Germline genetic variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA are associated with pathologic complete response to bevacizumab in breast cancer patients

Issam Makhoul, Valentina K. Todorova, Eric R. Siegel, Stephen W. Erickson, Ishwori Dhakal, Vinay R. Raj, Jeannette Y. Lee, Mohammed S. Orloff, Robert J. Griffin, Ronda S. Henry-Tillman, Vicki Klimberg, Laura F. Hutchins, Susan A. Kadlubar

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS). Methods: DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization. Results: After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90-37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes. Conclusion: Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population. Trial Registration: ClinicalTrials.gov NCT00203502.

Original languageEnglish (US)
Article numbere0168550
JournalPLoS One
Volume12
Issue number1
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

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vascular endothelial growth factor A
Angiopoietin-1
fibroblast growth factor 2
gelatinase B
Matrix Metalloproteinase 9
Fibroblast Growth Factor 2
breast neoplasms
Protein-Tyrosine Kinases
Vascular Endothelial Growth Factor A
single nucleotide polymorphism
tyrosine
Polymorphism
germ cells
phosphotransferases (kinases)
Single Nucleotide Polymorphism
Breast Neoplasms
Chemotherapy
Nucleotides
drug therapy
angiogenesis

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Germline genetic variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA are associated with pathologic complete response to bevacizumab in breast cancer patients. / Makhoul, Issam; Todorova, Valentina K.; Siegel, Eric R.; Erickson, Stephen W.; Dhakal, Ishwori; Raj, Vinay R.; Lee, Jeannette Y.; Orloff, Mohammed S.; Griffin, Robert J.; Henry-Tillman, Ronda S.; Klimberg, Vicki; Hutchins, Laura F.; Kadlubar, Susan A.

In: PLoS One, Vol. 12, No. 1, e0168550, 01.01.2017.

Research output: Contribution to journalArticle

Makhoul, I, Todorova, VK, Siegel, ER, Erickson, SW, Dhakal, I, Raj, VR, Lee, JY, Orloff, MS, Griffin, RJ, Henry-Tillman, RS, Klimberg, V, Hutchins, LF & Kadlubar, SA 2017, 'Germline genetic variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA are associated with pathologic complete response to bevacizumab in breast cancer patients', PLoS One, vol. 12, no. 1, e0168550. https://doi.org/10.1371/journal.pone.0168550
Makhoul, Issam ; Todorova, Valentina K. ; Siegel, Eric R. ; Erickson, Stephen W. ; Dhakal, Ishwori ; Raj, Vinay R. ; Lee, Jeannette Y. ; Orloff, Mohammed S. ; Griffin, Robert J. ; Henry-Tillman, Ronda S. ; Klimberg, Vicki ; Hutchins, Laura F. ; Kadlubar, Susan A. / Germline genetic variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA are associated with pathologic complete response to bevacizumab in breast cancer patients. In: PLoS One. 2017 ; Vol. 12, No. 1.
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abstract = "Background: We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41{\%} vs. 25{\%}, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS). Methods: DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina{\circledR} technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5{\%}, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization. Results: After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95{\%} CI 1.90-37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes. Conclusion: Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population. Trial Registration: ClinicalTrials.gov NCT00203502.",
author = "Issam Makhoul and Todorova, {Valentina K.} and Siegel, {Eric R.} and Erickson, {Stephen W.} and Ishwori Dhakal and Raj, {Vinay R.} and Lee, {Jeannette Y.} and Orloff, {Mohammed S.} and Griffin, {Robert J.} and Henry-Tillman, {Ronda S.} and Vicki Klimberg and Hutchins, {Laura F.} and Kadlubar, {Susan A.}",
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T1 - Germline genetic variants in TEK, ANGPT1, ANGPT2, MMP9, FGF2 and VEGFA are associated with pathologic complete response to bevacizumab in breast cancer patients

AU - Makhoul, Issam

AU - Todorova, Valentina K.

AU - Siegel, Eric R.

AU - Erickson, Stephen W.

AU - Dhakal, Ishwori

AU - Raj, Vinay R.

AU - Lee, Jeannette Y.

AU - Orloff, Mohammed S.

AU - Griffin, Robert J.

AU - Henry-Tillman, Ronda S.

AU - Klimberg, Vicki

AU - Hutchins, Laura F.

AU - Kadlubar, Susan A.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Background: We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS). Methods: DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization. Results: After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90-37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes. Conclusion: Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population. Trial Registration: ClinicalTrials.gov NCT00203502.

AB - Background: We previously reported improved pathologic complete response (pCR) in a prospective phase II study using neoadjuvant bevacizumab in combination with chemotherapy compared to chemotherapy alone in breast cancer patients (41% vs. 25%, p = 0.0291). In this study, we queried germline single-nucleotide polymorphisms (SNPs) in angiogenesis-related genes for their impact on pCR and overall survival (OS). Methods: DNA for genotyping was available from 34 subjects who received bevacizumab in addition to chemotherapy and 29 subjects who did not. Using Illumina® technology, we queried 504 SNPs with a minor allele frequency (MAF) of at least 5%, located in 10 angiogenesis-related genes, for their effect on pCR via logistic regression with an additive-inheritance model while adjusting for race and bevacizumab treatment. SNPs that showed significant associations with pCR were selected for additional characterization. Results: After adjusting for race and tumor type, patients who had bevacizumab added to their neoadjuvant therapy were found to experience a significantly improved rate of pCR compared to patients who did not (adjusted OR 8.40, 95% CI 1.90-37.1). When patients were analyzed for SNP effects via logistic regression with race and bevacizumab treatment included as covariates, two SNPs in angiopoietin 1 (ANGPT1), six in ANGPT2, three in fibroblast growth factor 2 (FGF2), four in matrix metalloproteinase 9 (MMP9), three in tyrosine kinase, endothelial (TEK) and two in vascular endothelial growth factor A (VEGFA) were associated with pCR (P<0.05). However, when overall survival was considered, there was no difference between treatment groups or between genotypes. Conclusion: Genetic variability in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA is associated with pCR in bevacizumab-treated patients. Consistent with other studies, adding bevacizumab to standard chemotherapy did not impact OS, likely due to other factors and thus, while SNPs in TEK, ANGPT1, ANGPT2, FGF2, MMP9 and VEGFA were associated with pCR, they were not predictive of OS in this patient population. Trial Registration: ClinicalTrials.gov NCT00203502.

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