1. By Cristina
Curcelli
August 13,
2015
COGNITIVE EFFECTS
OF HORMONAL THERAPY
IN BREAST CANCER
PATIENTS

2.  Background: Hormonal therapy
 Common uses
 Types:
 SERM v. AI
 Study designs
 Tamoxifen
 Tamoxifen vs. Aromatose Inhibitors
 Anastrozole
 Limits to Research
 Conclusions
OUTLINE

3. What is
hormonal
therapy?
BACKGROUND INFO

4.  Approx. 2/3 of breast cancers are hormone-receptor positive
 Most commonly used as adjuvant therapy
 Despite prevalence, relatively little research has looked at
possible cognitive effects.
HORMONAL THERAPY: COMMON USES

5.  Selective Estrogen Receptor Modulator (SERM):
 Selectively act as estrogen agonists or antagonists
 Action varies based on tissue type
 Ex: Tamoxifen
THERAPY TYPE: SERM

6.  Aromatose Inhibitor (AI):
 Aromatose: enzyme that synthesizes estrogen
 AIs block all production of estrogen
 Generally used on postmenopausal women only
 Have been shown to be more effective than tamoxifen in preventing
recurrence
 Types: exemestane, anastrozole, letrozole
THERAPY TYPE: AI

7.  Exemestane: irreversible, steroidal aromatose inactivator
 Acts by way of “suicide inhibition”
 Anastrozole: non-steroidal aromatose inhibiting drug
 Binds reversibly to enzyme by competitive inhibition
 Letrozole: non-steroidal aromatose inhibiting drug
 Competitive, reversible binding
AROMATOSE INHIBITOR TYPES, CONT.

8. Inclusion
criteria
STUDY DESIGNS
WHY STUDY HORMONAL THERAPY?

9.  Many Breast Cancer patients complained of cognitive
problems
 There is growing evidence that estrogen affects cognitive
function
 Estrogen-receptors (ERs) are present in the hippocampus and frontal
lobe, areas important for cognitive function
 Studies included here:
 Post-menopausal women
 Breast cancer (early - mid stage)
 Cross sectional and longitudinal designs
 Controlled for type of hormone (tamoxifen v. exemestame v.
anastrozole)
APPROACH TO RESEARCH

10. Studies
examining
effects of
Tamoxifen
against
controls
STUDIES: TAMOXIFEN

11.  Castellon et al, 2004:
 Cross sectional design
 Tamoxifen/chemo group, chemo only group, healthy controls
 Tamoxifen/chemo group showed greatest cognitive function
compromise
 Domains most severely affected:
 Visual memory
 Visuospatial function
 Verbal learning
STUDIES: EFFECTS OF TAMOXIFEN

12.  Boele et al, 2014: long-term tamoxifen therapy
 Cross sectional design
 Tamoxifen + surgery/radiation group, surgery/radiation only group,
healthy controls
 Tamoxifen group performed significantly worse on measures of verbal
memory.
EFFECTS OF TAMOXIFEN, CONT.

13. SERMs
vs.
AIs
STUDIES: COMPARISONS

14.  Because of differing mechanisms, AI therapies – specific
anastrozole -- are thought to affect cognitive function MORE
than tamoxifen (SERM).
 Exemstane:
 Schilder et al’s prospective study
 Tamoxifen group, exemestane group, healthy controls
 Tamoxifen users shown to have statistically lower verbal
memory and executive function at 1 year mark
 Exemestane users showed no difference.
SERM VS. AI THERAPY

15.  Anastrozole:
 Bender’s 2007 cross-sectional study
 Tamoxifen group, anastrozole group, healthy controls
 Anastrozole group showed poorer verbal and visual learning and
memory than tamoxifen group.
 Collins et al: 2008 prospective study
 Tamoxifen group, anastrozole group, healthy controls
 Reliable cognitive decline in both cancer groups
 Anastrozole, at 5-6 months after initial timepoint, showed more
significantly increased risk of decline compared to tamoxifen group
SERM VS. AI THERAPY, CONT.

16. Prospective
study
examining
effects of
Anastrazol
e
STUDY: ANASTRAZOLE

17.  Bender et al 2015
 Prospective study: 4 timepoints
 3 groups: anastrozole only, chemo + anastrozole, healthy controls
 Cancer groups showed poorer executive function at nearly all
timepoints
 Patterns of deterioration in cancer groups between 0 – 6 months
 Afffected domains:
 Working memory
 Concentration
Deterioration patters continued in anastrozole only group from 12-18
months
 Deterioration patters continued in anastrozole only group from 12-18
months
EFFECTS OF ANASTROZOLE

18. Limits
Conclusions
Future
Direction
CONCLUSIONS

19.  Cross sectional studies
 Small sample sizes
 Comparison between AIs and SERMs
 Difficulty in consistent exclusion/inclusion criteria
LIMITS TO CURRENT FINDINGS

20.  Commonly affected domains:
 Verbal memory + learning
 Executive function
 Relation to ER structural location
 Consistencies across studies
 Tamoxifen shown to affect executive function and verbal memory
 Both cross-sectional and prospective results
 Anastrozole shown to affect congitive function  in comparison to
Tamoxifen, effects have generally been more severe
CONCLUSIONS

21.  Further focus on prospective studies
 Understaning mechanisms of Tamoxifen
 Antagonist/agonist behavior
 Isolating type of Aromatose Inhibitor
 Exemestame
 Anastrozole
 Letrozole
DIRECTION OF FUTURE RESEARCH

22.  Agrawal K, Onami S, Mortimer JE, Pal SK. Cognitive changes associated with endocrine therapy for
breast cancer. Maturitas. 2010;67.
 Bender CM, et al. Memory impairments with adjuvant anastrozole versus tamoxfen in women with
early-stage breast cancer. Menopause. 2007; 14(6): 995 -998.
 Bender CM, et al. Patterns of Change in Cognitive Function with Anastrozole Therapy. Cancer. 2015
Aug 1;121(15):2627 -36.
 Boele FW, Schilder CMT, de Roode ML, Deijen JB, Schagen SB. Cognitive functioning during long -term
tamoxifen treatment in postemenopausal women with breast cancer. Menopause. 2014;22:1.
 Castellon, SA, et al. Neurocognitive Performance in Breast Cancer Survivors Exposed to Adjuvant
Chemotherapy and Tamoxifen. Journal of Clinical and Experimental Neuropsychology. 2004;26:7.
 Collins B, Mackenzie J, Stewart A, Bielajew C, Verma S. Cognitive effects of hormonal therapy in
early stage breast cancer patients: a prospective study. Psychooncology . 2009 Aug;18(8):811 -21
 Eberling JL, Wu C, Tong -Turnbeaugh R, Jagust, WJ. Estrogen- and tamoxifen-associated effects on
brain structure and function. NeuroImage . 2004; 21: 364 -371.
 Schilder CM, et al. Effects of Tamoxifen and Exemestane on Cognitive Functioning of
Postmenopausal Patients with Breast Cancer. Journal of Clinical Oncology. 2010;28:8
REFERENCES