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

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

doi:10.18632/oncotarget.12782

Cited by 15 publications

(11 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We have shown that patients who have the minor allele of the ERBB3 SNPs, (rs2229046 and rs77123) and who received TCH based treatment are significantly more likely to have a worse RFS than patients who received alternate therapies. To support our hypothesis that this is a TCH dependent effect, we previously demonstrated that patients who had the minor allele of the ERBB3 SNP rs2229046 and who received trastuzumab as part of their therapeutic regimen did not have a significantly worse RFS [ 10 ].…”

Section: Discussionmentioning

confidence: 84%

“…Previously we and others demonstrated that the minor allele of the ERBB–I655V SNP was associated with a worse RFS in women with HER2-positive breast cancer [ 9 , 10 ]. A limitation of these studies was that a patient’s specific therapeutic regimens were not considered when the analysis was done.…”

Section: Discussionmentioning

confidence: 99%

“…SNPs which are synonymous variants were until recently believed to be silent, resulting in little to no impact on the ensuing protein. However, recent studies have shown that synonymous SNPs can play an important role in the functionality of the cancer cell and how a patient responds to targeted therapies [ 8 , 10 , 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…In our initial SNP screen, we performed high depth sequencing on our discovery cohort, which contained 32 tumour formalin-fixed, paraffin-embedded (FFPE) samples, from patients with HER2-positive BC. Haematoxylin and eosin sections cut from the patient’s FFPE surgical blocks were analysed by a pathologist for tumour content and those with >50% tumour cellularity had a further 7*10μM sections cut, from which DNA was extracted using the Qiagen DDNA FFPE kit as outlined in a previous study [ 10 ].…”

Section: Methodsmentioning

confidence: 99%

“…Recent data has suggested that germline single nucleotide polymorphisms (SNPs) play a role in both sensitivity and resistance to targeted therapies [ 7 , 8 ]. In fact, we and others have shown that SNPs which occur in the epidermal growth factor receptor ( EGFR ), ERBB2 , ERBB3 or ERBB4 genes (HER-family genes) can be associated with either a worse relapse free survival (RFS) or worse overall survival (OS) rates in women with HER2-positive breast cancer who received adjuvant trastuzumab as part of their treatment regimen [ 9 , 10 ]. Mutations in HER-family genes have been shown to activate the PI3K/AKT signaling pathway and both germline SNPs and somatic mutations may act as biomarkers of sensitivity and resistance in both gastric and breast cancers [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Germline single nucleotide polymorphisms in ERBB3 and BARD1 genes result in a worse relapse free survival response for HER2-positive breast cancer patients treated with adjuvant based docetaxel, carboplatin and trastuzumab (TCH)

et al. 2018

Self Cite

View full text Add to dashboard Cite

Breast cancer is the leading cause of cancer related deaths in women worldwide and is classified into subtypes based on the cancer’s receptor status. Of these subtypes, those expressing the human epidermal growth factor receptor 2 (HER2) receptor were traditionally associated with poor prognosis. Several advances have been made in the treatment of HER2-positive breast cancer, yet issues of resistance and poor response to therapy remains prevalent. In this study we explored the impact of HER-family and homologous recombination deficiency SNPs on response to patients who received TCH-based (docetaxel (T), carboplatin (C), and trastuzumab (H)) treatment versus those who received other treatment regimens. Using Cox regression analysis, we identified 6 SNPs that correlate with recurrence free survival in our patients and supported our findings using support vector machines. We also used reverse phase protein array analysis to examine the impact ERBB3 SNPs may have on both the PI3K/AKT and MAPK/ERK signaling pathways. Finally, using cell line models, we correlated SNP status with sensitivity to platinum based drugs and docetaxel. We found that patients on a TCH based regimen with the minor allele of the ERBB3 (rs2229046 and rs773123) and BARD1 (rs2070096) SNPs, were significantly more likely to relapse than those women who were not. Additionally, we observed that patients with these ERBB3 SNPs had shown elevated protein expression/phosphorylation of Src kinase, c-MET (Y1234/1235), GSK-3β (S9) and p27, indicating that these SNPs are associated with non-PI3K/AKT signaling. Finally, using cell line models, we demonstrate that the BARD1 SNP (rs2229571) is associated with greater sensitivity to both carboplatin and cisplatin. The BARD1 and ERBB3 SNPs can potentially be used to determine those patients that will have a worse response to TCH based treatment, an effect that may arise from the SNPs impact on altered cellular signaling.

show abstract

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Germline single nucleotide polymorphisms in ERBB3 and BARD1 genes result in a worse relapse free survival response for HER2-positive breast cancer patients treated with adjuvant based docetaxel, carboplatin and trastuzumab (TCH)

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

SNPs Ability to Influence Disease Risk: Breaking the Silence on Synonymous Mutations in Cancer

Herreros

Janssens

Pepe

et al. 2022

Single Nucleotide Polymorphisms

View full text Add to dashboard Cite

Cancer arises when normal cells are transformed into malignant cells by acquiring a number of hallmarks such as sustained proliferative signaling; evading cell death, growth suppression and immune destruction; replicative immortality; and activation of invasion and metastasis (Hanahan et al. 2000, 2011). Sequential accumulation of genetic mutations is a major cause of acquiring these cancer hallmarks in the cell transformation process, and hence a complete characterization of the landscape of pathogenic somatic and congenital mutations in cancer cells forms a holy grail to fully understand cancer biology. Indeed, a lot of effort has gone towards characterizing somatic missense and nonsense single nucleotide variants in the protein coding regions of the genome that result in amino acid substitutions, small insertions and deletions, or a premature STOP codon in the encoded protein. Synonymous mutations on the other hand, nucleotide changes that do not result in an amino acid change in the protein for which they encode, have previously attracted significantly less at attention as candidate cancer driver mutations. However, in a variety of other diseases such as cystic fibrosis, ataxia telangiectasia and even in hereditary cancer syndromes, a causative role for synonymous mutations in disease pathogenesis has been described (Sauna et al. 2011). In addition, the number of synonymous mutations that have a significant impact on the corresponding RNA and protein expression level or isoform in different cancer types is rapidly rising. It is thus becoming clear that there might be a significant fraction of synonymous mutations that are not as ‘silent’ as they have long been considered to be. In this chapter, we will discuss why synonymous mutations have received little attention in the context of cancer. Furthermore, we will describe the recent progress that was made in characterizing the landscape of oncogenic synonymous mutations as well as the variety of molecular mechanisms by which synonymous mutations affect RNA and protein expression levels of oncogenes and tumor suppressors.

show abstract

Nanoparticle-Based Delivery of Phytochemical Compounds Against Major Maladies: Cancer, Diabetes, and Cardiovascular Disease

Banerjee

2020

Plant-Derived Bioactives

View full text Add to dashboard Cite

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

Cited by 15 publications

References 25 publications

Germline single nucleotide polymorphisms in ERBB3 and BARD1 genes result in a worse relapse free survival response for HER2-positive breast cancer patients treated with adjuvant based docetaxel, carboplatin and trastuzumab (TCH)

Germline single nucleotide polymorphisms in ERBB3 and BARD1 genes result in a worse relapse free survival response for HER2-positive breast cancer patients treated with adjuvant based docetaxel, carboplatin and trastuzumab (TCH)

SNPs Ability to Influence Disease Risk: Breaking the Silence on Synonymous Mutations in Cancer

Nanoparticle-Based Delivery of Phytochemical Compounds Against Major Maladies: Cancer, Diabetes, and Cardiovascular Disease

Contact Info

Product

Resources

About