Determinants of interval cancer and tumor size among breast cancer screening participants

Sammanfattning: Breast cancer is the most common cancer of women in Sweden and globally. In the more affluent countries, mammography screening has been in place for a few decades and has successfully reduced mortality. However, there is increasing interest in enhancing the impact of screening by going from the current age-based screening system to a risk-based system. There are two risk components that must be taken into account – the underlying breast cancer risk and the risk of delayed detection. Mammographic density, the amount of dense tissue in the breast, has been shown to be a risk factor for both. In this thesis, my aim was to identify novel determinants of delayed breast cancer detection by studying observed cases of interval cancer or large cancer at diagnosis. The potential risk factors for delayed detection were based on negative mammograms and other data that can be determined before diagnosis. Study I to III, were based on a retrospective case-only population, while Study IV was based on a prospective cohort. In Study I, we developed an estimate of the longitudinal fluctuation in mammographic percent density between screenings. Based on our results, we concluded that women that were subsequently diagnosed with interval cancer had higher density fluctuations than women with screen-detected cancer. In Study II, we went beyond density and examined 32 other image features which were computer-extracted from digitized mammograms. We identified two novel features that were associated with an increased risk of interval cancer compared to screen-detected cancer. One feature seemed to be related to the shape of the entire dense area, being flat rather than round increased the risk of interval cancer, possibly due to making clinical detection easier. The other feature seemed to be related to whether the density was more concentrated or instead was interspersed with fatty streaks. When density was more concentrated, the risk of interval cancer increased, possibly by making mammographic detection more difficult. In Study III, we determined risk factors for the cancer diagnosis being delayed until the cancer had reached a size larger than 2 cm. High density and high body mass index (BMI) were already known risk factors in general. Our aim was to understand if different factors were involved depending on the detection mode, screen-detection or interval cancer detection. We found that high BMI increased the risk of large cancer markedly among interval cancers and somewhat among screen-detected cancers. High density was associated with large cancer only among screen-detected cases. In survival analysis, we showed that high BMI increased the risk of disease progression, but only among women with interval cancer. In Study IV, we found that the localized density category at the site of the subsequent cancer was often different compared to the overall density. We examined the effect of high localized density, independent of overall density, and found that it was strongly associated with large cancer at diagnosis. In addition, it was associated with interval cancer among the less aggressive node-negative cases. It remains to be elucidated whether this effect is purely due to visual masking or also due to an association with biological characteristics of the tumor microenvironment. In conclusion, we have identified several novel determinants of delayed breast cancer detection, which could be further validated in trials of risk-stratified screening.