Sandrine Baffert

Clinical effect of molecular methods in sarcoma diagnosis (GENSARC): a prospective, multicentre, observational study

BACKGROUND Advances in molecular genetics of sarcoma have enabled the identification of type-specific aberrations. We aimed to assess the clinical effect of systematic implementation of molecular assays to improve sarcoma misdiagnosis. METHODS In this multicentre, observational study, we recruited patients from 32 centres of the French Sarcoma Group/Reference Network in Pathology of Sarcomas. Eligibility criteria included: biopsy or surgical resection; suspicion of: dermatofibrosarcoma protuberans (cohort 1), dedifferentiated liposarcoma (cohort 2), Ewings sarcoma family of tumours (cohort 3), synovial sarcoma (cohort 4), alveolar rhabdomyosarcoma (cohort 5), and myxoid or round cell liposarcoma (cohort 6); review by one sarcoma-expert pathologist; availability of frozen material (except for cohort 1 of patients with dermatofibrosarcoma protuberans because anti-CD34 immunohistochemistry is performed on paraffin-embedded tissue); and patient information. For each case, the pathologist made one primary diagnosis followed by up to two differential diagnoses, based on histological characteristics only. Each diagnosis was classified as certain, probable, or possible. For each case to determine the molecular classification, we did fluorescence in-situ hybridisation on paraffin-embedded samples. We also did comparative genomic hybridisation and quantitative PCR (cohort 2) or reverse transcriptase PCR (cohorts 3-6) on frozen and paraffin-embedded samples. We made a final diagnosis based on the molecular results. The clinical effect of diagnosis correction was assessed by a board of experts. FINDING Between June 22, 2009, and Oct 30, 2012, 395 patients were enrolled in the study, of which 384 were eligible for inclusion. The diagnosis was eventually modified by molecular genetics for 53 patients: eight (16%) of 50 patients with dermatofibrosarcoma (cohort 1), seven (23%) of 30 patients with dedifferentiated liposarcoma (cohort 2), 13 (12%) of 112 with Ewings sarcoma family of tumours (cohort 3), 16 (16%) of 97 patients with synovial sarcoma (cohort 4), seven (15%) of 46 patients with alveolar rhabdomyosarcoma (cohort 5), and two (4%) of 49 patients with myxoid or round cell liposarcoma (cohort 6), with an effect on primary management or prognosis assessment in 45 cases. INTERPRETATION Molecular genetic testing should be mandatory for diagnostic accuracy of sarcoma and appropriate clinical management, even when histological diagnosis is made by pathologist experts in this field. FUNDING French National Cancer Institute and Nice University Hospital.

Abstract OT3-4-06: Circulating tumor cells to guide the choice between chemotherapy and hormone therapy as first line treatment for hormone receptors positive metastatic breast cancer patients: the STIC CTC METABREAST trial

Background: Baseline CTC count already demonstrated its accuracy as an independent prognostic marker in metastatic breast cancer (MBC), before the start of any treatment (Cristofanilli, NEJM 2004; Pierga Ann Oncol 2011) for progression free survival and overall survival. Multivariate analyses performed in both a pooled analysis (Liu, ASCO 2011) and in the IC 2006–04 study showed that the other independent prognostic factors were the performance status and hormone-receptor (HR) status. Oppositely, the other criteria that are frequently used to choose between hormone therapy and chemotherapy for the treatment of first line hormone receptor-positive MBC patients (e.g. number of metastatic sites, visceral disease, metastasis-free interval…) were not independent prognostic factors. As CTC count is highly correlated to PFS, we designed a large pivotal phase III trial to evaluate the use of CTC to determine the disease aggressiveness and the choice of first line treatment in potentially hormonosensitive MBC. Trial design: First line metastatic breast cancer patients will be randomized between the clinician choice and CTC count-driven choice. In the CTC arm, patients with ≥5 CTC/7.5ml will receive chemotherapy whereas patients with Eligibility criteria: Main inclusion criteria include hormone receptor-positive metastatic breast cancer patients with no previous treatment for the metastatic disease, and who can receive either hormone therapy or chemotherapy as first line treatment. Statistical methods: As every patient will receive a treatment, this pivotal trial has been designed to show a non-inferiority of the CTC arm for PFS (primary clinical endpoint) and a superiority of the CTC arm for the medico-economics study (co-primary endpoint). Present accrual and target accrual: This trial began in March 2012 and more than 15 French cancer centers participate to this study. The accrual of 996 metastatic breast cancer patients should be completed in 2 to 3 years. 20 patients have been included in 2 months in the first opened center. Contact information for people with a specific interest in the trial The STIC CTC METABREAST trial has been funded by the French Ministry of Health (STIC program) and Veridex. The promoter is the Institut Curie (Paris). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-4-06.

Abstract OT3-4-05: Use of early CIRculating tumor CElls count changes to guide the use of chemotherapy in advanced metastatic breast cancer patients: the CirCe01 randomized trial

Background: After the SWOG0500 trial, the CirCe01 trial (NCT01349842) is the second randomized attempt to demonstrate that patients who received a first cycle of chemotherapy and whose CTC count did not drop should be switched off this chemotherapy. The clinical setting used here is a population with high chemoresistance prevalence, i.e. patients starting a third line chemotherapy; the CTC test will be also repeated at the beginning of every new chemotherapy line in patients randomized in the CTC arm ( i.e. to evaluate the 3 rd , 4 th , 5 th … lines). In the CTC arm, it has been hypothesized that many patients with chemoresistant tumor will experience repeated early chemotherapy changes (e.g. 3 chemotherapy regimens tested in 9 weeks), giving support to the discontinuation of inefficient, toxic and costly chemotherapies and the start of palliative care. It is believed, for this subgroup of patients, that such de-escalating management will benefit both patients and healthcare systems. For some other patients, it is also expected that they will benefit from the early chemotherapy turn-around and find earlier an efficient therapy among all those tested. Methods: The main inclusion criteria are metastatic breast cancer patients starting a third line of chemotherapy and an elevated CTC count at baseline. 304 metastatic breast cancer patients will be randomized between the standard arm, in which the treatment management is made following the current standard of care, and the CTC-driven arm, in which the “response” after every first cycle of any new chemotherapy line is assessed by CTC count made before the second cycle. Chemotherapies which did not lead to a significant reduction of CTC count are discontinued, and the patient might be offered another chemotherapy regimen (which will be also evaluated by CTC). The medical primary endpoint of the trial is the overall survival, whereas a medico-economic study as a co-primary endpoint. Several secondary endpoints are pre-planned, including progression-free survival, quality of life, anxiety/depression and comparison with serum markers. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-4-05.

Determinants of return at work of breast cancer patients: results from the OPTISOINS01 French prospective study

Introduction Return to work (RTW) after breast cancer (BC) is still a new field of research. The factors determining shorter sick leave duration of patients with BC have not been clearly identified. The aim of this study was to describe work during BC treatment and to identify factors associated with sick leave duration. Materials and methods An observational, prospective, multicentre study was conducted among women with operable BC. A logbook was given to all working patients to record sociodemographic and work-related data over a 1-year period. Results Work-related data after BC were available for 178 patients (60%). The median age at diagnosis was 50 years (27–77), 87.9% of patients had an invasive form of BC and 25.3% a lymph node involvement. 25.9% had a radical surgery and 24.2% had an axillary dissection. Radiotherapy was performed in 90.9% of patients and chemotherapy in 48.1%. Sick leave was prescribed for 165 patients (92.7%) for a median of 155 days. On univariate analysis, invasive BC (p=0.025), lymph node involvement (p=0.005), radical surgery (p=0.025), axillary dissection (p=0.004), chemotherapy (p<0.001), personal income <€1900/month (p=0.03) and not having received the patient information booklet on RTW (p=0.047) were found to be associated with a longer duration of sick leave. On multivariate analysis, chemotherapy was found to be associated with longer sick leave (OR: 3.5; 95% CI 1.6 to 7.9; p=0.002). The cost of sick leave to French National Health Insurance was fourfold higher in the case of chemotherapy (p<0.001). Conclusion Advanced disease and chemotherapy are major factors that influence sick leave duration during the management of BC. Trial registration number NCT02813317.

Cost of cancer diagnosis using next-generation sequencing targeted gene panels in routine practice: a nationwide French study

It is currently unclear if next-generation sequencing (NGS) technologies can be implemented in the diagnosis setting at an affordable cost. The aim of this study was to measure the total cost of performing NGS in clinical practice in France, in both germline and somatic cancer genetics.The study was performed on 15 French representative cancer molecular genetics laboratories performing NGS panels’ tests. The production cost was estimated using a micro-costing method with resources consumed collected in situ in each laboratory from a healthcare provider perspective. In addition, we used a top–down methodology for specific post-sequencing steps including bioinformatics, technical validation, and biological validation. Additional non-specific costs were also included. Costs were detailed per step of the process (from the pre-analytical phase to delivery of results), and per cost driver (consumables, staff, equipment, maintenance, overheads). Sensitivity analyses were performed.The mean total cost of NGS for targeted gene panels was estimated to 607€ (±207) in somatic genetics and 550€ (±140) in germline oncogenetic analysis. Consumables were the highest cost driver of the sequencing process. The sensitivity analysis showed that a 25% reduction of consumables resulted in a 15% decrease in total NGS cost in somatic genetics, and 13% in germline analysis. Additional costs accounted for 30–32% of the total NGS costs.Beyond cost assessment considerations, the diffusion of NGS technologies will raise questions about their efficiency when compared to more targeted approaches, and their added value in a context of routine diagnosis.

Preoperative clinical pathway of breast cancer patients: determinants of compliance with EUSOMA quality indicators

Background:The European Society of Breast Cancer Specialists (EUSOMA) has defined quality indicators for breast cancer (BC). The aim of this study was to describe the preoperative clinical pathway of breast cancer patients and evaluate the determinants of compliance with EUSOMA quality indicators in the Optisoins01 cohort.Methods:Optisoins01 is a prospective, multicentric study. Data from operable BC patients were collected, including results from before surgery to 1 year follow-up. Seven preoperative EUSOMA quality indicators were compared with the clinical pathways Optisoins01.Results:Six hundred and four patients were included. European Society of Breast Cancer Specialists targets were reached for indicator 1 (completeness of clinical and imaging diagnostic work-up), 3 (preoperative definitive diagnosis) and 5 (waiting time). For indicator 8 (multidisciplinary discussion), the minimum standard of 90% of the patients was reached only in general hospitals and comprehensive cancer centres. Having more than 1 medical examination within the centre was associated with an increased waiting time for surgery, whereas it was reduced by having an outpatient breast biopsy. The comprehensive cancer centre type was the only parameter associated with the other quality indicators.Conclusions:European Society of Breast Cancer Specialists quality indicators are a useful tool to evaluate care organisations. This study highlights the need for a standardised and coordinated preoperative clinical pathway.

Abstract OT2-04-01: Optisoins01: Optimizing the patient-breast cancer care pathway; An observational multicentric prospective study

Background: A care pathway is defined as patient-focused global care that addresses temporal (effective and coordinated management throughout the illness) and spatial issues (treatment is provided near the health territory in or around the patient9s home). Heterogeneity of the care pathways in breast cancer (BC) is presumed but not well evaluated. The OPTISOINS01 study aims to assess every aspect of the care pathway for early BC patients using a temporal and spatial scope. Trial design: An observational, prospective, multicenter study in a regional health territory (Ile-de-France, France) in different types of structures: university or local hospitals and comprehensive cancer centers. The study consists of three work-packages: - Cost of pathway The aim of this WP is to calculate the overall costs of the early BC pathway at one year from different perspectives (society, health insurance and patient) using a cost-of-illness analysis. Using a bottom-up method, we will assess direct costs, including medical direct costs and nonmedical direct costs (transportation, home modifications, home care services, and social services), and indirect costs (loss of production). - Patient satisfaction and work reintegration Three questionnaires will assess the patients9 satisfaction and possible return to work: the occupational questionnaire for employed women; the questionnaire on the need for supportive care, SCNS-SF34 (9breast cancer9 module, SCNS-BR8); and the OUTPASSAT-35 questionnaire. - Quality, coordination and access to innovation Quality will be evaluated based on visits and treatment within a set period, whether the setting offers a multidisciplinary consultative framework, the management by nurse coordinators, the use of a personalized care plan, the provision of information via documents about treatments and the provision of supportive care. The coordination between structures and caregivers will be evaluated at several levels. Day surgery, home hospitalization and one-stop breast clinic visits will be recorded to assess the patient9s access to innovation. Inclusion criteria: Histologically confirmed, previously untreated, operable breast cancer women; residence in the Yvelines, Hauts-de-Seine or Val d9Oise departments, Ile-de-France, France. Exclusion criteria: previous history of breast cancer; metastatic, locally advanced, or inflammatory breast cancer, as defined by the AJCC (7th Edition); unstable over the following 12 months. Statistical methods: Homogeneous groups of patients will be established based on the patients9 individual medical information, and care pathways will be compared. The endpoints are the costs of care pathways, patients9 satisfaction, work reintegration, readmissions and time lapses between care stages. A multiple correspondence analysis will be conducted with care resource use and socio-demographic and medical characteristics as active variables. The variables that constitute the endpoints will be projected onto a space defined by appropriate axes. Present accrual and target accrual: 307 patients have been included on 800 scheduled. Citation Format: Lerebours F, Hequet D, Baffert S, Hoang HL, Bredart A, Asselain B, Alran S, Berseneff H, Huchon C, Trichot C, Combes A, Alves K, Koskas M, Nguyen T, Roulot A, Rouzier R. Optisoins01: Optimizing the patient-breast cancer care pathway; An observational multicentric prospective study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT2-04-01.

Cost Of Genome Analysis: The Sanger Sequencing Method.

(1) University of Lyon, F-69007 Lyon, France; CNRS, GATE Lyon-St Etienne, UMR 5824, 69130, Ecully, France; (2) Direction of Clinical Research and Innovation, DRCI, Léon Bérard Cancer Centre, Lyon, France; (3) Department of Health Economy, Institute Curie, 26 rue d’Ulm, 75005 Paris, France; (4) Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France; (5) Assistance Publique –Hôpitaux de Paris, 3 avenue Victoria, 75004 Paris, France; (6) Developmental Biology and Genetics, Institute Curie, 26 rue d’Ulm, 75005 Paris, France; (7) Department of bio pathology, Léon Bérard Cancer Centre, Lyon, France; (8) Department of anatomy and cytology, Edouard Herriot Hospital, Lyon, France; (9) University hospital, Pessac, France; (10) Department of Medical Biology and Pathology, Gustave Roussy, 114 Rue Edouard Vaillant, 94800 Villejuif, France; (11) Institut Paoli Calmette, 232 Bd Sainte Marguerite, 13273 Marseille, France

Abstract 2410: Circulating tumor cells to guide the choice between chemotherapy and hormone therapy as first line treatment for metastatic breast cancer patients: the STIC CTC METABREAST trial.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background Baseline CTC count already demonstrated its very good performance as an independent prognostic marker in metastatic breast cancer (MBC), before the start of any treatment (Cristofanilli, NEJM 2004; Pierga Ann Oncol 2011). Multivariate analyses performed in both a pooled analysis (Liu, ASCO 2011) and in the IC 2006-04 study showed that the other independent prognostic factors were the performance status and hormone-receptor (HR) status. Oppositely, the other criteria that are frequently used to choose between hormone therapy and chemotherapy for the treatment of first line hormone receptor-positive MBC patients (e.g. metastatic sites, metastasis-free interval…) were not independent prognostic factors. On the basis that CTC count may be a better criterion for this important choice than the currently used empiric criteria, we designed a large pivotal phase III trial. Methods N=996 HR+ M+ breast cancer patients will be randomized between the clinician choice and CTC count-driven choice. Main inclusion criteria include hormone receptor-positive MBC patients with no previous treatment for the metastatic disease, and who can receive either hormone therapy or chemotherapy as first line treatment. In the CTC arm, patients with ≥5 CTC/7.5ml will receive chemotherapy whereas patients with <5 CTC/7.5ml will receive endocrine therapy as first line treatment. As every patient will receive a treatment, this pivotal trial has been designed to show a non-inferiority of the CTC arm for PFS (primary clinical endpoint) and a superiority of the CTC arm for the medico-economics study (co-primary endpoint). The STIC CTC METABREAST trial has been funded by the French Ministry of Health (STIC program) and Veridex. The promoter is the Institut Curie (Paris). Results This trial began in February 2012 and more than 15 French cancer centers participate to this study. The accrual should be completed in 2 to 3 years. Conclusion This large pivotal phase III trial is intended to demonstrate the clinical relevance of baseline CTC count. Citation Format: Jean-Yves Pierga, Sandrine Baffert, David Hajage, Etienne Brain, Sebastien Armanet, Cecile Simondi, Laurent Mignot, Bernard Asselain, Patricia Tresca, Francois-Clement Bidard. Circulating tumor cells to guide the choice between chemotherapy and hormone therapy as first line treatment for metastatic breast cancer patients: the STIC CTC METABREAST trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2410. doi:10.1158/1538-7445.AM2013-2410

Abstract OT3-1-10: ASTER 70s (UNICANCER phase III trial): Is personalized adjuvant treatment for women over 70 with luminal breast cancer the way to go?

Background The question of the additional benefit of adjuvant chemotherapy (CT) compared to hormonal therapy alone (HT) for women >70 with ER+ / HER2- breast cancer (BC) and aggressive characteristics is still unsolved. This trial compares the impact of both strategies on overall survival (OS). Trial design Following surgery, ∼2,000 patients will have a Genomic Grade (GG) centrally performed on FFPE specimens. Those with a high or equivocal GG will be randomized HT alone vs HT+CT. Patients with low GG will be followed as an observational cohort. The study, on-going in France since April 2012, has been recently activated in Belgium. Eligibility criteria Any ER+ HER2- BC after complete surgery, M0, any pT or pN. Normal organ functions. No specific BC treatment before surgery. Contralateral BC, invasive BC after ductal carcinoma in situ and isolated local invasive relapse when adjuvant systemic treatment is considered are all eligible. Multifocal or bilateral are eligible according to focus with worst GG. The G8 screening tool is used as stratification criteria for randomization. Specific aims OS (all deaths) is the primary endpoint. Secondary objectives include competing events, cost-effectiveness and Q-TWiST analysis, geriatric dimension, acceptability/willingness and health-related quality of life including specific ELD15. The Lee9s 4-year mortality score is calculated. Translational research will focus on prognostic biomarkers and pharmacogenetic, investigating also the impact of treatments on putative ageing biomarkers as CRAMP, stathmin, EF-1α and chitinase and telomeres length. Statistical methods Sample size based on 4-year OS (87.5 vs 80%), bilateral test, α = 0.05, β = 0.20 and HR = 0.60. In total, 129 events are expected, requiring 340 patients/arm. Considering those lost to follow-up, ∼700 patients in total should be included (5 extra patients/year). Present accrual and target accrual As of May 2013, 43 centres have included 406 Patients aged 70-88. Only 14 GG evaluations were not performed for the following reasons: Patients consent withdrawal (n = 3), tumour block not available for the GG test (n = 5), CT not a treatment option anymore (patients or investigator9s decision) (n = 2) or tumour status (ER+/HER2-) not confirmed by central review (n = 4). 8 GG evaluations are on-going. Of 384 cases with GG report, 160 (42%), 151 (39%) and 65 (17%) were respectively GG-1 (low risk), GG-3 (high risk) and GG-EQ (equivocal); 8 (2%) tests failed for technical reasons. The proportion of high GG in the study (53%) is similar to those observed in previous studies in general BC populations (40% to 60%). Of 216 GG-3/-EQ cases, 4 were not randomized because of distant metastases detected during extensive work-up (n = 3) and Patient refusal of CT treatment before randomization (n = 1). Five randomizations are on-going. GG determination was obtained in 384 leading to randomization in 207, totalizing so far 30% of the projected recruitment for the primary objective. This confirms the feasibility of such multicentre strategic program with an innovative prognostic signature in the elderly BC population. Contact information c-orsini@unicancer.fr. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-10.