Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial.

BACKGROUND: Antitumor activity of molecular-targeted agents is guided by the presence of documented genomic alteration in specific histological subtypes. We aim to explore the feasibility, efficacy and therapeutic impact of molecular profiling in routine setting. PATIENTS AND METHODS: This multicentric prospective study enrolled adult or pediatric patients with solid or hematological advanced cancer previously treated in advanced/metastatic setting and noneligible to curative treatment. Each molecular profile was established on tumor, relapse or biopsies, and reviewed by a molecular tumor board (MTB) to identify molecular-based recommended therapies (MBRT). The main outcome was to assess the incidence rate of genomic mutations in routine setting, across specific histological types. Secondary objectives included a description of patients with actionable alterations and for whom MBRT was initiated, and overall response rate. RESULTS: Four centers included 2579 patients from February 2013 to February 2017, and the MTB reviewed the molecular profiles achieved for 1980 (76.8%) patients. The most frequently altered genes were CDKN2A (N = 181, 7%), KRAS (N = 177, 7%), PIK3CA (N = 185, 7%), and CCND1 (N = 104, 4%). An MBRT was recommended for 699/2579 patients (27%), and only 163/2579 patients (6%) received at least one MBRT. Out of the 182 lines of MBRT initiated, 23 (13%) partial responses were observed. However, only 0.9% of the whole cohort experienced an objective response. CONCLUSION: An MBRT was provided for 27% of patients in our study, but only 6% of patients actually received matched therapy with an overall response rate of 0.9%. Molecular screening should not be used at present to guide decision-making in routine clinical practice outside of clinical trials.This trial is registered with ClinicalTrials.gov, number NCT01774409.

Surgery in reference centers improves survival of sarcoma patients: a nationwide study.

BACKGROUND: NETSARC (netsarc.org) is a network of 26 sarcoma reference centers with specialized multidisciplinary tumor boards (MDTB) aiming to improve the outcome of sarcoma patients. Since 2010, presentation to an MDTB and expert pathological review are mandatory for sarcoma patients nationwide. In the present work, the impact of surgery in a reference center on the survival of sarcoma patients investigated using this national NETSARC registry. PATIENTS AND METHODS: Patients' characteristics and follow-up are prospectively collected and data monitored. Descriptive, uni- and multivariate analysis of prognostic factors were conducted in the entire series (N = 35 784) and in the subgroup of incident patient population (N = 29 497). RESULTS: Among the 35 784 patients, 155 different histological subtypes were reported. 4310 (11.6%) patients were metastatic at diagnosis. Previous cancer, previous radiotherapy, neurofibromatosis type 1 (NF1), and Li-Fraumeni syndrome were reported in 12.5%, 3.6%, 0.7%, and 0.1% of patients respectively. Among the 29 497 incident patients, 25 851 (87.6%) patients had surgical removal of the sarcoma, including 9949 (33.7%) operated in a NETSARC center. Location, grade, age, size, depth, histotypes, gender, NF1, and surgery outside a NETSARC center all correlated to overall survival (OS), local relapse free survival (LRFS), and event-free survival (EFS) in the incident patient population. NF1 history was one of the strongest adverse prognostic factors for LRFS, EFS, and OS. Presentation to an MDTB was associated with an improved LRFS and EFS, but was an adverse prognostic factor for OS if surgery was not carried out in a reference center. In multivariate analysis, surgery in a NETSARC center was positively correlated with LRFS, EFS, and OS [P < 0.001 for all, with a hazard ratio of 0.681 (95% CI 0.618-0.749) for OS]. CONCLUSION: This nationwide registry of sarcoma patients shows that surgical treatment in a reference center reduces the risk of relapse and death.

Cancer-related fatigue management: evaluation of a patient education program with a large-scale randomised controlled trial, the PEPs fatigue study.

BACKGROUND: To assess the efficacy of a patient educational program built according to guidelines that aims at reducing cancer-related fatigue (CRF). METHODS: Randomised controlled trial, multicentre, comparing a patient education program, vs the standard of care. Patients were adult cancer outpatients with any tumour site. The primary outcome was fatigue severity assessed with a visual analogical scale (VAS), between the day of randomisation and week 7. Secondary outcomes were fatigue assessed with other scales, health-related quality of life, anxiety and depression. The time to fatigue severity deterioration was assessed. Analyses were performed in a modified intent-to-treat way, that is, including all patients with at least one baseline and 1 week 7 score. RESULTS: A total of 212 patients were included. Fatigue severity assessment was made on 79 patients in the experimental group and 65 in the control group. Between randomisation and week 7, the fatigue (VAS) improved by 0.96 (2.85) points in the experimental group vs 1.63 (2.63) points in the control group (P=0.15). No differences with the secondary outcomes were highlighted between two groups. No other factors were found to be associated with fatigue severity deterioration. CONCLUSIONS: Despite rigorous methodology, this study failed to highlight the program efficacy in fatigue reduction for cancer patients. Other assessment tools should be developed to measure the effect of the program on CRF and behaviour. The implementation of the program should also be explored in order to identify its mechanisms and longer-term impact.

Genomic alterations and radioresistance in breast cancer: an analysis of the ProfiLER protocol.

BACKGROUND: Breast cancer (BC) patients with comparable prognostic features have heterogeneous outcomes, party related to a possible radiotherapy resistance leading to local-regional recurrences (LRR). The objective of the present study was to identify predictive molecular biomarkers of LRR of BC. PATIENTS AND METHODS: Genetic profile of 146 BC patients' tumours included in the ProfiLER clinical trial (NC01774409) between 2013 and 2016 were analysed using next-generation-sequencing and comparative-genomic-hybridization tests. Patients and tumour characteristics were retrospectively collected and analysed for association with genomic rearrangements (mutations, amplification, deletions). Only gene alterations observed in >3% of the tumours were selected. RESULTS: A total of 193 genomic rearrangements were identified, and 16 were observed in >3% of tumours. One was statistically correlated to the risk of local relapse. A median loco-regional progression-free survival (LRPFS) of 23.6 years was reported for PIK3CA mutation carriers (n = 31, 21.2%) versus 9.9 years for PIK3CA wild-type patients (HR 0.27, 95% CI 0.12-0.65, P = 0.002 in univariate analysis). PIK3CA mutation was identified as an independent protective factor on LRR using multivariate analysis (HR 0.29, 95% CI 0.09-0.99, P = 0.047). All other mutations, amplifications or deletions were not found associated with LRPFS. CONCLUSION: PIK3CA mutation was associated with a lower risk of local relapse in this population of BCs. This is consistent with recent studies suggesting PIK3CA to be part of biological pathways impacting the radiosensitivity.

[ISO 9001 certification of innovation and clinical research departments: Extending the scope of health assessment]. / Certification ISO 9001 des Directions de la recherche clinique et de l'innovation : vers une extension du périmètre aux évaluations économiques.

BACKGROUND: The International organization for standardization (ISO) is the world leader in providing industrial and commercial standards and certifications. Beyond medical devices, four French clinical research and innovation departments have received an ISO 9001 certification (the standard for quality management). Simultaneously, medico-economic studies have become increasingly important in the public decision process. Using the clinical research and innovation department from the Léon-Bérard Cancer Center as an example, the purpose of this article is to show how the scope of the ISO 9001 certification has been extended to cover medico-economic studies. METHOD: All of the processes, procedures, operating modes, documents, and indicators used by the clinical research and innovation department of the Léon-Bérard center were investigated. Literature searches were conducted using Medline keywords. The recommendations from the French national authority for health and other organizations, such as the International society for pharmacoeconomics and outcomes research (ISPOR), were also considered, as well as the recommendations of the General inspectorate of social affairs. RESULTS: In accordance with the national and international recommendations, two procedures were created and four procedures were revised at this center. Five indicators of quality and an evaluation chart were developed. CONCLUSION: By adopting the ISO 9001 certification into its medico-economic studies, the clinical research and innovation department of the Léon-Bérard center has used an innovative approach in the context of the growing importance of economic studies in decision-making.

Paclitaxel plus bevacizumab or paclitaxel as first-line treatment for HER2-negative metastatic breast cancer in a multicenter national observational study.

BACKGROUND: Bevacizumab combined with paclitaxel as first-line chemotherapy for patients with HER2-negative metastatic breast cancer (MBC) has led to mixed results in randomized trials, with an improvement in progression-free survival (PFS) but no statistically significant overall survival (OS) benefit. Real-life data could help in assessing the value of this combination. PATIENTS AND METHODS: This study aimed to describe the outcome following first-line paclitaxel with or without bevacizumab in the French Epidemiological Strategy and Medical Economics (ESME) database of MBC patients, established in 2014 by Unicancer. The primary and secondary end points were OS and PFS, respectively. RESULTS: From 2008 to 2013, 14 014 MBC patient files were identified, including 10 605 patients with a HER2-negative status. Of these, 3426 received paclitaxel and bevacizumab (2127) or paclitaxel (1299) as first-line chemotherapy. OS adjusted for major prognostic factors was significantly longer in the paclitaxel and bevacizumab group compared with paclitaxel [hazard ratio (HR) 0.672, 95% confidence interval (CI) 0.601-0.752; median survival time 27.7 versus 19.8 months]. Results were consistent in all supportive analyses (using a propensity score for adjustment and as a matching factor for nested case-control analyses) and sensitivity analyses. Similar results were observed for the adjusted PFS, favoring the combination (HR 0.739, 95% CI 0.672-0.813; 8.1 versus 6.4 months). CONCLUSIONS: In this large-scale, real-life setting, patients with HER2-negative MBC who received paclitaxel plus bevacizumab as first-line chemotherapy had a significantly better OS and PFS than those receiving paclitaxel. Despite robust methodology, real-life data are exposed to important potential biases, and therefore, results need to be treated with caution. Our data cannot therefore support extension of current use of bevacizumab in MBC.

ELYPSE-7: a randomized placebo-controlled phase IIa trial with CYT107 exploring the restoration of CD4+ lymphocyte count in lymphopenic metastatic breast cancer patients.

BACKGROUND: Lymphopenia is a predictive factor for hematological toxicity, progression and early death in advanced cancers including metastatic breast cancer (MBC). CYT107 is a recombinant interleukin 7 (IL-7) (Cytheris, now Revimmune), well tolerated and able to expand lymphocyte pool in humans. The aims of this study were to determine the optimal schedule to deliver CYT107 and to assess its effect on clinical end points. PATIENT AND METHODS: This placebo-controlled, double blind, phase IIa was conducted in MBC patients with <1500/µl lymphocytes treated with capecitabine. Using a 2-by-2 factorial design, 20 patients were randomly allocated to four arms to receive (i) before chemotherapy: CYT107 or placebo; then (ii) during chemotherapy: CYT107 or placebo. The primary end point was CD4+ count changes before and during chemotherapy. Secondary end points were hematological toxicity, safety, overall response, progression-free survival (PFS) and overall survival (OS). Quantification and functional competence of circulating immune cells were also assessed. RESULTS: When administered before chemotherapy, CYT107 induced a significant increase of CD4+ [+148.1% in CYT107 versus +9.9% in placebo groups, (Wilcoxon, P = 0.002)] and CD8+ T-cell counts, including both naïve and memory subsets. When CYT107 was administered during chemotherapy, the magnitude of CD4+ and CD8+ increase was less important. No modulation of immune cell functional competence was observed. CYT107 was well tolerated with no related ≥grade 3 adverse events except 1 fatal suspected unexpected serious adverse reaction (SUSAR) of uncertain relationship. Of the 12 cases evaluable for response, 6 of 7 patients (86%) receiving CYT107 before chemotherapy achieved a response or stabilization, whereas two of five patients (40%) receiving placebo achieved the same result. No significant difference was observed for PFS or OS. CONCLUSION: In lymphopenic MBC, CYT107 increases CD4+ and other T-cell subset counts without altering their function. A larger clinical trial to demonstrate its impact on clinical outcome is warranted. CLINICALTRIALSGOV IDENTIFIER: NCT01362107.

Influence of imatinib interruption and rechallenge on the residual disease in patients with advanced GIST: results of the BFR14 prospective French Sarcoma Group randomised, phase III trial.

BACKGROUND: We previously demonstrated that interruption of imatinib mesylate (IM) in responding patients (pts) with advanced gastrointestinal stromal tumours (GISTs) results in rapid reprogression. The impact of interruption on residual tumour, quality of response and secondary resistance has not been fully investigated. PATIENTS AND METHODS: Within the BRF14 study, 71 non-progressing patients were randomly assigned in the interruption arms after 1, 3 or 5 years. IM was resumed in the case of progressive disease (PD). Tumour status at randomisation, relapse and after IM rechallenge, progression-free survival (PFS) and time to secondary resistance were analysed. RESULTS: At data cut-off, 51 of 71 patients had restarted IM following documented PD. Eighteen patients (35%) progressed on known lesions only, while 33 patients (65%) had new lesions, with concomitant progression of known lesions in 17 patients. Only 8 (42%) of complete remission (CR) patients and 12 (52%) of partial response (PR) patients at randomisation achieved a new CR and PR. Patients progressing rapidly after interruption had a poorer prognosis. Tumour status at randomisation influenced time to progression after rechallenge. CONCLUSION: In advanced GIST patients interrupting IM, quality of response upon reintroduction did not reach the tumour status observed at randomisation. Rapid progression after imatinib interruption is associated with poor PFS after reintroduction.

Imatinib rechallenge in patients with advanced gastrointestinal stromal tumors.

BACKGROUND: Imatinib is the standard of care for patients with advanced gastrointestinal stromal tumors (GIST). DESIGN: This article reviews recent data on the impact of imatinib treatment interruption and subsequent rechallenge in patients with advanced GIST. RESULTS: The randomized BFR14 trial showed that (i) interruption of imatinib after 1, 3, or 5 years of treatment in patients with nonprogressive GIST was associated with a high risk of progression even in patients with a complete response; (ii) rechallenge with imatinib restored tumor control in most patients, but the tumor response seldom reached that before treatment interruption; (iii) patients receiving continuous imatinib had a high rate of prolonged tumor control, which increased with longer imatinib treatment. The findings in the metastatic setting have important implications regarding the duration of adjuvant imatinib in GIST. CONCLUSIONS: Discontinuation of imatinib in responding patients with advanced GIST is associated with a high risk of progression and is therefore not recommended. Although rechallenge is a strategy for treating patients who relapse after stopping imatinib, suboptimal tumor response indicates that continuous kinase suppression is necessary to achieve the best clinical outcome. Three-year adjuvant imatinib is recommended for patients with resected 'high-risk' GIST; however, a longer duration may provide additional benefits.

The PhaSeal® system: impact of its use on workplace contamination and duration of chemotherapy preparation.

PURPOSE: The primary objective of this study was to compare the levels of environmental contamination before and after the introduction of PhaSeal® (closed-system drug transfer device) in two hospital pharmacies. Our secondary objective was to assess the impact of the device on the duration of drug preparation compared to procedures involving the use of needles and syringes. METHODS: The study involved two French hospitals, which prepared antineoplastic chemotherapy using a biological safety cabinet and an isolator. Five skilled pharmacy technicians at each hospital prepared a total of 100 chemotherapy preparations using the standard procedure and 100 using the PhaSeal® system. To control for possible contamination occurring in the course of the procedure, we used fluorescein which becomes fluorescent when exposed to UV light. To reply the second objective, we timed the duration of the different steps of the manipulation. RESULTS: Our findings showed a major reduction in the contamination of the work environment when using the PhaSeal® system for drug preparation. Reduction rates higher than 93% were obtained, whatever the type of protection used. On the duration of preparation, our results indicate that this duration would be approximately 1 h longer for the preparation of 100 samples. CONCLUSION: In conclusion, this study clearly establishes the benefit of using PhaSeal® for protecting the staff members who work with hazardous agents. It also indicates that the duration of drug preparation is not impacted by the use of the system.

Phase II study of carboplatin and etoposide in patients with anaplastic progressive metastatic castration-resistant prostate cancer (mCRPC) with or without neuroendocrine differentiation: results of the French Genito-Urinary Tumor Group (GETUG) P01 trial.

BACKGROUND: In the evolution of metastatic castration-resistant prostate cancer (mCRPC), patients present visceral metastases with or without neuroendocrine differentiation in 20% of cases. PATIENTS AND METHODS: We assessed the efficacy and toxicity of a platinum-based chemotherapy regimen in mCRPC patients with either neuroendocrine differentiation defined by high serum levels of chromogranin A (CgA) and neuron-specific enolase (NSE) or visceral metastases. Patients received the combination of carboplatin and etoposide every 3 weeks. Efficacy end points included prostate-specific antigen (PSA) and neuroendocrine marker response, objective response and toxicity. RESULTS: Of the 60 patients included from April 2005 to January 2008, 78.6% had bone metastases, 46.4% had lymph node involvement and 57.1% had liver and/or lung localizations. The objective response rate was 8.9% in the 46 patients with measurable disease. A neuroendocrine response was observed in 31% of cases for NSE and 7% for CgA. The PSA response rate was 8%. The most common grade 3-4 treatment-related toxic effects were neutropenia (65.5%), thrombocytopenia (32.7%) and anemia (27.3%). There was 7.2% febrile neutropenia, with one toxicity-related death. The median follow-up was 9.3 months [95% confidence interval (CI) 0.2-27.1] and the median overall survival 9.6 months (95% CI 8.7-12.7). CONCLUSION: The benefit-risk ratio of this regimen seems unfavorable due to poor response and high toxicity.

Imatinib for progressive and recurrent aggressive fibromatosis (desmoid tumors): an FNCLCC/French Sarcoma Group phase II trial with a long-term follow-up.

BACKGROUND: Imatinib evaluated as a new treatment option in patients with recurrent or established progressive aggressive fibromatosis/desmoid tumor (AF/DT). PATIENTS AND METHODS: Forty patients with unresectable and progressive symptomatic AF/DT were treated with imatinib (400 mg/day for 1 year) in a Simon's optimal two-stage phase II study (P(0) = 10%, P(1) = 30%, α = 5%, ß = 10%). The primary end point was non-progressive at 3 months (RECIST). RESULTS: The study population consisted of 28 women and 12 men, with a mean age of 41 (range 20-72 years). Most of the primary sites were extra-abdominal (24, 54.5%). Familial adenomatous polyposis was observed in six (15%) cases. The median follow-up was 34 months. Imatinib toxicity was similar to that previously reported in literature. Tumor assessment was validated by a central independent radiology committee for 35 patients At 3 months, one (3%) complete and three (9%) partial confirmed responses were observed. The non-progression rates at 3, 6 and 12 months were, respectively, 91%, 80% and 67%. The 2-year progression-free and overall survival rates were 55% and 95%, respectively. Two patients with mesenteric AF/DT died from progressive disease. CONCLUSION: Imatinib is active in the treatment of recurrent and progressive AF/DT, providing objective response and long-term stable disease in a large proportion of patients.

Evolution of overall survival and receipt of new therapies by subtype among 20 446 metastatic breast cancer patients in the 2008-2017 ESME cohort.

BACKGROUND: Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008. PATIENTS AND METHODS: We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2-; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD). RESULTS: The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2- MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2- and TNBC cohorts, respectively, whatever YOD. CONCLUSION: OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed.

Delayed care for patients with newly diagnosed cancer due to COVID-19 and estimated impact on cancer mortality in France.

BACKGROUND: The impact of the first coronavirus disease 2019 (COVID-19) wave on cancer patient management was measured within the nationwide network of the Unicancer comprehensive cancer centers in France. PATIENTS AND METHODS: The number of patients diagnosed and treated within 17 of the 18 Unicancer centers was collected in 2020 and compared with that during the same periods between 2016 and 2019. Unicancer centers treat close to 20% of cancer patients in France yearly. The reduction in the number of patients attending the Unicancer centers was analyzed per regions and cancer types. The impact of delayed care on cancer-related deaths was calculated based on different hypotheses. RESULTS: A 6.8% decrease in patients managed within Unicancer in the first 7 months of 2020 versus 2019 was observed. This reduction reached 21% during April and May, and was not compensated in June and July, nor later until November 2020. This reduction was observed only for newly diagnosed patients, while the clinical activity for previously diagnosed patients increased by 4% similar to previous years. The reduction was more pronounced in women, in breast and prostate cancers, and for patients without metastasis. Using an estimated hazard ratio of 1.06 per month of delay in diagnosis and treatment of new patients, we calculated that the delays observed in the 5-month period from March to July 2020 may result in an excess mortality due to cancer of 1000-6000 patients in coming years. CONCLUSIONS: In this study, the delays in cancer patient management were observed only for newly diagnosed patients, more frequently in women, for breast cancer, prostate cancer, and nonmetastatic cancers. These delays may result is an excess risk of cancer-related deaths in the coming years.

Immune checkpoint inhibitor treatment of a first cancer is associated with a decreased incidence of second primary cancer.

BACKGROUND: Second primary cancers (SPCs) are diagnosed in over 5% of patients after a first primary cancer (FPC). We explore here the impact of immune checkpoint inhibitors (ICIs) given for an FPC on the risk of SPC in different age groups, cancer types and treatments. PATIENTS AND METHODS: The files of the 46 829 patients diagnosed with an FPC in the Centre Léon Bérard from 2013 to 2018 were analyzed. Structured data were extracted and electronic patient records were screened using a natural language processing tool, with validation using manual screening of 2818 files of patients. Univariate and multivariate analyses of the incidence of SPC according to patient characteristics and treatment were conducted. RESULTS: Among the 46 829 patients, 1830 (3.9%) had a diagnosis of SPC with a median interval of 11.1 months (range 0-78 months); 18 128 (38.7%) received cytotoxic chemotherapy (CC) and 1163 (2.5%) received ICIs for the treatment of the FPC in this period. SPCs were observed in 7/1163 (0.6%) patients who had received ICIs for their FPC versus 437/16 997 (2.6%) patients receiving CC and no ICIs for the FPC versus 1386/28 669 (4.8%) for patients receiving neither CC nor ICIs for the FPC. This reduction was observed at all ages and for all histotypes analyzed. Treatment with ICIs and/or CC for the FPC are associated with a reduced risk of SPC in multivariate analysis. CONCLUSION: Immunotherapy with ICIs alone and in combination with CC was found to be associated with a reduced incidence of SPC for all ages and cancer types.