Bioavailable serum estradiol may alter radiation risk of postmenopausal breast cancer: a nested case-control study

Abstract

Purpose: Ionizing radiation and high levels of circulating estradiol are known breast cancer carcinogens. We investigated the risk of first primary postmenopausal breast cancer in relation to the combined effects of whole-body ionizing radiation exposure and prediagnostic levels of postmenopausal sex hormones, particularly bioavailable estradiol (bE₂).

Materials and methods: A nested case-control study of 57 incident breast cancer cases matched with 110 controls among atomic bomb survivors. Joint effects of breast radiation dose and circulating levels of sex hormones were assessed using binary regression and path analysis.

Results and conclusion: Radiation exposure, higher levels of bE₂, testosterone and progesterone, and established reproductive risk factors were positively associated with postmenopausal breast cancer risk. A test for mediation of the effect of radiation via bE₂ level suggested a small (14%) but significant mediation (p = 0.004). The estimated interaction between radiation and bE₂ was large but not significant (interaction = 3.86; p = 0.32). There is accumulating evidence that ionizing radiation not only damages DNA but also alters other organ systems. While caution is needed, some portion of the radiation risk of postmenopausal breast cancer appeared to be mediated through bE₂ levels, which may be evidence for cancer risks due to both direct and indirect effects of radiation.

Keywords: Breast cancer; estradiol; hormones; interaction; mediation; postmenopausal; radiation.

Figure 1.

Timeline of study. On average, subjects for this study were 30 years of age at the time of the bombings (1945) and 71 years of age at the time of breast cancer diagnosis. Cancer surveillance and clinical exams began in 1958. Serum collection began in 1969 and all samples were collected at least two years prior to diagnosis. Cases in this study were diagnosed between 1974 and 1996.

Figure 2.

Both Radiation exposure and postmenopausal level of estradiol are known breast cancer carcinogens. Previous findings indicated that radiation exposure can increase postmenopausal levels of estradiol in cancer-free women (dotted line). The research question is therefore whether estradiol mediates the radiation risk of postmenopausal breast cancer.

Figure 3.

Two-by-two representation of the joint effects of bioavailable estradiol and radiation exposure based on additive, multiplicative and interaction models. Estradiol levels in the reference group (“−”) were the geometric mean among the control subjects and the level in the “exposed” group (“+”) was one log unit above the geometric mean (i.e. 2.72-times higher on a linear scale). Radiation dose in the unexposed group was 0 Gy, and it was 1 Gy for the “exposed” group. The main effects were estimated using additive, multiplicative, and interaction models (without adjustment for other variables), and then the respective joint effects were manually calculated (see footnotes) and displayed in the bottom-right quadrant. The smallest deviance was observed using the interaction model.

Figure 4.

Results of a permutation test to determine if the effects of radiation were mediated through changes in the level of bioavailable estradiol (bE2). Hormone values were randomly permuted (5000 permutations) among case-control sets maintaining case status of the values; this preserves the main effects of bE₂ levels and radiation while rendering bE₂ levels random with respect to radiation dose (which would be true under the null hypothesis of no mediation). The distribution of the proportion explained is shown ([log(radiation risk) - log(radiation risk after adjustment of bE2))] ∕ log(radiation risk)). The solid line shows the actual proportion explained in the dataset (14%), which was outside of the expected range at a p-level of 0.004 (via permutation testing). This indicates that there was statistically significant evidence of mediation of the radiation risk via bE2 level changes.