Cancer, hormones, and cognition

Cognitive functions are mental processes that take place in the brain and are related to thinking, such as memory, attention, or planning. We know that patients who have cancer outside of the central nervous system sometimes experience cognitive problems during or following their cancer diagnosis and treatment¹. Examples are forgetfulness, or difficulty concentrating. These cognitive problems can have various causes. Cancer treatment can be one of them, but fatigue and mood alterations also influence cognitive function. Cognitive problems can significantly impact daily life and affect quality of life.

Anti-hormonal therapy is a cornerstone treatment for various types of cancer, including breast cancer and prostate cancer. Because it is usually prescribed for several years, research into possible side effects is highly relevant. For hormone receptor-positive breast cancer, tamoxifen is the oldest and most widely used type of anti-hormonal therapy. Tamoxifen is known to cause a variety of side effects, including hot flashes and mood alterations². Cognitive problems are a biologically plausible side effect as well: estrogen plays an important role in the brain in areas important for cognitive function, with which tamoxifen may interfere³. Surprisingly, only a few studies have investigated cognitive function in relation to tamoxifen. These studies provide increasing evidence for adverse effects of tamoxifen on cognitive function^4,5.

The TOTAM trial

It has, however, never been investigated whether tamoxifen’s effects on cognition could depend on the level of exposure to tamoxifen. The TOTAM (Therapeutic drug monitoring Of TAMoxifen) trial provided us the perfect opportunity to study this: In the TOTAM trial, hormone-receptor positive breast cancer patients were followed during the first two years of their treatment with tamoxifen. At several hospital visits, blood levels of tamoxifen (and its active metabolite endoxifen) were measured and the tamoxifen dose was adjusted if necessary. Because patients had different tamoxifen (and endoxifen) blood levels and received different doses of tamoxifen, patients all had different levels of exposure.

In the largest study so far, we assessed cognitive function in these patients with the Amsterdam Cognition Scan (ACS; www.cognitionscan.org). The ACS is a validated, online neuropsychological test battery developed by the Netherlands Cancer Institute, covering a broad spectrum of cognitive domains^6,7. We related patients’ cognitive function to the tamoxifen exposure level measures.

Figure: Cognitive tests of the Amsterdam Cognition Scan

What we found

We found that tamoxifen was adversely associated with cognitive function, confirming the findings of previous studies: compared to cancer-free controls, patients on tamoxifen showed significantly lower performance in verbal learning, processing speed, executive functioning, and motor functioning. Nearly half (47%) of the patients met criteria for cognitive impairment, which was double the rate observed in controls (28%). Patients reported mild but noticeable memory and concentration problems themselves. These self-reported complaints were linked to fatigue, anxiety, and depression.

Higher blood levels of tamoxifen and endoxifen were associated with worse performance in several cognitive domains, including memory and motor functioning. The impact appeared more pronounced in younger women (below 57 years), who may maintain their cognitive performance at low levels of exposure, but decline when exposed to higher levels. Older women (above 57 years) seemed most vulnerable to the adverse effects of tamoxifen on cognition, performing worse already at low levels of exposure.

Figure: Cognitive test performance (Figure 1 in the published article)

Moving forward

For women navigating breast cancer treatment, these findings hold important implications. Our research underscores the importance to be aware of potential cognitive side effects. Understanding these allows patients and their healthcare providers to anticipate challenges and take steps to manage them. Our study also raises important questions about how tamoxifen affects the brain and whether changes in dosing could help improve cognitive outcomes. Our findings hint at the possibility of personalizing tamoxifen therapy. By monitoring drug levels in patients’ blood, doctors could adjust doses to minimize side effects without compromising the cancer treatment.

Cognitive problems – what now?

What if a patient experiences cognitive problems. Is there anything we can do about it? Our findings emphasize that patients should receive adequate treatment for cognitive problems. When a patient presents with cognitive complaints, it is important to assess what underlies these complaints to refer to appropriate care. Patients with cognitive complaints but without cognitive impairments on neuropsychological tests may benefit more from interventions targeting underlying psychological factors such as fatigue, anxiety, or depression to alleviate their distress. Patients with cognitive impairments may benefit most from compensatory strategies to learn how to cope with them.

References

1. Wefel JS, Kesler SR, Noll KR, Schagen SB. Clinical characteristics, pathophysiology, and management of noncentral nervous system cancer-related cognitive impairment in adults. CA Cancer J Clin 2015; 65(2): 123-138.
2. Land SR, Wickerham DL, Costantino JP, Ritter MW, Vogel VG, Lee M et al. Patient-reported symptoms and quality of life during treatment with tamoxifen or raloxifene for breast cancer prevention: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006; 295(23): 2742-2751.
3. Arevalo MA, Azcoitia I, Garcia-Segura LM. The neuroprotective actions of oestradiol and oestrogen receptors. Nat Rev Neurosci 2015; 16(1): 17-29.
4. Lee Meeuw Kjoe PR, Kieffer JM, Small BJ, Boogerd W, Schilder CM, van der Wall E, et al. Effects of tamoxifen and exemestane on cognitive function in postmenopausal patients with breast cancer. JNCI Cancer Spectr 2023; 7(2): pkad022.
5. Underwood EA, Rochon PA, Moineddin R, Lee PE, Wu W, Pritchard KI, et al. Cognitive sequelae of endocrine therapy in women treated for breast cancer: a meta-analysis. Breast Cancer Res Treat 2018; 168: 299-310.
6. Feenstra HEM, Murre JMJ, Vermeulen IE, Kieffer JM, Schagen SB. Reliability and validity of a self-administered tool for online neuropsychological testing: The Amsterdam Cognition Scan. J Clin Exp Neuropsychol 2018; 40(3): 253-273.
7. Feenstra HE, Vermeulen IE, Murre JM, Schagen SB. Online Self-Administered Cognitive Testing Using the Amsterdam Cognition Scan: Establishing Psychometric Properties and Normative Data. J Med Internet Res 2018; 20(5): e192.