Modulation of Secondary Cancer Risks from Radiation Exposure by Sex, Age and Gonadal Hormone Status: Progress, Opportunities and Challenges

Abstract

Available data on cancer secondary to ionizing radiation consistently show an excess (2-fold amount) of radiation-attributable solid tumors in women relative to men. This excess risk varies by organ and age, with the largest sex differences (6- to more than 10-fold) found in female thyroid and breasts exposed between birth until menopause (~50 years old) relative to age-matched males. Studies in humans and animals also show large changes in cell proliferation rates, radiotracer accumulation and target density in female reproductive organs, breast, thyroid and brain in conjunction with physiological changes in gonadal hormones during the menstrual cycle, puberty, lactation and menopause. These sex differences and hormonal effects present challenges as well as opportunities to personalize radiation-based treatment and diagnostic paradigms so as to optimize the risk/benefit ratios in radiation-based cancer therapy and diagnosis. Specifically, Targeted Radionuclide Therapy (TRT) is a fast-expanding cancer treatment modality utilizing radiopharmaceuticals with high avidity to specific molecular tumor markers, many of which are influenced by sex and gonadal hormone status. However, past and present dosimetry studies of TRT agents do not stratify results by sex and hormonal environment. We conclude that cancer management using ionizing radiation should be personalized and informed by the patient sex, age and hormonal status.

Keywords: cancer therapy; ionizing radiation; menopause; menstrual cycle; sex differences; targeted radionuclide therapy; theranostics.

Figure 1

Cancers attributable to radiation exposure vary by organ, sex and age at exposure. Y axis: attributable cancer cases/100,000 persons/0.1 Gy. X axis: Age at exposure in years. Derived from [3].

Figure 2

Effects of menstrual cycle on ovarian accumulation of [¹¹C]vorozole, an aromatase inhibitor. Pseudocolored (rainbow spectrum) examples of ¹¹C-vorozole uptake. axial images (A–E) were overlaid on the attenuation scan obtained immediately before the emission scan: (A) female, level of breasts and lungs; (B) female, level of liver; (C) female at midcycle, level of ovary; (D) female, level of lower pelvis; (E) male, level of lower pelvis. Quantitative analysis published in [126].