Integration of Tumor and Host Factors – Implications for Breast Cancer Prognosis

Sammanfattning: Breast cancer is the most common cancer among women worldwide, although the mortality rates have decreased in the last decades. Breast cancer is a heterogeneous disease, and treatment resistance is a significant clinical problem in spite of the overall high survival rates. Improved screening programs, novel surgical techniques, and adjuvant treatments have contributed to the improved survival, but more extensive detection of breast cancer and subsequent treatment also imply higher rates of overtreatment. Therefore, it is vitally important to identify new tumor markers or host factors for patients who are at risk of recurrence, as well as patients who would benefit from less treatment. This approach would lead to more personalized breast cancer treatment. The aim of this thesis is to elucidate whether combining host factors, including genetic constitution and lifestyle factors, with tumor characteristics could yield a more comprehensive understanding than either factor alone for the prognosis of breast cancer. In paper I, moderate to high coffee consumption was associated with higher frequency of ER-negative tumors but a lower risk of early breast cancer events among tamoxifen-treated patients with ER-positive tumors. Furthermore, the combinations of low coffee consumption with the germline CYP1A2 rs762551 C-allele and CYP2C8'3, respectively, were associated with a significantly increased risk of early breast cancer events, indicating that integrating genotype and lifestyle factors may impact the prognosis of breast cancer. In paper II, any preoperative or postoperative alcohol consumption was weakly associated with a lower risk of early breast cancer events. This association was modified by axillary lymph node status, in that any alcohol consumption was associated with a significantly lower risk of early breast cancer events among patients with axillary lymph node involvement but not in patients without axillary lymph node involvement. The results do not support recommending that all breast cancer patients abstain from low to moderate alcohol consumption. In paper III, the CYP1A2 rs762551 C-allele was strongly associated with a higher risk of breast cancer events among aromatase inhibitor-treated patients, and the main impact was found within the first five years. In addition, the impact of the CYP1A2 rs762551 C-allele was modified by genotypes of AhR Arg554Lys and CYP19A1 rs4646, and the combined genotypes could further improve the prediction of aromatase inhibitor response. If validated, these genotypes could be used as predictive markers for aromatase inhibitor response. In paper IV, tumor-specific COX-2 expression was associated with significantly less aggressive tumor characteristics and was independently associated with a lower risk of early breast cancer events. The association was modified by a history of oral contraceptive (OC) use, preoperative non-steroidal anti-inflammatory drug (NSAID) use, and tumor size. If the findings were validated in an independent prospective cohort or within a randomized trial, history of OC use and tumor size might need to be considered when designing or evaluating clinical outcomes in a randomized controlled trial of adjuvant NSAIDs or COX-2 selective inhibitors for breast cancer patients. In conclusion, a more comprehensive view of tumor characteristics combined with host factors could be beneficial when assessing breast cancer prognosis and may provide a method for more personalized medicine in the treatment of breast cancer patients.