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Aromatase Inhibitors in Breast Cancer

Aromatase Inhibitors in Breast Cancer. Development of Aromatase Inhibitors: Activity Profiles. Toxicity. Specificity. Potency. First generation. Rash, etc. - Aminoglutethimide*. 1. Second generation. - Fadrozole - 4-OHA. 100. Third generation. - Anastrozole - Exemestane

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Aromatase Inhibitors in Breast Cancer

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  1. Aromatase Inhibitors in Breast Cancer

  2. Development of Aromatase Inhibitors: Activity Profiles Toxicity Specificity Potency First generation Rash, etc. - Aminoglutethimide* 1 Second generation - Fadrozole - 4-OHA 100 Third generation - Anastrozole - Exemestane - Letrozole No adrenal insufficiency, etc. 500 to 10,000 *No approved indication for breast cancer in the United States.

  3. Case #1 • Clinical presentation • 63 year-old postmenopausal woman • 3 cm. lump detected in upper outer quadrant of left breast • Ipsilateral axilla clinically negative • Remainder of physical exam normal / ECOG 0 • No significant co-morbidities • Risk factors • HRT x 9 years • No family history • No prior breast abnormalities

  4. Work Up • Lumpectomy + ALND • 3.2 cm Grade 3/3 infiltrating ductal carcinoma • Resection margins clear • 4/12 nodes positive • ER+, PgR–, and HER2– • CXR, bone scan, Abdominal CT negative • Laboratory profile is normal

  5. Prognosis • 32.5% probability of living @ 10 yrs • 60% probability of cancer death • 7.5% probability of non cancer death • Absolute benefit of chemotherapy 10% • Absolute benefit of hormonal therapy 11% • Absolute benefit of combined therapy 21%

  6. Post-operative Management Stop HRT CA X 4  Paclitaxel X 4 Local Radiation Therapy Adjuvant Endocrine Therapy • ? Tamoxifen • ? Aromatase Inhibitor • how long • which inhibitor

  7. Case #2 • Clinical presentation • 75 year-old postmenopausal woman • Mammographically-detected right-sided suspicious calcifications • Physical exam normal / ECOG 1 • Risk factors • Past history of postmenopausal vaginal bleeding • Endometrial polyp with atypia

  8. Work Up • Core biopsy reveals infiltrating lobular carcinoma • Wire localization excision + SLND • 1.2 cm grade 2/3 tumor with clear margins • 0 nodes positive • ER+, PgR+, and HER2– • CXR negative • Laboratory profile negative

  9. Prognosis • 65% probability of living @ 10 yrs • 7% probability of cancer death • 28% probability of non cancer death • Absolute benefit of chemotherapy 1% • Absolute benefit of hormonal therapy 2% • Absolute benefit of combined therapy 3%

  10. Post-operative Management Local Radiation Therapy Adjuvant Endocrine Therapy • Tamoxifen • ? Aromatase Inhibitor • how long • which inhibitor

  11. 1998 Overview: Effectiveness Of Adjuvant Therapy On Breast Cancer Mortality Tam Chemo Combined < 50 ER+ 25% 25% 45% ER- 0% 35% -- > 50 ER+ 25% 10% 35% ER- 0% 20% --

  12. Risk Reduction in Early Breast Cancer in Estrogen ReceptorPositive Patients Mortality From Any Cause Recurrence as First Event 100 100 91.8 Tamoxifen (~5 y) Tamoxifen (~5 y) 87.4 90 90 89.3 Control Control 78.9 79.2 80.1 80 80 74.9 Tamoxifen (~5 y) Tamoxifen (~5 y) Node -ve 73.3 Node -ve 70 70 75.6 Control Control 64.3 74.2 61.4 60 60 59.7 Node +ve 58.3 Node +ve % Alive 50 50 % Recurrence-free 50.5 40 40 44.5 30 30 Absolute Mortality Reduction Absolute Recurrence Reduction Node -ve: 5.6% SD 1.3: 2P<0.00001 Node +ve: 10.9% SD 2.5: 2P<0.00001 20 20 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 10 10 0 0 0 5 10+ 0 5 10+ Years Years Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451.

  13. NSABP B-14 Trial: 10 Years of Tamoxifen vs Stopping Placebo 100 P=0.03 Tamoxifen 80 Disease-free survival (%) 60 Patients re-randomized after 5 years of tamoxifen 40 0 1 2 3 4 Year after second randomization Number at Risk TAM 570 560 433 250 176 Stop583 567 411 251 163 Fisher et al. J Natl Cancer Inst. 2001;93:684.

  14. Rationale for Aromatase Inhibitors in Adjuvant Therapy • Mortality is reduced by only ~ 1/4 by Tamoxifen • Aromatase inhibitors • Effective after Tamoxifen • May be superior to Tamoxifen first-line • Well tolerated • Low risk of endometrial carcinoma, thromboembolic events

  15. Potential Risks: Vasomotor Urogenital Bone Lipid Cognitive ? Other Potential Benefits: Inhibit breast cancer Fewer endometrial cancers Less thromboembolism Potential Considerations in Evaluating Aromatase Inhibitors in the Adjuvant Setting

  16. Clinical Trial Strategies in Adjuvant Therapy with Aromatase Inhibitors TAMOXIFEN ANASTROZOLE ATAC LETROZOLE EXEMESTANE ARNO PLACEBO MA-17 BIG 1-98(BIG FEMTA) ICCG Study 96 NSABP B33 TEAM

  17. Postmenopausal women with invasive breast cancer â Completion of primary therapy* â Randomization 1:1:1 for 5 years å æ â Anastrozole placebo+Tamoxifen 20mg od Anastrozole 1mg od+Tamoxifen placebo Anastrozole 1mg od+Tamoxifen 20mg od + â Regular follow-up monitoring adverse events â Trial endpoints ATAC Trial Design * Surgery + radiotherapy + chemotherapy (Patients may start trial therapy while still receiving radiotherapy)

  18. ATAC Update SABCS 2002 • Median follow up: 47 months • Median duration of therapy: 37 months • Number of events: 1373 • Patients receiving >3 yrs of Rx: ~50% • Breast cancer event rate (%): • Yr. 1: A=2.49 T=2.30 HR=1.08 • Yr. 2: A=2.61 T=4.28 HR=0.61 • Yr. 3: A=2.94 T=3.72 HR=0.77 Bianco, et al. SABCS 2002,#632

  19. First Events in Overall Population Anastrozolen=3125 (%) Tamoxifenn=3116 (%) First event 413 (13.2) 472 (15.1) Locoregional recurrence 84 (2.7) 101 (3.2) Distant recurrence 195 (6.2) 222 (7.1) Contralateral (invasive) 20 (0.6) 35 (1.1) Contralateral (DCIS) 5 (0.2) 5 (0.2) Death (non-breast cancer) 109 (3.5) 109 (3.5)

  20. 20 15 Anastrozole Tamoxifen 10 5 AbsoluteDifference2.6% AbsoluteDifference 1.8% 0 Probability of Recurrence inReceptor-positive Population HR 95% CI p-value AN vs TAM 0.78 0.65–0.93 0.007 Proportion with recurrence (%) 0 0 6 12 18 24 30 36 42 48 54 No. of Pts. at risk Time to event (months) AN TAM 2617 2598 2533 2516 2436 2386 2243 2180 1258 1210 602 574 * Censoring non-BC deaths before recurrence

  21. 4-yearrecurrence-free rate: 92.2% 89.6% Comparison of ATAC data with EBCTCG 1995 Overview1: Receptor-positive Patients >50 Years 100 90 Estimated % without recurrence 80 70 0 years 0 1 2 3 4 5+ 1Lancet 1998;351: 1451–1467 Control (EBCTCG) Tamoxifen (EBCTCG) Anastrozole (ATAC) Tamoxifen (ATAC)

  22. Receptor status +ve –ve Nodal status 0 1–3 4+ Previous chemo no yes Time to Recurrence by Subgroups 0.30 0.40 0.60 0.80 1.00 1.25 1.50 2.00 In favour of Anastrozole In favour of Tamoxifen Hazard ratio (AN/TAM)

  23. ATAC Trial:Adverse Events In favor of anastrozole In favor of tamoxifen Hot flushes -5.4% 6.6% MSK disorders Weight gain* -1.8% 2.1% Fractures 0.8% Fractures of hip,spine, wrist Vag. bleeding -3.6% Vag. discharge -8.6% Endo ca -0.4% ICVA -1.1% VTE -1.4% DVT -0.7% -10 -5 0 5 10 Difference between anastrozole and tamoxifen AEs (%) *Proportion with ³10% gain in body weight from baseline to year 2. Baum et al. San Antonio Breast Cancer Symposium. 2001.

  24. ATAC Trial: Bone Mineral Density A (80) T(87) Comb.(82) Cont.(39) % change @ 1 yr LS Spine -2.59 1.01 0.21 -.36 Femur -1.68 0.48 0.78 -.13 Eastell R. ESMO. 2002

  25. Lipid Effects of Aromatase Inhibitors • Anastrazole (n=1,021) LDL • Letrozole (n=20) TC, LDL, HDL • Exemestane (n=76) TG TC, HDL,TC/HDL ratio unchanged

  26. Summary of ASCO Panel Consensus • Results of ATAC are preliminary • 5 years of Tamoxifen remains standard • There is no reported survival advantage with anastrozole • All 3 AI’s are generally comparable in MBC, the only data in adjuvant setting is with Arimidex • Use Arimidex if Tamoxifen contraindicated, have already received Tamoxifen (?raloxifene) or significant side effects with Tamoxifen

  27. Case #3 • 70 years old with performance status 0 • Presents with 7 cm mass in right breast that has been present for > one year • Biopsy reveals ER+, PgR+, HER2– breast cancer • CT reveals a single liver metastasis • Bone scan + with several areas of uptake

  28. Treatment Options • Tamoxifen • Anastrozole • Letrozole • Exemestane • Chemotherapy

  29. Third-Generation AIs in First-Line Studies Tamoxifen 20 mg RANDOMIZE • Third-generation AIs • Anastrozole 1 mg or • Letrozole 2.5 mg or • Exemestane 25 mg

  30. Indirect Comparison of AI’s and Tamoxifen Phase III First-Line Data Letr. Tam. Anast. Tam. Exem. Tam Patients(n) 294 305 305 306 31 32 TTP(mo) 9.7 6.0 10.7 6.4 8.9 5.2 Survival(mo) 34 30 NR NR NR NR

  31. 99% of patients crossed over by 36 months Initial therapy: Letrozole Tamoxifen Letrozole vs Tamoxifen Overall Survival 2 yr. survival rate 1-yr. survival rate Overall Survival 100 Letrozole 83% 64% 35 mo 90 Tamoxifen 75% 58% 32 mo 0.8 P 0.004 0.02 (log-rank test) 0.514 0.7 0.6 0.5 Kaplan-Meier Estimate (%) 0.4 0.3 0.2 0.1 0.0 0 1 2 3 4 5 Years Mouridsen et al. J Clin Oncol. 21:2101-2109, 2003.

  32. Letrozole vs Tamoxifen: Time to Chemotherapy 1.0 Median time to chemotherapy Letrozole 16 moTamoxifen 9 mo P=0.005 (log-rank test) 0.9 0.8 0.7 0.6 0.5 Kaplan-Meier estimate 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 42 48 54 60 Months Initial therapy: Letrozole (n=453) Tamoxifen (n=454) Mouridsen et al. J Clin Oncol. 21:2101-2109, 2003.

  33. Anastrazole v Tamoxifen as First Line Therapy in MBC. (#255 SABCS 2002. Thuerlimann et al, Switzerland) • Swiss patients enrolled in protocol 027 • 60 pts: ER/Pr +: 56, 4 unknown A (31) T (29) TTP 1st line 11.3 mo 8.3 mo TTP 2nd line 6mo 6mo Total TTP 28.2mo 19.5 mo* *p=.36 (18) (19)

  34. Exemestane After Failure of Nonsteroidal AI’s • Phase II trial • N= 241 • Prior therapies • aminoglutethimide, letrozole, anastrazole, vorozole • Rx: Exemestane 25 mg daily Lonning et al. JCO.11:2234, 2000

  35. Exemestane After Failure of Nonsteroidal AI’s • OR n (%) 16 (6.6) • CR n (%) 3 (1.2) • PR n (%) 13 (5.4) • SD (>6mo) (%) 42 (17.4) • Clinical benefit 74 (24.3) Lonning et al. JCO.11:2234, 2000

  36. GONO-MIG 8: Sequential Use of AI’s in Metastatice Breast Cancer A Letrozole or anastrazole No Prior AI Exemestane B Letrozole or anastrazole Prior Exemestane C Prior letrozole or anastrazole Exemestane Bertelli, ASCO 2002.238

  37. GONO-MIG 8: Sequential Use of AI’s in Metastatice Breast Cancer EL/A L/AE A (32) B(10) C(24) PR n (%) 6 (18.4) 1(10) 1(4.2) SD>6mo 9 (28.1) 3(30) 5(20.8) Clin. Benefit 15(46.9) 4(40) 6(25) Bertelli, ASCO 2002.238

  38. Randomized Trials of AIs in First Line Setting : Conclusions • The aromatase inhibitors (anastrazole, letrozole, exemestane) are at least as effective as tamoxifen • TTP favors AI in all trials • Survival data reported only for letrozole • No direct comparisons available • Optimal sequence not clear

  39. Category P Value Letrozole Tamoxifen Odds Ratio Let vs Tam ErbB1/2+ ER+ 15/17 (88%) 4/19 (21%) 28 (4.5-177) 0.0004 Neoadjuvant Femara vs. Tamoxifen: Response by ErbB1+ and ErbB2+ Category Analysis on ER positive and/or PgR positive cancers only ErbB1/2– ER+ 55/101 (54%) 42/100 (42%) 1.7 (0.9-2.9) 0.078 Ellis MJ et al. J Clin Oncol. 19:3808-3816, 2001.

  40. P R E V E N T I O N Adjuvant Tamoxifen Or Anastrazole First line Nonsteroidal AI or SERD or Tam Second line SERD Or Steroidal AI Third line Steroidal AI Or MA Tamoxifen Breast Cancer-2003Sequential Use of Hormones R E S I S T A N C E

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