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P Pronzato

P Pronzato. Endocrine resistance. Eterogeneity of HR+ tumors. Kaplan-Meier Survival Estimates of Relapse-free Survival and Overall Survival among the 225 Patients with ER+ Disease ,. Fan C et al. N Engl J Med 2006;355:560-569.

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P Pronzato

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  1. P Pronzato

  2. Endocrine resistance

  3. Eterogeneity of HR+ tumors

  4. Kaplan-Meier Survival Estimates of Relapse-free Survival and Overall Survival among the 225 Patients with ER+ Disease, Fan C et al. N Engl J Med 2006;355:560-569

  5. Classification of Tumor Samples from the 225 Patients with ER+ Disease, According to the Model Used Fan C et al. N Engl J Med 2006;355:560-569

  6. Classification of Tumor Samples from the 225 Patients with ER+ Disease, According to the Model Used Fan C et al. N Engl J Med 2006;355:560-569

  7. Tamoxifen resistance

  8. Tamoxifen resistance 1 A Milano, Eur J Cancer 2006

  9. Tamoxifen Resistance 2 A Milano, Eur J Cancer 2006

  10. Tamoxifen Resistance 3 A Milano, Eur J Cancer 2006

  11. Tamoxifen Resistance 4 A Milano, Eur J Cancer 2006

  12. Tamoxifen resistance • Causes • Perturbationof ER coregulatoryproteins • Cross-talkbetween ER and HER-2 and EGFR pathways and/or their downstream effectors • Cross-talkbetween ER and IGF-IR • Emergence • De Novo • Acquired

  13. Tamoxifen resistance • Causes • Perturbationof ER coregulatoryproteins • Cross-talkbetween ER and HER-2 and EGFR pathways and/or their downstream effectors • Cross-talkbetween ER and IGF-IR • Emergence • De Novo • Acquired

  14. OvercomingTamoxifenResistance

  15. The action and reaction model Dependence on multiple different estrogen independent pathways Normanno et al 2005

  16. Adjuvant pretreatments • Tamoxifen alone in premenopause • Tamoxifen + LHRHa • NSAI alone • 2 or 3-year Tamoxifen  NSAI or SAI • 5-year Tamoxifen  NSAI

  17. PREMENOPAUSE

  18. Hormonotherapy of metastatic breast cancer- Premenopause

  19. POSTMENOPAUSETamoxifen Sensitive

  20. Randomized phase III studiesof anti-Aromatase Agents vs Tamoxifenas Initial Therapy of Metastatic Breast Cancer Anastrozole Anastrozole Letrozole Exemestane Patients, N 170 vs 182 340 vs 328 453 vs 454 182 vs 189 OR, % 21 vs 17 33 vs 33 30 vs 20* 46 vs 31* Clin. Benefit, % 59 vs 46* 56 vs 56 49 vs 38* 66 vs 49* Med. PFS, mo 11 vs 6* 8 vs 8 9 vs 6* 10 vs 6* ER unknown, % 11 vs 11 56 vs 54 34 vs 33 15 vs 11 Significantly different from Tamoxifen (*) Nabholtz et al. J Clin Oncol. 2000;18:3758-3767; Bonneterre et al. J Clin Oncol. 2000;18:3748-3757; Mouridsen et al. J Clin Oncol. 2001;19:2596-2606; Mouridsen et al. Breast Cancer Res Treat. 2001;69:211, abst 9;

  21. POSTMENOPAUSETamoxifen Resistant

  22. Anti-aromatase agents vs megestrol acetate (MA): pivotal trials Study design: Multicentre, international, Phase III Eligibility: MBC, postmenopausal status Failure of prior tamoxifen therapy R A N D O M R Letrozole 0.5 mg po qd A N Letrozole 2.5 mg po qd D O Exemestane25 mg po qd MA 40 mg po qid M I S R A N D O M Anastrozole 1 mg po qd MA 40 mg po qid A T Anastrozole 10 mg po qd I O MA 40 mg po qid N

  23. Anti-aromatase agents vs MA:results Exemestane 25 mg vs MA Anastrozole 1 mg vs MA Letrozole 2.5 mg vs MA No patients 366 vs 403 263 vs 253 174 vs 189 CR + PR EXE=MA AN=MA LET>MA TTP EXE>MA AN=MA LET=MA Survival EXE>MA AN>MA (pooled data) LET=MA Patients received tamoxifen for adjuvant or metastatic disease

  24. Anti-aromatase agents vs MA:results Exemestane 25 mg vs MA Anastrozole 1 mg vs MA Letrozole 2.5 mg vs MA No patients 366 vs 403 263 vs 253 174 vs 189 CR + PR EXE=MA AN=MA LET>MA TTP EXE>MA AN=MA LET=MA Survival EXE>MA AN>MA (pooled data) LET=MA Patients received tamoxifen for adjuvant or metastatic disease

  25. RANDOMIZE Letrozole 2.5 mg Postmenopausal women with ER/PgR+ or unknown metastatic breast cancer who have progressed on TAM Anastrozole 1 mg Letrozole vs Anastrozole in Second-Line Treatment of MBC: FEM-INT-01 Enrollment: Open-label • Recruited from 105 centers in 19 countries • 713 patients entered the trial Anastrozole n=357 Letrozole n=356 Data collection stopped at visit 12 (30 months) End Points TTP ORR Response Duration Survival

  26. Letrozole vs Anastrozole:Response Rate Letrozole 19.1% Anastrozole 12.3% *P=0.013

  27. Fulvestrant Pivotal Phase III Trial Design Postmenopausal women with advanced breast cancer receiving prior endocrine treatment for early or advanced breast cancer Trial 0020: International, randomized 1:1, open, parallel-group Trial 0021: North American, randomized 1:1, double-blind, double-dummy, parallel-group Anastrozole 1mg daily orally Trial 0020: (n=229) Trial 0021: (n=194) Fulvestrant 250mg i.m. once monthly Trial 0020: 1 x 5ml (n=222) Trial 0021: 2 x 2.5ml (n=206) Analysis after 340 events(progression or death prior to progression)

  28. 1.0 Median TTP: Fulvestrant 5.5 months Anastrozole 4.1 months 0.9 0.8 Median follow-up 15.1 months 0.7 Fulvestrant 250mg 0.6 Anastrozole 1mg Proportion not progressed 0.5 0.4 0.3 0.2 0.1 0.0 0 6 12 18 24 30 36 Time to progression (months) Fulvestrant (‘Faslodex’): Prospective Combined Analysis — Time to Progression Hazard ratio (95.14% CI): 0.95(0.82–1.10); p=0.48 Robertson JFR et al. Cancer 2003; 98: 229–238.

  29. Fulvestrant (‘Faslodex’): Prospective Combined Analysis - Best Objective Response Number of patients (%) Fulvestrant(n=428) Anastrozole(n=423) Complete response (CR) Partial response (PR) Objective response (CR+PR) 20 (4.7) 11 (2.6) 62 (14.5) 59 (13.9) 82 (19.2) 70 (16.5)* Stable disease ³24 weeks Clinical benefit (CR+PR+SD ³24 weeks) 104 (24.3) 103 (24.3) 186 (43.5) 173 (40.9) *Odds ratio (95.14% CI):1.21 (0.84–1.74); p=0.31 Robertson JFR et al. Cancer 2003; 98: 229–238.

  30. 0.35 0.30 0.25 Fulvestrant 250mg 0.20 Anastrozole 1mg Proportion responding 0.15 0.10 0.05 0.00 0 18 12 24 30 36 40 6 Duration of response (months) Fulvestrant (‘Faslodex’): Kaplan–Meier Estimates for DoR from Onset of Response to Disease Progression (all randomised patients) Ratio of average response durations = 1.30; 95%CI 1.13–1.50; p<0.01 Robertson JFR et al. Cancer 2003; 98: 229–238.

  31. POSTMENOPAUSEPrior Aromatase Inhibitor

  32. Tamoxifen Non-steroidal AI Steroidal AI Agents after Progression on Tam and a Non-steroidal AI Exemestane(n=105) CB 20%1 Exemestane(n=30) CB 43%2 Formestane(n=20) *CB 55%3 *55% of patientsreceived tamoxifen CB = clinical benefit 1Lønning PE et al. J Clin Oncol 2000; 18: 2234–2244 2Carlini et al. Ann Oncol 2002; 13 (Suppl 5): 48, Abstr 171P 3Carlini et al. Ann Oncol 2001; 12: 1539–1543

  33. Sequences of Aromatase Inhibitors • CB with Exemestane in 43.5% of pts progressing on NSAI • CB with NSAI in 55.6% of pts progressing on Exemestane G Bertelli, Oncology 2005

  34. Fulvestrant Following Failure of Tamoxifen and an AI (SAKK) • Phase II, multicentre trial • Postmenopausal patients Faslodex (n=36) CB 34% Tamoxifen AI Perey L et al. Breast Cancer Res Treat 2002; 76 (Suppl 1): S72

  35. A Phase II trial of the the NorthCentral Cancer Treatment Group • Postmenopausal women with ER and/or PgR +ve breast cancer • Disease progression following a third-generation AI • No more than one additional prior hormonal therapy Eligibility criteria Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409

  36. Efficacy Prior treatment Total(n=77) AI alone(n=21) AI + tamoxifen(n=56) PR SD 6 months CB rate 10 (13)* 15 (19) 32% 5 (24)* 6 (29) 52% 5 (9)* 9 (16) 25% * median duration of 10 months (range 2-20 months) • Median time to disease progression: 3 months • 1-year progression-free rate: 16.4% (95% CI 9.6–28.2) • Median survival: 21 months • 1-year survival rate: 70.4% (95% CI 60.5–82.0) Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409

  37. AI(n=22) CB 50%2 Faslodex Faslodex Efficacy of AI after Progression on Faslodex AI(n=46) CB 41%1 Tamoxifen CB = clinical benefit 1Vergote I et al, Breast Cancer Res Treat 2003; 79: 207–211. 2Howell A, Robertson J. Ann Oncol 2002; 13 (Suppl 5): 48, Abstr 173P.

  38. 500 mg Day 1, 250 mg Day 14 & 28, and monthly Prior non-steroidal AI failure Fulvestrant loading dose + placebo for exemestane (n=330) Exemestane 25 mg orally daily + placebo for fulvestrant (n=330) Progression Progression Survival Survival 138 centres worldwide 693 women randomised from Aug 2003-Nov 2005 Analysis after 580 events (progression or death)

  39. Demographic characteristics Median age RaceCaucasianBlackOrientalOther Metastatic sitesBoneLungLiver Fulvestrantn=351 63 years Exemestanen=342 63 years 89.2%3.1%1.1%6.6% 67.2%34.5%31.1% 91.2%3.8%1.2%3.8% 66.4%36.3%32.2%

  40. Time to progression (ITT) Median (months) Fulvestrant 3.7 Exemestane 3.7 Proportion of patients progression-free 1.0 HR = 0.963, 95% CI (0.819, 1.133), p=0.6531 Cox analysis, p=0.7021 0.8 0.6 Fulvestrant Exemestane 0.4 0.2 0.0 0 3 6 9 12 15 18 21 24 27 Months At risk: Fulvestrant Exemestane 351 195 96 50 25 12 4 2 0 0 342 190 98 41 21 12 8 6 1 0

  41. Objective response and clinical benefit rate (evaluable for response population) OR rate (CR + PR) CB rate (OR + SD ≥24 wks) Fulvestrant 7.4% (20/270) 32.2% (87/270) Exemestane 6.7% (18/270) 31.5% (85/270) Odds ratio*(95% CI) 1.120 (0.578, 2.186) 1.035 (0.720, 1.487) p-value 0.7364 0.8534 * Analyses are not adjusted for baseline covariates

  42. Duration of response (from randomisation) Median (months) Fulvestrant 13.5 Exemestane 9.8 Proportion of patients responding 1.0 0.8 0.6 0.4 0.2 Fulvestrant Exemestane 0.0 0 3 6 9 12 15 18 21 24 27 Months At risk: Fulvestrant Exemestane 20 20 16 11 8 3 0 0 0 0 18 18 15 10 5 4 3 3 3 3

  43. Duration of clinical benefit Median (months) Fulvestrant 9.3 Exemestane 8.3 Proportion of patients progression-free 1.0 0.8 0.6 0.4 0.2 Fulvestrant Exemestane 0.0 0 3 6 9 12 15 18 21 24 27 Months At risk: Fulvestrant Exemestane 87 87 71 40 20 10 3 1 1 0 85 85 69 28 14 10 6 5 1 0

  44. Forest plot – TTP Receptor status ER+ & PgR+ Not ER+ & PgR+ Visceral involvement With Without AI sensitive / resistant Sensitive Resistant Measurable disease Yes No Age <65 years 65 years No. of prior 1 Prior hormonal treatments 2 Prior All patients 0.40 0.60 0.80 1 1.25 1.5 1.75 Hazard Ratio (Fulvestrant vs Exemestane) and 95% CI

  45. Adverse events Patient had an AE Drug-related AE Withdrawal due to AE AE of grade 3 or higher Serious AE Drug-related SAE Death due to AE Death due to drug-related AE Fulvestrantn=351 Exemestanen=340 88.9% 45.9% 2.0% 21.7% 11.4% 1.1% 0.9% 0% 88.8% 48.8% 2.6% 22.6% 12.4% 0.6% 0.9% 0%

  46. 40 35 30 25 Predicted concentration (ng/ml) 20 15 10 5 0 0 28 56 84 112 140 168 196 224 Time (day) Population pharmacokinetic profile (EFECT) Fulvestrant loading dose Fulvestrant 250 mg/month

  47. Conclusions • It is the first phase III study to confirm endocrine treatment options post-non-steroidal AI • Similar efficacy seen on both treatment arms • No differences were seen in reported AEs between fulvestrant and exemestane • Confirmed efficacy of fulvestrant in patients who have progressed on a NSAI BUT NOT SUPERIORITY to Exemestane

  48. Strategie di trattamento sequenziale Opzione 1 Tamoxifen Adiuvante I^ Linea Fulvestrant AI II^ Linea AI Fulvestrant Exemestane III^ Linea Exemestane Exemestane Fulvestrant IV^ Linea MAP ?

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