Abstract 3402: The impact of germline single nucleotide polymorphisms (SNPs) in ERBB-family genes and genes associated with homologous recombination deficiency (HRD) on response to taxotere, platinum and trastuzumab (TCH) based therapy in the treatment of HER2-positive breast cancer patients
Authors: Madden Stephen F. , Toomey Sinead , Furney Simon , Milewska Malgorzata , Fay Joanna , Kay Elaine W. , Crown John , Kennedy Susan , Hennessy Bryan T. , Eustace Alex J. 
Published: July 2017

BACKGROUND: We have shown that ERBB (EGFR, ERBB2, ERBB and ERBB4) germline single nucleotide polymorphisms (SNPs) have a negative impact on the outcome of trastuzumab treated HER2-positive breast cancer (BC) patients. Currently TCH (taxotere, platinum and trastuzumab) based therapy is used to treat early stage HER2-positive BC. We investigate the importance of germline SNPs in ERBB genes and those genes involved in homologous recombination deficiency (HRD), on how patients respond to TCH therapy.

PATIENTS AND METHODS: ERBB/HRD SNPs were identified in a panel of 32 HER2-positive BC patients by next generation sequencing (NGS). Agena MassArray analysis confirmed the genotype of these SNPs in a further 157 women. Kaplan-Meier estimates and Cox regression analysis identified that both ERBB/HRD SNPs were associated with relapse free survival (RFS) in patients who received a TCH based treatment versus those who received alternate therapies. Protein extracted from formalin fixed paraffin embedded tumours (n=60), was run on an RPPA platform to measure expression and phosphorylation of proteins (69 antibodies). Logistical regression identified protein levels associated with the presence/absence of ERBB/HRD SNPs that were significantly associated with RFS.

RESULTS: Ten ERBB/HRD SNPs were profiled in 157 trastuzumab treated HER2-positive BC patients. The minor alleles of the ERBB2 (rs1136201), ERBB3 (rs2229046) and BARD1 (rs2070096) SNPs significantly associated with a worse RFS in patients who received TCH based therapy relative to those who had the reference allele (ERBB2: HR=2.67 (CI=1.05-6.78), p=0.04; ERBB3 rs2229046: HR=4.95 (CI=1.91-12.79), p=9.75x10-4; BARD1: HR=3.27 (CI =1.16-9.17), p=0.02). The impact of ERBB/HRD SNPs on RFS was not observed in patients who did not receive TCH treatment. The minor allele of the RNF8 rs2284922 SNP is associated with a worse RFS (RNF8: HR=12.42 (CI =2.00-77.19), p=6.89x10-3) relative to those who had the reference allele only in patients who did not receive TCH treatment. RPPA analysis identified that patients who received TCH therapy and had the minor allele of the ERBB3 SNPs were significantly associated with the expression of HER2, p27 and MEK1/2 (rs2229046; minor allele associated with low expression of p27 (p=7.22x10-3) and with high expression of HER2 (p=6.53x10-3); rs773123, minor allele associated with low expression of p27 (p=5.38x10-4) and with high expression of MEK1/2 (p=6.24x10-3).

CONCLUSIONS: The presence of germline ERBB/HRD SNPs may play an important role in how a patient responds to TCH based therapy, and clinical assessment of these SNPs by targeted genetic screening of patients' blood may allow for stratification of patients prior to treatment.

Citation Format: Stephen F. Madden, Sinead Toomey, Simon Furney, Malgorzata Milewska, Joanna Fay, Elaine W. Kay, John Crown, Susan Kennedy, Bryan T. Hennessy, Alex J. Eustace. The impact of germline single nucleotide polymorphisms (SNPs) in ERBB-family genes and genes associated with homologous recombination deficiency (HRD) on response to taxotere, platinum and trastuzumab (TCH) based therapy in the treatment of HER2-positive breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3402. doi:10.1158/1538-7445.AM2017-3402