Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100

Schneider, Bryan P.; Li, L.; Shen, Fei; Miller, Kathy D.; Radovich, Milan; O’Neill, Anne; Gray, Robert J.; Lane, David P.; Flockhart, David A.; Jiang, Guanglong; Wang, Z.; Lai, Dongbing; Koller, Daniel L.; Pratt, J. Howard; Dang, Chau T.; Northfelt, Donald W.; Perez, Edith A.; Shenkier, Tamara; Cobleigh, Melody A.; Smith, Mary Lou; Railey, Elda; Partridge, Ann H.; Gralow, Julie R.; Sparano, Joseph A.; Davidson, Nancy E.; Foroud, Tatiana; Sledge, George W.

doi:10.1038/bjc.2014.430

Cited by 40 publications

(29 citation statements)

References 31 publications

(34 reference statements)

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“…15,17,18 In this study we have compared the likelihood of each of these clinically relevant toxicities between AAs and EAs. We report a numerically higher likelihood for each of these toxicities for AA's; with odds ratios ranging from 1.4-2.9.…”

Section: Discussionmentioning

confidence: 99%

“…Genome-wide SNP arrays (either Illumina HumanOmni1-Quad or Human OmniExpress) were performed in two distinct study subsets as described previously. 15 A principal component analysis was performed using Eigenstrat and reference data from 11 HapMap phase III populations to identify clusters using the first two eigenvectors computed using all SNPs. 16 Samples clustering with those of African Ancestry (AA) and those of European Ancestry (EA) were used in these analyses; Supplemental figure 1.…”

Section: Methodsmentioning

confidence: 99%

“…We had previously published biomarker data on each of these toxicities 15,17,18 and set out to compare the frequency of all toxicities between AAs and EAs and to assess the impact of race on dose modifications with the current study. Statistical analysis was performed using R (v3.3.0) and the chi-square test.…”

Section: Methodsmentioning

confidence: 99%

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Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-5103

Schneider

Shen

Jiang

et al. 2017

JCO Precision Oncology

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Purpose Racial disparity in breast cancer outcomes exists between African American and Caucasian women in the United States. We have evaluated the impact of genetically determined ancestry on disparity in efficacy and therapy-induced toxicity for breast cancer patients in the context of a randomized, phase III adjuvant trial. Patients and Methods This study compared outcomes between 386 patients of African ancestry (AA) and 2473 patients of European ancestry (EA) in a randomized, phase III breast cancer trial; ECOG-ACRIN-E5103. The primary efficacy endpoint, invasive disease free survival (DFS) and clinically significant toxicities were compared including: anthracycline-induced congestive heart failure (CHF), taxane-induced peripheral neuropathy (TIPN), and bevacizumab-induced hypertension. Results Overall, AAs had significantly inferior DFS (p=0.002; HR=1.5) compared with EAs. This was significant in the estrogen receptor-positive subgroup (p=0.03); with a similar, non-significant trend for those who had triple negative breast cancer (TNBC; p=0.12). AAs also had significantly more grade 3-4 TIPN (OR=2.9; p=2.4 ×10-11) and grade 3-4 bevacizumab-induced hypertension (OR=1.6; p=0.02), with a trend for more CHF (OR=1.8; p=0.08). AAs had significantly more dose reductions for paclitaxel (p=6.6 ×10-6). In AAs, dose reductions in paclitaxel had a significant negative impact on DFS (p=0.03); whereas in EAs, dose reductions did not impact outcome (p=0.35). Conclusion AAs had inferior DFS with more clinically important toxicities in ECOG-ACRIN-E5103. The altered risk to benefit ratio for adjuvant breast cancer chemotherapy should lead to additional research with the focus centered on the impact of genetic ancestry on both efficacy and toxicity. Strategies to minimize dose reductions for paclitaxel, especially due to TIPN, are warranted for this population.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-5103

Schneider

Shen

Jiang

et al. 2017

JCO Precision Oncology

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“…Two studies have shown increased susceptibility of African Americans to bevacizumab-related hypertension; one showing a 1.6-fold increase in bevacizumab-induced hypertension (14), and a second showing bevacizumab-induced exacerbation of pre-existing hypertension disproportionately affecting African Americans (28). The former study included a GWAS of bevacizumab-induced hypertension which excluded the African American sample during quality control to avoid confounding population substructure (29). …”

Section: Ancestral Differences In Prevalence Of Chemotherapeutic Toximentioning

confidence: 99%

Genome-Wide Association Studies of Chemotherapeutic Toxicities: Genomics of Inequality

Mapes

Charif

Al-Sawwaf

et al. 2017

Clinical Cancer Research

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With an estimated global population of cancer survivors exceeding 32 million and growing, there is a heightened awareness of the long-term toxicities resulting from cancer treatments and their impact on quality of life. Unexplained heterogeneity in the persistence and development of toxicities, as well as an incomplete understanding of their mechanisms have generated a growing need for the identification of predictive pharmacogenomic markers. Early studies addressing this need used a candidate gene approach; however, over the last decade, unbiased and comprehensive genome-wide association studies (GWAS) have provided markers of phenotypic risk and potential targets to explore the mechanistic and regulatory pathways of biological functions associated with chemotherapeutic toxicity. In this review, we provide the current status of GWAS of chemotherapeutic toxicities with an emphasis on examining the ancestral diversity of the representative cohorts within these studies. Persistent calls to incorporate both ancestrally diverse and/or admixed populations into genomic efforts resulted in a recent rise in the number of studies utilizing cohorts of East Asian descent; however, few pharmacogenomic studies to date include cohorts of African, Indigenous American, Southwest Asian, and admixed populations. Through comprehensively evaluating sample size, composition by ancestry, genome-wide significant variants, and population-specific minor allele frequencies as reported by HapMap/dbSNP using NCBI PubMed, and the NHGRI-EBI GWAS Catalog, we illustrate allele frequencies and effect sizes tend to vary among individuals of differing ancestries. In an era of Personalized Medicine, the lack of diversity in genome-wide studies of anticancer agent toxicity may contribute to the health disparity gap.

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“…Ten single nucleotide polymorphisms (SNPs) were associated with bevacizumab-induced hypertension (p £ 0.05) but none of these overcome the threshold of multiple logistic regression (p < 0.0002). Conversely a genomewide association study in two randomized Phase III breast cancer trials (ECOG-5130 and ECOG-2100) revealed a compelling association between bevacizumab-induced grade 3/4 hypertension and an SNP in SV2C (rs6453204) (p = 0.037; Odds Ratio = 2.4) [51].…”

Section: Toxicitymentioning

confidence: 99%

Current opinion on bevacizumab on endometrial cancer treatment

Bogliolo

Cassani

Gardella

et al. 2014

Expert Opinion on Biological Therapy

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Bevacizumab in combination with others targeted therapies, chemotherapy or radiotherapy demonstrated promising anti-tumor activity. Despite the good oncological outcomes of these recent clinical experiences, caution must be used in light of significant toxicity reported in this subset of heavily pre-treated patients. The identification of biomarkers able to predict either the efficacy or toxicity of anti-angiogenic drugs is a compelling need.

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Genetic variant predicts bevacizumab-induced hypertension in ECOG-5103 and ECOG-2100

Cited by 40 publications

References 31 publications

Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-5103

Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-5103

Genome-Wide Association Studies of Chemotherapeutic Toxicities: Genomics of Inequality

Current opinion on bevacizumab on endometrial cancer treatment

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