Thyroid function and breast cancer. Risk and clinical outcome in relation to thyroid hormones (free T3/T4), TSH, TPO-Antibodies and genetic variants

Sammanfattning: Thyroid hormone level has been positively associatedwith breast cancer cell proliferation andtumour growth in experimental studies. However,previous observational studies have been contradictoryon the relationship between thyroidfunction and breast cancer. Age is a known riskfactor for breast cancer but its role as a prognosticfactor is less clear. The present thesis thereforeaimed to examine the contradictory relation betweenthyroid function and breast cancer risk,progression and survival. Also, age at breast cancerdiagnosis was evaluated as a prognostic factor.The first paper was a baseline study on theinfluence of age at diagnosis on breast cancermortality in different diagnostic periods (follow-upuntil 2001). The study was conductedon 4,453 women diagnosed with breast cancer.We found that women under 40 years of age hada poor prognosis, and this association seemedto be strongest among young women with axillarylymph node negative breast cancer. Furthermore,an age of 80 years or more was a prognosticfactor for poor survival, independent of stageat diagnosis and diagnostic period.The second paper evaluated pre-diagnosticlevels of free triiodothyronine (free T3), freethyroxine (free T4), thyroid-stimulating hormone(TSH), and thyroid peroxidase antibodies(TPO-Ab) in relation to breast cancer subgroupsand aggressiveness. The cohort used wasthe Malmö Diet and Cancer Study, which is apopulation based cohort of 17,035 women recruitedbetween 1991 and 1996. Our resultsindicated that high pre-diagnostic free T4 levelsand low pre-diagnostic TPO-Ab levels wereassociated with an increased risk of breast cancer.This increase was mainly limited to a higherincidence rate of less aggressive forms of breastcancer.In the third paper we examined if the effect ofthyroid function on breast cancer subgroups alsoinfluenced breast cancer survival. We displayeda positive association between free T4 levels andan improved breast cancer survival.The possible effect of genetic markers for freeT4 and TPO-Ab on breast cancer risk was assessedin the fourth paper. We identified fivemarkers that influenced the risk of breast cancer,of which rs2235544 (D101 gene) was the mostinteresting. This was the first study to suggestan association between thyroid-related geneticvariants and breast cancer risk.The potential association between thyroidfunction and breast cancer is complex, as it exertsits effect through several pathways. This thesishas contributed to our understanding of howthyroid function influences breast cancer riskand breast cancer mortality. In addition, it hasenlightened the importance of age at diagnosisas a prognostic factor.