Predictive gene signature of response to the anti-TweakR mAb PDL192 in patient-derived breast cancer xenografts.
OBJECTIVE
(1) To determine TweakR expression in human breast cancers (BC), (2) evaluate the antitumor effect of the anti-TweakR antibody PDL192, used alone or after chemotherapy-induced complete remission (CR), on patient-derived BC xenografts (PDX) and (3) define predictive markers of response.


METHODS
TweakR expression was analyzed by IHC on patients and PDXs BC samples. In vivo antitumor effect of PDL192 was evaluated on eight TweakR-positive BC PDXs alone or after complete remission induced by a combination of doxorubicin and cyclophosphamide. Using both responding and resistant PDX tumors after PDL192 administration, RT-QPCR were performed on a wide list of selected candidate genes to identify predictive markers of response.


RESULTS
TweakR protein was expressed in about half of human BC samples. In vivo PDL192 treatment had significantly anti-tumor activity in 4 of 8 TweakR-positive BC PDXs, but no correlation between the expression level of the Tweak receptor and response to therapy was observed. PDL192 also significantly delayed tumor relapse after CR. Finally, an 8 gene signature was defined from sensitive and resistant PDXs.


CONCLUSIONS
PDL192 was highly efficient in some BC PDXs. We found 8 genes that were differentially expressed in responding and resistant tumors and could constitute a gene expression signature which would need to be extended to other xenograft models for confirmation. These data confirm the therapeutic potential of TweakR targeting in BC and the possibility of prospectively selecting patients who might benefit from therapy.
Laboratory of preclinical investigation, Translational Research Department, Institut Curie, Paris, France.
Ludmilla
L
de Plater
Department of Tumor Biology, Institut Curie, Paris, France.
Anne
A
Vincent-Salomon
Department of Biostatistics, Institut Curie, Paris, France; INSERM U900, Paris, France.
Frédérique
F
Berger
Department of Tumor Biology, Institut Curie, Paris, France.
André
A
Nicolas
Department of Genetics, Institut Curie, Paris, France.
Sophie
S
Vacher
Department of Biostatistics, Institut Curie, Paris, France.
Eléonore
E
Gravier
Laboratory of preclinical investigation, Translational Research Department, Institut Curie, Paris, France.
Aurélie
A
Thuleau
Laboratory of preclinical investigation, Translational Research Department, Institut Curie, Paris, France.
Narjesse
N
Karboul
Department of Tumor Biology, Institut Curie, Paris, France.
Marion
M
Richardson
Laboratory of preclinical investigation, Translational Research Department, Institut Curie, Paris, France.
Clément
C
Elbaz
Laboratory of preclinical investigation, Translational Research Department, Institut Curie, Paris, France.
Elisabetta
E
Marangoni
Department of Genetics, Institut Curie, Paris, France.
Ivan
I
Bièche
Department of Biostatistics, Institut Curie, Paris, France; INSERM U900, Paris, France.
Xavier
X
Paoletti
Translational Research Department, Institut Curie, Paris, France.
Sergio
S
Roman-Roman
AbbVie Biotherapeutics, Redwood City, California, United States of America.
Patricia A
PA
Culp
Department of Biostatistics, Institut Curie, Paris, France; INSERM U900, Paris, France.
Bernard
B
Asselain
Department of Oncogenetic, Institut Curie, Paris, France.
Véronique
V
Diéras
Laboratory of preclinical investigation, Translational Research Department, Institut Curie, Paris, France; Department of Oncogenetic, Institut Curie, Paris, France.
Didier
D
Decaudin
D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000074050:TWEAK Receptor; D016896:Treatment Outcome
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; D004317:Doxorubicin; D003520:Cyclophosphamide; C578859:enavatuzumab