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These slides were released by the speaker for internal use by Novartis. Risk/benefit analysis: tamoxifen vs aromatase inhibitors. Edith A Perez (Mayo Clinic, Jacksonville, FL; Mayo Foundation, Rochester, MN, USA). Tamoxifen Hot flushes Genitourinary symptoms Endometrial cancer

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risk benefit analysis tamoxifen vs aromatase inhibitors
Risk/benefit analysis: tamoxifen vs aromatase inhibitors
  • Edith A Perez
  • (Mayo Clinic, Jacksonville, FL; Mayo Foundation, Rochester, MN, USA)
adverse event profiles
Tamoxifen

Hot flushes

Genitourinary symptoms

Endometrial cancer

Thromboembolism

Favorable effects on lipids?

Reduction in baseline CVD?

Protective effect on bone

AIs

Hot flushes

Arthralgia/arthritis

Myalgia

Bone loss/fractures

vs tamoxifen

Increase in CVD & hypercholesterolemia?

Fewer gynecological symptoms

Fewer endometrial cancers

Fewer thromboembolic and DVT events (including grade 3–5)

Adverse event profiles
hot flushes reported in adjuvant ai trials
Hot flushes reported in adjuvant AI trials
  • Significant reduction vs tamoxifen with upfront AI (anastrozole, letrozole)
  • No significant reduction vs tamoxifen with sequential tamoxifen-AI therapy (exemestane, anastrozole)
  • Significant increase vs placebo with extended adjuvant letrozole

ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

gynecological symptoms endometrial cancer reported in adjuvant ai trials
Gynecological symptoms/endometrial cancer reported in adjuvant AI trials
  • Compared with tamoxifen
    • Significant reduction in vaginal bleeding, vaginal discharge, endometrial biopsies
    • Non-significant reduction in endometrial cancer
  • Compared with placebo
    • Significant reduction in vaginal bleeding

ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

thromboembolic te events reported in adjuvant ai trials
Thromboembolic (TE) events reported in adjuvant AI trials
  • Compared with tamoxifen
    • Significant reduction in TE events including venous TE, deep venous TE and SAEs
  • Compared with placebo
    • No difference in incidences of TE events or stroke/transient ischemic attack

ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

arthralgia reported in adjuvant ai trials
Arthralgia reported in adjuvant AI trials
  • In upfront and switching trials
    • All AIs associated with significant increase in arthralgia vs tamoxifen
    • AIs 5.4–36% vs tamoxifen 3.6–29%
  • In extended adjuvant setting
    • Significant increase in arthralgia vs placebo

ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

cv disease reported in adjuvant ai trials
CV disease reported in adjuvant AI trials

Within the limitations of trial methodology and cross-trial comparisons, data suggest

  • Non-significant increase in CV events: AI vs tamoxifen
    • ATAC
    • BIG 1-98
    • IES
    • ABCSG-8/ARNO
  • No difference in CV events: AI vs placebo
    • MA.17 core analysis
    • post-unblinding analysis

Letrozole is not licensed in all European countries for use in the early adjuvant setting

ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

cardioprotective effect of tamoxifen
Cardioprotective effect of tamoxifen
  • EBCTCG experience at 15 years1
    • Subset of ~15,000 women treated with 5 years of tamoxifen vs control
    • 189 vs 169 vascular deaths (tamoxifen vs control, NS)
  • 32 trials comparing tamoxifen with control group: metastatic, adjuvant, and prevention settings2
    • > 52,000 patients
    • Relative risk ratio for fatal MIs, tamoxifen vs control: 0.62 (95% CI: 0.41–0.93)

1. EBCTCG Lancet 2005;365:1687–717; 2. Braithwaite et al. J Gen Intern Med 2003;18:937–47

hypercholesterolemia reported in adjuvant ai trials
Hypercholesterolemia reported in adjuvant AI trials

Data from adjuvant AI trials suggest

  • Non-significant increase in hypercholesterolemia: AI vs tamoxifen
    • ATAC: 9% vs 3.5% (p = NR)
    • BIG 1-98: All grades: 43.5% vs 19.1% (p = NR)

Grade 1: 35.1% vs 17.3% (p = NR)

    • ITA: 9.3% vs 4.0% (p = 0.04)
    • IES: NR
    • ABCSG-8/ARNO: NR
  • No difference in hypercholesterolemia: AI vs placebo (fasting)
    • MA.17: 16% vs 16% (p = 0.79)

NR: not reported

Letrozole is not licensed in all European countries for use in the early adjuvant setting

Arimidex PI www.arimidex.com Sept 2005; Thürlimann et al.N Engl J Med 2005;353:2747–57; Coombes et al. N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Goss et al. J Natl Cancer Inst 2005;97:1262–71

differences in data capture
Differences in data capture

In BIG 1-98 cholesterol data were collected every 6 months

Simpler data collection in the ATAC trial – non-specific request to report AE

big 1 98 targeted ae cholesterol
BIG 1-98 targeted AE: cholesterol
  • All grades: 43% vs 19%
  • Measurements: 90% non-fasting, variable time of day
  • ≥ grade 1 hypercholesterolemia: any cholesterol measurement above ULN at 6-month visit
  • No central laboratory measurements
effect of letrozole vs tamoxifen on total serum cholesterol

15

Letrozole

Tamoxifen

10

Total cholesterol (mmol/L*)

5

0

18

60

0

6

12

42

48

54

30

36

24

Months

Let 3209

Tam 3226

2606

2599

2660

2671

2546

2588

2264

2255

1716

1679

1253

1226

863

831

698

695

527

519

6

25

Effect of letrozole vs tamoxifen on total serum cholesterol†

Cholesterol values remained stable in the letrozole arm and decreased in the tamoxifen arm by ~12%

*To convert mmol/L to mg/dL, multiply by 39

Perez E. Personal communication

lipid lowering effect of tamoxifen
Lipid lowering effect of tamoxifen?
  • Yes
    • Tamoxifen studies
      • 10 trials, 6 vs placebo; 657 patients
      • Decrease in cholesterol seen in all studies
      • Median decrease: 12.5% (range 3–17)
      • Decrease due to LDL cholesterol

Herrington & Klein Womens Health Issues 2001;11:95102

effect of ai on lipid levels vs placebo
Effect of AI on lipid levels vs placebo
  • ATENA1 and MA.17 lipid substudy2
    • Increase in serum cholesterol observed 6 months after tamoxifen discontinuation
    • No relevant difference between two treatment groups for any lipid parameters
  • LEAP study3 (early results)
    • Anastrozole (n = 29), exemestane (n = 32) and letrozole (n = 29) have similar, non-detrimental effects on serum lipids in postmenopausal women
  • Conclusion
    • AIs lack the lipid-lowering effects of tamoxifen

1. Markopoulos et al. Anticancer Drugs 2005;16:879–83; 2. Wasan et al. Ann Oncol 2005;16:707–15

3. McCloskey et al. Breast Cancer Res Treat 2005;94:(abstract 2052)

osteoporosis fractures reported in adjuvant ai trials
Osteoporosis/fractures reported in adjuvant AI trials
  • Compared with tamoxifen
    • Upfront trials: significant increase in osteoporosis and/or fractures
    • Switching trials: significant increase in osteoporosisSignificant increase or trend for increase in fractures
  • Compared with placebo
    • Significant increase in new patient-reported osteoporosis
    • No significant increase in fracture rate

ATAC Trialists’ Group Lancet 2005;365:60–2; Thürlimann et al.N Engl J Med 2005;353:2747–57;Coombes et al.N Engl J Med 2004;350:1081–92; Jakesz et al.Lancet 2005;366:455–62; Boccardo et al. J Clin Oncol 2005;23:5138–47;Goss et al. J Natl Cancer Inst 2005;97:1262–71; Mincey & Perez ASCO Edu Book 2005;27–34

management of aes bone loss osteoporosis and fractures
Management of AEs Bone loss, osteoporosis and fractures
  • Tamoxifen protects against bone loss in postmenopausal women
  • HRT – contraindicated in patients with BC
  • Routine monitoring, calcium/vitamin D supplements
  • Bisphosphonates prevent bone loss
    • Efficacy differs between agents
    • Early generation oral bisphosphonates often poorly tolerated
    • CTIBL more rapid than ‘natural’ postmenopausal bone loss – may need more potent IV agents

CTIBL, cancer treatment-induced bone loss

HRT, hormone replacement therapy

z fast zo fast and e zo fast

Letrozole + upfront ZOL

Letrozole + delayed ZOL

Overall difference

p value

Mean D in BMD(total hip)

+1.40%

-2.10%

3.50%

< 0.001

Z-FAST, ZO-FAST and E-ZO-FAST

RANDOMIZE

Upfront zoledronic acid 4 mg q 6 months

+ Letrozole (2.5 mg/day) x 5 years

Delayed* zoledronic acid 4 mg q 6 months

+ Letrozole (2.5 mg/day) x 5 years

BMD at 12 months1

Accrual completed: ZO-FAST, n = 1066; Z-FAST, n = 602; E-ZO-FAST: n = 500

*Initiation of zoledronic acid determined by post-baseline BMD

1. Brufsky et al. J Clin Oncol 2005;23:12s(abstract 533)

ncctg n03cc
NCCTG N03CC

Upfront or delayed bisphosphonate for women receiving letrozole after tamoxifen

Inclusion criteria

  • Postmenopausal
  • Prior tamoxifen
  • T-score ≥ -2.0 SD

(n = 550)

RANDOMIZE

Upfront zoledronic acid 4 mg q 6 months

Delayed* zoledronic acid 4 mg q 6 months

Letrozole x 5 years Calcium, vitamin D (all patients)

*Initiation of zoledronic acid determined by post-baseline BMD T-score < -2.0 SD 10/05: enrollment complete; PI: BA Mincey

asco bone health guidelines
ASCO bone health guidelines
  • BMD screening in breast cancer
    • All women aged > 65 years
    • All women aged 60–64 years with risk factors
    • Postmenopausal women of any age receiving AIs
    • Premenopausal women with medical/surgical premature menopause
  • Repeat BMD annually after initial exam
  • Treatment
    • T-Score > -1.5: lifestyle, reassurance
    • T-Score -1.5 to -2.5: calcium, vitamin D
    • T-Score <-2.5: bisphosphonates

Hillner et al.J Clin Oncol 2003;21:4042–57

effect of ais on qol
Effect of AIs on QoL
  • Censoring at recurrence may underestimate QoL advantage of AIs
  • No significant adverse effects of AIs on QoL reported in adjuvant trials to date
    • AI vs tamoxifen: anastrozole (ATAC), exemestane (IES)
    • AI vs placebo: letrozole (MA.17)

Fallowfield et al.J Clin Oncol 2004;22:4261–71; Fallowfield et al.J Clin Oncol 2006;24:910–17;

Whelan et al.J Clin Oncol 2005;23:6931–40

adverse event profiles conclusions
Adverse event profilesConclusions
  • Tamoxifen associated with thromboembolic and gynecological events
  • AIs generally well tolerated but associated with some bone loss and arthralgia
    • Tamoxifen protects against postmenopausal bone loss
    • Routine monitoring, calcium/vitamin D supplements can minimize fracture risk in most patients
    • Bisphosphonates can prevent AI-associated bone loss
  • Further investigation of effects on cardiovascular system and lipid metabolism
    • Beneficial effects of tamoxifen
    • No increase in cardiovascular disease or hypercholesterolemia, letrozole vs placebo (MA.17)
  • AEs associated with AIs generally more preventable or manageable than AEs associated with tamoxifen