Leon Bérard from 1993 to 2017, and examined characteristics of patients with SPC, frequencies of first primary cancer (FPC) localization in the global population of patients with SPC, and time to SPC. Data set was extracted on January 1, 2018. RESULTS: Among 296,530 EPRs, we identified 157,187 patients with FPC, including 13,002 (8%) patients with SPC. Between 2000 and 2010, the rate of SPC was 34%, and 52% of SPC were identified in the last years (2010-2017). In men, main cancers were head and neck cancer, lymphoma, and prostate carcinoma accounting for 15.6%, 12.8%, and 10.5% of FPC, while the three most common SPC were head and neck cancer (13.2%), lung cancer (11.8%) and lymphoma (9.2%). In women, breast cancers, lymphoma, and skin cancers accounted for 48.8%, 8%, and 5.1% of first cancers, and for 31.1%, 7% and 6% of SPC. CONCLUSION: The data mining tool ConSoRe contributes to access to real world data, and to better characterize patients with SPC. Expanding such approach to any comprehensive center will allow a global overview of the follow-up of patients with cancer, and help to improve long-term management and adapt surveillance.

Design and methods of a national, multicenter, randomized and controlled trial to assess the efficacy of a physical activity program to improve health-related quality of life and reduce fatigue in women with metastatic breast cancer: ABLE02 trial.

BACKGROUND: Patients with a metastatic breast cancer suffer from a deteriorated health-related quality of life and numerous symptoms such as pain, severe fatigue and a decrease of their physical fitness. As the feasibility of a physical activity program has been demonstrated in this population, ABLE02 aims to assess the efficacy of a 6 month-physical activity program using connected devices to improve health-related quality of life and to reduce fatigue in women with metastatic breast cancer. METHODS: ABLE02 is a prospective, national, multicenter, randomized, controlled and open-label study. A total of 244 patients with a metastatic breast cancer, with at least one positive hormone receptor and a first-line chemotherapy planned, will be randomly assigned (1:1 ratio) to: (i) the intervention arm to receive physical activity recommendations, an activity tracker to wear 24 h a day during the whole intervention (6 months) with at least three weekly walking sessions and quizzes each week on physical activity and nutrition (ii) the control arm to receive physical activity recommendations only. Health-related quality of life will be assessed every 6 weeks and main assessments will be conducted at baseline, M3, M6, M12 and M18 to evaluate the clinical, physical, biological and psychological parameters and survival of participants. All questionnaires will be completed on a dedicated application. DISCUSSION: An activity program based on a smartphone application linked to an activity tracker may help to improve quality of life and reduce fatigue of patients with a metastatic breast cancer. The growth of e-health offers the opportunity to get real-time data as well as improving patient empowerment in order to change long-term behaviors. TRIAL REGISTRATION: NCT number: NCT04354233 .

Cost-effectiveness of an exercise and nutritional intervention versus usual nutritional care during adjuvant treatment for localized breast cancer: the PASAPAS randomized controlled trial.

We undertook a cost-effectiveness analysis (CEA) to compare an exercise and nutritional program with the usual nutritional care concomitant to adjuvant chemotherapy in localized breast cancer patients. The CEA was designed as part of the interventional, controlled, randomized, single-center, open-label PASAPAS study. Breast cancer patients receiving first-line adjuvant chemotherapy at a French Comprehensive Cancer Center were randomized 2:1 to a 6-month exercise program of supervised indoor and outdoor group sessions in addition to usual nutritional care (exercise arm) or a usual nutritional care group receiving dietary and physical activity counseling (control arm). Costs were assessed from the French national insurance perspective (in Euros, 2012). Incremental cost-effectiveness ratios (ICERs) were calculated for four criteria: body mass index, waist circumference, body fat percentage, and estimated aerobic capacity. Uncertainty around the ICERs was captured by a probabilistic analysis using a non-parametric bootstrap method. The analysis was based on 60 patients enrolled between 2011 and 2013. Average intervention costs per participant were €412 in the exercise arm (n = 41) and €117 (n = 19) in the control arm. Total mean costs were €17,344 (standard deviation 9,928) and €20,615 (standard deviation 14,904), respectively, did not differ significantly (p = 0.51). The 6-month exercise program was deemed to be cost-effective compared with usual care for the estimated aerobic capacity. Multicenter randomized studies with long-term costs and outcomes should be done to provide additional evidence. Clinical trial: The PASAPAS study is registered under ClinicalTrials.gov. Trial registration ID: NCT01331772.

Oral etoposide in heavily pre-treated metastatic breast cancer: results from the ESME cohort and comparison with other chemotherapy regimens.

INTRODUCTION: HER2-negative metastatic breast cancer (MBC) is a common setting in which chemotherapy could be effective even in later lines of treatment. Oral etoposide has demonstrated clinical activity in this setting in small-scale studies, but its efficacy has not been compared to that of other chemotherapy regimens. METHODS: We used the ESME database (Epidemiological Strategy and Medical Economics), a real-life national French multicentre cohort of MBC patients initiating therapy between 1 January 2008 to 31 December 2014. HER2-negative MBC patients who received oral etoposide as > 3rd chemotherapy line and for more than 14 days were included. Primary objective was progression-free survival (PFS); secondary objectives were overall survival (OS), and propensity-score matched Cox models including comparison with other therapies in the same setting. RESULTS: Three hundred forty-five out of 16,702 patients received oral etoposide and 222 were eligible. Median PFS was 3.2 months [95% CI 2.8-4] and median OS 7.3 months [95% CI 5.7-10.3]. Median PFS did not significantly differ according to the therapeutic line. The only prognostic factor for both PFS and OS was the MBC phenotype (hormone receptor-positive versus triple-negative, HR = 0.71 [95% CI 0.52-0.97], p = 0.028 for PFS and HR = 0.65 [0.46-0.92], p = 0.014 for OS). After matching for the propensity score, no differential effect on PFS or OS was observed between oral etoposide and other chemotherapy regimens administered in the same setting (HR = 0.94 [95% CI 0.77-1.15], p = 0.55 for PFS and HR = 1.10 [95% CI 0.88-1.37], p = 0.40 for OS). CONCLUSION: Oral etoposide retains some efficacy in selected heavily pre-treated patients with HER2-negative MBC, with the advantages of oral administration.

A 96-hour continuous wound infiltration with ropivacaine reduces analgesic consumption after liver resection: A randomized, double-blind, controlled trial.

BACKGROUND: Continuous wound infiltration (CWI) with local anesthetics to reduce morphine consumption in postoperative pain management after open liver resection in patients with cancer. METHODS: This single-center randomized double-blind study allocated patients requiring resection of liver metastases to receive a 3.75 mg/mL ropivacaine (ROP) infiltration, followed by a 2 mg/mL ROP CWI, or placebo (P) for 96 hours. Postoperative analgesia included acetaminophen and patient-controlled analgesia morphine pump. The primary endpoint was to investigate the reduction of total morphine consumption (mg/kg) over the first 96 postoperative hours. RESULTS: Eighty-five patients were recruited, and randomized (ROP: 42, P: 43) between 2009 and 2014. The median morphine consumption significantly decreased in the ROP arm in the first 96 postoperative hours (ROP: 1.0, P: 1.5 mg/kg; P = 0.026). Twenty-three (27%) patients had grade 3 adverse events (ROP: 14, P: 9) and four experienced grade 3 treatment-related adverse events (ROP: mental confusion [n = 1], hallucinations [n = 2], P: hematoma [n = 1]). Two (5%) patients showed a wound inflammation (ROP: 1, P: 1). Nine (11%) patients experienced at least one serious adverse event (ROP: 6, P: 3); none related to treatment. CONCLUSION: Preperitoneal CWI of 2 mg/mL ROP significantly reduces intravenous morphine consumption during the 96 postoperative hours resulting in an absolute reduction of 0.5 mg/kg.

Does a homeopathic medicine reduce hot flushes induced by adjuvant endocrine therapy in localized breast cancer patients? A multicenter randomized placebo-controlled phase III trial.

PURPOSE: Endocrine therapy (ET) used to reduce the risk of recurrence in hormone receptor-expressing disease (75% of breast cancers) is associated with worsening of climacteric symptoms with a negative impact on quality of life (QoL). Homeopathy might allow a better management of hot flushes (HF). METHODS: In this multicenter randomized double-blind placebo-controlled phase III study ( ClinicalTrials.gov NCT01246427), we enrolled ≥ 18 years old women with histologically proven non metastatic localized breast cancer, with Eastern Cooperative Oncology Group-Performance Status (ECOG-PS) ≤ 1, treated for at least 1 month with adjuvant ET, and complaining about moderate to severe HF. Patients should not be scheduled for chemotherapy or radiotherapy, and had no associated pathology known to induce HF. After a 2- to 4-week placebo administration, we randomly assigned (1:1) patients with HFS ≥ 10 using an interactive web-based centralized platform to BRN-01 homeopathic medicine complex (Actheane®) in arm A or Placebo (Arm P). Randomization was stratified by adjuvant ET (taxoxifen/aromatase inhibitor) and recruiting site. HF scores (HFS) were calculated as the mean of HF frequencies before randomization, at 4, and at 8 weeks post-randomization (pre-, 4w,- and 8w-) weighted by a 4-level intensity scale. Primary endpoint was assessed at 4-week post-randomization, as the variation between pre- and 4w-HFS. Secondary endpoints included HFS variation between pre- and 8w-HFS, compliance and tolerance assessed 8 weeks after randomization, and QoL and satisfaction assessed at 4- and 8-week post-randomization. RESULTS: Two hundred ninety-nine patients were included, and 138 (46.2%) randomized (A, 65; P, 73). Median 4w-HFS absolute variation (A, - 2.9; P, - 2.5 points, p = 0.756) and relative decrease (A, - 17%; P, - 15%, p = 0.629) were not statistically different. However, 4w-HFS decreased for 46 (75%) in A vs 48 (68%) patients in P arm. 4w-QoL was stable or improved for respectively 43 (72%) vs 51 (74%) patients (p = 0.470). CONCLUSIONS: The efficacy endpoint was not reached, and BRN-01 administration was not demonstrated as an efficient treatment to alleviate HF symptoms due to adjuvant ET in breast cancer patients. However, the study drug administration led to decreased HFS with a positive impact on QoL. Without any recommended treatment to treat or alleviate the HF-related disabling symptoms, Actheane® could be a promising option, providing an interesting support for better adherence to ET, thereby reducing the risk of recurrence with a good tolerance profile.

Feasibility of an exercise and nutritional intervention for weight management during adjuvant treatment for localized breast cancer: the PASAPAS randomized controlled trial.

PURPOSE: Lack of physical activity (PA), weight gain, and overweight have been associated with increased risk of recurrence and mortality after breast cancer diagnosis. We evaluated the feasibility of implementing an individualized exercise program and nutritional counseling during adjuvant treatment of localized invasive breast cancer. METHODS: Sixty-one patients eligible for adjuvant chemotherapy were randomized 2:1 to receive a 6-month program of weekly aerobic exercises associated with nutritional counseling (n = 41) or usual care with nutritional counseling (n = 20, one withdrawal). The primary endpoints were the proportion of patients compliant with two weekly supervised sessions and their overall adherence (i.e., proportion of supervised and unsupervised sessions completed versus planned sessions). RESULTS: Ten percent of patients in the intervention group were compliant with the two weekly supervised sessions for 6 months, but the overall median adherence rate was 85% of supervised and non-supervised sessions completed. Non-adherence was mainly due to intrinsic reasons (medical, organizational, psychological barriers). Adherence was positively associated with education and baseline PA level and inversely associated with baseline weight and tumor grade. No statistically significant benefits were observed in the intervention group, even if overall PA level and body composition improved and anthropometrics were maintained over time (p < 0.05). CONCLUSIONS: Overall, there was good adherence with the 6-month exercise program during adjuvant treatment for breast cancer, despite poor compliance to twice-weekly supervised sessions. This study highlights the need for flexible exercise modalities and innovative experimental design to reach patients who would most adhere and benefit from intervention. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01331772. Registered 8 April 2011, https://clinicaltrials.gov/ct2/show/NCT01331772?term=pasapas&rank=1.

Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial.

BACKGROUND: Pigmented villonodular synovitis (alternatively known as diffuse-type giant cell tumour) is a rare, locally aggressive tumour driven by a specific translocation resulting in the overexpression of colony-stimulating factor 1 (CSF1). CSF1 receptor (CSF1R) inhibitors (ie, tyrosine kinase inhibitors and antibodies) induce a response in patients with pigmented villonodular synovitis. We investigated the safety and efficacy of a CSF1R tyrosine kinase inhibitor, nilotinib, in patients with locally advanced non-resectable pigmented villonodular synovitis. METHODS: In this phase 2, open-label, single-arm study, we enrolled patients from 11 cancer centres of hospitals in four countries (France, Netherlands, Italy, and Australia). Eligible patients were aged at least 18 years with a WHO performance status of 2 or less, and histologically confirmed progressive or relapsing pigmented villonodular synovitis that was inoperable, or resectable only with mutilating surgery. Patients received oral nilotinib (400 mg twice per day) until disease progression, unacceptable toxicity, or completion of 1 year of treatment. The primary endpoint was the proportion of patients who were progression free at 12 weeks, which was centrally assessed according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were by modified intention to treat (ie, all patients with no major protocol violations who were treated with nilotinib for at least 3 weeks were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT01261429, and the results presented here are the final analysis of the trial. FINDINGS: Between Dec 15, 2010, and Sept 28, 2012, we enrolled 56 patients with pigmented villonodular synovitis and treated them with nilotinib. Five (9%) patients discontinued study treatment before week 12; therefore, 51 patients were evaluable for the primary endpoint at 12 weeks. The estimated proportion of patients who were progression free at 12 weeks was 92·6% (95% credible interval 84·3-97·9). 54 (96%) of 56 patients had a treatment-related adverse event. Six (11%) of 56 patients had at least one grade 3 treatment-related adverse event (headache, dizziness, and hepatic disorders [n=1], pruritus and toxidermia [n=1], diarrhoea [n=1], increased γ-glutamyl transferase concentration [n=1], anorexia [n=1], and increased headache [n=1]). No grade 4 or 5 adverse events were reported. One patient had a treatment-related serious adverse event (toxidermia) and two patients had serious adverse events not considered to be related to the study drug (borderline ovarian tumour [n=1] and pilonidal cyst excision [n=1]). INTERPRETATION: More than 90% of patients with locally advanced unresectable progressive pigmented villonodular synovitis achieved disease control with 12 weeks of nilotinib treatment. These results indicate that CSF1R tyrosine kinase inhibitors have anti-tumour activity with manageable toxicity in patients with inoperable progressive pigmented villonodular synovitis. Randomised trials investigating the efficacy of nilotinib for patients with unresectable pigmented villonodular synovitis are warranted. FUNDING: Novartis, Institut National du Cancer, EuroSARC, French National Cancer Institute, General Directorate of Care Supply, Lyon Research Innovation for Cancer, L'Agence nationale de la recherche, Laboratory of Excellence, Fondation ARC pour la recherche sur le cancer, Ligue contre le Cancer (comité de l'Ain), Info Sarcomes, and Association DAM'S.