Oncotarget

Research Papers:

A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer

Cesar August Santa-Maria _, Taigo Kato, Jae-Hyun Park, Kazuma Kiyotani, Alfred Rademaker, Ami N. Shah, Leeaht Gross, Luis Z. Blanco, Sarika Jain, Lisa Flaum, Claudia Tellez, Regina Stein, Regina Uthe, William J. Gradishar, Massimo Cristofanilli, Yusuke Nakamura, Francis J. Giles

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Oncotarget. 2018; 9:18985-18996. https://doi.org/10.18632/oncotarget.24867

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Abstract

Cesar August Santa-Maria4,*, Taigo Kato2, Jae-Hyun Park2, Kazuma Kiyotani2, Alfred Rademaker1, Ami N. Shah1, Leeaht Gross1, Luis Z. Blanco1, Sarika Jain1, Lisa Flaum1, Claudia Tellez1, Regina Stein1, Regina Uthe1, William J. Gradishar1, Massimo Cristofanilli1, Yusuke Nakamura2,3 and Francis J. Giles1

1Northwestern University, Robert H. Lurie Comprehensive Cancer Center, Chicago, Illinois, USA

2The University of Chicago, Department of Medicine, Chicago, Illinois, USA

3The University of Chicago, Department of Surgery, Chicago, Illinois, USA

4Johns Hopkins, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA

*These authors contributed equally to this work

Correspondence to:

Cesar August Santa-Maria, email: csantam2@jhmi.edu

Keywords: metastatic breast cancer; immune checkpoint; T cell receptor sequencing; immunogenomics

Received: January 02, 2018     Accepted: March 06, 2018     Published: April 10, 2018

ABSTRACT

Immune checkpoint inhibitors produce modest responses in metastatic breast cancer, however, combination approaches may improve responses. A single arm pilot study was designed to determine the overall response rate (ORR) of durvalumab and tremelimumab, and evaluate immunogenomic dynamics in metastatic endocrine receptor (ER) positive or triple negative breast cancer (TNBC). Simon two-stage design indicated at least four responses from the first 18 patients were needed to proceed with the second stage. T-cell receptor (TCR) sequencing and immune-gene expression profiling were conducted at baseline and two months, whole exome sequencing was conducted at baseline. Eighteen evaluable patients were accrued (11 ER-positive; seven TNBC). Only three patients had a response (ORR = 17%), thus the study did not proceed to the second stage. Responses were only observed in patients with TNBC (ORR = 43%). Responders versus non-responders had upregulation of CD8, granzyme A, and perforin 1 gene expression, and higher mutational and neoantigen burden. Patients with TNBC had an oligoclonal shift of the most abundant TCR-beta clonotypes compared to those with ER-positive disease, p = 0.004. We conclude responses are low in unselected metastatic breast cancer, however, higher rates of clinical benefit were observed in TNBC. Immunogenomic dynamics may help identify phenotypes most likely to respond to immunotherapy.


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