Longitudinal study of premenopausal IGF-1 serum levels and changes in breast density over menopause.

A186

Background: High mammographic density is a strong risk factor for breast cancer development. Normally, breast density declines with age, particularly around menopause due to the natural breast involution process, but not to the same extent in all women. The mitogenic and anti-apoptotic peptide Insulin-like Growth Factor-I (IGF-I) has been hypothesized to influence breast cancer risk by its effect on breast density. Objectives: To study, in a prospective longitudinal setting, whether high premenopausal serum levels of IGF-I are related with high mammographic density and a slower decline in mammographic density over menopause. Design and Methods: We performed this study among participants of the Dutch Prospect-EPIC cohort (European Prospective Investigation into Cancer and Nutrition). Women were recruited from among breast cancer screening participants aged 50-70 years. We identified 684 participants who were premenopausal at enrollment and postmenopausal at the time of the follow-up questionnaire, sent approximately 5 years later, and for whom blood samples were available (drawn at enrollment) as well as pre- and postmenopausal mammograms. Premenopausal IGF-I levels were measured in serum. Pre- and postmenopausal breast measurements were assessed using a computer-assisted method. We measured the absolute dense and non-dense areas and percent breast density as well as changes in these measures over menopause. Mean values of breast measures were calculated for quartiles of serum IGF-I, using linear regression analysis. Results were adjusted for other breast cancer risk factors. Results: A decline in percent mammographic density and absolute dense area was observed over the menopause (-8.7% and -13.0 cm2, respectively, mean follow-up 5.4 years) and a slight increase in the non-dense (fatty) area (+3.7 cm2). The absolute mean decline in percent density was significantly smaller in women with high IGF-I levels (4^th quartile - 7.9%) than in those with low IGF-I levels (1^st quartile -11.3%, p=0.02). The decrease in absolute dense area, however, is only slightly smaller among those in the highest IGF-I quartile (-12.2 cm² versus -12.9 cm² in the 1^st quartile, p=0.43). At the same time, women with high IGF-I levels showed a smaller increase in the non-dense (fat) area than those with low IGF-I levels (4^th quartile +2.1 cm² versus 1^st quartile +7.3 cm², p=0.06). Conclusion and discussion: Women with higher premenopausal IGF-I levels show a significantly slower decline in percent density over menopause. This seems to be largely explained by the effect of IGF-I on the fat (non-dense) tissue, more than by its effect on the fibroglandular (dense) tissue, which is the presumed 'target tissue'.