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Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy.

ABSTRACT: Breast cancer (BC) is one of the most prevalent types of cancer worldwide with high morbidity and mortality rates. Treatment modalities include systemic therapy, in which chemotherapy is a major component in many cases. Several chemotherapeutic agents are used in combinations or as single agents with many adverse events occurring in variable frequencies. These events can be a significant barrier in completing the treatment regimens. Germline genomic variants are thought of as potential determinants in chemotherapy response and the development of side effects. Some pharmacogenomic studies were designed to explore germline variants that can be used as biomarkers for predicting developing toxicity or adverse events during chemotherapy in BC. In this review, we reassess and summarize the major findings of pharmacogenomic studies of chemotherapy toxicity during BC management. In addition, deficiencies hampering utilizing these findings and the potential targets of future research are emphasized. Main insufficiencies in toxicity pharmacogenomics studies originate from study design, sample limitations, heterogeneity of selected genes, variants, and toxicity definitions. With the advent of high throughput genotyping techniques, researchers are expected to explore the identified as well as the potential genetic biomarkers of toxicity and efficacy to improve BC management. However, to achieve this, the limitations of previous work should be evaluated and avoided to reach more conclusive and translatable evidence for personalizing BC chemotherapy.

SUBMITTER: Al-Mahayri ZN

PROVIDER: S-EPMC7174767 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy.

Al-Mahayri Zeina N ZN Patrinos George P GP Ali Bassam R BR

Frontiers in pharmacology 20200415

Breast cancer (BC) is one of the most prevalent types of cancer worldwide with high morbidity and mortality rates. Treatment modalities include systemic therapy, in which chemotherapy is a major component in many cases. Several chemotherapeutic agents are used in combinations or as single agents with many adverse events occurring in variable frequencies. These events can be a significant barrier in completing the treatment regimens. Germline genomic variants are thought of as potential determina ...[more]

PMID: 32351390

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Project description:Background: Numerous studies have focused on the PI3K/AKT/mTOR pathway in estrogen receptor positive (ER) breast cancer (BC), as a linear signal transduction pathway and reported its association with worse clinical outcomes. To gain better insight into the relative contribution of each of the signalling pathways which lie downstream to PI3K (namely AKT and mTOR) to BC outcomes, we have developed a novel in silico approach which assessed the activation of each of these signalling pathways separately. Methods: By analysing gene expression and matched proteomic data in ER-positive patients from the TCGA repository, we developed gene signatures that reflect the level of expression of phosphorylated-Serine473-AKT (pAKT) and phosphorylated-Serine2448-mTOR (p-mTOR) separately, capturing their corresponding level of pathway activation. Using pooled analysis of gene-expression data from over 7,000 patients with ER-positive early BC, we then investigated the association between pathway activation and outcomes. Results: Our analysis revealed that the pAKT pathway activation (as measured by the developed signature) was associated with luminal A BC while the p-mTOR pathway activation was more associated with luminal B BC (Kruskal-Wallis test p<10-10). pAKT pathway activation was significantly associated with better outcomes (multivariable HR, 0.79; 95% CI, 0.74 to 0.85; p=2.5x10-10) whereas p-mTOR pathway activation showed worse outcomes (multivariable HR, 1.1; 95% CI, 1.1 to 1.2; p=9.9x10-4). Similar associations between activation and outcomes were obtained when the analysis was performed in patients who were treated with hormonal therapy. Additionally, pAKT pathway activation predicted better outcomes irrespective of the BC molecular subtypes (luminal A multivariable HR, 0.85; 95% CI, 0.75 to 0.96; p=0.01; luminal B HR, 0.91; 95% CI, 0.83 to 0.99; p=0.033). pAKT pathway activation was associated with PIK3CA mutations (p=0.0001) while p-mTOR pathway activation was associated with p53 mutations (p=0.04). Finally, we show that pAKT pathway activation was associated with less response to Everolimus. Conclusions: Our data show that pAKT and p-mTOR pathway activation have differing impact on prognosis and suggest that they are not linearly connected in luminal breast cancers. These findings add to our understanding of signalling through the PI3K pathway and could have important implications for the treatment of luminal BC.

Dataset Information

Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy.

Publications

Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy.

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