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Adjuvant therapy of HER2 positive early breast cancer The Evidences

Adjuvant therapy of HER2 positive early breast cancer The Evidences. Antonio Frassoldati Oncologia Clinica - Ferrara. Evidences on adjuvant trastuzumab are based on randomized trials in over 14,000 women . S= sequential; C= concomitant

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Adjuvant therapy of HER2 positive early breast cancer The Evidences

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  1. Adjuvant therapy of HER2 positive early breast cancerThe Evidences Antonio Frassoldati Oncologia Clinica - Ferrara

  2. Evidences on adjuvant trastuzumab are based on randomized trials in over 14,000 women S= sequential; C= concomitant * Early release after second interim analysis (arm A, B) and first interim analysis (arm B,C)

  3. Paclitaxel q3w x 4 AC q3w x 4 Paclitaxel x 4, H qw x 52 Carboplatin + Docetaxelq3w† x 6 H qw x 18, q3w x 12 Main trial designs of adjuvant Trastuzumab NSABP B-31 Node positive Paclitaxel qw x 12 N9831 Node pos/neg HR Paclitaxel qw x 12 H qw x 52 AC q3w x 4 Paclitaxel qw x 12, H qw x 52 BCIRG 006 Node pos/neg HR AC q3w x 4 Docetaxelq3w x 4 Docetaxelq3w x 4 AC q3w x 4 H qw x 12, q3w† x 14 HERA Chemotherapy (any) Node pos/neg HR Chemotherapy (any) H qw x 52 Chemotherapy (any) H qw x 104

  4. Main research questions in trials of adjuvant trastuzumab • Does trastuzumab reduce the rate of recurrence (and death)? (All) • Does the schedule of trastuzumab administration matter? (N9831, BCIRG006) • Does the duration of trastuzumab matter? (HERA) • Does the chemotherapy regimen influence the activity and safety of trastuzumab? (BCIRG006)

  5. Cross-comparison among the trials of adjuvant trastuzuamb ° Pts in HERA trial were randomized after the end of adjuvant therapy

  6. B31/N9831Efficacy results Relapse HR 0.52 (0.45-0.60) Perez, JCO 2011

  7. B31/N9831Efficacy results Death HR 0.61 (0.50-0.75) Perez, JCO 2011

  8. HERA: DFS and overall survival over time Median follow-up (% follow-up time after selective crossover) Median follow-up (% follow-up time after selective crossover) No. of DFS eventsH 1 year vs. observation No. of deathsH 1 year vs. observation DFS benefit OS benefit 200511 year(0%) 200511 year (0%) 127 vs. 220p<0.0001 29 vs. 37p=0.26 200622 years(4.1%) 200622 years (4.3%) 59 vs. 90p=0.0115 218 vs. 321p<0.0001 200834 years (33.8%) 200834 years(30.9%) 182 vs. 213p=0.1087 369 vs. 458p<0.0001 0 1 2 0 1 2 Favourstrastuzumab Favours notrastuzumab Favourstrastuzumab Favours notrastuzumab HR HR 1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 2011

  9. HERA - Observation patients by status on 16 May 2005 1698 patients originally randomised to observation 1354 patients alive and disease free 344 patients DFS event or lost to follow-up198 alive post DFS event 2005 16 May 469 patients remained on observation 344 patients ineligible for crossover 885 patients crossed over to trastuzumab Gianni, Lancet Oncol 2011

  10. HERA - DFS (landmark analysis): selective crossover and no crossover 100 80 60 Patients alive and disease free (%) 40 HR 0.68 (0.51-0.90) p=0.0077 20 Selective crossover*No crossover 0 0 6 12 18 24 30 36 42 48 Months from randomisation 885 885 884 878 870 851 822 690 480 No. at risk * Median time to start trastuzumab: 22.8 mos (4.5-52.7) Gianni, Lancet Oncol 2011 469 468 455 438 408 388 358 302 232

  11. N9831Efficacy results Sequential vs Concomitant + sequential Perez, JCO 2011

  12. BCIRG006Efficacy results DFS HR AC-TH vs AC-T 0.64 TCH vs AC-T 0.75 Slamon, NEJM 2011

  13. FinHEREfficacy results Joensuu, JCO 2009

  14. Efficacy of adjuvant trastuzuambon Survival ° ITT, not adjusted for selective crossover

  15. Efficacy in subgroupsER and Nodal status AC-TH-H TCH Slamon, NEJM 2011

  16. Time-dependent Hazard Rate for recurrence by hormone receptor status ER positive ER negative HERA trial Untch, Ann Oncol 2008

  17. Efficacy in subgroupsSmall tumors 97.2% 86.4% MDACC Hazard Ratio for recurrence 5.3 965 pT1a-b N0 Gonzalez-Angulo, JCO 2009

  18. Efficacy in subgroupsSmall tumors BCIRG006 Slamon, NEJM 2011

  19. Efficacy in subgroupsTopo2A status With Topo2A coamplification Without Topo2A coamplification Slamon, NEJM 2011

  20. Cardiac safety ° >10 points relative reduction in LVEF *after CT

  21. HERA: risk-benefit ratio with adjuvant trastuzumaba Obs; DFS events H; DFS events H; any cardiac end point Obs; any cardiac end point 0.25 0.20 0.15 Probability 0.10 0.05 0.00 0 6 12 18 24 Monthsa No. at risk Observation 1693 1106 784 455 226 Trastuzumab 1139 861 520 260 1693 aMedian follow-up 12 months; DFS, disease-free survival Suter et al 2007

  22. Cardiac outcomes after any type of cardiac endpoint Trastuzumab patients who have any type of CE (n=73) 19.2% 80.8% Trastuzumab patients who reached acute recovery after any type of CE (n=59) Trastuzumab patients who had a further LVEF drop to <50% (n=59) 28.8% 35.3% 71.2% 64.7%

  23. Duration of Trastuzumab

  24. Adjuvant HER2- directed Therapy Questions to be solved: • Indication for the better regimen for combination with trastuzumab (Anthracycline/taxane or docetaxel/carboplatin) • Role of shorter trastuzumab regimens • Treatment of triple-positive tumor migth avoid chemotherapy, particularly on small tumors (T1a,b N0) • Prediction of response to individual HER2-directed agents • Role of dual HER2 inhibition

  25. Double inhibition of HER2

  26. Trastuzumab clearly changed the prognosis of HER2 breast cancer patients. Several new ways for further improvements can now to be explored HER2 street

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