Search

Summary Background In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events. Methods PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901. Findings 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3–8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93–1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group. Interpretation The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months. Funding The French National Cancer Institute.

Background: Eribulin mesylate (E7389) is a non-taxane microtubule dynamics inhibitor with a novel mode of action. EMBRACE was the first trial to compare overall survival (OS) of this new chemotherapeutic agent to real-life treatment choices (treatment of physician's choice; TPC) in heavily pretreated subjects with advanced breast cancer. TPC was any monotherapy (cytotoxic, hormonal, biologic) or supportive care only. It was previously reported that the study met its primary endpoint with a significant improvement in OS by a median of 2.5 months with eribulin vs. TPC. That primary analysis was based on 422 of 762 events that occurred by May 12, 2009; here we present an updated survival analysis requested by the FDA of the pivotal Phase 3 study through March 3, 2010. Methods: This report is an updated survival analysis based on 589 of 762 (77.3%) events that occurred by March 3, 2010. Data were censored for subjects who were still alive, lost to follow-up, or withdrew consent on or before the date of data cut-off (March 3, 2010). A treatment arm comparison of OS was performed (with geographic region, HER2/neu status and prior capecitabine use as stratification factors for randomization) using a stratified log-rank test. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated to assess the magnitude of the treatment benefit. Results: Seven hundred sixty two women were randomized in the study; 508 to the eribulin arm and 254 to the TPC arm. 386 (76.0%) events occurred in the eribulin-treated arm while 203 (79.9%) events were recorded in the TPC-treated group. Nine (1. 8%) eribulin and 5 (2.0%) TPC patients were lost to follow-up or withdrew consent. OS was significantly longer in the eribulin treatment arm as compared with the TPC treated arm. (p=0.014; HR 0.805; 95% CI 0.677, 0.958). Median OS was 403 days (13.2 months) compared with 321 days (10.5 months) for TPC. A sensitivity analysis in the following 3 populations showed that the HR was similar to the primary (intent to treat) analysis and the treatment difference was statistically different: population of subjects treated (p = 0.016; HR 0.806; 95% CI 0.676, 0.960), at the cut-off of 572 (75%) deaths (p=0.008; HR 0.787; 95% CI 0.660, 0.939) and with no stratification terms (p=0.024; HR 0.822; 95% CI 0.694, 0.975). Based on the Kaplan-Meier analysis, eribulin-treated subjects had a 1-yr and 2-yr survival rate estimate of 54.5 and 21.9% compared with 42.8 and 19.2% for TPC, respectively. Conclusions: The OS advantage associated with eribulin treatment reported in the primary analysis was maintained throughout the observation period. The results of this OS-updated analysis support the initial OS analysis of the pivotal trial EMBRACE, demonstrating the superiority of eribulin over TPC in heavily pretreated women with advanced breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-18.

Introduction Les donnees en vie reelle apportent des informations complementaires aux essais cliniques et contribuent a l’amelioration des connaissances scientifiques. Les etablissements de sante (EDS) (CLSS, CHU, CH et etablissements prives) gerent un nombre important de donnees sur le diagnostic, la prise en charge (PEC) therapeutique et le suivi de patients traites pour un cancer bronchopulmonaire (CBP). Suite au developpement des connaissances sur la biologie moleculaire et a l’arrivee de nouvelles therapies, l’objectif de ce projet est de constituer une base de donnees (BDD) en vie reelle, representative au niveau national pour permettre de decrire et comprendre les impacts de l’evolution de la PEC des CBP. Methodes Dans le cadre du Programme epidemio-strategie medicoeconomique (ESME), R&D Unicancer, sous l’egide d’un Groupe scientifique ESME compose de pneumologues, d’oncologues et methodologistes, a constitue un echantillon de 36 EDS prenant en charge les CBP. R&D Unicancer coordonne ainsi une BDD fondee sur un recueil standardise et evolutif de donnees sur les caracteristiques des patients (sociodemographiques, comorbidites), les caracteristiques de la tumeur, integrant la biologie moleculaire, les caracteristiques de prise en charge (type de traitements, nombres de lignes, effets secondaires significatifs…), les consommations de soins (hospitalisations, medicaments, actes…) et le suivi des patients tout au long de la PEC du CBP. L’interrogation de la BDD est accessible pour toute question de recherche validee par le GS ESME CBP, sous l’autorite des comites scientifique et de deontologie. Resultats La selection des EDS participants est en cours de constitution. Debut 2018, les donnees des 4000 premiers patients sont attendues dans la BDD, avec un objectif de 26 000 patients d’ici 2022. L’analyse des donnees permettra de repondre aux interrogations des medecins chercheurs des EDS participants sur l’evolution des differentes strategies therapeutiques et leurs determinants. Les partenaires industriels pourront solliciter des analyses specifiques pour alimenter par exemple des dossiers destines aux autorites de sante. Conclusion Cette BDD vise a devenir une source unique en Europe de donnees en vie reelle sur la PEC du CBP. Le projet ESME CBP, ouvert a tout industriel, est a ce jour soutenu par AstraZeneca.

Resume Le vieillissement n'est pas une maladie. Toutefois, avec l'âge, l'incidence des cancers augmente. La prise en charge des personnes âgees atteintes de cancer a ses specificites « techniques » qui aboutissent a decider ou non, a appliquer ou non et a ajuster ou non les traitements du cancer de la facon la plus individuelle qui soit. Cela sous-entend une approche globale et pluridisciplinaire du malade âge atteint de cancer. Parmi les acteurs de soins, les psycho-oncologues auront a explorer le monde bien vaste et encore peu connu des comportements des personnes âgees atteintes de cancer et leur retentissement sur la maladie et les resultats des traitements et sur la qualite de vie des patients. C'est ce qu'attend « l'onco-un peu psychologue » du « psycho-un peu oncologue »…

La chimiosensibilite du cancer de l’ovaire est reconnue depuis plus de 30 ans. Pourtant, cette pathologie n’est chimiocurable que dans de tres faibles proportions aux stades evolues. C’est pourquoi plusieurs strategies ont ete envisagees pour consolider ou maintenir l’effet antitumoral obtenu par le traitement de premiere ligne: la poursuite de la chimiotherapie a dose conventionnelle, la chimiotherapie a haute dose avec support hematologique, la chimiotherapie intraperitoneale, l’immunotherapie et, plus recemment, les therapeutiques ciblees.

Systemic therapy for triple negative breast cancer (TNBC) is mostly based upon chemotherapy. Epithelial Growth Factor Receptor (EGFR) is overexpressed in around 50% of TNBC and may play a role in its pathogenesis. Consequently, we performed a multicentric pilot Phase II neoadjuvant trial of cetuximab (anti-EGFR antibody) combined with docetaxel for patients with operable, Stage II-III TNBC. Therapy consisted of weekly cetuximab (first infusion: 400 mg/m(2), then 250 mg/m(2)) combined with six cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Subsequently, all patients underwent surgery. The primary endpoint was pathological complete response (pCR) while clinical response, toxicity and ancillary studies were secondary endpoints. Paraffin-embedded and frozen tumor samples were systematically collected in order to identify predictive biomarkers of efficacy and resistance. From a total of 35 accrued patients, 25 were assessable for pathologic response. The pCR rate was 24% [95% CI: 7.3-40.7]. Complete clinical response rate (cCR) was observed in 22% of cases. Conservative surgery was performed in 75% of patients. Toxicity, mostly cutaneous and hematologic, was manageable. The pre-therapy ratio between CD8+ and FOXP3+ tumor-infiltrating lymphocytes equal or higher than 2.75 was predictive of pCR: 43% versus 0%, p = 0.047. Cetuximab in combination with docetaxel displays a modest activity, but acceptable toxicity as neoadjuvant therapy of operable TNBC. Similarly to previous observations using panitumumab, another anti-EGFR antibody, the immune component of the tumor microenvironment may play an important role in predicting TNBC response to the neoadjuvant therapy.

Weight variation has been reported as a side effect of chemotherapy treatment in early breast cancer patients and has been identified as a factor of poor prognosis. Causes of weight variation during chemotherapy and mechanisms involved in the poor prognosis have been little studied. Here is reviewed the current knowledge about the main causes and mechanisms involved in body weight change. Special emphasis is placed on factors associated with weight variation which could potentially be involved in the risk of relapse in breast cancer survivors. In recent decades, some studies have investigated the causes of weight variation by studying energy balance of breast cancer patients during chemotherapy. Weight gain or loss may be the consequence of energy imbalance through different factors linked with chemotherapy, such as poor treatment tolerance, decreased muscle mass and function, or hormonal alterations. This results in body composition modifications in favour of fat gain and/or lean body mass loss. Increased adipose tissue, especially in the abdominal region, could induce metabolic disturbances such as insulin resistance, through various pathways involving adipokines. These molecules have growth properties and could therefore play a role in cancer relapse. Understanding such mechanisms is key to developing preventive strategies for improving the prognosis of early-stage breast cancer patients.

Background Platinum rechallenge or weekly topotecan in combination have not been evaluated in randomized trials for resistant recurrent ovarian cancer (ROC). Methods Patients with ROC after first- or second-line treatment including a platinum and taxane and progression within 6 months were randomized to weekly paclitaxel (wP, 80 mg/m2/week) alone or in combination with carboplatin (C, area under the curve of 5 mg/ml/min every 4 weeks) or weekly topotecan (wT, 3 mg/m2/week). Primary end point was progression-free survival (PFS) comparing wP and combination therapy. Results Patients (n = 165) received a median three cycles in each arm. Nonhematologic toxicity was not different, except increased hypersensitivity reactions with wP + C. Grade 3–4 hematologic toxic effects with wP, wP + C, and wP + wT, respectively, were neutropenia in 13%, 54%, and 42%; febrile neutropenia in 0%, 4%, and 5%; and anemia in 6%, 19%, and 29%. Response rates were 35%, 37%, and 39%, and median PFS times were 3.7, 4.8, and 5.4 months, respectively. PFS was not significantly different among the treatment arms [hazard ratio (HR) 0.922; 95% confidence interval (CI) 0.765–1.111; P = 0.46] or between monotherapy and combination therapy (HR 0.951; 95% CI 0.686–1.318; P = 0.76). Conclusions Combination chemotherapy in platinum-resistant ROC was more toxic than weekly paclitaxel and did not significantly prolong PFS.

Introduction Vu les exigences croissantes relativement aux aspects financiers de la recherche et des soins, il devient imperatif, avant d’accepter de participer a un essai ou avant d’en promouvoir, de prevoir les besoins en personnels et les flux financiers qui en decoulent. Les grilles d’evaluation proposees pour les PHRC par exemple ne sont pas suffisantes, en particulier pour evaluer dans le temps les besoins en ressources humaines (RH). Methodes Depuis plus de 20 ans au Centre Jean-Perrin, un logiciel fonctionnant sous Windows avec une BdD Access permet de centraliser les essais cliniques, de comptabiliser les inclusions et d’evaluer les couts associes. Une derniere extension de ce logiciel propose aujourd’hui de gerer retrospectivement et prospectivement les besoins en personnels et de gerer les flux financiers (ex. declencher les facturations aupres des industries pharmaceutiques). Pour ce faire, differents elements, principalement fournis par les conventions, sont saisis : – couts fixes : principalement le temps passe pour le demarrage de l’essai ; – couts variables, c’est-a-dire proportionnels au nombre d’inclusions : besoins en RH selon la fonction (medecin, ARC, chef de projet, infirmiere…) ; – montant des compensations financieres prevues : globalement et par patient inclus/screene ; Ces informations peuvent etre associees a des delais et des retards, ce qui permet de les etaler dans le temps. Le logiciel realise ensuite les calculs sur un ou plusieurs essais et pour l’intervalle de temps demande. Resultats La centralisation de ces informations fournit des tableaux de bord avec les besoins mensuels en RH, avec les surcouts engendres par la recherche clinique et enfin les flux financiers comprenant les facturations a declencher et l’encaissement des factures emises. Ces informations sont exportables sous forme de tableaux EXCEL et peuvent ensuite etre transmises aux services comptables ou aux organismes de tutelle. Les resultats de l’annee 2014 montrent une bonne adequation entre prediction et realisation. Conclusion La precision des previsions depend evidemment de la « finesse » des informations entrees. Plusieurs donnees influent de maniere majeure sur les resultats produits : – la justesse du nombre prevu d’inclusions par essai ; – une declaration detaillee dans le protocole et la convention des actes a realiser en plus ; – la duree des suivis ; – et enfin la quantite d’information a entrer dans les CRF. Pour la facturation, si les sorties d’essai sont gerees, il s’est avere parfois difficile de denombrer les actes effectivement realises pour les protocoles palliatifs ou les traitements n’ont pas une duree fixe mais durent jusqu’a progression. L’entree des informations comptables et temporelles requiert une certaine expertise et necessite un temps non negligeable. Ce logiciel permet aussi d’affecter les surcouts de la recherche clinique aux differents services produisant des actes (pharmacie, imagerie, laboratoires, unites de soin…). Ce logiciel peut etre fourni en l’etat ou bien servir de base a de nouveaux developpements.

Background Tumor EGFR and KRas mutations are both predictive and prognostic biomarkers in patients with advanced NSCLC. We analyzed the correlation between these biomarkers and treatment outcomes in a phase III trial of 3rd/4th line sorafenib in patients with NSCLC. Methods The global, randomized, placebo-controlled MISSION trial enrolled 703 patients with advanced relapsed/refractory NSCLC of predominantly non-squamous histology. The primary study endpoint was overall survival (OS). EGFR and KRas mutations were analyzed in archival tumor samples and in circulating tumor DNA isolated from plasma. Results Tumor and/or plasma mutation data were available from 347 patients (49%). EGFR and KRas mutations were detected in 89 (26%) and 68 (20%) patients, respectively, and were well balanced between treatment arms. Analysis of the interaction between EGFR mutation status and treatment effect on survival suggested that patients with EGFR mutations (mEGFR) benefitted from sorafenib, while those with wild-type EGFR (wtEGFR) did not (p = 0.023). Median OS was two-fold longer in mEGFR patients receiving sorafenib versus placebo (423 vs 197 days, HR 0.48, p = 0.002). There was no significant difference in OS between patients with wtEGFR receiving sorafenib or placebo (253 vs 256 days, HR 0.92, p = 0.559). An interaction was also seen between EGFR mutation status and the sorafenib effect on PFS (p = 0.015). Patients with mEGFR treated with sorafenib had better outcomes compared to placebo based on Cox regression analysis (HR 0.27, p Conclusion Post-hoc analyses of efficacy outcomes in MISSION suggest that advanced NSCLC patients with EGFR mutations may derive a survival benefit from receiving 3rd/4th line sorafenib. These results must be interpreted with caution due to the small, non-representative nature of the genetic biomarker subpopulation analyzed in this trial. Further prospective investigation may be warranted. Disclosure T.S.K. Mok: Honoraria: AstraZeneca, Roche, Eli Lilly, Merck Serono, Eisai, BMS, BeiGene, AVEO, Pfizer, Taiho, Boehringer Ingelheim, and GSK Biologicals Speaker: Astrazeneca, Roche, Eli Lilly, Boehringer Ingelheim, and Merck Serono Research funding: Astrazeneca. L. Paz-Ares: Dr. Paz-Ares has received honoraria from Bayer HealthCare Pharmaceuticals, Lilly, Roche and Pfizer. Y. Wu: Dr. Wu has received lecture fees from Roche, AstraZeneca, Eli Lilly, and Pfizer. V. Hirsh: Member of the steering committee for the MISSION trial. C. Lathia: Dr. Lathia is an employee of Bayer HealthCare. T.J. Ong: Dr. Ong is an employee of, and owns shares in, Bayer HealthCare. C. Pena: Dr. Pena is an employee of Bayer HealthCare. All other authors have declared no conflicts of interest.

A 33-year-old woman developed progressive ovarian cancer resistant to classical chemotherapy agents. We performed a bone marrow allograft after a myeloablative regimen. During hematological recovery, she developed acute graft-versus-host disease (GVHD). From this time her tumor diminished progressively. One year post transplant she has limited chronic liver GVHD and is still free of disease. The complete remission of advanced ovarian cancer was probably related to the GVHD which might therefore provide a new treatment option for this disease.

Background : Studies have demonstrated the feasibility and accuracy of sentinel lymph node (SLN) biopsy after neoadjuvant chemotherapy (NAC) in breast cancer. Some SLN-positive patients have low risk of non-sentinel lymph node (non-SLN) involvement. The aim of the present study performed on this group of SLN-positive patients after NAC was to determine clinicopathological factors associated with non-SLN involvement and to test scoring systems predicting the risk of additional nodal metastases currently available for SLN-positive patients not treated with NAC.Patients and methods : Patients with infiltrating breast carcinoma (n= 132) were studied prospectively. All patients received NAC. At surgery, SLN biopsy followed by axillary lymph node dissection was performed. Lymphatic mapping was done using the isotope method. Fifty-one patients were SLN positive.Results : In univariate analysis, tumor size more than 26 mm (P= 0.016) and the size of SLN metastases more than 2 mm (P= 0.0055) were significantly correlated with the presence of non-SLN metastases. In multivariate analysis, SLN macrometastases conferred a 10.2-fold greater risk of non-SLN positivity than SLN micrometastases (P= 0.047, 95%-confidence interval, 1.15-90.2). The Memorial Sloan-Kettering Cancer Center nomogram was not reliably predictive for non-SLN metastases (AUC, area under the receiver operating characteristic curve, of 0.542), whereas the MD Anderson (AUC= 0.716) and Tenon scoring systems (AUC= 0.778) were validated.Conclusion: Our results suggest that clinicopathological factors predicting non-SLN involvement in SLN-positive patients with and without NAC are essentially the same. The risk of involvement may be assessed using existing nomograms, but additional large prospective studies are needed to determine their accuracy in patients after NAC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1011.

Background: NCT is increasingly used for operable breast cancer to allow breast conservation. Our objective was to evaluate clinical and pathological response after sequential NCT of 3 cycles of FEC 100- 3 cycles of T. This chemotherapy is currently the reference in the adjuvant setting in France.In PACS 01 trial (Roche et al. J Clin Oncol, 2006) FEC followed by T significantly improved 5 years overall survival rates (90.7%) compared to 6 FEC 100 in node-positive breast cancer. However this active combination has not yet been evaluated in NCT.Methods: 101 patients (pts) from February 2005 to September 2008 with pathologically confirmed stage II-III untreated operable breast cancer received 3 cycles (c) of FEC 100 (epirubicin 100 mg/m² + 5-fluorouracil and cyclophosphamide 500mg/m²) followed by 3 c of T (100mg/m²) every 3 weeks. pCR was defined according to Chevallier's (Am J Clin Oncol, 1993) as level 1 and 2 and to Sataloff's classification (J Am Coll Surg, 1995) as grade A. A clinical, mammography and ultrasound breast evaluation was performed at baseline, after 3 c and before surgery.Results: Median age was 52.3 years [28-72]. Median diameter of the tumor was 42 mm [14-100]. 83 pts had a ductal, 14 a lobular, 3 ductal and lobular, 1 another carcinoma. 8.9% were grade I SBR, 58.4% grade II SBR, 28.7% grade III SBR and 4% unspecified. 74 (73.3%) tumors were HR+, 9(8.9%) Her-2 + and 18(17.8%) triple negative. 55 pts (54.4%) were premenopausal.After 3 cycles of FEC 100, ultrasound objective response rate (ORR) was 15%: 13 pts had a partial response and 2 pts had a complete response.After 6 cycles of NCT, ultrasound ORR was 62.5%: 53 pts had a partial response and 7 pts had a complete response.Most frequent grade (G) 3-4 adverse events were neutropenia which occured in 16 pts (15.8%) with G 3 febrile neutropenia in 11 pts (10.9%) (G-CSF optional). Most frequent G 1-2 averse events were nausea which occured in 43 pts(42.6%), myalgia in 27 pts(26.7%) and stomatitis in 23 pts(22.8%).After the completion of NCT, 76 pts (75.2%) underwent breast-conserving surgery. 12(11.9%) achieved pCR using Chevallier's classification and 15(14.8%) using Sataloff's classification.Conclusion: Sequential NCT with FEC followed by T was active and relatively well tolerated. Breast-conserving rate appeared satisfactory. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1105.

5557 Background: For ROC patients (pts) with early progression during or after (< 6 months) platinum and 3 weekly P, use of single non-platinum agent including wP is standard (Kristensen G, et al. J Clin Oncol 26: 2008 abstr 5508). Few randomized trials have explored combination therapy in this setting. Methods: Pts with ROC after a first or second line including a platinum and a taxane were randomized to receive wP (80 mg/m2/week) alone or in combination with wT (3mg/m2/week) or C (AUC 5 every 4 weeks). The primary end-point was the comparison of progression-free survival (PFS) between single non-platinum agent and combination therapy (wP+wT or wP+C). Secondary objectives included safety, QoL, response rate (RR) and overall survival. Results: From April 2004 to August 2008, 165 pts were accrued (wP 57, wP+wT 57, wP+C 51). Median number of cycles and P dose-intensity (mg/m2/week) was 4.6 and 70, 4.2 and 63 in monotherapy and combination therapy arms respectively. Non-hematological toxicity was not different between the arms, except an excess of hypersensitivity reactions in the wP+C arm. Grade 3–4 neutropenia (48 vs 13% of pts), and anemia (24 vs 6%) were more frequent in combination therapy than in single agent arm and similar with wT or C combination. Febrile neutropenia was experienced by 5 pts treated with combination therapy. Discontinuation from drug treatment was more frequent with combination therapy (24% of pts) than with monotherapy (4%), mainly due to hematotoxicity. RR was 34, 38 and 39% for wP, wP+wT and wP+C respectively. Median PFS of pts treated with single agent (112 days) was not significantly different from those treated with combination therapy (149 days) (p = 0,62) and was similar in wP+wT (152 days) or wP+C (146 days) arms. Treatment with single non-platinum agent or combination therapy was not found an independent parameter when added to a Cox model including prognostic variables. Conclusions: Combination therapy (CT) in platinum resistant ovarian cancer was found more toxic than weekly paclitaxel and the PFS advantage from CT was not statistically significant. No significant financial relationships to disclose.