Oncotarget

Research Papers:

The impact of ERBB-family germline single nucleotide polymorphisms on survival response to adjuvant trastuzumab treatment in HER2-positive breast cancer

Sinead Toomey, Stephen F. Madden, Simon J. Furney, Yue Fan, Mark McCormack, Carragh Stapleton, Mattia Cremona, Gianpiero L. Cavalleri, Malgorzata Milewska, Naomi Elster, Aoife Carr, Joanna Fay, Elaine W. Kay, Susan Kennedy, John Crown, William M. Gallagher, Bryan T. Hennessy and Alex J. Eustace _

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Oncotarget. 2016; 7:75518-75525. https://doi.org/10.18632/oncotarget.12782

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Abstract

Sinead Toomey1,*, Stephen F. Madden2,*, Simon J. Furney3, Yue Fan4, Mark McCormack5, Carragh Stapleton5, Mattia Cremona1, Gianpiero L. Cavalleri5, Malgorzata Milewska1, Naomi Elster1, Aoife Carr1, Joanna Fay6, Elaine W. Kay6, Susan Kennedy7, John Crown7, William M. Gallagher4, Bryan T. Hennessy1,8,**, Alex J. Eustace1,**

1Medical Oncology Group, Department of Molecular Medicine, Royal College of Surgeons in Ireland, Ireland

2Population Health Sciences Division, Royal College of Surgeons in Ireland, Ireland

3School of Medicine, University College Dublin, Ireland

4University College Dublin, UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, Ireland

5Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Ireland

6Department of Histopathology, Beaumont Hospital, Dublin, Ireland

7St Vincent’s University Hospital, Dublin, Ireland

8Department of Oncology, Beaumont Hospital, Dublin, Ireland

*These authors contributed equally to this work

**Joint senior authors

Correspondence to:

Alex J. Eustace, email: alexeustace@rcsi.ie

Keywords: ERBB-family germline mutations, single nucleotide polymorphisms, high depth sequencing, survival impact

Received: May 03, 2016     Accepted: October 12, 2016     Published: October 20, 2016

ABSTRACT

Background: Trastuzumab treatment for women with HER2-positive breast cancer (BC) resulted in the significant improvement of both relapse free survival (RFS) and overall survival (OS). However, many women who are classified as HER2-positive do not respond. Many studies have focused on the role of somatic mutations rather than germline polymorphisms in trastuzumab resistance.

Results: We completed an Agena MassArray screen of 10 ERBB-family single nucleotide polymorphisms (SNPs) in 194 adjuvant trastuzumab treated HER2-positive BC patients. SNPs in EGFR genes have a significant association with RFS and OS. Patients with the minor allele of EGFR N158N had significantly worse OS (hazard ratio (HR) = 4.01, (confidence interval (CI) = 1.53– 10.69), p = 0.05) relative to those with either the heterozygous or wild-type (WT) allele. Patients with the minor allele of EGFR T903T (HR = 3.52, (CI = 1.38– 8.97), p = 0.05) had worse RFS relative to those with either the heterozygous or WT allele.

Patients and methods: Using next generation sequencing (NGS) we identified ERBB-family (EGFR, HER2, HER3 and HER4) single nucleotide polymorphisms (SNPs) that occurred in 2 or more patients of a 32 HER2-positive BC patient cohort. Agena MassArray analysis confirmed the frequency of these SNPs in 194 women with HER2-positive BC who received trastuzumab in the adjuvant setting. Using Kaplan-Meier estimates and Cox regression analysis we correlated the presence of ERBB-family SNPs with both RFS and OS.

Conclusions: The presence of germline ERBB-family SNPs may play an important role in how a patient responds to adjuvant trastuzumab, and clinical assessment of these SNPs by targeted genetic screening of patients’ blood may be important to stratify patients for treatment.


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