By Cristina Curcelli

August 13, 2015

COGNITIVE EFFECTS OF HORMONAL THERAPY

IN BREAST CANCER PATIENTS

Background: Hormonal therapy Common uses Types:

SERM v. AI

Study designs Tamoxifen Tamoxifen vs. Aromatose Inhibitors Anastrozole

Limits to Research

Conclusions

OUTLINE

What is hormonal therapy?BACKGROUND INFO

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

Selective Estrogen Receptor Modulator (SERM): Selectively act as estrogen agonists or antagonists Action varies based on tissue type Ex: Tamoxifen

THERAPY TYPE: SERM

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

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.

Inclusion criteriaSTUDY DESIGNS

WHY STUDY HORMONAL THERAPY?

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

Studies examining effects of Tamoxifen against controls

STUDIES: TAMOXIFEN

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

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.

SERMs vs. AIs

STUDIES: COMPARISONS

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

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.

Prospective study examining effects of Anastrazole

STUDY: ANASTRAZOLE

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 ConcentrationDeterioration patters continued in anastrozole only group from 12-18 months

Deterioration patters continued in anastrozole only group from 12-18 months

EFFECTS OF ANASTROZOLE

Limits

Conclusions

Future Direction

CONCLUSIONS

Cross sectional studies

Small sample sizes

Comparison between AIs and SERMs

Difficulty in consistent exclusion/inclusion criteria

LIMITS TO CURRENT FINDINGS

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

Further focus on prospective studies

Understaning mechanisms of Tamoxifen Antagonist/agonist behavior

Isolating type of Aromatose Inhibitor Exemestame Anastrozole Letrozole

DIRECTION OF FUTURE RESEARCH

Agrawa l K , Onami S , Mor t imer JE , Pa l SK . Cogn i t i ve changes assoc ia ted w i th endoc r ine the rapy fo r b reas t cancer. Matu r i t as . 2010 ;67 .

Bender CM , e t a l . Memory impa i rmen t s w i th ad juvan t anast ro zo le versus tamox fen i n women w i th ea r ly - s tage b reas t cancer. Menopause . 2007 ; 14 (6 ) : 995-998 .

Bender CM , e t a l . Pa t te rns o f Change i n Cogn i t i ve Func t ion w i th Anas t rozo le T herapy. Cancer. 2015 Aug 1 ;121 (15 ) :2627 -36 .

Boe le FW, Sch i l de r CMT , de Roode ML , De i jen JB , Schagen SB . Cogn i t i ve func t i on ing du r ing long -te rm tamox i fen t rea tment in pos temenopausa l women w i th b reas t cancer. Menopause . 2014;22 :1 .

Caste l lon , S A , e t a l . Neu rocogn i t i ve Per fo rmance i n Breas t Cancer Su rv i vo rs Exposed to Ad juvant Chemotherapy and Tamox i fen . J ou rna l o f C l i n i c a l and Expe r imen ta l Neu ropsycho logy. 2004;26 :7 .

Co l l i ns B , Mac kenz ie J , S tewar t A , B ie l a jew C , Ve rma S . Cogn i t i ve effec t s o f ho rmona l t herapy i n ea r l y s t age b reast c anc er pa t i en ts : a p rospec t ive s tudy. Psychoonco logy . 2009 Aug ;18(8 ) :811-21

Eber l ing JL , Wu C , Tong -Tu rnbeaugh R , J agus t , WJ . Es t rogen- and t amox i fen -assoc ia ted effec ts on b ra in s t ruc tu re and func t ion . Neuro Image . 2004 ; 21 : 364 -371 .

Sc h i lder CM , e t a l . Effec ts o f Tamox i fen and Exemestane on Cogn i t i ve Func t i on ing o f Pos tmenopausa l Pa t i en ts w i th Breas t Cance r. J ou rna l o f C l in i c a l Onco logy. 2010;28 :8

REFERENCES