Tamoxifen and AIs: Safety

P. Neven et al.

MBC, UZ-Leuven

BBM, 13-14/10/2006

Tamoxifen vs AIsRisk & Endocrine Responsiveness

Endocrine Response

Risk for Relapse

UncertainPR absent, ER low, HER-2+

CertainPR present, ER high, HER-2-

LowT1 &Grade 1& VSI-& Node- & HER-2-

AI

Tam AI

Tam Alone

for 5 Years

Intermediate & HighAny high risk factor

AI

Tam AI Tam AI

Grade 2 lesions (55%of all ER+PR+)

We should tailor therapy ~ co-morbidity

Postmenopausal breast cancer patients with an ER+ breast cancer

Breast Oncology Handbook; LKI Aug. 2006

I. We have some long-term follow-upData Available

• ATAC 6186 68/12• BIG 1-98 8010 25/12

– BIG-1-98 1200 60/12

• IES 4742 55.7/12• ARNO/ABCSG 3224 28/12• ITA 448 36/12• MA.17 5187 30/12

– MA.17 54/12

Safety of tamoxifen ~ >20 year follow-up Safety of AIs ?

II. Other problems

• Self-reporting of side effects

• Poor data collection

• Poor data on cognition, sexual dysfunction

• Pre-existing conditions, co-morbidity

• Co-medications

• Symptoms outside clinical trials differ!– Compliance

Important Background Info

• 1/3 postmenopausals will fracture bone

• C-V disease is cause N° 1 of death

• Don’t compare AIs between each orther

• Comparing AIs with tamoxifen– Bone, CV-effect, Sexual Dysfunction

• Tamoxifen has a unique safety profile

Tamoxifen and AIs: Safety

Uterus

VTEs

Tamoxifen

BoneJoints

CV-disease

AIs

QOLCompliance

Others…

►Tam Protects Against Fractures◄

Fracture data in P1 at 7Yrs FU (≥ 50 years)1

Placebo: 4.13 / 1000 / Year Tamoxifen: 2.95 / 1000 / Year

Fisher et al. JNCI 2005

Bone and tamoxifen

Bone and AIsExemestane better?Consistency between 3 compounds

ATAC* 68 monthsBIG-98 25.8/51 months

IES* 55.7 monthsARNO/IBCSG 30 months

MA.17* 30/54 monthsLonning 24 months

(*) bone subprotocol

LEAP trial: Direct comparisonHealthy postmenopausals

McCloskey et al. ASCO 2006

5 years data

Coleman et al ASCO 2006

▼ T-score:What does this mean Only ‘One’ Risk Factor for Fractures

• T-score: ▼‘-1’ = BMD loss of 8 – 10 %

RR Hip Fracture ▲X 2.6

• T-score ≤ -2.5 : Lumbar Spine # Risk

At 65 yrs 8% / 5 years

At 85 yrs 15%/ 5 years

*Lifetime risk ‘hip fracture’ at the age of 50 years varies from 1% in women from Turkey to 28.5% in women from Sweden. (Kanis et al. J. Bone Metabol Res 2002)

Geography is another risk factor!

Age

Baseline T-score !

Bone Study ATAC5 years of Follow-up

Median (range) percentage change in BMD from baseline to 1, 2, and 5 years

Lumbar spine BMD Total hip BMD

Anastrozole(n=81)

Tamoxifen(n=86)

Anastrozole(n=81)

Tamoxifen(n=86)

1 year-2.2(-14.8 to 3.6)

1.4(-6.9 to 9.6)

-1.5(-12.2 to 4.9)

0.9(-6.2 to 9.9)

2 years-4.0(-13.3 to 2.4)

2.1(-7.6 to 11.1)

-3.9(-12.7 to 8.1)

1.2(-8.9 to 11.5)

5 years-6.1(-17.7 to 2.6)

2.8(-12.7 to 17.7)

-7.2(-20.4 to 3.8)

0.7(-14.1 to 9.2)

n=number of patients in the primary analysis population

Coleman et al. ASCO 2006 Abstr. 511

If normal bone at start there was no osteoporosis at year 5

What is meaningfull?“Fracture Data”

• ATAC 68.0 Ana (11.0%) Tam (7.7%)• ATAC 33.0 Ana (5.9%) Tam (3.7%)• Arno 28.0 Ana (2%) Tam (1%)• BIG1-98 25.8 Let (5.6%) Tam (4%)

BIG1-98 51.0 Let (?) Tam (?)• IES 55.7 Exe (7%) Tam (4.9%)• MA.17* 30 Let (5.3%) Plac (4.6%)

MA.17 54 Let (%) Plac (?)

*n.s.: tamoxifen pre-treated

Comparison of Mean LS T Scores ABCSG-12 vs Z-FAST Trials

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

Mean

T S

core

Baseline Follow-up*

ABCSG-12 Z-FAST

*Follow-up—ABCSG-12 at 36 mo; Z-FAST at 12 moAna=anastrozole; Del=delayed; Let=letrozole; Up=upfront; ZA=zoledronic acid

Ana Ana + ZA Let + ZA Let

Bisfosphonates

Joints …Consistency between 3 compounds?

ATAC 68 monthsBIG-98 25.8/51 monthsTEAM 12 monthsIES 55.7 monthsARNO/IBCSG 30 months

MA.17 30/54 monthsLonning 24 months

There clearly is an underreporting of arthralgia in clinical trials comparing AIs with tamoxifen in women with M+ breast cancer. It is a class effect

It may hamper compliance when using AIs in adjuvant setting

J Clin Oncol 2001 RCF Leonard et al.

Gut FeelingT<A< E,L

ATACBuzdar et al ASCO 2006

Debilitating musculoskeletal pain and stiffness with AIs

Tenosynovial changes on MRI

Leilani Morales et al.

UZ-Leuven

Breast Cancer Res Treat 2006

hands, knees, feet, hips, lower back, and shouldersR/ is NSAIDs, Analgetics, Tamoxifen

Tenosynovial MRI changes on AIs

• 12 postmenopausals on AI’s• Severe early morning stiffness• Severe debilitating hand/wrist pain• Impaired ability to close/stretch hand/fingers• 6/12 discontinued AI therapy

• Clinical signs: CTS, trigger finger

• US: Fluid accumulation in tendon sheath surrounding the digital flexor tendons

Breast Cancer Res Treat 2006

Arthralgia

Co-Morbidity & Side effects

All 12 patients had enhancement and thickening of tendon sheathSome had fluid in tendon sheaths DFTSome had fluid in extensor tendons, joints…

Poor effect of NSAIDs

PALOPRAI

Lipids & vascular eventsPoor data

ATAC 68 monthsBIG-98 25.8/51 months

IES 55.7 monthsARNO/IBCSG 30 months

MA.17* 30/54 monthsLonning 24 months

Tamoxifen & Cardio-Vascular

• It lowers LDL, total cholesterol• It increases triglycerides

• NSABP P-1 prevention trial– DVT: + 0.6/1000/yrs– PE: +0.7/1000/yrs*– Stroke: +0.9/1000/yrs

• Risk factors– Age– BMI– Sedentary life

It lowers ischemic CV-events

It increases VTE-eventsIBIS-1

STAR: Raloxifene less thrombogenic

AIs and Lipids: Poor reporting

• “Self reported” hypercholesterolemia– ATAC: Ana (9.0%) vs Tam (3.5%)– ITA: Ana (9.3%) vs Tam (4.0%)– MA.17: No difference Let vs Plac– MA.17 Lipid substudy: No difference

• Apolipoprotein B/A1: increased on Exe• HDL

– Lonning: Exe (- 6-9%) vs Plac (+ 1-2%)

Letrozole upfront !?

But …

Thrombo-embolic Event: Grade

2

23

147 43

42

32

14

30

10

20

30

40

50

60

70

Gr 1 Gr 2 Gr 3 Gr 4 Gr 5

Nu

mb

er

of

Pati

en

ts

Let (2448) Tam (2447)

P < 0.001

BIG 1-985 year data

ESMO 2006

RR = X 2

Cardio-Vascular DiseaseCompared with tamoxifen…

• ATAC*– Ischemic disease +0.8%– Angina pectoris +0.8%

• IES– Cardiovascular +1.3%

• Ischemic disease +0.5%

X 2

Any Cardiac Event: Grade

3426

39

24

11

63

24 21

95

0

10

20

30

40

50

60

70

Gr 1 Gr 2 Gr 3 Gr 4 Gr 5

Nu

mb

er

of

Pati

en

ts

Let (2448) Tam (2447)

P n.s.

BIG 1-9851 months

ESMO 2006

Ischemic Heart Disease: Grade

39

18 19

510 10 12

72

0

10

20

30

40

50

60

70

Gr 1 Gr 2 Gr 3 Gr 4 Gr 5

Nu

mb

er

of

Pati

en

ts

Let (2448) Tam (2447)

P n.s.

BIG 1-9851 months

ESMO 2006

MA.17: n= 5187 2 yrs Letrozole vs Placebo

30 months of follow-up More common: Hot flushes (+4.0%), arthralgia/myalgia(+4.0%), new diagnosis of osteoporosis (+ 2.1%), alopecia(+2%),anorexia (+2%), stop for toxicity (+1.4%).

Less common: Vaginal bleeding (-2%)

Frequency of vaginal dryness, diarrhea, fractures, lower compliance, cardiovascular ischemic events was not significantly different.

*A statistically significant mean decrease in BMD in the hip/LSoccurred at 24 months on letrozole.

FDA data regarding safety of letrozoleClin Cancer Res. 2005;11: 5671-7J Natl Cancer Inst 2005; 97: 1262–71

“reported by patients”* Bone subprotocol: 1.6 years of FU

QoL: Not differentNo data on change of QoL

Compares therapies

• ATAC: 1021 women & 2 year data

• IES: 582 women & 2 year data

• MA.17: 3612 women & 3 year data

Randomized

Completed Treatment

Withdrawn

2352 2372

1807 1832

513 506

0

500

1000

1500

2000

2500

Exemestane Tamoxifen

Patient Compliance

Adverse Event/Patient RefusalRecurrence/Death

Protocol Violation/LTFU/Other

322

251

132

194

59 61

0

50

100

150

200

250

300

350

Exemestane Tamoxifen

Reasons for withdrawing

Tamoxifenand the Uterus

TAGAS

Postmenopausal Bleeding Long term tamoxifen use

– Guidelines: consensus FGOG: Brussels ‘04

< 5 m m an d reg u la rW ait an d S ee

> 5 m m or Irreg u la rS IS /H ys te roscop y & B iop sy

E n d om etria l fo llow -u p yearly, s ta rt in g a t year th reeTV U : en d om etria l p a tte rn an d Th ickn ess

Pre-T reatm ent - T VU - Uterine Assessm entR eg u la r Th in E n d om etriu m < 5 m m : wa it an d seeIrreg u la r o r > 5 m m : S IS o r H ys te roscop y & B iop sy

Neven et al. Eur J Cancer 2004Amant et al. Lancet 2005

Postmenopausal Bleeding

Endometrial assessment TVU

Endometrial Biopsy

ConclusionAIs versus Tam

• Arthralgia (A,L,E)– CTS (E)

• Fractures (A,L,E)• Diarrhea (E)• Gastric Ulcer (E)• Nausea & vomiting (A,E)• Skin rash (A)• Alopecia (A,L)• Fatigue (E) • AHT (A, E)• MI (A,L,E)• Headache (E)• *Cognitive function (A)• Sexual dysfunction (A)

Uterine bleedingHysterectomy ratePolypsEcaDVTPEStrokeHot flashesOther cancers

*Bioavailable oestrogens protect against cognitive decline. Yaffe K et al. J Am Geriatr Soc 1998

AI versus TamoxifenConclusion: Manageable Side Effects

• Bone – Periodic BMD screening– Calcium + Vit D, Bisfosfonate, Statines

• Joints• Lipids and Heart

– Statines, Behavioral Changes, Obestiy, Sedentary life

• Risk of relapse versus comorbidity• Likelihood of treatment compliance

Tamoxifen for 5 years is not dead Conflict of interest: None

Cardiovascular / Thromboembolic

22.1 v 20.9, 0.34

1.8 v 1.8, 0.941.0 v 0.8, 0.51

2.5 v 2.4, 0.89

1.9 v 3.1, 0.01

0.1 v 0.1, 0.69

9.9 v 8.6, 0.121.3 v 0.8, 0.08

11.3 v 11.2, 0.96

E%* v T%¥, P-value

Favors TamoxifenFavors Exemestane

*N=2320, ¥N=2338

Odds ratio (99% CI)

Thromboembolic

Other cardiac

Sudden death

CVA

PVD+ Heart failure

Angina MI

Ischemic cardiac

All CV / TE

0.4 0.6 0.8 1.0 1.2 1.82.0

7.1 v 6.5, 0.44

+ PVD = Peripheral Vascular Disease

IES55 Months

9.2 v 7.2, 0.01

Musculoskeletal / Other

Incidence rate per 1000 women years (99% CI) for fractures (allowing more than one fracture event per patient) are E = 19.2 (15.9, 23.1) & T = 15.1 (12.2, 18.7)

E%* v T%¥, P-value

17.5 v 14.6, 0.008

7.0 v 4.9, 0.0030.6 v 0.4, 0.290.6 v 0.2, 0.041.1 v 1.3, 0.525.0 v 3.4, 0.007

25.7 v 20.3, <0.00120.8 v 15.1, <0.001

2.0 v 1.1, 0.01

2.5 v 4.4, <0.001

1.2 v 0.3, 0.001

2.8 v 0.4, <0.001

*N=2320, ¥N=2338

Favors TamoxifenFavors Exemestane

Odds ratio (99% CI)

Musculoskeletal pain

Carpal tunnel

Gastric ulcer

Cramp Joint stiffness

Arthralgia

Arthritis (All types) Osteoporosis

Other fracture Wrist fracture Spine fracture Hip fracture

Fracture

0.4 0.8 1.0 2.0 3.0 4.0 6.0 8.00.6

IES55 months

Postmenopausal breast cancer Mean % change BMD: No R/, TAM, AI

Love et al. NEJM 19921

Powles et al. JCO 19962

Perez et al. BCRT Suppl 20043

Coleman et al. BCRT Suppl 20054

Coleman et al. Eur J Cancer Suppl 20045

Coleman et al. ASCO 2006

No further treatment1 ► 2 Year data for Spine - 2,0%

Tamoxifen1,2 ► 3 Year data for Spine + 2,5% ► 3 Year data for Hip + 3,0%

Aromatase Inhibitors3-5 ► 5 Year data for Spine - 6.1%► 5 Year data for Hip - 7.2%