Association Between Hormone-Modulating Breast Cancer Therapies and Incidence of Neurodegenerative Outcomes for Women With Breast Cancer

Branigan, Gregory L; Soto, M. Álvarez Mon; Neumayer, Leigh; Rodgers, Kathleen E.; Brinton, Roberta Dı́az

doi:10.1001/jamanetworkopen.2020.1541

Cited by 35 publications

(57 citation statements)

References 63 publications

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“…We did not find evidence to support an association between ET in the definitive treatment of non-metastatic breast cancer and dementia risk, which differs from some prior studies showing a protective effect. 3 , 5 We found that 10.2% of individuals in the ET group and 13.9% of individuals in the no-ET had dementia, which is in line with the 11.5% of Medicare Fee‐for‐Service beneficiaries aged ≥65 years with dementia. 10 Our analysis showed a protective effect of ET on dementia in fully adjusted models that completely attenuated when accounting for the competing risk of death, which is critical when examining incident outcomes in older individuals 7 and was not accounted for in all prior studies.…”

Section: Discussionsupporting

confidence: 80%

“…Our study accounted for the competing risk of death when analyzing the association of ET use and dementia risk and this may primarily explain the difference between our results and those observed in prior studies showing a protective effect. 5 A competing risk is an alternative outcome, such as death, that alters the probability of the outcome of interest. In traditional survival analyses individuals who are censored for any reason are considered at risk for the primary outcome for the remaining duration of the study.…”

Section: Discussionmentioning

confidence: 99%

“… 4 A recent study using Humana claims data examined 326,485 women with breast cancer and found a 12% relative dementia risk reduction. 5 However, this and prior studies are limited by potential sources of bias through the inclusion of heterogenous populations (composition bias) such as those with local and metastatic disease, incompletely accounting for immortal time (immortal time bias), and the competing risk of death (competing risk bias). 6–8 Here we utilize data from SEER-Medicare to investigate the association of ET utilized in the definitive setting to treat non-metastatic breast cancer with dementia risk accounting for multiple potential sources of bias and confounding.…”

Section: Introductionmentioning

confidence: 99%

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Association of Endocrine Therapy and Dementia in Women with Breast Cancer

Thompson¹,

Niu²,

Lei³

et al. 2021

BCTT

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Purpose Prior studies have reported differing results regarding the association between endocrine therapy (ET) in the treatment of breast cancer and dementia risk. However, existing findings may be limited by common sources of bias and confounding. Here we investigate the association of ET utilized in the definitive setting to treat non-metastatic breast cancer with dementia risk accounting for multiple potential sources of bias and confounding. Patients and Methods We conducted a retrospective study in SEER-Medicare of women aged ≥ 66 years with non-metastatic breast cancer. We examined the risk of all-cause dementia among ET users versus non-ET users using multivariable regression models, accounting for the competing risk of death, and using a start of the follow-up period as 12-months following breast cancer diagnosis for both groups to avoid immortal time bias. Results Among 25,777 individuals there were 2,869 incident dementia cases. We found a statistically significantly decreased risk of any dementia among ET users in unadjusted and adjusted models that completely attenuated when accounting for the competing risk of death (hazard ratio, 0.98; 95% confidence interval, 0.90–1.07). Conclusion When accounting for common sources of bias and confounding we did not find evidence to support an association between ET in the definitive treatment of non-metastatic breast cancer and dementia risk. These results suggest that ET may not be associated with dementia risk.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Association of Endocrine Therapy and Dementia in Women with Breast Cancer

Thompson¹,

Niu²,

Lei³

et al. 2021

BCTT

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“…Among them were two breast cancer drugs (exemestane and estradiol). The use of aromatase inhibitors in BRCA treatment has recently been found to reduce the risk of AD as well as other dementias [110], and new evidence suggests that estradiol replacement therapy could prevent the tau protein from adopting its pathological conformation, helping to prevent AD [111]. Additionally, epidemiological data suggest that estrogen replacement therapy significantly decreases the risk of the onset and development of AD and PD.…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic and Genetic Associations between Alzheimer’s Disease, Parkinson’s Disease, and Cancer

Forés-Martos

Boullosa²,

Rodrigo-Domínguez

et al. 2021

Cancers

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Alzheimer’s (AD) and Parkinson’s diseases (PD) are the two most prevalent neurodegenerative disorders in human populations. Epidemiological studies have shown that patients suffering from either condition present a reduced overall risk of cancer than controls (i.e., inverse comorbidity), suggesting that neurodegeneration provides a protective effect against cancer. Reduced risks of several site-specific tumors, including colorectal, lung, and prostate cancers, have also been observed in AD and PD. By contrast, an increased risk of melanoma has been described in PD patients (i.e., direct comorbidity). Therefore, a fundamental question to address is whether these associations are due to shared genetic and molecular factors or are explained by other phenomena, such as flaws in epidemiological studies, exposure to shared risk factors, or the effect of medications. To this end, we first evaluated the transcriptomes of AD and PD post-mortem brain tissues derived from the hippocampus and the substantia nigra and analyzed their similarities to those of a large panel of 22 site-specific cancers, which were obtained through differential gene expression meta-analyses of array-based studies available in public repositories. Genes and pathways that were deregulated in both disorders in each analyzed pair were examined. Second, we assessed potential genetic links between AD, PD, and the selected cancers by establishing interactome-based overlaps of genes previously linked to each disorder. Then, their genetic correlations were computed using cross-trait LD score regression and GWAS summary statistics data. Finally, the potential role of medications in the reported comorbidities was assessed by comparing disease-specific differential gene expression profiles to an extensive collection of differential gene expression signatures generated by exposing cell lines to drugs indicated for AD, PD, and cancer treatment (LINCS L1000). We identified significant inverse associations of transcriptomic deregulation between AD hippocampal tissues and breast, lung, liver, and prostate cancers, and between PD substantia nigra tissues and breast, lung, and prostate cancers. Moreover, significant direct (same direction) associations of deregulation were observed between AD and PD and brain and thyroid cancers, as well as between PD and kidney cancer. Several biological processes, including the immune system, oxidative phosphorylation, PI3K/AKT/mTOR signaling, and the cell cycle, were found to be deregulated in both cancer and neurodegenerative disorders. Significant genetic correlations were found between PD and melanoma and prostate cancers. Several drugs indicated for the treatment of neurodegenerative disorders and cancer, such as galantamine, selegiline, exemestane, and estradiol, were identified as potential modulators of the comorbidities observed between neurodegeneration and cancer.

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“…From this analysis, the most impactful risk factors that target biological mechanisms and pathways underlying AD risk include the metabolic, immune, cardiovascular, and endocrine systems. 9 , 33 , 47 , 48 , 49 , 50 …”

Section: Discussionmentioning

confidence: 99%

Preventing Alzheimer's disease within reach by 2025: Targeted‐risk‐AD‐prevention (TRAP) strategy

Vitali

Branigan

Brinton

2021

A&D Transl Res & Clin Interv

Self Cite

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Introduction Alzheimer's disease (AD) is a progressive neurodegenerative disease that currently affects 6.2 million people in the United States and is projected to impact 12.7 million worldwide in 2050 with no effective disease‐modifying therapeutic or cure. In 2011 as part of the National Alzheimer's Project Act, the National Plan to Address Alzheimer's Disease was signed into law which proposed to effectively prevent AD by 2025, which is rapidly approaching. The preclinical phase of AD can begin 20 years prior to diagnosis, which provides an extended window for preventive measures that would exert a transformative impact on incidence and prevalence of AD. Methods A novel combination of text‐mining and natural language processing strategies to identify (1) AD risk factors, (2) therapeutics that can target risk factor pathways, and (3) studies supporting therapeutics in the PubMed database was conducted. To classify the literature relevant to AD preventive strategies, a relevance score (RS) based on STRING (search tool for the retrieval of interacting genes/proteins) score for protein–protein interactions and a confidence score (CS) on Bayesian inference were developed. To address mechanism of action, network analysis of protein targets for effective drugs was conducted. Collectively, the analytic approach, referred to as a targeted‐risk‐AD‐prevention (TRAP) strategy, led to a ranked list of candidate therapeutics to reduce AD risk. Results Based on TRAP mining of 9625 publications, 364 AD risk factors were identified. Based on risk factor indications, 629 Food and Drug Administration‐approved drugs were identified. Computation of ranking scores enabled identification of 46 relevant high confidence (RS & CS > 0.7) drugs associated with reduced AD risk. Within these candidate therapeutics, 16 had more than one clinical study supporting AD risk reduction. Top‐ranked therapeutics with high confidence emerged within lipid‐lowering, anti‐inflammatory, hormone, and metabolic‐related drug classes. Discussion Outcomes of our novel bioinformatic strategy support therapeutic targeting of biological mechanisms and pathways underlying relevant AD risk factors with high confidence. Early interventions that target pathways associated with increased risk of AD have the potential to support the goal of effectively preventing AD by 2025.

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Association Between Hormone-Modulating Breast Cancer Therapies and Incidence of Neurodegenerative Outcomes for Women With Breast Cancer

Cited by 35 publications

References 63 publications

Association of Endocrine Therapy and Dementia in Women with Breast Cancer

Association of Endocrine Therapy and Dementia in Women with Breast Cancer

Transcriptomic and Genetic Associations between Alzheimer’s Disease, Parkinson’s Disease, and Cancer

Preventing Alzheimer's disease within reach by 2025: Targeted‐risk‐AD‐prevention (TRAP) strategy

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