Breast cancer is the most commonly diagnosed cancer among women in the United States, with 83% of invasive cases occurring in women aged 50 and above. Although breast cancer incidence rates have risen by 0.5% annually since 2000, declining mortality rates have led to over 2.5 million survivors aged 65 and older. This increase raises concerns about treatment-related complications, particularly the risk of ADRD. While hormone-modulating therapy (HMT) has improved survival rates, its impact on cognitive function and Alzheimer and related dementias (ADRD) risk remains unclear. In a recent study published in JAMA Network Open, researchers investigated the association between hormone-modulating therapy (HMT) for breast cancer treatment and the risk of developing ADRD in women aged 65 years or older.
The study cohort, drawn from the Surveillance, Epidemiology and End Results (SEER)-Medicare-linked database, included sociocultural, demographic, and clinical information for individuals diagnosed with breast cancer. The database links SEER cancer registry data with Medicare claims, allowing comprehensive assessment over a patient’s coverage period. Women aged 65 and older with newly diagnosed breast cancer from 2007 to 2009 were included, excluding those with preexisting ADRD or prior HMT use. Of 184,979 newly diagnosed breast cancer patients (2007-2009), 18,808 women met inclusion criteria. Among them, 12,356 (65.7%) received HMT within three years post-diagnosis, while 6,452 (34.3%) did not.
The most common age group was 75 to 79 years. Most women were white: HMT cohort had 809 black (6.6%), 10,904 white (88.3%), and 643 other (5.2%); non-HMT cohort had 457 Black (7.1%), 5,622 White (87.1%), and 373 other (5.7%). Mean age at diagnosis was 75 years (HMT) and 76 years (non-HMT). HMT initiation: 76.1% aromatase inhibitors (ARIs), 23.6% selective estrogen receptor modulators (SERMs), 0.3% selective estrogen receptor degraders (SERDs). The mean HMT duration was 24 months. Propensity score weighting addressed potential confounding effects and enhanced comparability between the non-HMT and HMT groups. Among 18,808 women, 2,926 (23.7%) HMT users and 1,802 (27.9%) non-HMT users developed ADRD by the end of the follow-up period.
HMT use was associated with a statistically relative reduction in ADRD risk (p = 0.005). Specifically, the hazzard ratios for initiating ARI and SERM were significant (ARI: p = 0.02; SERM: p = 0.005), while SERD was not. Racial differences were evident, with Black women experiencing greater reductions in ADRD risk compared to White women. For Black women aged 65-74, HMT significantly reduced ADRD risk, with ARIs showing a slightly greater effect. White women aged 65-74 also benefited, especially with SERMs. To summarize, HMT is crucial for treating hormone-positive breast cancer but raises concerns about cognitive impairment. However, the study found a 7% relative risk reduction in ADRD among HMT users.
Therefore, the increased risk for cognitive decline in breast cancer survivors that have used estrogen.interfering therapies is not equivalent for the drug classes. Estrogens are neuroprotective hormones that show a trophic effects on brain cells, especially neurons and astroglia. They upregulate antioxidant defences, stimulate protein synthesis and protect neurons from programmes cell death (apoptosis) induced by oxidative stress, beta-amyloid and glutamate excitotoxicity (e.g in epilepsy and amiotrophic lateral sclerosis or ALS), They also enhance sinaptic strenght and despite woman are advanteged over men for their presence, their decline with post-menopause may represent a significant risk factor for age-dependent cognitive impairment.
Though there are at this point any conceptual proof, there migh be an explanation why ARI and SERM use may get women prone to cognitive impairment. ARI and SERM may interfere with signaling pathway needs the presence of estradiol interacting with ER-alpha. However, estrogen signaling also rely on ER-beta and the surfare receptor GPER. Though they do not overlap in terms of signaling platform, they may have different roles in the cellular milieu. ER-alpha and -beta directly affect gene expression and preferentially activate the neurotrophic PI3K/c-Akt signaling, which is anti-apoptotic and regulate synaptic plasticity. GPER, on the the other hand, preferentially leads to the activation of MAPK/ERK signaling, which may be mitogenic and regulate gene expression.
However, MAPK-dependent gene expression activated by GPER and gene expression activated by ER-bound estradiol do not overlap; rather they become complementary for a full biological effect. This is why SERD treatment was found to represent a risk for cognitive decline. This class of drugs induce the cellular degradation of intracellular estrogen receptors while leaving GPER untouched. In few words, SERDs enhance the loss of ER-alpha and/or ER-beta which would affect neurotrophism, while GPER signaling would have a minor effect on cognition. Though not official, this could represent a good hypothesis for the observed effects of HMT drugs on cognitive risk in breast cancer survivors.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Cai C, Strickland K et al. JAMA Network Open 2024; 7(7):e2422493.
Fardell JE et al. J Natl Cancer Inst Cancer Spectr. 2023; 7(2):pkad026.
Haggstrom LR, Vardy JL et al. Cancers (Basel). 2022; 14(4):920.