Is chemotherapy necessary for premenopausal women with lower-risk node-positive, endocrine responsive breast cancer? 10-year update of International Breast Cancer Study Group Trial 11-93.

INTRODUCTION: International Breast Cancer Study Group (IBCSG) Trial 11-93 is the largest trial evaluating the role of the addition of chemotherapy to ovarian function suppression/ablation (OFS) and tamoxifen in premenopausal patients with endocrine-responsive early breast cancer. METHODS: IBCSG Trial 11-93 is a randomized trial comparing four cycles of adjuvant chemotherapy (AC: doxorubicin or epirubicin, plus cyclophosphamide) added to OFS and 5 years of tamoxifen versus OFS and tamoxifen without chemotherapy in premenopausal patients with node-positive, endocrine-responsive early breast cancer. There were 174 patients randomized from May 1993 to November 1998. The trial was closed before the target accrual was reached due to low accrual rate. RESULTS: Patients randomized tended to have lower risk node-positive disease and the median age was 45. After 10 years median follow up, there remains no difference between the two randomized treatment groups for disease-free (hazard ratio=1.02 (0.57-1.83); P=0.94) or overall survival (hazard ratio=0.97 (0.44-2.16); P=0.94). CONCLUSION: This trial, although small, offers no evidence that AC chemotherapy provides additional disease control for premenopausal patients with lower-risk node-positive endocrine-responsive breast cancer who receive adequate adjuvant endocrine therapy. A large trial is needed to determine whether chemotherapy adds benefit to endocrine therapy for this population.

Clinical Prognostic Factors Predicting Outcomes Of Patients With Recurrent Gbm And Nomograms

BACKGROUND: Prognostic models and nomograms were recently developed to predict survival of patients with newly diagnosed glioblastoma multiforme (GBM).1 To improve predictions, models should be updated with the most recent patient and disease information. Nomograms predicting patient outcome at the time of disease progression are required. METHODS: Baseline information from 299 patients with recurrent GBM recruited in 8 phase I or II trials of the EORTC Brain Tumor Group was used to evaluate clinical parameters as prognosticators of patient outcome. Univariate (log rank) and multivariate (Cox models) analyses were made to assess the ability of patients' characteristics (age, sex, performance status [WHO PS], and MRC neurological deficit scale), disease history (prior treatments, time since last treatment or initial diagnosis, and administration of steroids or antiepileptics) and disease characteristics (tumor size and number of lesions) to predict progression free survival (PFS) and overall survival (OS). Bootstrap technique was used for models internal validation. Nomograms were computed to provide individual patients predictions. RESULTS: Poor PS and more than 1 lesion had a significant prognostic impact for both PFS and OS. Antiepileptic drug use was significantly associated with worse PFS. Larger tumors (split by the median of the largest tumor diameter >42.5 mm) and steroid use had shorter OS. Age, sex, neurologic deficit, prior therapies, and time since last therapy or initial diagnosis did not show independent prognostic value for PFS or OS. CONCLUSIONS: This analysis confirms that PS but not age is a major prognostic factor for PFS and OS. Multiple or large tumors and the need to administer steroids significantly increase the risk of progression and death. Nomograms at the recurrence could be used to obtain accurate predictions for the design of new targeted therapy trials or retrospective analyses. (1. T. Gorlia et al., Nomograms for predicting survival of patients with newly diagnosed glioblastoma. Lancet Oncol 9 (1): 29-38, 2008.)

Temozolomide combined with bevacizumab in metastatic melanoma. A multicenter phase II trial (SAKK 50/07)

Background: Single agent DTIC is the standard therapy for metastatic melanoma (MM) with response rates of 5−20%. Temozolomide (Tem) as an oral drug has shown equal efficacy in phase III trials. Preclinical models have shown an inhibitory effect for bevacizumab (Bev) on the proliferation of melanoma cells as well as on sprouting endothelial cells. Therefore, a therapeutic approach that combines angiogenesis inhibitors with cytotoxic agents may provide clinical benefit in MM. Methods: Design: Multicenter phase II trial. Primary endpoint: Clinical benefit (CR, PR and SD) at 12 weeks; secondary endpoints: best overall response by RECIST, response duration, progression free survival, adverse events, survival after 6 months and overall survival. Sample size was calculated according to Simon's two stage optimal design (5% significance level and 80% power) with an overall sample size of 62 patients (pts) to test H0: 20% versus H1: 35% rate of clinical benefit. Response assessment was done every 6 weeks (3 cycles). Eligibility: Stage IV MM, ECOG PS 0−2, no prior treatment for metastatic disease. Treatment regimen: One cycle consisted of Tem at 150 mg/m2 days 1−7 po and Bev at 10 mg/kg day 1 over 30 min iv and was repeated every 2 weeks until progression or unacceptable toxicity. Results: Between January 2008 and April 2009, 62 pts (40 male/22 female) at a median age of 61 years (range 30−86) with stage IV (M1a:4, M1b:12, M1c:46) melanoma were enrolled in 9 centers. The first 50 pts, who received 415 cycles are included in this interim report. The overall response rate was 26% (CR: 1 pt, PR: 12 pts; PR not confirmed yet in 3 pts), and 44% (22 pts) had stable disease over 1.5−7.5 months (median: 3). Only 30% (15 pts) had disease progression at the first evaluation at week 6. The hematological grade 3/4 toxicities according to NCI CTAE 3.0 were thrombocytopenia 10% (5 pts), neutropenia 8% (4 pts), lymphopenia and leucocytopenia each 2% (1 pt). Cumulative non-hematological toxicities grade 3/4 were nausea and fatigue each 6% (3 pts), hypertension, vomiting and hemorrhage, each 4% (2 pts), thrombosis/embolism, infection, constipation, anorexia, elevation of alkaline phosphatase, bilirubin, GGT, ALT and AST each 2% (1 pt). Conclusion: In metastatic melanoma the combination of Tem/Bev is a safe regimen with a promising efficacy and few grade 3/4 toxicities. Updated results of all 62 pts will be presented.

New prognostic factors and calculators for outcome prediction in patients with recurrent glioblastoma: A pooled analysis of EORTC Brain Tumour Group phase I and II clinical trials.

BACKGROUND: Prognostic models have been developed to predict survival of patients with newly diagnosed glioblastoma (GBM). To improve predictions, models should be updated with information at the recurrence. We performed a pooled analysis of European Organization for Research and Treatment of Cancer (EORTC) trials on recurrent glioblastoma to validate existing clinical prognostic factors, identify new markers, and derive new predictions for overall survival (OS) and progression free survival (PFS).¦METHODS: Data from 300 patients with recurrent GBM recruited in eight phase I or II trials conducted by the EORTC Brain Tumour Group were used to evaluate patient's age, sex, World Health Organisation (WHO) performance status (PS), presence of neurological deficits, disease history, use of steroids or anti-epileptics and disease characteristics to predict PFS and OS. Prognostic calculators were developed in patients initially treated by chemoradiation with temozolomide.¦RESULTS: Poor PS and more than one target lesion had a significant negative prognostic impact for both PFS and OS. Patients with large tumours measured by the maximum diameter of the largest lesion (⩾42mm) and treated with steroids at baseline had shorter OS. Tumours with predominant frontal location had better survival. Age and sex did not show independent prognostic values for PFS or OS.¦CONCLUSIONS: This analysis confirms performance status but not age as a major prognostic factor for PFS and OS in recurrent GBM. Patients with multiple and large lesions have an increased risk of death. With these data prognostic calculators with confidence intervals for both medians and fixed time probabilities of survival were derived.

Predictive value of the MGMT promoter methylation status in metastatic melanoma patients receiving first-line temozolomide plus bevacizumab in the trial SAKK 50/07.

The O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation status is a predictive parameter for the response of malignant gliomas to alkylating agents such as temozolomide. First clinical trials with temozolomide plus bevacizumab therapy in metastatic melanoma patients are ongoing, although the predictive value of the MGMT promoter methylation status in this setting remains unclear. We assessed MGMT promoter methylation in formalin-fixed, primary tumor tissue of metastatic melanoma patients treated with first-line temozolomide and bevacizumab from the trial SAKK 50/07 by methylation-specific polymerase chain reaction. In addition, the MGMT expression levels were also analyzed by MGMT immunohistochemistry. Eleven of 42 primary melanomas (26%) revealed a methylated MGMT promoter. Promoter methylation was significantly associated with response rates CR + PR versus SD + PD according to RECIST (response evaluation criteria in solid tumors) (p<0.05) with a trend to prolonged median progression-free survival (8.1 versus 3.4 months, p>0.05). Immunohistochemically different protein expression patterns with heterogeneous and homogeneous nuclear MGMT expression were identified. Negative MGMT expression levels were associated with overall disease stabilization CR + PR + SD versus PD (p=0.05). There was only a poor correlation between MGMT methylation and lack of MGMT expression. A significant proportion of melanomas have a methylated MGMT promoter. The MGMT promoter methylation status may be a promising predictive marker for temozolomide therapy in metastatic melanoma patients. Larger sample sizes may help to validate significant differences in survival type endpoints.

Early prediction of response to sunitinib after imatinib failure by 18F-fluorodeoxyglucose positron emission tomography in patients with gastrointestinal stromal tumor.

PURPOSE: Positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET) was used to evaluate treatment response in patients with gastrointestinal stromal tumors (GIST) after administration of sunitinib, a multitargeted tyrosine kinase inhibitor, after imatinib failure. PATIENTS AND METHODS: Tumor metabolism was assessed with FDG-PET before and after the first 4 weeks of sunitinib therapy in 23 patients who received one to 12 cycles of sunitinib therapy (4 weeks of 50 mg/d, 2 weeks off). Treatment response was expressed as the percent change in maximal standardized uptake values (SUV). The primary end point of time to tumor progression was compared with early PET results on the basis of traditional Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Progression-free survival (PFS) was correlated with early FDG-PET metabolic response (P < .0001). Using -25% and +25% thresholds for SUV variations from baseline, early FDG-PET response was stratified in metabolic partial response, metabolically stable disease, or metabolically progressive disease; median PFS rates were 29, 16, and 4 weeks, respectively. Similarly, when a single FDG-PET positive/negative was considered after 4 weeks of sunitinib, the median PFS was 29 weeks for SUVs less than 8 g/mL versus 4 weeks for SUVs of 8 g/mL or greater (P < .0001). None of the patients with metabolically progressive disease subsequently responded according to RECIST criteria. Multivariate analysis showed shorter PFS in patients who had higher residual SUVs (P < .0001), primary resistance to imatinib (P = .024), or nongastric GIST (P = .002), regardless of the mutational status of the KIT and PDGFRA genes. CONCLUSION: Week 4 FDG-PET is useful for early assessment of treatment response and for the prediction of clinical outcome. Thus, it offers opportunities to individualize and optimize patient therapy.

Évaluation de la perfusion myocardique par TEP-TDM. [Myocardial perfusion imaging using PET/CT.]

For the past decade, PET and PET/CT have been widely studied for myocardial perfusion imaging. Several studies demonstrated the incremental value of PET for the diagnostic and prognostic assessment of patients with coronary artery disease. Moreover, PET allows for non-invasively quantifying myocardial blood flow and myocardial flow reserve, that both are recognized as surrogate marker of cardiac event free survival. By enabling the exploration of epicardial disease and the microvasculature, PET constitutes a unique tool to study pathophysiogical mechanisms leading to atherosclerosis genesis. The recent emergence of high-tech hybrid machines may even provide further incremental information about coronary function and morphology. By taking the best of each modality, a better assessment of patients with coronary artery disease is expected. (C) 2011 Elsevier Masson SAS. All rights reserved.

Recurrent TET2 mutations in peripheral T-cell lymphomas correlate with TFH-like features and adverse clinical parameters.

Inactivating mutations of the Ten-Eleven Translocation 2 (TET2) gene were first identified in myeloid malignancies and more recently in peripheral T-cell lymphomas (PTCLs). In the present study, we investigated the presence of TET2 coding sequence mutations and their clinical relevance in a large cohort of 190 PTCL patients. TET2 mutations were identified in 40 of 86 (47%) cases of angioimmunoblastic T-cell lymphoma (AITL) and in 22 of 58 (38%) cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), but were absent in all other PTCL entities, with the exception of 2 of 10 cases of enteropathy-associated T-cell lymphoma. Among PTCL-NOS, a heterogeneous group of lymphoma-comprising cases likely to derive from Th follicular (T(FH)) cells similarly to AITL, TET2 mutations were more frequent when PTCL-NOS expressed T(FH) markers and/or had features reminiscent of AITL (58% vs 24%, P = .01). In the AITL and PTCL-NOS subgroups, TET2 mutations were associated with advanced-stage disease, thrombocytopenia, high International Prognostic Index scores, and a shorter progression-free survival.

Consolidation whole abdomen irradiation following adjuvant carboplatin-paclitaxel based chemotherapy for advanced uterine epithelial cancer: feasibility, toxicity and outcomes.

BACKGROUND: To evaluate feasibility and preliminary outcomes associated with sequential whole abdomen irradiation (WAI) as consolidative treatment following comprehensive surgery and systemic chemotherapy for advanced endometrial cancer. METHODS: We conducted a retrospective analysis of patients treated at our institution from 2000 to 2011. Inclusion criteria were stage III-IV endometrial cancer patients with histological proof of one or more sites of extra-uterine abdomen-confined disease, treated with WAI as part of multimodal therapy. Endpoints were feasibility, acute toxicity, late effects, recurrence-free survival (RFS) and overall survival (OS). Twenty patients were identified. Chemotherapy consisted of 3 to 6 cycles of a platinum-paclitaxel regimen in 18 patients. WAI was delivered using conventional technique to a median total dose of 27.5 Gy. RESULTS: No grade 4 toxicities occurred during chemotherapy or radiotherapy. No radiation dose reduction was necessary. Three patients developed small bowel obstruction, all in the context of recurrent intraperitoneal disease. Kaplan-Meier estimates and 95% confidence intervals for RFS and OS at one year were 63% (38-80%) and 83% (56-94%) and at 3 years 57% (33-76%) and 62% (34-81%), respectively. On univariate Cox analysis, stage IVB and serous papillary (SP) histology were found to be statistically significantly (at the p = 0.05 level) associated with worse RFS and OS. The peritoneal cavity was the most frequent site of initial failure. CONCLUSIONS: Consolidative WAI following chemotherapy is feasible and can be performed without interruption with manageable acute and late toxicity. Patients with endometrioid adenocarcinoma, especially stage FIGO III, had favorable outcomes possibly meriting prospective evaluation of the addition of WAI following chemotherapy in selected patients. Patients with SP do poorly and do not routinely benefit from this approach.

Early high-dose treatment: SCT results from the European High Risk Neuroblastoma Study

Aims: The HR-NBL1 Study of the European SIOP Neuroblastoma Group (SIOPEN) randomised two high dose regimens to learn about potential superiority and toxicity profiles.Patients and Methods: At interim analysis 1483 high risk neuroblastoma patients (893 males) were included since 2002 with either INSS stage 4 disease (1383 pts) above 1 year, or as infants (59 pts) and stage 2&3 of any age (145 pts) with MYCN amplification. The median age at diagnosis was 2.9 years (1 month-19.9 years) with a median follow up of 3 years. Response eligibility criteria prior randomisation after Rapid Cojec Induction (J Clin Oncol, 2010) ± 2 courses of TVD (Cancer, 2003) included complete bone marrow remission and at least partial response at skeletal sites with no more than 3, but improved mIBG positive spots and a PBSC harvest of at least 3x10E6 CD34/kgBW. The randomised regimens were BuMel [busulfan oral till 2006, 4x150mg/m² in 4 ED; or intravenous use according to body weight as licenced thereafter; melphalan 140mg/m²/day) and CEM [carboplatinum ctn. infusion (4x AUC 4.1mg/ml.min/day, etoposid ctn. infusion (4x 338mg/m²/day or [4x 200mg/m²/day]*, melphalan (3x70mg/m²/day; 3x60mg/m²/day*;*reduced dosis if GFR< 100ml/min/1.73m²). Supportive care followed institutional guidelines. VOD prophylaxis included ursadiol, but randomised patients were not eligible for the prophylactic defibrotide trial. Local control included surgery and radiotherapy of 21Gy.Results: Of 1483 patients, 584 were being randomised for the high dose question at data lock. A significant difference in event free survival (3-year EFS 49% vs. 33%, p<0.001) and overall survival (3-year OS 61% vs. 48%, p=0.003) favouring the BuMel regimen over the CEM regimen was demonstrated. The relapse/progression rate was significantly higher after CEM (0.60±0.03) than after BuMel (0.48±0.03)(p<0.001). Toxicity data had reached 80% completeness at last analysis. The severe toxicity rate up to day 100 (ICU and toxic deaths) was below 10%, but was significantly higher for CEM (p= 0.014). The acute toxic death rate was 3% for BuMel and 5% for CEM (NS). The acute HDT toxicity profile favours the BuMel regimen in spite of a total VOD incidence of 18% (grade 3:5%).Conclusions: The Peto rule of P<0.001 at interim analysis on the primary endpoint, EFS was met. Hence randomization was stopped with BuMel as recommended standard treatment in the HR-NBl1/SIOPEN trial which is still accruing for the randomised immunotherapy question.

Thrombocytosis as a prognostic marker in stage III and IV serous ovarian cancer.

OBJECTIVE: Thrombocytosis is an adverse prognostic factor in many types of cancer. We investigated if pre-treatment increased platelet counts provide prognostic information specifically in patients with stage III and IV serous ovarian cancer which is the most common clinical presentation of ovarian cancer. METHODS: Platelet number on diagnosis of stage III and IV serous ovarian adenocarcinoma was evaluated in 91 patients for whom there were complete follow-up data on progression and survival. Survival and progression free survival of patients with normal platelet counts (150-350 ×10(9)/L) was compared with that of patients with thrombocytosis (>350×10(9)/L) by χ(2) and logrank tests. RESULTS: The median age of the patients was 66 years-old. From the 91 patients, 52 (57.1%) had normal platelet counts (median, 273×10(9)/L; range, 153-350) at diagnosis of their disease and 39 patients (42.9%) had thrombocytosis (median, 463×10(9)/L; range, 354-631). In the group of patients with normal platelet counts, 24 of the 52 patients had died with a median survival of 43 months (range, 3-100). In the group of patients with thrombocytosis, 24 of the 39 patients had died with a median survival of 23 months (range, 4-79). In the entire group of 91 patients there was a statistically significant difference of the overall survival and progression-free survival between the two groups (logrank test P=0.02 and P=0.007, respectively). CONCLUSION: In this retrospective analysis of stage III and IV ovarian cancer patients, thrombocytosis at the time of diagnosis had prognostic value regarding overall survival and progression-free survival.

Fulvestrant with or without selumetinib, a MEK 1/2 inhibitor, in breast cancer progressing after aromatase inhibitor therapy: A multicentre randomised placebo-controlled double-blind phase II trial, SAKK 21/08.

BACKGROUND: Second line endocrine therapy has limited antitumour activity. Fulvestrant inhibits and downregulates the oestrogen receptor. The mitogen-activated protein kinase (MAPK) pathway is one of the major cascades involved in resistance to endocrine therapy. We assessed the efficacy and safety of fulvestrant with selumetinib, a MEK 1/2 inhibitor, in advanced stage breast cancer progressing after aromatase inhibitor (AI). PATIENTS AND METHODS: This randomised phase II trial included postmenopausal patients with endocrine-sensitive breast cancer. They were ramdomised to fulvestrant combined with selumetinib or placebo. The primary endpoint was disease control rate (DCR) in the experimental arm. ClinicalTrials.gov Indentifier: NCT01160718. RESULTS: Following the planned interim efficacy analysis, recruitment was interrupted after the inclusion of 46 patients (23 in each arm), because the selumetinib-fulvestrant arm did not reach the pre-specified DCR. DCR was 23% (95% confidence interval (CI) 8-45%) in the selumetinib arm and 50% (95% CI 27-75%) in the placebo arm. Median progression-free survival was 3.7months (95% CI 1.9-5.8) in the selumetinib arm and 5.6months (95% CI 3.4-13.6) in the placebo arm. Median time to treatment failure was 5.1 (95% CI 2.3-6.7) and 5.6 (95% CI 3.4-10.2) months, respectively. The most frequent treatment-related adverse events observed in the selumetinib-fulvestrant arm were skin disorders, fatigue, nausea/vomiting, oedema, diarrhoea, mouth disorders and muscle disorders. CONCLUSIONS: The addition of selumetinib to fulvestrant did not show improving patients' outcome and was poorly tolerated at the recommended monotherapy dose. Selumetinib may have deteriorated the efficacy of the endocrine therapy in some patients.

Five-year outcome of catheter ablation of persistent atrial fibrillation using termination of atrial fibrillation as a procedural endpoint.

BACKGROUND: This study aimed to determine 5-year efficacy of catheter ablation for persistent atrial fibrillation (AF) using AF termination as a procedural end point. METHODS AND RESULTS: One hundred fifty patients (57±10 years) underwent persistent AF ablation using a stepwise ablation approach (pulmonary vein isolation, electrogram-guided, and linear ablation) with the desired procedural end point being AF termination. Repeat ablation was performed for recurrent AF or atrial tachycardia. AF was terminated by ablation in 120 patients (80%). Arrhythmia-free survival rates after a single procedure were 35.3%±3.9%, 28.0%±3.7%, and 16.8%±3.2% at 1, 2, and 5 years, respectively. Arrhythmia-free survival rates after the last procedure (mean 2.1±1.0 procedures) were 89.7%±2.5%, 79.8%±3.4%, and 62.9%±4.5%, at 1, 2, and 5 years, respectively. During a median follow-up of 58 (interquartile range, 43-73) months after the last ablation procedure, 97 of 150 (64.7%) patients remained in sinus rhythm without antiarrhythmic drugs. Another 14 (9.3%) patients maintained sinus rhythm after reinitiation of antiarrhythmic drugs, and an additional 15 (10.0%) patients regressed to paroxysmal recurrences only. Failure to terminate AF during the index procedure (hazard ratio 3.831; 95% confidence interval, 2.070-7.143; P<0.001), left atrial diameter ≥50 mm (hazard ratio 2.083; 95% confidence interval, 1.078-4.016; P=0.03), continuous AF duration ≥18 months (hazard ratio 1.984; 95% confidence interval, 1.024-3.846; P<0.04), and structural heart disease (hazard ratio 1.874; 95% confidence interval, 1.037-3.388; P=0.04) predicted arrhythmia recurrence. CONCLUSIONS: In patients with persistent AF, an ablation strategy aiming at AF termination is associated with freedom from arrhythmia recurrence in the majority of patients over a 5-year follow-up period. Procedural AF nontermination and specific baseline factors predict long-term outcome after ablation.

Adjuvant radiotherapy for gastric carcinoma: 10 years follow-up of 244 cases from a single institution.

BACKGROUND: Postoperative chemoradiotherapy (CRT) of gastric carcinoma improves survival among high- risk patients. This study was undertaken to analyse long-term survival probability and the impact of certain covariates on the survival outcome in affected individuals. MATERIALS AND METHODS: Between January 2000 and December 2005, 244 patients with gastric cancer underwent adjuvant radiotherapy (RT) in our institution. Data were retrieved retrospectively from patient files and analysed with SPSS version 21.0. RESULTS: A total of 244 cases, with a male to female ratio of 2.2:1, were enrolled in the study. The median age of the patients was 52 years (range, 20-78 years). Surgical margin status was positive or close in 72 (33%) out of 220 patients. Postoperative adjuvant RT dose was 46 Gy. Median follow-up was 99 months (range, 79-132 months) and 23 months (range, 2-155 months) for surviving patients and all patients, respectively. Actuarial overall survival (OS) probability for 1-, 3-, 5- and 10-year was 79%, 37%, 24% and 16%, respectively. Actuarial progression free survival (PFS) probability was 69%, 34%, 23% and 16% in the same consecutive order. AJCC Stage I-II disease, subtotal gastrectomy and adjuvant CRT were significantly associated with improved OS and PFS in multivariate analyses. Surgical margin status or lymph node dissection type were not prognostic for survival. CONCLUSIONS: Postoperative CRT should be considered for all patients with high risk of recurrence after gastrectomy. Beside well-known prognostic factors such as stage, lymph node status and concurrent chemotherapy, the type of gastrectomy was an important prognostic factor in our series. With our findings we add to the discussion on the definition of required surgical margin for subtotal gastrectomy. We consider that our observations in gastric cancer patients in our clinic can be useful in the future randomised trials to point the way to improved outcomes.

Targeted Therapy for Patients with BRAF-Mutant Lung Cancer: Results from the European EURAF Cohort.

INTRODUCTION: Approximately 2% of lung adenocarcinomas have BRAF (v-Raf murine sarcoma viral oncogene homolog B) mutations, including V600E and other types. Vemurafenib, dabrafenib, and sorafenib as BRAF inhibitors are currently tested in clinical trials, but access for patients is limited. The aim of this study was to document the clinical course of patients treated outside of clinical trials. METHODS: We conducted a retrospective multicenter cohort study in Europe of patients with advanced BRAF-mutant lung cancer treated with known BRAF inhibitors. Data were anonymized and centrally assessed for age, gender, smoking, histology, stage, local molecular diagnostic results, systemic therapies, and survival. Best response was assessed locally by RECIST1.1. RESULTS: We documented 35 patients treated in 17 centers with vemurafenib, dabrafenib, or sorafenib. Median age was 63 years (range 42-85); gender was balanced; 14 (40%) were never smokers; all (100%) had adenocarcinoma; 29 (83%) had V600E; 6 (17%) had other mutations; one of them had a concomitant KRAS mutation. Thirty (86%) patients had chemotherapy in the first line. Overall survival with first-line therapy was 25.3 months for V600E and 11.8 months for non-V600E. Thirty-one patients received one BRAF inhibitor, and four received a second inhibitor. Overall response rate with BRAF therapy was 53%, and disease control rate was 85%. Median progression-free survival with BRAF therapy was 5.0 months, and overall survival was 10.8 months. CONCLUSIONS: These results confirm the activity of targeted therapy in patients with BRAF-mutant lung adenocarcinoma. Further trials are warranted to study combination therapies and drug resistance mechanisms.