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Tamoxifen and AIs: Safety

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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  1. Tamoxifen and AIs: Safety P. Neven et al. MBC, UZ-Leuven BBM, 13-14/10/2006

  2. 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

  3. Safety of tamoxifen ~ >20 year follow-up Safety of AIs ? I. We have some long-term follow-upData 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

  4. 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

  5. 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

  6. Tamoxifen and AIs: Safety QOL Compliance Tamoxifen AIs Uterus VTEs Bone Joints CV-disease Others…

  7. 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

  8. Bone and AIsExemestane better?Consistency between 3 compounds ATAC* 68 months BIG-98 25.8/51 months IES* 55.7 months ARNO/IBCSG 30 months MA.17* 30/54 months Lonning 24 months (*) bone subprotocol

  9. LEAP trial: Direct comparison Healthy postmenopausals McCloskey et al. ASCO 2006

  10. 5 years data Coleman et al ASCO 2006

  11. ▼ 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)

  12. Baseline T-score !

  13. 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

  14. 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

  15. 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

  16. Joints …Consistency between 3 compounds? ATAC 68 months BIG-98 25.8/51 months TEAM 12 months IES 55.7 months ARNO/IBCSG 30 months MA.17 30/54 months Lonning 24 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.

  17. ATAC Buzdar et al ASCO 2006

  18. 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

  19. 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

  20. 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

  21. PALOPRAI

  22. Lipids & vascular eventsPoor data ATAC 68 months BIG-98 25.8/51 months IES 55.7 months ARNO/IBCSG 30 months MA.17* 30/54 months Lonning 24 months

  23. 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

  24. 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 !?

  25. Thrombo-embolic Event: Grade BIG 1-98 5 year data P < 0.001 RR = X 2 ESMO 2006

  26. Cardio-Vascular DiseaseCompared with tamoxifen… • ATAC* • Ischemic disease +0.8% • Angina pectoris  +0.8% • IES • Cardiovascular +1.3% • Ischemic disease +0.5% X 2

  27. Any Cardiac Event: Grade BIG 1-98 51 months P n.s. ESMO 2006

  28. Ischemic Heart Disease: Grade BIG 1-98 51 months P n.s. ESMO 2006

  29. 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

  30. 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

  31. 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

  32. Tamoxifen and the Uterus TAGAS

  33. 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

  34. 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

  35. 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

  36. 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

  37. 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)

  38. 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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