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Ann Oncol. 2017 May 1;28(5):1070-1077. doi: 10.1093/annonc/mdx048.

Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial.

Author information

1
McDonnell Genome Institute at Washington University School of Medicine, St Louis, USA
2
Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, USA
3
Siteman Cancer Center, Washington University School of Medicine, St Louis, USA
4
Department of Genetics, Washington University School of Medicine, St Louis, USA
5
Department of Pathology & Immunology, Washington University School of Medicine, St. Louis.
6
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, USA
7
Duke University Medical Center, Durham.
8
Alliance Statistics and Data Center, Mayo Clinic, Rochester.
9
The University of Texas MD Anderson Cancer Center, Houston.
10
The University of Texas Southwestern Medical Center, Dallas.
11
Mayo Clinic, Rochester, USA
12
Doctors Hospital of Laredo, Laredo, USA
13
Institute for Genomic Medicine, The Research Institute at Nationwide Children's Hospital, Columbus, USA
14
Department of Pediatrics, The Ohio State University College of Medicine, Columbus, USA.

Abstract

Background:

HER2 (ERBB2) gene amplification and its corresponding overexpression are present in 15-30% of invasive breast cancers. While HER2-targeted agents are effective treatments, resistance remains a major cause of death. The American College of Surgeons Oncology Group Z1041 trial (NCT00513292) was designed to compare the pathologic complete response (pCR) rate of distinct regimens of neoadjuvant chemotherapy and trastuzumab, but ultimately identified no difference.

Patients and methods:

In supplement to tissues from 37 Z1041 cases, 11 similarly treated cases were obtained from a single institution study (NCT00353483). We have extracted genomic DNA from both pre-treatment tumor biopsies and blood of these 48 cases, and performed whole genome (WGS) and exome sequencing. Coincident with these efforts, we have generated RNA-seq profiles from 42 of the tumor biopsies. Among patients in this cohort, 24 (50%) achieved a pCR.

Results:

We have characterized the genomic landscape of HER2-positive breast cancer and investigated associations between genomic features and pCR. Cases assigned to the HER2-enriched subtype by RNA-seq analysis were more likely to achieve a pCR compared to the luminal, basal-like, or normal-like subtypes (19/27 versus 3/15; P = 0.0032). Mutational events led to the generation of putatively active neoantigens, but were overall not associated with pCR. ERBB2 and GRB7 were the genes most commonly observed in fusion events, and genomic copy number analysis of the ERBB2 locus indicated that cases with either no observable or low-level ERBB2 amplification were less likely to achieve a pCR (7/8 versus 17/40; P = 0.048). Moreover, among cases that achieved a pCR, tumors consistently expressed immune signatures that may contribute to therapeutic response.

Conclusion:

The identification of these features suggests that it may be possible to predict, at the time of diagnosis, those HER2-positive breast cancer patients who will not respond to treatment with chemotherapy and trastuzumab.

ClinicalTrials.gov identifiers:

NCT00513292, NCT00353483.

KEYWORDS:

ERBB2; HER2; breast cancer; pathologic complete response; residual disease; trastuzumab

PMID:
28453704
PMCID:
PMC5790063
DOI:
10.1093/annonc/mdx048
[Indexed for MEDLINE]
Free PMC Article

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