Role of mammographic density and other risk factors in the development and detection of breast cancer

Thesis

Mammographic density (MD) is the extent of radiologically dense breast tissue. It is an important risk factor for breast cancer and it reduces mammographic screening sensitivity. Menopausal hormone therapy (MHT) is known to reduce screening sensitivity due to its association with increased MD. The aim of this thesis was to elucidate the role of MD, alongside various other risk factors, in the development and detection of breast cancer. This was done through 1) a systematic review and meta-analysis of the association of breast cancer risk factors with MD; 2) a cross-sectional analysis of the association of breast cancer risk factors with MD in the Million Women Study (MWS), a UK-based screening cohort; 3) a prospective analysis of the effects of MHT, an important determinant of MD, on screening sensitivity in the MWS; and finally 4) developing overall breast cancer and subtype-specific (based on mode of detection and grade) risk prediction models using easily collectable risk factor information from questionnaires, and determining if given risk factors were better at predicting specific breast cancer subtypes, are were more likely to be missed at screening.

The systematic review, with 59 studies, suggested that higher alcohol intake and later age at first birth and menarche were associated with higher MD, while parity and smoking were inversely associated with MD. These results were largely in agreement with the analysis of the MWS, with MD data on 8190 women, in which current/recent MHT use, older age at first birth, alcohol consumption, physical activity, and benign breast disease were positively associated with MD, whereas age, parity, smoking and BMI were inversely associated with MD. The prospective analysis of MHT use, with 27,564 breast cancer cases, found that screening sensitivity was reduced in current/recent MHT users and that although this impact on screening sensitivity declined after stopping MHT use, it remained elevated 10+ years post-cessation, likely due to some persistence in the effects of MHT use on MD. The overall and subtype-specific risk prediction models using easily collectable questionnaire data (not including MD) performed poorly. MHT was only marginally predictive of cancers diagnosed out of screening, and none of the other risk factors were notably better at predicting specific breast cancer subtypes.

This thesis has confirmed and expanded upon existing knowledge regarding the role of MD and other breast cancer risk factors on breast cancer risk and detection at screening. Identifying those at greater risk of breast cancer or having their cancers missed at screening will ultimately guide future public education decisions, MHT prescribing practices, lifestyle advice, and – after further economic evaluation – possible personalised screening strategies.

Authors: Thakrar, D

• DOI: 10.5287/ora-a4x9n9nvv
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: mammographic density; breast cancer; breast screening sensitivity; menopausal hormone therapy; risk prediction