Bidirectional association between breast cancer and dementia: a systematic review and meta-analysis of observational studies

Introduction

In 2020, breast cancer emerged as the most prevalent malignancy globally, accounting for the highest incidence and mortality rates among women. Specifically, breast cancer constitutes 12.50% of all cancer cases and 6.92% of cancer-related deaths (2021–2023). Data from the Global Burden of Disease (GBD) indicated a significant increase in breast cancer incidence in the Western Pacific region (WPR) over the past 30 years, with the number of cases rising from 143,889.3 to 551,442.2. This upward trend is projected to continue from 2020 to 2044. Age is a critical factor in breast cancer development, with the risk notably increasing after the age of 40 (Wu et al., 2024). Fortunately, advancements in early detection and tailored therapeutic interventions have led to substantial improvements in survival rates. Currently, the 5- to 10-year survival rate for breast cancer patients ranges from 85% to 90% (Nardin et al., 2020). Despite these positive developments, many women who are diagnosed and treated for breast cancer experience significant short-term and long-term consequences, including cancer-related cognitive impairment (CRCI) (Carreira et al., 2021; Chapman, Derakshan & Grunfeld, 2023). Studies have documented that patients with breast cancer undergoing chemotherapy may experience cognitive disorders that persist for up to two decades (Koppelmans et al., 2012).

Cognitive decline following cancer treatment can vary from mild cognitive impairment to severe dementia. Dementia is characterized by acquired cognitive impairments that significantly affect a patient’s thinking and daily functioning (GBD 2019 Dementia Forecasting Collaborators, 2022). This condition typically develops gradually, initially impacting daily activities and eventually limiting social interactions. With improved treatment outcomes and increased lifespan among patients with breast cancer, the incidence of cognitive impairment, Alzheimer’s disease, dementia, and other neurodegenerative disorders has also risen significantly (Du, Xia & Hardy, 2010). Identifying risk factors for cognitive impairment is thus crucial for the early detection of high-risk cancer and for developing strategies to alleviate the medical burden in an aging population.

Kao, Yeh & Chen (2023) reviewed literature on cognitive impairment across various cancer types, including lung, breast, head and neck, gastric, prostate, colorectal, and brain tumors/metastases, assessing the impact of different treatments. Breast cancer treatments include surgery, chemotherapy, hormone therapy, and radiotherapy, with chemotherapy being a core component aimed at targeting proliferating cells. However, chemotherapy can adversely affect the central nervous system, leading to cognitive impairment in a significant number of patients, both during and after treatment. Long-term studies indicate that 17% to 75% of breast cancer may experience impairments in attention, concentration, planning, and working memory even 6 months to 20 years post-chemotherapy (Ahles, Root & Ryan, 2012).

There is ongoing debate regarding the association between cancer and dementia risk. Some community-based cohort studies suggest that cancer diagnosis may be linked to a lower pathological burden of Alzheimer’s disease and reduced cognitive impairment (Karanth et al., 2022), a finding also reported in breast cancer (Oh et al., 2023). Conversely, other studies indicate that breast cancer is associated with an increased risk of dementia (Baxter et al., 2009; Blanchette et al., 2020; Bromley et al., 2019; Carreira et al., 2021; Raji et al., 2009; Thompson et al., 2021; Wennberg et al., 2023). Thus, a systematic review and meta-analysis are warranted to elucidate the relationship between breast cancer and dementia risk, providing valuable insights for identifying risk factors and developing preventive strategies.

Methods

Results

Literature search

A total of 4,778 records were collected through the search. After title and abstract screening, 84 articles were considered potentially relevant. Thirteen studies were included after full text review, which reported the risk of dementia or breast cancer. The selection process was presented in Fig. 1.

Breast cancer and the risk of dementia

There were seven studies report the risk of breast cancer associated with dementia (Baxter et al., 2009; Jørgensen et al., 2012; Khan et al., 2011; Kurita et al., 2017; Musicco et al., 2013; Oh et al., 2023; Roderburg et al., 2021). The pooling analysis showed that patients with breast cancer reveal a lower risk of dementia (OR = 0.56, 95% CI [0.27–1.18], I² = 99.1%, P = 0.128, Fig. 2). Sensitivity analysis showed that none of the individual studies reversed the pooled-effect size, which means that the results are robust (Fig. S1, and Table S5).

Dementia and the risk of breast cancer

There were seven studies mentioned the risk of dementia associated with breast cancer (Attner et al., 2010; Heun et al., 2013; Musicco et al., 2013; Ording et al., 2019; Ou et al., 2013; Ren et al., 2022; Valentine et al., 2022). In the total OR, we were not included one study for not mentioned the overall OR (Ording et al., 2019). The result suggest that individuals with dementia showed a lower risk of breast cancer (OR = 0.79, 95% CI [0.51–1.22], I² = 94.5%, P = 0.290, Fig. 3). Sensitivity analysis showed that none of the individual studies reversed the pooled-effect size, which means that the results are robust (Fig. S2, and Table S6).

Discussion

This meta-analysis included 13 studies with a total of 346,051 individuals, providing a thorough evaluation of the bidirectional relationship between breast cancer and dementia. Our findings suggest a decreased risk of dementia among individuals with breast cancer compared to non-breast cancer controls, implying that breast cancer may not be a significant risk factor for dementia. Similarly, the risk of breast cancer appeared to be reduced in individuals with dementia, suggesting that dementia might not be a risk factor for breast cancer either. The population studied, predominantly over 60 years of age, may indicate that the low co-occurrence of these disorders is characteristic of older adults.

Previous research has reported that the presence of both cancer and dementia can lead to diminished cancer-specific and overall survival rates (Kimmick et al., 2014; Möhl et al., 2021), and approximately 7–10% of breast cancer patients also experience cognitive impairment or dementia (Ahmad et al., 2024). The co-existence of dementia impacts cancer treatment and was associated with higher mortality rates for breast cancer patients (Ewertz et al., 2018; Raji et al., 2008). Neurotoxicity from cancer treatments, such as systemic chemotherapy, is common and can affect both central (e.g., headache, seizures, encephalopathy) and peripheral nervous systems (e.g., peripheral neuropathy, plexopathy), which may contribute to dementia. Additionally, adjuvant hormonal therapies for breast cancer, such as corticosteroids and tamoxifen, can impact cognitive function and prognosis (Albers, Kieffer & Schagen, 2024; Brunner et al., 2005; Liao, Lin & Lai, 2017). Cognitive impairments, often referred to as “chemo brain”, might suggest a connection between these two conditions (Chen et al., 2019). In patients with dementia, increased apoptosis may reduce the likelihood of developing breast cancer. Various biological processes, including systemic inflammation, oxidative stress, and disrupted brain structures, may suggest an association between dementia and breast cancer (Nixon, 2017; Nudelman et al., 2019; Shafi, 2016). BRCA1, a key tumor suppressor, has been linked to both dementia and neuronal cell death (Wezyk et al., 2018). Furthermore, mechanisms that lead to DNA damage, such as oxidative stress and deficient DNA repair, are significant in both conditions, potentially indicating a shared pathophysiology. Understanding these mechanisms could be crucial for predicting disease progression and developing new treatments.

Interestingly, our study found a reduced incidence of dementia associated with breast cancer and vice versa. This result may be due to biological factors or diagnostic biases, such as patients being unable to communicate breast cancer symptoms or physicians and families potentially neglecting to investigate symptoms in dementia patients.

The strength of our meta-analysis lied in the inclusion of 13 relevant observational studies, offering a comprehensive view of the relationship between breast cancer and dementia. We provide the first detailed examination of this mutual relationship, exploring both the likelihood of dementia in individuals with breast cancer and the risk of breast cancer in those with dementia. However, our study has limitations. First, the studies included in our research often conflate patients currently diagnosed with cancer and long-term cancer survivors. We had hoped to isolate individuals based on their cancer diagnosis or survival time, but unfortunately, most of the studies did not provide separate data on these groups. Second, there were only 13 studies included in this meta-analysis, seven studies investigated the risk of dementia among patients with breast cancer, and seven studies explored the risk of breast cancer in individuals with dementia, which may raises concerns about the statistical power and generalizability of the findings. Although, our statistical methods were standardized, the studies have no significant publication bias, and the result was robust suggested by sensitivity analysis, more studies are needed to strengthen the study. Third, there was no subgroup analysis due to the limited number of studies, so factors such as age, follow-up years, survival threshold, breast cancer type, dementia type, or therapy were not examined. Future large-scale population-based studies are needed to better understand the breast cancer-dementia relationship. Forth, variability in treatment plans and follow-up durations among breast cancer could introduce clinical heterogeneity, and differences in the quality of inclusion criteria among studies may lead to methodological heterogeneity. Despite some heterogeneity, our study’s results remain robust, as indicated by sensitivity analyses (Li et al., 2023; Wang et al., 2024).

Conclusions

The result shown that breast cancer was less likely to develop to dementia, and dementia is similarly low associated with risk of breast cancer. Our findings will provide clinicians with essential insights into the prevention and monitoring of neurodegenerative diseases in this patient population. Nonetheless, it is important to acknowledge the limitations of this study.

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