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INTERNATIONAL CONGRESS OF

PharmacoGenetics

• Pharmacogenomic Predictors of Toxicity and Efficacy in Combined Targeted Therapy and Radiochemotherapy: A Systematic Review

• Soroush Mohammadi,^1,* Elham Khakshour,² Zahra Aliabadi,³ Mohammad Amin Shahram,⁴
  1. Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
  2. Cellular and Molecular Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
  3. Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
  4. Non-Communicable Diseases Research Center, Sabzevar University of Medical Sciences, Sabzevar, Iran
  
  
  
• Introduction: Both combined targeted therapy and radiochemotherapy, as two advanced methods, are used to combat cancer. These methods that can be employed simultaneously or separately, have some toxic effects that can deter patients from completing the treatment. Moreover, the efficacy of these methods depends on various factors such as the type of cancer, genetic characteristics of the tumor and tumor drug resistance. Some genomic variants are considered as potential determinants in the radiochemotherapy response and the severity of side effects. Several pharmacogenomic studies were conducted in order to explore these variants, as potential biomarkers, for predicting developing adverse effects and the effectiveness of these methods. We, in this review, aimed to provide and discuss the important findings of pharmacogenomic research projects of both toxicity and effectiveness of radiochemotherapy and combined targeted therapy during cancer management.
• Methods: This systematic review was performed by searching multiple databases, including PubMed, Web of Science, Google Scholar and Scopus up to August 2024. While several keywords, such as “Combined Targeted Therapy”, “Radiochemotherapy” and “Pharmacogenomics”, were used to find related articles. In the present review, the authors reassess and summarize recent studies including clinical data, clinical trials, basic research, meta-analyses and systematic reviews evaluating the predictive values of pharmacogenomic biomarkers of drug toxicity or efficacy in combined targeted therapy or radiochemotherapy. Exclusion criteria comprised non-English studies, case reports, case series, and studies not focused on cancer or lacking relevant outcome data.
• Results: This systematic review identified several important pharmacogenomic biomarkers that play a crucial role in toxicity and efficacy of cancer treatments involving combined targeted therapy and radiochemotherapy. Genetic variations in genes like TP53, EGFR, and CYP2D6 were often linked to common toxicities such as mucositis, hematologic toxicity, and radiation-induced dermatitis. Additionally, certain variants in ERCC1 and XRCC1 were consistently associated with better survival rates, particularly in colorectal and breast cancers, emphasizing the potential of customized treatment plans based on genetic profiles. The review also highlighted specific variants in BRCA1/2, ATM, and CHEK2, which were found to increase sensitivity to radiotherapy and the risk of severe side effects like myelosuppression and gastrointestinal damage. Moreover, mutations in the PI3K/AKT pathway contributed to drug resistance, specially mTOR inhibitors and HER2-targeted agents. Loss of function mutations in TP53 were associated with both reduced treatment effectiveness and increased late-onset side effects in lung and breast cancers, indicating that combination therapies including protective agents might offer better outcomes for these individuals.
• Conclusion: Pharmacogenomic biomarkers show great promise for predicting the toxicity and efficacy of combined cancer therapies, suggesting their potential as valuable tools in personalized medicine. Incorporating genetic testing into routine clinical practice can optimize their effectiveness while minimizing side effects, guiding therapeutic decisions based on individual patient profiles. The variability in pharmacogenomic predictors across different tumor types emphasizes the need for tailored treatment approaches. Future research should focus on validating these biomarkers through prospective studies and expanding the understanding of how these genetic factors interact with specific tumors. This will enhance the precision of cancer therapies and ultimately improve patient outcomes.
• Keywords: Pharmacogenomics, Combined Targeted Therapy, Radiochemotherapy, Genetic Variants, Biomarkers