Blood mRNA expression profiling predicts survival in patients treated with tremelimumab.
OBJECTIVE
Tremelimumab (ticilimumab, Pfizer), is a monoclonal antibody (mAb) targeting cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Ipilimumab (Yervoy, BMS), another anti-CTLA-4 antibody, is approved by the U.S. Federal Drug Administration (FDA). Biomarkers are needed to identify the subset of patients who will achieve tumor control with CTLA-4 blockade.


METHODS
Pretreatment peripheral blood samples from 218 patients with melanoma who were refractory to prior therapy and receiving tremelimumab in a multicenter phase II study were measured for 169 mRNA transcripts using reverse transcription polymerase chain reaction (RT-PCR). A two-class latent model yielded a risk score based on four genes that were highly predictive of survival (P < 0.001). This signature was validated in an independent population of 260 treatment-naïve patients with melanoma enrolled in a multicenter phase III study of tremelimumab.


RESULTS
Median follow-up was 297 days for the training population and 386 days for the test population. Expression levels of the 169 genes were closely correlated across the two populations (r = 0.9939). A four-gene model, including cathepsin D (CTSD), phopholipase A2 group VII (PLA2G7), thioredoxin reductase 1 (TXNRD1), and interleukin 1 receptor-associated kinase 3 (IRAK3), predicted survival in the test population (P = 0.001 by log-rank test). This four-gene model added to the predictive value of clinical predictors (P < 0.0001).


CONCLUSIONS
Expression levels of CTSD, PLA2G7, TXNRD1, and IRAK3 in peripheral blood are predictive of survival in patients with melanoma treated with tremelimumab. Blood mRNA signatures should be further explored to define patient subsets likely to benefit from immunotherapy.
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, CanadaAuthors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada yvonne.saenger@mssm.edu.
Yvonne
Y
Saenger
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.
Jay
J
Magidson
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.
Bobby
B
Liaw
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.
Ellen
E
de Moll
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.
Sara
S
Harcharik
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.
Yichun
Y
Fu
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.
Karl
K
Wassmann
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.
David
D
Fisher
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.
John
J
Kirkwood
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.
William K
WK
Oh
Authors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, CanadaAuthors' Affiliations: Division of Hematology and Oncology, Tisch Cancer Institute, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York; Statistical Innovations, Belmont; Department of Dermatology, Harvard Medical School, Boston, Massachusetts; Departments of Medicine, Dermatology and Translational Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Gene News, Ontario, Canada.
Philip
P
Friedlander
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality*; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D055815:Young Adult
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C520704:tremelimumab