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Summary

In this study, Branigan and colleagues [1] assessed whether the use of endocrine therapy (tamoxifen, raloxifene, aromatase inhibitors (AI)) among breast cancer patients was associated with risk of neurodegenerative diseases including all-cause dementia, Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). They conducted a retrospective cohort study of 57,843 women aged 45 and older with a diagnosis of breast cancer between January 1, 2007, and March 31, 2017, using a Humana insurance claims dataset primarily comprised of women in the Southeastern region of the United States. The use of endocrine therapy was defined by at least one medication charge occurring after the diagnosis of breast cancer; neurodegenerative diseases were diagnosed based on ICD-9 or ICD-10 codes. To minimize confounding, propensity score matching was conducted based on age at receiving endocrine therapy, race/ethnicity, comorbidities, and the Charlson comorbidity index. In the propensity score-matched cohort, endocrine therapy users were at a reduced risk of AD, but not non-AD dementia, MS, PD, or ALS. When stratifying by type of endocrine therapy, both tamoxifen and aromatase inhibitors, but not raloxifene, were associated with a reduced risk of AD. Removal of women who received intravenous chemotherapy in the unadjusted analyses did not change the results. The authors conclude that the results show the beneficial effects of endocrine therapy as a prophylactic treatment for the potential prevention of AD.

Commentary

Almost 13% of women will receive a breast cancer diagnosis in their lifetime[2]. About 75% of all breast cancers are hormone receptor-positive, and patients are typically advised to undergo endocrine therapy, about two-thirds of which take at least one type. Of women with estrogen-receptor-positive tumours, those who are premenopausal typically receive tamoxifen with or without ovarian suppression, whereas those who are postmenopausal often receive AI alone, tamoxifen followed by AI or AI followed by tamoxifen [3]. Raloxifene is currently recommended for breast cancer prevention in postmenopausal women.

Given the large number of women who take endocrine therapies and the increased survival after breast cancer, it is important to assess the long-term benefits and risks of use. Clinical trials and large epidemiological studies have examined the associations between endocrine therapy use and cognitive decline or risk of dementia, with mixed results typically showing either a detrimental effect of the use on cognition and risk of dementia or no effect [4-7]. In contrast, one study using the Taiwanese National Health Insurance Research Database reported that the use of tamoxifen for five years or more was associated with a reduced risk of dementia [8]. The current study by Branigan and colleagues [1] also found a reduced risk of AD dementia, but not other dementias, with the use of tamoxifen or AI.

Given that the Branigan et al. study [1] is the largest to date, with over 50,000 women, the question arises as to whether the study results should lead to consideration of tamoxifen or AI as a prophylactic treatment for the prevention of AD? The short answer is no.

The study has a number of important limitations, some of which are acknowledged by the authors. First, findings are based on an observational study of a claims database that cannot infer causality. As with other claims databases, neurodegenerative disease outcomes are only identified by diagnosis code, and this method is known to have low sensitivity.

Second, information on menopause status, stage of breast cancer, the status of first breast cancer diagnosis versus recurrence, hormone receptor status, and previous use of menopausal hormone therapy was not available. These factors, as previously discussed, can significantly impact the association between endocrine therapy use and risk of dementia and are important to consider in the study design [3]. Indeed, since endocrine therapy is generally only used for the treatment of hormone-positive tumours, without knowledge of tumour status it is difficult to determine whether an association with dementia risk is due to the endocrine therapy or the characteristics of the tumour.

Third, and a common limitation of many studies is the short duration between the start of endocrine therapy and the diagnosis of dementia. The median (standard deviation) time to diagnosis of AD was 3.1 (2.4) years for those not taking endocrine therapy, and 3.3 (2.2) among endocrine therapy users. AD is a slowly progressive neurodegenerative disease with a long duration of cognitive symptoms prior to a diagnosis. Thus, some of the women had cognitive symptoms at the time of the breast cancer diagnosis. It is likely these symptoms could impact the type of breast cancer therapy prescribed; propensity matching could not account for this bias.

In summary, the findings from the current study should not provide the impetus to prescribe tamoxifen or AI for the prevention of AD. Limitations of this study do highlight the difficulty in examining associations between endocrine therapy and AD and the need to consider multiple factors when interpreting the associations.

References

  1. Branigan GL, Soto M, Neumayer L, Rodgers K, Brinton RD. Association between hormone-modulating breast cancer therapies and incidence of neurodegenerative outcomes for women with breast cancer. JAMA Netw Open 2020; 3:e201541.
    https://pubmed.ncbi.nlm.nih.gov/32207833/
  2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69:7-34.
    https://acsjournals.onlinelibrary.wiley.com/doi/full/10.3322/caac.21551
  3. Zwart W, Terra H, Linn SC, Schagen SB. Cognitive effects of endocrine therapy for breast cancer: keep calm and carry on? Nat Rev Clin Oncol 2015; 12:597-606.
    https://pubmed.ncbi.nlm.nih.gov/26196252/
  4. Schilder CM, Seynaeve C, Beex LV, Boogerd W, Linn SC, Gundy CM, Huizenga HM, Nortier JW, van de Velde CJ, van Dam FS, Schagen SB. Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. J Clin Oncol 2010; 28:1294-1300.
    https://pubmed.ncbi.nlm.nih.gov/20142601/
  5. Legault C, Maki PM, Resnick SM, Coker L, Hogan P, Bevers TB, Shumaker SA. Effects of tamoxifen and raloxifene on memory and other cognitive abilities: cognition in the study of tamoxifen and raloxifene. J Clin Oncol 2009; 27:5144-5152.
    https://pubmed.ncbi.nlm.nih.gov/19770382/
  6. Ording AG, Jensen AB, Cronin-Fenton D, Pedersen L, Sorensen HT, Lash TL. Null association between tamoxifen use and dementia in Danish breast cancer patients. Cancer Epidemiol Biomarkers Prev 2013; 22:993-996.
    https://pubmed.ncbi.nlm.nih.gov/23548343/
  7. Bromley SE, Matthews A, Smeeth L, Stanway S, Bhaskaran K. Risk of dementia among postmenopausal breast cancer survivors treated with aromatase inhibitors versus tamoxifen: a cohort study using primary care data from the UK. J Cancer Surviv 2019; 13:632-640.
    https://pubmed.ncbi.nlm.nih.gov/31641936/
  8. Sun LM, Chen HJ, Liang JA, Kao CH. Long-term use of tamoxifen reduces the risk of dementia: a nationwide population-based cohort study. QJM 2016; 109:103-109.
    https://pubmed.ncbi.nlm.nih.gov/25852154/
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