Genetic and Molecular Biomarkers Associated with Radiotherapy-Related Pain among Breast Cancer Patients

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death in American women. Compared to surgery alone, post-surgery adjuvant radiotherapy (RT) significantly reduces local-regional recurrence and mortality, and currently there are more than 3.5 million breast cancer survivors in the United States. Therefore, it is important to address quality of life issues related to RT-induced side effects and pain is one of the most prevalent side effects from cancer treatments. However, predictors and molecular mechanisms for the development of RT-related pain in breast cancer survivors have not been well defined. Therefore, to achieve our long-term goal in improving quality of life, particularly pain, as an important breast cancer survivorship issue, the 3 Specific Aims of the PhD dissertation are to: 1) Characterize the risk factors associated with clinically-relevant pain in breast cancer patients undergoing adjuvant RT after lumpectomy in a prospectively followed tri-racial/ethnic cohort of 375 breast cancer patients, 2) Evaluate the association between an inflammatory biomarker, C-reactive protein (CRP) and RT-related pain stratified by the number of comorbid conditions in 366 breast cancer patients, and 3) Investigate susceptible loci and related biological pathways underlying RT-related pain using genome-wide association study (GWAS) and pathway analysis among 1,112 breast cancer patients. Using multivariable logistic regression models, we identified multiple clinical risk factors separately for pre-, post-, and RT-associated pain. Pre-RT pain and comorbid conditions were the most significant risk factors for post-RT pain. In addition, there were racial/ethnic disparities in pain severity: African-American and Hispanic-white women were more likely to report RT-related pain. The RT-related CRP change (\u3e1 mg/L) was significantly associated with RT-related pain (OR=2.04, 95% CI=1.04-4.01) and RT-related extreme pain score increase (OR=3.24, 95% CI=1.33-7.88). Using GWAS, we identified 3 promising genetic regions of LIG3/RFFL, ABCC4/MRP4, and EGFL6. In addition, and pathway analysis with DAVID functional annotation clustering module suggested the enrichment of glucuronidation and olfactory receptor activity in post-RT pain. Taken together, the results highlight the complex, polygenic nature of RT-related pain, that is influenced by multiple molecular mechanisms in different pathways, such as inflammation, DNA damage/repair, detoxification, and signal transduction. The outcomes of this research, if validated by other larger studies, will contribute to our understanding of the genetic/molecular mechanisms in RT-related pain and targeted intervention strategies, and ultimately improve quality of life of breast cancer survivors