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.

Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer (ERIGE trial). Clinical and pharmacogenetic results on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC)

“… 39 , 40 , 41 Nevertheless, ~50% of TNBC do not present biomarkers predictive of response to targeted therapies and, in this population, there is no general agreement on the best first- or second-line treatment to provide for metastatic disease, especially if patients already received adjuvant regimens including anthracyclines and taxanes (+/− carboplatin). 42 Considering the complementary mechanisms of action of eribulin and gemcitabine, the activity of their combination observed in the ERIGE trial, and the manageable toxicity, we propose the use of our regimen in patients with ‘biomarker-orphan’, metastatic TNBC.…”

“…Apart from the guidelines regarding dihydropyrimidine dehydrogenase (DPYD) genetic testing before fluoropyrimidine use, there are no other guidelines related to other chemotherapeutic agents used in BC. 42 To our knowledge, the ERIGE trial is the first trial prospectively investigating the role of SNPs involved in the metabolism of eribulin and gemcitabine in predicting toxicities and efficacy of those drugs. SNPs in CYP3A4 and FGD4 genes were associated with increased risk of liver toxicity.…”

Efficacy of chemotherapy for lymph node-positive luminal A subtype breast cancer patients: an updated meta-analysis

“…Drug treatment may also include endocrine therapy, drugs that target the HER2 receptor, and chemotherapy. For luminal type A, endocrine therapy is often more applicable [ 6 ]. However, there is still controversy about whether oncologists should include chemotherapy for luminal A, lymph node-positive breast cancer.…”

Drug combination and nanooncology for improvement in the treatment of breast cancer: a review

“…And these classes of chemotherapeutic drugs can be combined: CAF/FAC (cyclophosphamide / DOX / 5-fluorouraci (5-FU)), FEC (5-fluorouraci(5-FU) / epirubicin / cyclophosphamide), AC (DOX / cyclophosphamide), EC (epirubicin / cyclophosphamide), CMF (cyclophosphamide / methotrexate / 5-fluorouraci (5-FU)), docetaxel / capecitabine, GT (gemcitabine / PTX), gemcitabine / carboplatin, PTX / bevacizumab. Thus being more effective in treatment due to the possibilities of drug combinations (Al-Mahayri et al, 2020;Fisusi & Akala, 2019) .…”