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Clin Cancer Res. 2016 Dec 1;22(23):5755-5764. Epub 2016 May 16.

TransCONFIRM: Identification of a Genetic Signature of Response to Fulvestrant in Advanced Hormone Receptor-Positive Breast Cancer.

Author information

1
Susan F. Smith Center for Women's Cancers, Dana Farber Cancer Institute, Boston, Massachusetts. myles_brown@dfci.harvard.edu rinath_jeseloshn@dfci.harvard.edu.
2
Center for Functional Caner Epigenetics, Dana Farber Cancer Institute, Boston, Massachusetts.
3
Susan F. Smith Center for Women's Cancers, Dana Farber Cancer Institute, Boston, Massachusetts.
4
Department of Biostatistics and Computational Biology, Dana Farber Cancer Institute, Boston, Massachusetts.
5
Translational Research Unit, Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
6
"Sandro Pitigliani" Medica Oncology Unit, Istituto Toscano Tumori, Prato, Italy.
7
Astra Zeneca Pharmaceuticals, Macclesfield, United Kingdom.

Abstract

PURPOSE:

Fulvestrant is an estrogen receptor (ER) antagonist and an approved treatment for metastatic estrogen receptor-positive (ER+) breast cancer. With the exception of ER levels, there are no established predictive biomarkers of response to single-agent fulvestrant. We attempted to identify a gene signature of response to fulvestrant in advanced breast cancer.

EXPERIMENTAL DESIGN:

Primary tumor samples from 134 patients enrolled in the phase III CONFIRM study of patients with metastatic ER+ breast cancer comparing treatment with either 250 mg or 500 mg fulvestrant were collected for genome-wide transcriptomic analysis. Gene expression profiling was performed using Affymetrix microarrays. An exploratory analysis was performed to identify biologic pathways and new signatures associated with response to fulvestrant.

RESULTS:

Pathway analysis demonstrated that increased EGF pathway and FOXA1 transcriptional signaling is associated with decreased response to fulvestrant. Using a multivariate Cox model, we identified a novel set of 37 genes with an expression that is independently associated with progression-free survival (PFS). TFAP2C, a known regulator of ER activity, was ranked second in this gene set, and high expression was associated with a decreased response to fulvestrant. The negative predictive value of TFAP2C expression at the protein level was confirmed by IHC.

CONCLUSIONS:

We identified biologic pathways and a novel gene signature in primary ER+ breast cancers that predicts for response to treatment in the CONFIRM study. These results suggest potential new therapeutic targets and warrant further validation as predictive biomarkers of fulvestrant treatment in metastatic breast cancer. Clin Cancer Res; 22(23); 5755-64. ©2016 AACR.

PMID:
27185372
PMCID:
PMC5124409
DOI:
10.1158/1078-0432.CCR-16-0148
[Indexed for MEDLINE]
Free PMC Article

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