Risk assessment and prevention of breast cancer

Abstract: One woman in eight develops breast cancer during her lifetime in the Western world. Measures are warranted to reduce mortality and to prevent breast cancer. Mammography screening reduces mortality by early detection. However, approximately one fourth of the women who develop breast cancer are diagnosed within two years after a negative screen. There is a need to identify the short-term risk of these women to better guide clinical followup. Another drawback of mammography screening is that it focuses on early detection only and not on breast cancer prevention. Today, it is known that women attending screening can be stratified into high and low risk of breast cancer. Women at high risk could be offered preventive measures such as low-dose tamoxifen to reduce breast cancer incidence. Women at low risk do not benefit from screening and could be offered less frequent screening. In study I, we developed and validated the mammographic density measurement tool STRATUS to enable mammogram resources at hospitals for large scale epidemiological studies on risk, masking, and therapy response in relation to breast cancer. STRATUS showed similar measurement results on different types of mammograms at different hospitals. Longitudinal studies on mammographic density could also be analysed more accurate with less nonbiological variability. In study II, we developed and validated a short-term risk model based on mammographic features (mammographic density, microcalcifications, masses) and differences in occurrences of mammographic features between left and right breasts. The model could optionally be expanded with lifestyle factors, family history of breast cancer, and genetic determinants. Based on the results, we showed that among women with a negative mammography screen, the short-term risk tool was suitable to identify women that developed breast cancer before or at next screening. We also showed that traditional long-term risk models were less suitable to identify the women who in a short time-period after risk assessment were diagnosed with breast cancer. In study III, we performed a phase II trial to identify the lowest dose of tamoxifen that could reduce mammographic density, an early marker for reduced breast cancer risk, to the same extent as standard 20 mg dose but cause less side-effects. We identified 2.5 mg tamoxifen to be non-inferior for reducing mammographic density. The women who used 2.5 mg tamoxifen also reported approximately 50% less severe vasomotor side-effects. In study IV, we investigated the use of low-dose tamoxifen for an additional clinical use case to increase screening sensitivity through its effect on reducing mammographic density. It was shown that 24% of the interval cancers have a potential to be detected at prior screen. In conclusion, tools were developed for assessing mammographic density and breast cancer risk. In addition, two low-dose tamoxifen concepts were developed for breast cancer prevention and improved screening sensitivity. Clinical prospective validation is further needed for the risk assessment tool and the low-dose tamoxifen concepts for the use in breast cancer prevention and for reducing breast cancer mortality.