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Cognitive Impairment, Aromatase Inhibitors, and Age

Medical Oncology, G. Di Maria Hospital, Avola, Italy

Francesco Ferrau'

Medical Oncology, San Vincenzo Hospital, Taormina, Italy

To the Editor:

The recommendations published in the January issue of the Journal of Clinical Oncology¹ regarding the use of aromatase inhibitors (AIs) confirm the advantages of using this drug in the adjuvant setting, and at the same time, underline the importance of monitoring the possible side effects, particularly for the subgroup of women for whom the risks and inconvenience of AI could outweigh the potential benefits.

One of the most common side effects following AI therapy that can have repercussions on the patient's quality of life, is bone fracturing,² which is attributed to the reduced level (systemic and local) of estrogen as determined by the treatment.^3,4 In fact, this estrogen deficiency reduces bone mineral density and causes osteoporosis, bone fractures, hot flushes, and arthritic discomfort. It has also recently been reported to have an effect on cognitive status, and in particular, short and long-term memory, which is correlated with estrogen deficiency.⁵ Estrogen receptors (ERs), including ER- and ER-ß, are located throughout the brain, especially in the areas involved in learning and memory, such as the hippocampus and amygdala.⁶ The enzymes necessary for sex steroid biosynthesis have been identified in these same areas, suggesting that estrogen has an important role in the brain.⁷ Estrogen therapy has been one of the most compelling potential strategies for the prevention of dementia. The results from different studies suggest that hormonal therapy exerts its protective effect when used in the very early phases of the disease process or even before the disease begins. At the same time, because mild cognitive impairment frequently progresses to dementia,⁸ preventative action becomes a relevant issue, especially for elderly patients. In fact, age itself, through the reduction of estrogen exposure and the presence of comorbidities, can promote cognitive impairment, which is strictly correlated with the loss of independence in elderly patients.

The preliminary data on AI assumption suggests a possible impact on cognitive function: 94 women enrolled in the ATAC study and 35 healthy women were evaluated for cognitive function, after controlling for age and the use of hormone-replacement therapy. The women who received hormonal therapy manifested an impairment of verbal memory (P = .026) and task processing speed (P = .032).⁹ Preliminary results from the TEAM (tamoxifen versus examestane) trial indicated a significantly higher incidence of impaired word finding in women who were treated with examestane compared with tamoxifen.¹⁰

To conclude, this evidence supports the hypothesis that cognitive impairment could also be a late side effect of adjuvant hormonal therapy. With this in mind, it is essential to obtain an indication as to the true incidence rates and entity of the therapy and in particular to evaluate the actual conditioning that is brought about in terms of a reduction of the patient's activity of daily living and of their independence.

Therefore, we believe that the assessment of cognitive status should become a systematic component of drug and schedule (tamoxifen-AI) safety evaluation for prospective clinical trials employing AI and that, in the meantime, it is also important for physicians to consider this possibility, especially for elderly patients with initial memory impairment.¹¹

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Winer EP, Hudis C, Burnstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: Status report 2004. J Clin Oncol 23:619-629, 2005[Abstract/Free Full Text]

2. ATAC Trialists' Group, Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60-62, 2005

3. Evans TR, Di Salle E, Ornati G, et al: Phase I and endocrine study of examestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women, Cancer Res 52:5933-5939, 1992

4. Zilembo N, Noberasco C, Bajetta E, et al: Endocrinological and clinical evaluation of examestane, a new steroidal aromatase inhibitor. Br J Cancer 72:1007-1012, 1995[Medline]

5. Sherwin BB: Estrogen and cognitive functioning in women. Endocr Rev 24:133-151, 2003[Abstract/Free Full Text]

6. Shughrue PJ, Lane MV, Merchenthaler I: Comparative distribution of estrogen receptor-alpha and -beta mRNA in the rat central nervous system. J Comp Neurol 388:507-525, 1997[CrossRef][Medline]

7. Stoffel-Wagner B: Neurosteroid metabolism in the human brain. Eur J Endocrinol 145:669-679, 2001[Abstract]

8. McEwen BS: Clinical review 108: The molecular and neuroanatomical basis for estrogen effects in the central nervous system. J Clin Endocrinol Metab 84:1790-1797, 1999[Free Full Text]

9. Jenkins VA, Schilling V, Fallowfield LJ, et al: Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. PsychoOncology 13:61-66, 2004[CrossRef][Medline]

10. Jones J, Vukelja S, Cantrell J, et Al: A planned comparison of menopausal symptoms during year 1 in patients receiving either examestane or tamoxifene in a double-blind adjuvant hormonal study. Breast Cancer Res Treat 82:S31, 2003

11. Tralongo P, Dimari A, Repetto L: Aromatase inhibitors and mental function. J Am Geriatr Soc 53:166, 2005[Medline]

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