Sex, Hormonal Status and Targeted Radionuclide Therapy: Comparison
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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. Recent advances in cancer therapy with radioactive substances involve parenteral administration of a radiopharmaceutical or radiolabeled antibody which is designed to preferentially accumulate in neoplasms, termed Targeted Radionuclide Therapy (TRT) and Radioimmunotherapy, respectively. Development of new TRT agents is increasingly accompanied by the use of companion diagnostics and individual dosimetry since, systemic radiopharmaceutical therapy with associated companion diagnostics “is the embodiment of precision medicine” and dosimetry is the optimal tool to predict individual safety and efficacy of TRT.
  • cancer therapy
  • ionizing radiation
  • Hormonal Status
  • sex

1. Introduction

Exposure to external ionizing radiation in the context of war, nuclear accidents and medical procedures poses well-known health risks, including acute radiation sickness (tissue reaction or deterministic effects), which may result in death, as well as an increase in the risk of cancer in the years following exposure (stochastic effects) [1,2][1][2]. The risk of radiation-induced cancer increases with dose and decreases with age at exposure, and is further modulated by the organ/tissue involved and biological sex [1[1][2][3],2,3], such that the risks of radiation-induced solid tumors are consistently (approximately 2-fold) higher in women relative to men, regardless of the exposure mechanism. In particular, breast and thyroid in young girls and women exhibit the largest increase in relative and absolute risk of radiation-induced tumors [3,4,5,6,7][3][4][5][6][7]. Importantly, despite the well-known effects of female gonadal hormones, especially estradiol, on cell cycle, proliferation and differentiation in breasts and other estrogen-receptor-containing organs, including the thyroid [8[8][9][10],9,10], gonadal hormone status (e.g., puberty, stage of the menstrual cycle, menopause) at the time of exposure has not been included in most published studies on cancer risks related to exposure to external ionizing radiation [3,4,5,6,7][3][4][5][6][7].
Compared to external radiation risks, literature on sex differences in secondary cancer risks due to internal radiation exposure following ingestion of contaminated foods or diagnostic/therapeutic injection of radioactive compounds is sparser and sometimes contradictory [11[11][12][13][14][15][16][17][18],12,13,14,15,16,17,18], which is possibly related to the acknowledged uncertainties in estimating organ dose under these circumstances [11]. Despite these caveats, the majority of publications agree that the risk of secondary cancer among those exposed to internal radiation are similar to those reported in the literature on exogeneous radiation.

1. Sex and Age Modulate Cancer Risks from Radioactive Iodine Therapy of Thyroid Disease

The earliest example of TRT is the use of radioactive iodine for treatment of thyroid cancer [77,78][19][20]. An early study of I-131 therapy focusing on female reproductive function reported slightly earlier onset of menopause in some women treated with I-131 and some occurrences of spontaneous and induced abortion in the first 12 months following treatment, but no significant decrease in fertility and no increase in birth defects [79][21]. The same study reported an increased risk of secondary breast cancer, further supported by a more recent study demonstrating a significant association between radioiodine dose and risk of secondary breast cancer [80][22]. Hyperthyroidism is also treated with radioactive iodine, though at lower doses than those used for treating thyroid cancer. A 2019 study of 18,805 patients showed that in radioactive iodine-treated patients with hyperthyroidism, greater organ-absorbed doses were modestly though statistically significantly associated with an increased risk of female breast cancer [17]. The results of this study were criticized by others [18], though the relationship between dose and cancer risk was later supported in a very recent meta-analysis of cancer risks following radioactive iodine therapy for hyperthyroidism [5], which reported a significant association between radioactive iodine dose and breast cancer mortality. The study also reported a significant elevation in thyroid cancer incidence and mortality which was not stratified by sex—rather, they compared risks in studies including more than 80% females to those including 80% or less [5], probably since females represented the large majority of patients in all studies [17]. The strong relationship between sex, age, hormonal status and potential risks of radioactive iodine was recently highlighted in a 2021 paper by Al-Jabri and colleagues [81][23]. The stated aim of the study was to investigate whether Tc-99 thyroid uptake may be used in place of I-131 uptake for implementing personalized treatments. The investigators found that patient age and the time difference between the two respective uptake measurements significantly influenced the uptake correlation in females but not in males, and uptake was correlated with hormone levels. Consequently, the uptake of the two tracers was significantly more correlated in males than in females (r2 = 0.71 vs. 0.38, p < 0.001) and estimating I-131 uptake based on Tc-99m uptake was predictive in male but not female patients (91% vs. 16%). The authors conclude that their finding highlight “the potential need for gender consideration when planning 131I patient management and when reporting s istudies results” [82]. This is in variance with the American Thyroid Association’s Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer published in 2015 [81][23], which does not address sex by age interaction or hormonal status.

2. TRT for Central Nervous System, Neuroendocrine and Other Tumors: Too Early to Call?

In recent years, TRT has expanded to treat a wider range of targets and tumors in addition to thyroid, with a steadily increasing number of radiopharmaceuticals in preclinical and clinical development [19,20,73,74,83,84,85,86,87,88,89,90,91,92,93][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Consequently, TRT represents an unprecedented opportunity for personalizing medical radiation by sex and hormonal status before rather than after the patients who are the most vulnerable (namely, young females) and can benefit most from individualized, well-informed therapy, become statistics in the large and long follow-up studies necessary to establish secondary cancer risks from medicinal irradiation. To elaborate, clinical trials using I-131 MIBG, e.g., [86[31][32][33],87,88], did include females, but did not analyze any risks by sex and age/hormonal status. Since neuroblastoma is typically treated during childhood and is associated with increased risk of secondary cancer [94[39][40],95], it is particularly important to understand the specific long-term impact of radionuclide therapies on young females. In this regard, while gonadal failure following I-131 MIBG treatment had previously been attributed to damage caused by concurrent chemotherapy, the first two cases of ovarian failure in patients treated with only I-131 MIBG for childhood neuroblastoma were reported in 2014 [95][40], suggesting that it was the radiation treatment which damaged the female gonads. It is noteworthy in this regard that MIBG targets the norepinephrine transporter, the function of which has been shown to be sex dependent and modulated by the menstrual cycle [96,97][41][42]. Similarly, various TRT radiopharmaceuticals targeting somatostatin-receptor (SSTR) positive neoplasms are increasingly in use in trials and practice to treat neuroendocrine tumors, which are also relatively common in children, but long-term follow-up and risks of secondary cancer which take a long time to develop, such as breast cancer, have not been published to date; and studies of acute and subacute toxicity do not stratify results by sex, age or hormonal status [98][43]. Notably, SSTR are expressed in the human endometrium and appear to change locations throughout the menstrual cycle [99,100][44][45]. Furthermore, estradiol has been shown to affect somatostatin receptor expression in female rat pituitary and human prostate cells in culture [101,102][46][47]. Inflammatory markers (beta-3-integrin, interleukin-6, PGE2 receptor types EP2/EP4, and COX-1) which are overexpressed in tumor vasculature also serve as potential targets for radionuclide therapy [84,103,104][29][48][49]. All of these targets are expressed in the female reproductive system and their expression varies significantly across the menstrual cycle [105,106,107][50][51][52]. Yet another example is the Orexin receptor type 1 (OX1R), a GPCR cell surface receptor expressed in peripheral cancers and a putative target for TRT [91][36]. The expression of this receptor in animal models was shown to be upregulated in ovaries and modulated by the estrous cycle [108][53].

3. The Challenge of TRT Risk Prediction and Modulation in Females

TRT presents a challenge for risk modulation to healthy organs since healthy tissue sparing strategies which can be deployed with external radiation [51][54] are not relevant when the radioactive agent is administered systemically. Instead, TRT trials incorporate individual dosimetry to predict risk of toxicity as well as efficacy [98,109,110,111][43][55][56][57]. TRT clinical development may also involve the use of “theranostic” (or theragnostic) agents whereby a pair of radiopharmaceuticals targeting the same molecule are used to assess bio-distribution and “personalized” dosimetry with a low energy, short half-life isotope and achieve tumor response with a higher-energy emitter. Although the principle is not new, it is receiving a lot of attention recently [112,113,114,115,116,117][58][59][60][61][62][63]. This approach is predicated on the assumption that the bio-distribution of the target is stable within individuals over time, which is patently untrue for reproductively competent women who experience large changes in levels of multiple biomarkers during puberty, menstrual cycle, pregnancy, lactation and menopause [96,97,118,119][41][42][64][65]. These changes are likely to modulate the susceptibility of females to environmental hazards and influence the uptake of targeted therapeutic and diagnostic radiopharmaceuticals, their safety and efficacy [120,121,122,123,124,125,126,127,128,129,130,131,132,133][66][67][68][69][70][71][72][73][74][75][76][77][78][79]. Despite the solid evidence for sex and hormone modulation of current and potential radiopharmaceutical target abundance summarized above, dosimetry studies which address or stratify data by sex or hormonal status are extremely rare. Thus, a study of [18F]fluoroestradiol radiation dosimetry which included 49 women and 2 men mentions that 19 of the women were premenopausal, rather than just noting the age distribution. The authors do mention that the results of the two men were similar to those of the women, but there is no mention of stratification by hormonal status, menstrual cycle phase in the premenopausal women or direct measurement of uptake and organ dose in the ovary [131]. A subsequent dosimetry of another estrogen receptor targeting radiopharmaceutical (4-fluoro-11beta-methoxy-16alpha-18F-fluoroestradiol) ascertained hormonal status in all 10 participants (all women) [132][78]. The six premenopausal women were scanned during the early follicular stage of their menstrual cycle, when endogenous estrogen levels are at their lowest [133][79] and least likely to compete with the tracer for the receptor, thus providing the “worst case scenario” for organ exposure for this target. The authors reported significantly lower uterine uptake (%ID) at 120 min after injection in pre- relative to postmenopausal subjects (0.075 ± 0.033%ID and 0.163 ± 0.026%ID, respectively;nly study p = 0.003, two-tailed unpaired t-test). The only study reporting on the effect of menstrual cycle phase and menopause on tracer uptake and organ dose was published in 2015 [126][72]. In this study, 11C-vorozole, an aromatase inhibitor, was injected in 13 men and 20 women (10 premenopausal and 10 post-menopausal) and the young (premenopausal) women were scanned at 2 discrete phases of the menstrual cycle (midcycle and late luteal). The results were quite striking: Standardized uptake values and organ doses for (dominant) ovary in women scanned at midcycle were 3-fold and >30-fold higher, respectively, compared to the same women at other stages of the cycle as well as postmenopausal women, making the ovary (84.2 μSV/MBq), rather than liver (15.5), kidney (6.06) or spleen (6.1), the dose limiting organ for young ovulating women [126][72]. Notwithstanding these findings, dosimetry studies for new TRT agents in development published 2 years later [134,135,136,137][80][81][82][83] do not stratify data by sex, menopause or menstrual cycle phase, nor do they even mention the sex of the subjects [137][83]. In addition to radionuclide accumulation, sex and hormonal status influence the pharmacokinetics and pharmacodynamics of TRT drugs. For example, biological sex and hormonal status affect distribution volume, protein binding, transport and metabolism of many classes of drugs [138,139][84][85]. Overall, women have lower BMI, have less surface area and less water in the body. Cardiac output and regional blood flow, particularly relevant to TRT because it is administered intravenously, varies between sexes [128][74]. Plasma protein binding is also sex-dependent: females taking estrogen-containing oral contraceptives have even more pronounced differences relative to males [139][85]. While correction for height, weight, surface area and body composition eliminate sex differences for some drugs, several drugs still affect women and men differently due to large differences in metabolism and elimination. Hepatic metabolism of drugs by cytochrome p450-linked liver monooxygenases (CYPs) is modulated by gonadal hormones; men typically have a faster oxidative metabolism [138][84]. Renal elimination, measured by renal blood flow and GFR, is highest in pregnant women, followed by men and then non-pregnant women, while pulmonary elimination is highest in men, followed by pregnant women and then non-pregnant women [139][85]. Lastly, pharmacodynamics, including number of receptors, binding affinity and signal transduction, also vary by sex and hormonal status [99,100,105,106,107,108,127,139][44][45][50][51][52][53][73][85].

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