1542P - Exploratory analyses of candidate predictive and prognostic tissue biomarkers (BMs) in the open-label randomised phase III TANIA trial of bevacizum...

Date 10 October 2016
Event ESMO 2016 Congress
Session Poster display
Topics Breast Cancer, Metastatic
Translational Research
Presenter Christoph Zielinski
Citation Annals of Oncology (2016) 27 (6): 526-544. 10.1093/annonc/mdw392
Authors C. Zielinski1, J. Gligorov2, N. Marschner3, F. Puglisi4, E. Vrdoljak5, J. Cortes Castan6, S. de Ducla7, R. Deurloo7, V. Easton8, G. von Minckwitz9
  • 1Department Of Medicine I, Comprehensive Cancer Center, Medical University Vienna and Central European Cooperative Oncology Group (CECOG), 1090 - Vienna/AT
  • 2Medical Oncology Department, Assistance Publique Hôpitaux de Paris – Tenon, IUC-UPMC, Sorbonne University, Paris/FR
  • 3Internal Medicine / Hematology, Outpatient Cancer Center, 79110 - Freiburg/DE
  • 4Department Of Medical And Biological Sciences, University of Udine and Department of Oncology, University Hospital of Udine, Udine, Udine/IT
  • 5Department Of Oncology, Center of Oncology, Split/HR
  • 6Medical Oncology, Ramon y Cajal University Hospital, Madrid and Vall d’Hebron Institute of Oncology (VHIO), 08035 - Barcelona/ES
  • 7Pharma Development Medical Affairs, F Hoffmann-La Roche Ltd, Basel/CH
  • 8Pdma Operations (biometrics), Stamford Consultants AG on behalf of F Hoffmann-La Roche Ltd, Basel/CH
  • 9Department Of Medical Oncology, German Breast Group, Neu-Isenburg/DE



In the TANIA trial (NCT01250379), adding BEV to 2nd-line chemotherapy (CT) significantly improved 2nd-line progression-free survival (PFS, primary endpoint; hazard ratio [HR] 0.75, 95% CI 0.61–0.93; p = 0.0068) in BEV-pretreated LR/mBC. No difference in 3rd-line PFS or overall survival (OS) was observed. Post hoc analyses explored potential associations between 6 candidate BMs (based on previous results/biological hypotheses) and 2nd-line PFS and OS.


Patients (pts) with BEV-pretreated HER2-negative LR/mBC were randomised to receive 2nd-line CT ± BEV until disease progression (PD), unacceptable toxicity or withdrawal. At 2nd PD, 3rd-line CT was given without BEV in the CT arm and with BEV in the BEV + CT arm. Archival primary or metastatic tumour samples collected before 2nd-line BEV from pts consenting to optional translational research were analysed by immunohistochemistry using median expression levels for each BM as the cut-off for high vs low BM subgroups.


Samples (mainly primary tumour) were available from 210 (43%) of 494 randomised pts. Baseline characteristics and efficacy in these pts were broadly representative of the ITT population. High CA9 and CD31 were associated with worse prognosis but larger BEV benefit, although neither was consistently predictive across endpoints (table). Pts with high CA9 had median PFS of 4.6 vs 1.9 mo with BEV + CT vs CT, respectively; pts with high CD31 had median OS of 19.3 vs 13.0 mo, respectively. No BM was associated with a detrimental BEV effect.

BM 2nd-line PFS HR (95% CI) Interaction p-valuea OS HR (95% CI) Interaction p-valuea
≤Median >Median ≤Median >Median
CD31 No. of vessels 1.02 (0.68–1.55) 0.60 (0.39–0.93) 0.110 1.42 (0.88–2.27) 0.60 (0.37–0.99) 0.016
CD31 volume fraction 0.85 (0.57–1.29) 0.74 (0.48–1.15) 0.585 1.20 (0.74–1.95) 0.75 (0.47–1.22) 0.179
tVEGF-A 1.10 (0.73–1.65) 0.63 (0.41–0.95) 0.091 0.99 (0.63–1.55) 0.86 (0.53–1.38) 0.626
CA9 cytoplasm H-score 0.92 (0.64–1.30) 0.49 (0.30–0.81) 0.064 0.93 (0.62–1.39) 0.93 (0.54–1.60) 0.878
CA9 membrane H-score 0.90 (0.65–1.27) 0.41 (0.23–0.74) 0.017 0.99 (0.67–1.47) 0.70 (0.38–1.27) 0.258
PD-L1 immune cell 0.84 (0.59–1.19) 0.61 (0.36–1.04) 0.357 1.01 (0.68–1.51) 0.68 (0.37–1.26) 0.196
PD-L1 tumour cell 0.79 (0.58–1.06) 0.96 (0.17–5.38) 0.795 0.92 (0.65–1.29) 0.36 (0.04–3.16) 0.469
CD8 invasive margin 0.77 (0.44–1.33) 1.07 (0.63–1.83) 0.357 0.87 (0.46–1.65) 1.35 (0.73–2.48) 0.313
CD8 tumour centre 0.61 (0.40–0.93) 0.97 (0.63–1.49) 0.155 0.87 (0.55–1.37) 1.00 (0.62–1.63) 0.711
CD163 invasive margin 1.00 (0.55–1.80) 0.96 (0.56–1.64) 0.891 0.76 (0.40–1.44) 1.65 (0.87–3.14) 0.094
CD163 tumour centre 1.09 (0.71–1.67) 0.71 (0.47–1.06) 0.262 0.91 (0.57–1.45) 0.93 (0.58–1.48) 0.886

aNot adjusted for multiplicity. CA9 = carbonic anhydrase 9; PD-L1 = programmed cell death 1 ligand 1; tVEGF-A = tumour vascular endothelial growth factor-A.


Continued BEV significantly improved 2nd-line PFS irrespective of BM levels in LR/mBC. Exploratory analyses suggested potential predictive effects of CA9 (PFS) and CD31 (OS), suggesting involvement of tumour and endothelium characteristics in the therapeutic concept of anti-angiogenesis.

Clinical trial identification

EUDRACT 2010-020998-16

Legal entity responsible for the study

F Hoffmann-La Roche


F Hoffmann La Roche


C. Zielinski: Honoraria (Advisory Boards): Roche J. Gligorov: Consultant for Roche/Genentech and Eisai and honoraria from Novartis/GlaxoSmithKline, Genomic Health and Teva. N. Marschner: Honoraria Roche for consultancy and advisory boards, as well as grants for scientific projects. F. Puglisi: Honoraria from AstraZeneca, Amgen, Celgene, Ipsen, Novartis, Pierre Fabre and Roche. E. Vrdoljak: Funding for clinical trials from Roche and Pfizer, and consulting honoraria from Bayer, AstraZeneca, Amgen, Merck, MSD, GlaxoSmithKline, Novartis, Pfizer and Roche. J. Cortes Castan: Consultancy fees from Roche, Celgene and AstraZeneca, and honoraria from Roche, Celgene, Novartis and Eisai. S. de Ducla, R. Deurloo: Employee of Roche and holds shares in Roche. V. Easton: Employee of Stamford Consultants AG contracted to Roche. G. von Minckwitz: Institution received research funds from Pfizer, GSK, Sanofi-Aventis, Amgen, Roche, Novartis, Celgene, Teva, Boehringer-Ingelheim, AstraZeneca and Myriad Genetics.