Tamoxifen and ais safety
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Tamoxifen and AIs: Safety. P. Neven et al. MBC, UZ-Leuven. BBM, 13-14/10/2006. Postmenopausal breast cancer patients with an ER + breast cancer. Tamoxifen vs AIs Risk & Endocrine Responsiveness. Grade 2 lesions (55%of all ER+PR+). We should tailor therapy ~ co-morbidity.

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Tamoxifen and AIs: Safety

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Tamoxifen and ais safety

Tamoxifen and AIs: Safety

P. Neven et al.

MBC, UZ-Leuven

BBM, 13-14/10/2006


Tamoxifen vs ais risk endocrine responsiveness

Postmenopausal breast cancer patients with an ER+ breast cancer

Tamoxifen vs AIsRisk & Endocrine Responsiveness

Grade 2 lesions

(55%of all ER+PR+)

We should tailor therapy ~ co-morbidity

Breast Oncology Handbook; LKI Aug. 2006


I we have some long term follow up data available

Safety of tamoxifen ~ >20 year follow-up

Safety of AIs ?

I. We have some long-term follow-upData Available

  • ATAC618668/12

  • BIG 1-98801025/12

    • BIG-1-98120060/12

  • IES474255.7/12

  • ARNO/ABCSG322428/12

  • ITA44836/12

  • MA.17518730/12

    • MA.1754/12


Ii other problems

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

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 safety1

Tamoxifen and AIs: Safety

QOL

Compliance

Tamoxifen

AIs

Uterus

VTEs

Bone

Joints

CV-disease

Others…


Tamoxifen and ais safety

Bone and tamoxifen

►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 ais exemestane better consistency between 3 compounds

Bone and AIsExemestane better?Consistency between 3 compounds

ATAC*68 months

BIG-9825.8/51 months

IES*55.7 months

ARNO/IBCSG30 months

MA.17*30/54 months

Lonning24 months

(*) bone subprotocol


Tamoxifen and ais safety

LEAP trial: Direct comparison

Healthy postmenopausals

McCloskey et al. ASCO 2006


Tamoxifen and ais safety

5 years data

Coleman et al ASCO 2006


T score what does this mean only one risk factor for fractures

▼ 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

Age

Geography is another risk factor!

*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)


Tamoxifen and ais safety

Baseline T-score !


Bone study atac 5 years of follow up

Bone Study ATAC5 years of Follow-up

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

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

Coleman et al. ASCO 2006 Abstr. 511


What is meaningfull fracture data

What is meaningfull?“Fracture Data”

  • ATAC68.0Ana (11.0%)Tam (7.7%)

  • ATAC33.0Ana (5.9%)Tam (3.7%)

  • Arno28.0Ana (2%)Tam (1%)

  • BIG1-9825.8Let (5.6%)Tam (4%)

    BIG1-9851.0Let (?)Tam (?)

  • IES55.7Exe (7%)Tam (4.9%)

  • MA.17*30Let (5.3%)Plac (4.6%)

    MA.1754Let (%)Plac (?)

*n.s.: tamoxifen pre-treated


Comparison of mean ls t scores abcsg 12 vs z fast trials

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

Bisfosphonates

Ana Ana + ZA Let + ZA Let

ABCSG-12 Z-FAST

*Follow-up—ABCSG-12 at 36 mo; Z-FAST at 12 mo

Ana=anastrozole; Del=delayed; Let=letrozole; Up=upfront; ZA=zoledronic acid


Joints consistency between 3 compounds

Joints …Consistency between 3 compounds?

ATAC68 months

BIG-9825.8/51 months

TEAM12 months

IES55.7 months

ARNO/IBCSG30 months

MA.1730/54 months

Lonning24 months

Gut Feeling

T<A< E,L

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.


Tamoxifen and ais safety

ATAC

Buzdar et al ASCO 2006


Debilitating musculoskeletal pain and stiffness with ais

Debilitating musculoskeletal pain and stiffness with AIs

hands, knees, feet, hips, lower back, and shoulders

R/ is NSAIDs, Analgetics, Tamoxifen

Tenosynovial changes on MRI

Leilani Morales et al.

UZ-Leuven

Breast Cancer Res Treat 2006


Tenosynovial mri changes on ais

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


Tamoxifen and ais safety

All 12 patients had enhancement

and thickening of tendon sheath

Some had fluid in tendon sheaths DFT

Some had fluid in extensor tendons, joints

Co-Morbidity &

Side effects

Poor effect of NSAIDs

Arthralgia


Tamoxifen and ais safety

PALOPRAI


Lipids vascular events poor data

Lipids & vascular eventsPoor data

ATAC68 months

BIG-9825.8/51 months

IES55.7 months

ARNO/IBCSG30 months

MA.17*30/54 months

Lonning24 months


Tamoxifen cardio vascular

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-events

IBIS-1

STAR: Raloxifene less thrombogenic


Ais and lipids poor reporting

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%)

But …

Letrozole upfront !?


Thrombo embolic event grade

Thrombo-embolic Event: Grade

BIG 1-98

5 year data

P < 0.001

RR = X 2

ESMO 2006


Cardio vascular disease compared with tamoxifen

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

Any Cardiac Event: Grade

BIG 1-98

51 months

P n.s.

ESMO 2006


Ischemic heart disease grade

Ischemic Heart Disease: Grade

BIG 1-98

51 months

P n.s.

ESMO 2006


Ma 17 n 5187 2 yrs letrozole vs placebo 30 months of follow up

MA.17: n= 5187 2 yrs Letrozole vs Placebo30 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/LS

occurred at 24 months on letrozole.

FDA data regarding safety of letrozole

Clin Cancer Res. 2005;11: 5671-7

J Natl Cancer Inst 2005; 97: 1262–71

“reported by patients”

* Bone subprotocol: 1.6 years of FU


Qol not different no data on change of qol compares therapies

QoL: Not differentNo data on change of QoLCompares therapies

  • ATAC: 1021 women & 2 year data

  • IES: 582 women & 2 year data

  • MA.17: 3612 women & 3 year data


Patient compliance

2372

2352

2500

1832

2000

1807

1500

350

1000

322

513

506

300

500

251

250

0

194

200

Exemestane

Tamoxifen

132

150

100

61

59

50

0

Exemestane

Tamoxifen

Patient Compliance

Reasons for withdrawing

Adverse Event/Patient Refusal

Recurrence/Death

Protocol Violation/LTFU/Other

Randomized

Completed Treatment

Withdrawn


Tamoxifen and ais safety

Tamoxifen

and the Uterus

TAGAS


Postmenopausal bleeding long term tamoxifen use

Postmenopausal Bleeding Long term tamoxifen use

  • Guidelines: consensus FGOG: Brussels ‘04

Postmenopausal Bleeding

Endometrial assessment

TVU

Endometrial Biopsy

Neven et al. Eur J Cancer 2004

Amant et al. Lancet 2005


Conclusion ais versus tam

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 bleeding

Hysterectomy rate

Polyps

Eca

DVT

PE

Stroke

Hot flashes

Other cancers

*Bioavailable oestrogens protect against cognitive decline.

Yaffe K et al. J Am Geriatr Soc 1998


Ai versus tamoxifen conclusion manageable side effects

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

Favors Exemestane

Favors Tamoxifen

Cardiovascular / Thromboembolic

IES

55 Months

E%* v T%¥, P-value

22.1 v 20.9, 0.34

All CV / TE

0.1 v 0.1, 0.69

Sudden death

9.9 v 8.6, 0.12

Ischemic cardiac

1.3 v 0.8, 0.08

MI

7.1 v 6.5, 0.44

Angina

11.3 v 11.2, 0.96

Other cardiac

1.8 v 1.8, 0.94

Heart failure

1.0 v 0.8, 0.51

PVD+

2.5 v 2.4, 0.89

CVA

1.9 v 3.1, 0.01

Thromboembolic

*N=2320, ¥N=2338

0.4

0.6

0.8

1.0

1.2

1.8

2.0

Odds ratio (99% CI)

+ PVD = Peripheral Vascular Disease


Musculoskeletal other

Favors Exemestane

Favors Tamoxifen

IES

55 months

Musculoskeletal / Other

E%* v T%¥, P-value

7.0 v 4.9, 0.003

Fracture

0.6 v 0.4, 0.29

Hip fracture

0.6 v 0.2, 0.04

Spine fracture

1.1 v 1.3, 0.52

Wrist fracture

5.0 v 3.4, 0.007

Other fracture

9.2 v 7.2, 0.01

Osteoporosis

17.5 v 14.6, 0.008

Arthritis (All types)

25.7 v 20.3, <0.001

Musculoskeletal pain

20.8 v 15.1, <0.001

Arthralgia

2.8 v 0.4, <0.001

Carpal tunnel

2.0 v 1.1, 0.01

Joint stiffness

Cramp

2.5 v 4.4, <0.001

1.2 v 0.3, 0.001

Gastric ulcer

0.4

0.6

0.8

1.0

2.0

3.0

4.0

6.0

8.0

*N=2320, ¥N=2338

Odds ratio (99% CI)

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)


Postmenopausal breast cancer mean change bmd no r tam ai

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

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%

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


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