Matteo Lambertini (Genoa, Italy)
IRCCS Ospedale Policlinico San Martino Hospital – University of GenovaAuthor Of 4 Presentations
If your premenopausal patient with ER+ early breast cancer requires OFS, do you always combine it with an aromatase inhibitor? NO (ID 452)
69P - Impact of statin use on survival outcomes of patients with HER2-positive early breast cancer in the APHINITY trial (ID 84)
- Christian Maurer (Köln, Germany)
- Elisa Agostinetto (Brussels, Belgium)
- Lieveke Ameye (Brussels, Belgium)
- Matteo Lambertini (Genoa, Italy)
- Samuel Martel (Greenfield Park, Canada)
- Noam F. Ponde (Morrisville, United States of America)
- Mariana Brandão (Brussels, Belgium)
- Francesca Poggio (Genova, Italy)
- Arlindo R. Ferreira (Lisbon, Portugal)
- Rachel Schiff (Houston, United States of America)
- Carmine De Angelis (Napoli, Italy)
- Richard D. Gelber (Boston, United States of America)
- Susan Dent (Durham, United States of America)
- Christoph Thomssen (Halle (Saale), Germany)
- Martine Piccart (Brussels, Belgium)
- Evandro De Azambuja (Brussels, Belgium)
Abstract
Background
Preclinical data suggest a protective role of statins in patients (pts) with breast cancer. Clinical data are controversial with limited data on the benefit for pts with HER2-positive early breast cancer (HER2+ EBC). We investigated the association of statin use with survival outcomes in pts with HER2+ EBC enrolled in APHINITY (BIG 4-11/NCT01358877).
Methods
APHINITY is a prospective, randomized, double-blind, phase III trial testing the addition of pertuzumab to trastuzumab and chemotherapy in pts with HER2+ EBC. All pts evaluated in APHINITY were included in the present analysis (N=4804). Pts who received statins at baseline, or started statins within one year from randomization were considered as statin users. Pts’ characteristics were compared according to statin use by chi-square test. Survival analysis for invasive-disease-free survival (IDFS), distant relapse-free interval (DRFI), and overall survival (OS) were performed using the Kaplan Meier method and log-rank test. A multivariate analysis using a Cox proportional hazard model was used to generate hazard ratios (HR), adjusting for tumor size, nodal status, hormone receptor status, age, menopausal status, body mass index (BMI) ≥ 30 kg/m2, treatment arm and statin use.
Results
Median follow-up was 6 years. Statin users (N=423) were more frequently ≥65 years old, postmenopausal, obese (BMI ≥ 30 kg/m2) and were treated more often with breast conserving surgery compared to non-statin users (N=4381) (all p<.001). In multivariate analysis, no significant impact of statin use on any of the survival outcomes was observed (IDFS, HR 1.17, 95% confidence interval [CI] 0.86-1.59; DRFI, HR 1.22, 95% CI 0.83-1.79; OS, HR 1.18, 95% CI 0.80-1.72). No significant interaction between statin use, obesity, treatment arm, hormone receptor status and survival could be detected (p>.05).
Conclusions
In this analysis, statin use was not associated with improved survival outcomes in the relatively young EBC population enrolled in APHINITY. We acknowledge the retrospective and exploratory nature of the present analysis. Further research should explore the potential clinical benefit of statins in a higher risk (e.g. older age) EBC population.
Clinical trial identification
BIG 4-11/ BO 25 126/ TOC 4939g.
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd. and Genentech, Inc.
Funding
Has not received any funding.
Disclosure
C. Maurer: Financial Interests, Personal, Other, Travel grant: Mundipharma; Financial Interests, Personal, Other, Travel grant: Amgen; Financial Interests, Personal, Other, Travel grant: Servier Deutschland GmbH; Financial Interests, Personal, Other, Travel grant: AbbVie; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Celgene/BMS. E. Agostinetto: Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Other, Travel grant: Novartis; Financial Interests, Personal, Other, Travel grant: Roche; Financial Interests, Personal, Other, Travel grant: Eli Lilly; Financial Interests, Personal, Other, Travel grant: Genetic. M. Lambertini: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Takeda; Financial Interests, Personal, Invited Speaker: Sandoz; Financial Interests, Personal, Invited Speaker: Ipsen; Financial Interests, Personal, Invited Speaker: Libbs; Financial Interests, Personal, Invited Speaker: Knight; Financial Interests, Personal, Advisory Board: Exact Sciences; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Gilead. S. Martel: Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Knight Therapeutics; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Taiho; Financial Interests, Personal, Advisory Board: Exact Science; Financial Interests, Personal, Advisory Board: Apobiologix. N.F. Ponde: Financial Interests, Personal, Full or part-time Employment: IQVIA Biotech. M. Brandão: Financial Interests, Personal, Invited Speaker: Roche/GNE; Financial Interests, Personal, Invited Speaker: Janssen; Financial Interests, Personal, Other, Travel grant: Roche/GNE; Financial Interests, Personal, Other, Travel grant: Sanofi; Financial Interests, Institutional, Research Grant: Roche/GNE; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: GSK/Novartis; Financial Interests, Institutional, Research Grant: Servier. F. Poggio: Financial Interests, Personal, Invited Speaker: Eli Lilly; Financial Interests, Personal, Invited Speaker: Novartis. A.R. Ferreira: Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Other, Travel grant: Roche. R. Schiff: Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: GlaxoSmithKline; Financial Interests, Institutional, Funding: Puma; Financial Interests, Institutional, Funding: Biotechnology Inc.; Financial Interests, Institutional, Funding: Gilead Sciences; Financial Interests, Personal, Advisory Board: Eli Lilly; Financial Interests, Personal, Advisory Board: Macrogenics; Financial Interests, Personal, Royalties: UpToDate; Other, Co-inventor in the Patent application # PCT/US21/70543 (Methods for breast cancer treatment and prediction of therapeutic response): Other. C. De Angelis: Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly; Financial Interests, Personal, Speaker’s Bureau: GSK; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Institutional, Research Grant: Novartis; Other, Co-inventor in the Patent application # PCT/US21/70543 (Methods for breast cancer treatment and prediction of therapeutic response): Other. R.D. Gelber: Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Merck. S. Dent: Financial Interests, Institutional, Funding: Novartis; Financial Interests, Personal, Other, Honoraria: Novartis. C. Thomssen: Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Celgene; Financial Interests, Personal, Advisory Board: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Eisai; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Mylan; Financial Interests, Personal, Advisory Board: NanoString; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Puma; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Vifor; Financial Interests, Institutional, Funding, Discount prizes: Amercian Diagnostica; Financial Interests, Institutional, Funding, Discount prizes: Affymetrix; Financial Interests, Institutional, Funding, Discount prizes: NanoString. M. Piccart: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Other, Consultant: Camel-IDS; Financial Interests, Personal, Advisory Board: Debiopharm; Financial Interests, Personal, Advisory Board: Immunomedics; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Advisory Board: Menarini; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Advisory Board: Odonate; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Advisory Board, Consultant and invited speaker: Roche-Genentech; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Immutep; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Invited Speaker, Scientific Board: Oncolytics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: Immunomedics; Financial Interests, Institutional, Research Grant: Lilly; Financial Interests, Institutional, Funding: Menarini; Financial Interests, Institutional, Funding: MSD; Financial Interests, Institutional, Funding: Novartis; Financial Interests, Institutional, Funding: Pfizer; Financial Interests, Institutional, Funding: Radius; Financial Interests, Institutional, Funding: Roche-Genentech; Financial Interests, Institutional, Funding: Servier; Financial Interests, Institutional, Funding: Synthon. E. de Azambuja: Financial Interests, Personal, Advisory Board: Roche/GNE; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Seattle Genetics; Financial Interests, Personal, Advisory Board: Zodiac; Financial Interests, Personal, Advisory Board: Libbs; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Other, Travel grant: Roche/GNE; Financial Interests, Personal, Other, Travel grant: GSK/Novartis; Financial Interests, Institutional, Research Grant: Roche/GNE; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Research Grant: GSK/Novartis; Financial Interests, Institutional, Research Grant: Servier. All other authors have declared no conflicts of interest.
113P - Axillary lymph node management in early breast cancer patients with positive sentinel lymph node: a systematic review and meta-analysis of randomized trials. (ID 126)
- Tommaso Ruelle (Genova, Italy)
- Marta Perachino (Genova, Italy)
- Eva Blondeaux (Genova, Italy)
- Marco Bruzzone (Genova, Italy)
- Alessandra Fozza (Genova, Italy)
- Alessandro Garlaschi (Genova, Italy)
- Liliana Belgioia (Genova, Italy)
- Francesca Pitto (Genova, Italy)
- Alessia Levaggi (Genova, Italy)
- Marco Sparavigna (Genova, Italy)
- Lucia Del Mastro (Genova, Italy)
- Matteo Lambertini (Genoa, Italy)
- Piero Fregatti (Genova, Italy)
Abstract
Background
Omitting axillary lymph node dissection (ALND) in patients with early breast cancer and 1 or 2 positive sentinel lymph nodes (SLNs) is still debated especially in those undergoing mastectomy. We aim to provide updated evidence on this topic.
Methods
This is a systematic review and meta-analysis of randomized trials evaluating the omission of ALND in patients with positive SLN. Included studies compared ALND vs. no ALND in breast cancer patients with tumors ≤5 cm and up to 2 metastatic SLNs. In the no ALND group, patients could receive sentinel lymph node dissection (SLND) only or SLND and complementary axillary radiotherapy (SLND + AR). We assessed differences in overall survival (OS), disease free survival (DFS), axillary recurrence rate (ARR) and surgical outcomes (lymphoedema and neuropathy) in ALND vs. SLND alone group and ALND vs. SLND + AR group. Pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random effects models.
Results
Of 3,638 identified records, 7 (6 studies) were included in our meta-analysis. All six studies were randomized non-inferiority trials with a total of 4789 included patients. Four trials evaluated ALND compared to SLND alone (N=2890). By hypothesizing a non-inferiority margin of 1.25 in survival endpoints, we found that SLND alone is non-inferior to ALND in both OS (HR 0.81, 95% CI 0.62-1.05) and DFS (HR 0.91, 95% CI 0.75-1.09). However, the non-inferiority could not be demonstrated for ARR (HR 1.18, 95% CI 0.64-2.15). Compared to ALND, SLND alone resulted in lower incidence of lymphoedema (OR 0.35, 95% CI 0.15-0.81) but no significant reduction in neuropathy (OR 0.31, 95 CI%, 0.08-1.22).Two trials compared ALND versus SLND + AR (N=1899). In this comparison, the non-inferiority of SLND + AR could not be demonstrated in OS (HR 0.90, 95% CI 0.52-1.58), DFS (HR 0.99, 95% CI 0.66-1.49) and ARR (HR 1.35, 95% CI 0.63-2.89).
Conclusions
SLND is non-inferior compared to ALND in terms of OS and DFS, with lower rates of post-surgical lymphoedema. SLND + AR could be inferior compared to ALND in the survival endpoints evaluated. We were not able to perform subgroup analysis on patients undergoing breast conserving surgery or mastectomy.
Legal entity responsible for the study
San Martino.
Funding
Has not received any funding.
Disclosure
L. Del Mastro: Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Ipsen; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Genomic Health; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Seattle Genetics; Financial Interests, Personal, Advisory Role: Eisai; Financial Interests, Personal, Advisory Role: Pierre Fabre; Financial Interests, Personal, Advisory Role: Daiichi Sankyo Travel; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Novartis; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Personal, Invited Speaker: MSD Oncology. M. Lambertini: Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Theramex; Financial Interests, Personal, Speaker’s Bureau: Takeda; Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Speaker’s Bureau: Lilly; Financial Interests, Personal, Speaker’s Bureau: Novartis; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Sandoz. All other authors have declared no conflicts of interest.
177P - Low HER2 expression does not influence prognosis in metastatic triple-negative breast cancer: results from an international, multicenter analysis coordinated by the Austrian Group Medical Tumor Therapy (AGMT) (ID 185)
- Simon Peter Gampenrieder (Salzburg, Austria)
- Vincent Dezentjé (Amsterdam, Netherlands)
- Matteo Lambertini (Genoa, Italy)
- Alexandre De Nonneville (Marseille, France)
- Maximilian Marhold (Vienna, Austria)
- Fanny Le Du (Rennes, France)
- Cristina Saavedra Serrano (Madrid, Spain)
- Diogo Alpuim Costa (Lisbon, Portugal)
- Eva Blondeaux (Genova, Italy)
- Lucia Del Mastro (Genova, Italy)
- François Bertucci (Marseille, France)
- Anthony Gonçalves (Marseille, France)
- Rupert Bartsch (Vienna, Austria)
- Antoine Deleuze (Rennes, France)
- Alfonso Cortes Salgado (Madrid, Spain)
- Marina Vitorino (Amadora, Portugal)
- Christoph Tinchon (Leoben, Austria)
- Ladislav Pecen (Prague, Czech Republic)
- Gabriel Rinnerthaler (Salzburg, Austria)
- Richard Greil (Salzburg, Austria)
Abstract
Background
Triple-negative breast cancer (TNBC) is associated with poor prognosis. Therefore, new treatment options are urgently needed. About 35% of triple-negative primary tumors show a low expression of HER2 (HER2-low), a potential target for anti-HER2-drugs currently under investigation. In contrast to early breast cancer, little is known about the frequency and the prognostic value of HER2-low in metastatic TNBC.
Methods
In this international, multicenter analysis, we retrospectively evaluated TNBC patients from five European countries (Austria, France, Italy, Portugal, and Spain). Triple-negativity had to be shown in a metastatic site or in the primary breast tumor diagnosed simultaneously or within 3 years prior to metastatic disease. HER2-low was defined as immunohistochemically (IHC) 1+ or 2+ and lack of HER2 gene amplification measured by in-situ hybridization. HER2-0 was defined as IHC 0+. Univariable survival probabilities were calculated by the Kaplan-Meier method and compared by the log-rank test. Multivariable hazard ratios were estimated by Cox regression models.
Results
In total, 691 patients, diagnosed between Jan/2006 and Feb/2021, were evaluable. The incidence of HER2-low was 32.0% (95%CI 28.5-35.5%), with similar proportions in samples from metastatic sites (n=265; 29.8%; 95%CI 24.3-35.3%) and primary tumors (n=425; 33.4%; 95%CI 28.9-37.9%; P=0.324). Median OS in HER2-low and HER2-0 TNBC was 18.6 months (95% CI 16.5-20.3) and 16.1 months (95% CI 14.5-18.6), respectively, which was not statistically significantly different (HR 1.00; 95%CI 0.83-1.19; P=0.969). Similarly, in multivariable analysis HER2-low had no significant impact on OS (HR 0.95; 95%CI 0.79-1.13; P=0.545). In addition, we did not identify a difference in prognosis between HER2 IHC 0/1+ and IHC 2+ tumors (median OS 16.8 vs. 18.2 months; HR 0.89; 95%CI 0.69-1.17; P=0.414).
Conclusions
In this dataset of metastatic TNBC, the largest published until now, the frequency of HER2-low was 32.0%, which is similar as reported in early TNBC populations. In contrast to the early stages, HER2-low did not influence OS in metastatic TNBC.
Legal entity responsible for the study
Austrian Study Group of Medical Tumor Therapy (AGMT).
Funding
Austrian Study Group of Medical Tumor Therapy (AGMT), Grant for statistics by Daiichy Sankyo.
Disclosure
S.P. Gampenrieder: Financial Interests, Personal, Invited Speaker: Travel Grant; Financial Interests, Personal, Advisory Board: Novartis, Roche, BMS, AstraZeneca, MSD, Pfizer, Lilly, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: Roche; Financial Interests, Personal, Other, Travel Grant: Roche, Amgen, Shire, Novartis, Pfizer, Bayer, Celgene, Daiichi Sankyo. V. Dezentjé: Financial Interests, Personal, Other, Honoraria: Roche, Daiichi Sankyo. M. Lambertini: Financial Interests, Personal, Other, Honoraria: Roche, Sandoz, Takeda, Pfizer, Eli Lilly, and Novartis; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Eli Lilly, and Novartis. A. de Nonneville: Financial Interests, Institutional, Research Grant: Pfizer, Novartis, Lilly; Financial Interests, Institutional, Other, Travel Grant: Amgen, Daiichi Sankyo. M. Marhold: Financial Interests, Personal, Other, Honoraria: Roche, Eli Lilly, Novartis, AstraZeneca, Daiichi Sankyo, Pfizer, MSD, Medmedia; Financial Interests, Personal, Advisory Board: Roche, Lilly, Novartis, AstraZeneca, Daiichi Sankyo, Pfizer; Financial Interests, Personal, Other, Travel grant: Amgen, Roche, Novartis, Pierre Fabre, Daiichi Sankyo. F. Le Du: Financial Interests, Personal, Other, Honoraria: Novartis, Roche, Daiichi, Pfizer, Lilly, Seagen, Sandoz, AMGEN; Financial Interests, Personal, Advisory Board: Novartis, Roche, Daiichi, Pfizer, Lilly, Seagen, Sandoz; Financial Interests, Personal, Other, Travel Grant: Novartis, Roche, Daiichi, Pfizer, Lilly, Seagen, Pierre Fabre, Amgen. C. Saavedra Serrano: Financial Interests, Personal, Other, Travel Grant: Lilly, Pfizer. D. Alpuim Costa: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Roche, Merck KGaA, Novartis, NTT DATA, Pfizer, Uriage; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme, Novartis, Pfizer; Financial Interests, Personal, Research Grant: Cuf Oncologia, AstraZeneca; Financial Interests, Personal, Other, Travel Grant: Daiichi Sankyo, Merck KGaA, Merck Sharp & Dohme, Novartis, OM Pharma; Financial Interests, Personal, Full or part-time Employment: NTT DATA. L. Del Mastro: Financial Interests, Personal, Other, Honoraria: Roche, Novartis, Pfizer, MSD, Genomic Health, Takeda, Ipsen, Eisai, Eli Lilly and Celgene. F. Bertucci: Financial Interests, Institutional, Research Grant: Pfizer, Novartis, Lilly. A. Gonçalves: Financial Interests, Institutional, Research Grant: Pfizer, Novartis, Lilly; Financial Interests, Personal and Institutional, Other, Travel Grant: Novartis. R. Bartsch: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Puma, Roche, Seagen; Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Novartis, Pfizer, Pierre Fabre, Roche, Seagen; Financial Interests, Personal, Research Grant: Daiichi Sankyo, MSD, Novartis, Roche; Financial Interests, Personal, Other, Travel Grant: Roche, Daiichi Sankyo, Lilly, Pfizer. A. Cortés Salgado: Financial Interests, Personal, Other, Honoraria: GSK, AstraZeneca, Roche, MSD, Eisai; Financial Interests, Personal, Advisory Board: Clovis, Lilly, Pfizer, GSK, Ferrer, Roche; Financial Interests, Personal, Research Grant: Pfizer; Financial Interests, Personal, Other, Travel Grant: Roche, Daiichi Sankyo, Pfizer. L. Pecen: Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo, SOTIO Biotech, Beckman-Coulter. G. Rinnerthaler: Financial Interests, Personal, Other, Honoraria: Roche, Gilead, Pfizer, Eli Lilly, Novartis; Financial Interests, Personal, Advisory Role: Roche, AstraZeneca, Daiichi Sankyo, Pfizer, Pierre Fabre, Eli Lilly, MSD, Novartis, Amgen, Merk. R. Greil: Financial Interests, Personal, Other, Honoraria: Celgene, Novartis, Roche, BMS, Takeda, AbbVie, AstraZeneca, Janssen C., MSD, Merck, Gilead, Daiichi Sankyo, Sanofi, Pfizer; Financial Interests, Personal, Advisory Board: Celgene, Novartis, Roche, BMS, Takeda, AbbVie, AstraZeneca, Janssen C., MSD, Merck, Gilead, Daiichi Sankyo, Sanofi, Pfizer; Financial Interests, Personal, Other, Travel Grant: Roche,Amgen,Janssen,AstraZeneca. All other authors have declared no conflicts of interest.