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We thank Lagiou and colleagues for their insightful letter in which they discuss indirect evidence in support of a possible negative association between circulating levels of IGF-II and breast cancer risk. There is insufficient direct evidence to determine whether or not IGF-II levels influence the risk of breast cancer. To our knowledge only two small prospective studies have examined the role of IGF-II levels on breast cancer risk with inconsistent results1-2. Similarly, few studies have examined the role of IGF-II on mammographic density. Lagiou et al. discussed our finding of an unexpected negative association between IGF-II levels and density in pre-menopausal women but, as we highlighted in our paper, this finding should be interpreted with caution as the association disappeared upon adjustment for body mass index (BMI). Moreover, no association between IGF-II levels and density was found in another study of pre-menopausal women3 although findings from studies conducted among post-menopausal women are more consistent with a possible inverse association3-4.
Lagiou et al. reported higher levels of umbilical cord blood IGF-II in Asians compared to Caucasians. Interestingly, cross-sectional studies suggest that such ethnic gradients may not persist into adulthood, with young adult Asians having significantly lower circulating levels of this growth factor than Caucasians5, perhaps reflecting ethnic differences in body composition and other lifestyle variables. Similarly, Afro-Caribbean post-menopausal women, known to have a lower breast cancer risk than Caucasians, have been shown to have lower levels of IGF-II6. In fact, ethnic difference in circulating levels of IGF-II, as well as in levels of IGF-I, IGFBP3 and sex steroid hormones, explained little of the ethnic gradient in mammographic density which, as expected, was higher among Caucasian than Afro-Caribbean women6. Unfortunately, no similar comparisons have been carried out among pre-menopausal women.
We agree with Lagiou et al. that the associations between IGF-II, mammographic density and breast cancer risk have so far been vastly overlooked, and based on the findings of studies of IGF-I and IGFBP3, they should be investigated separately in pre- and post-menopausal women.