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NPJ Breast Cancer. 2016;2. pii: 15023. doi: 10.1038/npjbcancer.2015.23. Epub 2016 Jan 6.

PAM50 gene signatures and breast cancer prognosis with adjuvant anthracycline- and taxane-based chemotherapy: correlative analysis of C9741 (Alliance).

Author information

1
Department of Oncology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
2
Department of Biostatistics and Bioinformatics, Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC, USA.
3
The Genome Institute, Washington University, St. Louis, MO, USA.
4
Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
5
Alliance for Clinical Trials in Oncology, University of Chicago, Chicago, IL, USA.
6
Department of Pathology, Washington University, St. Louis, MO, USA.
7
Department of Pathology, New York University Medical Center, New York, NY, USA.
8
Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
9
Department of Medicine, Mayo Clinic, Jacksonville, FL, USA.
10
The Angeles Clinic and Research Institute, Santa Monica, CA, USA.
11
Department of Medical Oncology, Hofstra North Shore-LIJ School of Medicine, ProHEALTH Care Associates, Lake Success, NY, USA.
12
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
13
Department of Medicine, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
14
Department of Medicine, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
15
Department of Pathology, Huntsman Cancer Center, University of Utah, Salt Lake City, UT, USA.
16
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, USA.
17
Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
18
Department of Medical Oncology, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
19
Department of Biostatistics and Computational Biology, Alliance Statistics and Data Center, Dana Farber Cancer Institute, Boston, MA, USA.

Abstract

PAM50 intrinsic breast cancer subtypes are prognostic independent of standard clinicopathologic factors. CALGB 9741 demonstrated improved recurrence-free (RFS) and overall survival (OS) with 2-weekly dose-dense (DD) versus 3-weekly therapy. A significant interaction between intrinsic subtypes and DD-therapy benefit was hypothesized. Suitable tumor samples were available from 1,471 (73%) of 2,005 subjects. Multiplexed gene-expression profiling generated the PAM50 subtype call, proliferation score, and risk of recurrence score (ROR-PT) for the evaluable subset of 1,311 treated patients. The interaction between DD-therapy benefit and intrinsic subtype was tested in a Cox proportional hazards model using two-sided alpha = 0.05. Additional multivariable Cox models evaluated the proliferation and ROR-PT scores as continuous measures with selected clinical covariates. Improved outcomes for DD therapy in the evaluable subset mirrored results from the complete data set (RFS; hazard ratio = 1.20; 95% confidence interval = 0.99-1.44) with 12.3-year median follow-up. Intrinsic subtypes were prognostic of RFS (P < 0.0001) irrespective of treatment assignment. No subtype-specific treatment effect on RFS was identified (interaction P = 0.44). Proliferation and ROR-PT scores were prognostic for RFS (both P < 0.0001), but no association with treatment benefit was seen (P = 0.14 and 0.59, respectively). Results were similar for OS. The prognostic value of PAM50 intrinsic subtype was greater than estrogen receptor/HER2 immunohistochemistry classification. PAM50 gene signatures were highly prognostic but did not predict for improved outcomes with DD anthracycline- and taxane-based therapy. Clinical validation studies will assess the ability of PAM50 and other gene signatures to stratify patients and individualize treatment based on expected risks of distant recurrence.

Conflict of interest statement

COMPETING INTERESTS SRD has stock or other ownership in NanoString Techologies. PSB has a patent, intellectual property, or royalties from Bioclassifier. TON has a consulting or advisory role with Bioclassifier and a relationship with Nanostring Technologies. CMP has a leadership role and stock or other ownership with Bioclassifier. MJE has a leadership role and stock or other ownership with Bioclassifier, and he has a consulting or advisory role with NanoString Technologies. The remaining authors declare no conflict of interest.

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