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Adjuvant Treatment Tamoxifen and Aromatase Inhibitors: EFFICACY

Adjuvant Treatment Tamoxifen and Aromatase Inhibitors: EFFICACY. Rudy Van den Broecke Véronique Cocquyt UZ Ghent Belgian Breast Meeting Brussels 2006. Content. The aim of adjuvant treatment Trial designs with Aromatase Inhibitors and results Take home messages.

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Adjuvant Treatment Tamoxifen and Aromatase Inhibitors: EFFICACY

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  1. Adjuvant TreatmentTamoxifen and Aromatase Inhibitors: EFFICACY Rudy Van den Broecke Véronique Cocquyt UZ Ghent Belgian Breast Meeting Brussels 2006

  2. Content • The aim of adjuvant treatment • Trial designs with Aromatase Inhibitors and results • Take home messages

  3. The aim of adjuvant treatment

  4. How to increase survival? EBCTCG Lancet 2005 Vol 365: 1687-1716

  5. Recurrence rate/year(%) 16 12 8 Node +ve 4 Node -ve 0 0 2 4 6 8 10 Time (years) Randomisation Recurrence history Adapted from EBCTCG. Lancet 1998;352:930-942

  6. How to evaluate Efficacy? • Disease Free Survival • Time To Recurrence • Time To Distant Recurrence • Overall Survival

  7. ATAC Time from randomization to first of: Locoregional distant recurrence new primary breast cancer death from any cause BIG 1-98 Time from randomization to first of: Invasive recurrence in Ipsilateral breast Chest wall Regional site (internal mammary/axilla) Distant site (including ipsi supraclavicular) Contralateral breast (invasive) Second (non breast) malignancy Death without prior cancer event Disease Free Survival

  8. Randomisation Initial adjuvant trial (ATAC, BIG 1-98) 5 years Tamoxifen 5 years Aromatase Inhibitor Randomisation Switch trial (ITA, ARNO/ABCSG 8, IES) 2-3 years’ prior tamoxifen 3-2 y Tamoxifen 3-2 y Aromatase Inh Randomisation Aromatase Inhibitor Randomisation Extended adjuvant trial (MA17, ABCSG 6a) 5 years’ prior tamoxifen No treatment Prospective Sequencing trial (ABCSG 8, BIG 1-98,TEAM) 2 y Tamoxifen 3 years Aromatase Inh 5 years Tamoxifen or Aromatase inh Randomisation Prospective Sequencing trial (BIG 1-98) 2 y Arom Inh 3 years Tamoxifen 5 years Tamoxifen or Aromatase inh 0 5 Time (years) Aromatase Inhibitors:Adjuvant trial designs

  9. Node +ve Node -ve Aromatase inhibitors as initial therapyPatients Newly Diagnosed Recurrence rate/year(%) 16 12 8 4 0 0 2 4 6 8 10 Time (years) Randomisation Tamoxifen ATAC Anastrozole Initial adjuvant Tamoxifen BIG 1-98 Letrozole Adapted from EBCTCG. Lancet 1998;352:930-942

  10. p-value 0.0002 0.0005 A 282 402 T 370 498 HR 0.74 0.79 95% CI (0.64–0.87) (0.70-0.90) HR+ ITT ATAC: Time to recurrencefor HR+ patients Median follow-up time 68 months 25 20 15 Patients (%) Anastrozole (A) 10 Tamoxifen (T) 5 Absolute difference: 1.7% 2.4% 2.8% 3.7% 1.7% 0 0 1 2 3 4 5 6 Follow-up time (years) At risk: Anastrozole 2618 2540 2448 2355 2268 2014 830 2598 2516 2398 2304 2189 1932 774 Tamoxifen SABCS Dec 2004 Lancet 2005 (365): 60-62

  11. ATAC smoothed hazard-rates for recurrenceHR+ve population, 68 months’ median follow-up Annual hazard rates (%) 3.0 2.5 2.0 1.5 1.0 Tamoxifen 0.5 Anastrozole 0.0 0 1 2 3 4 5 6 Follow-up time (years) HR+ve, hormone receptor-positive Howell A. SABCS 2004

  12. At risk: 4003 3892 2964 1261 892 567 Letrozole 4007 3896 2926 1238 866 544 Tamoxifen BIG 1-98Median follow-up time 25.8 months ASCO 2005 2004 NEJM 2005 353; 26: 2747-2757

  13. Conclusion • Both anastrozole and letrozole significanly reduce the risk of recurrence compared with tamoxifen • They should be offered to newly diagnosed postmenopausal patients with receptor positive disease as initial treatment

  14. Patients already on adjuvant therapy (2-3 years of tamoxifen) Recurrence rate/year(%) 16 12 8 Node +ve 4 Node -ve 0 0 2 4 6 8 10 Time (years) Randomisation Tamoxifen Tamoxifen ITA ; ABCSG 8 / ARNO 95; Meta-analysis Tamoxifen Anastrozole Switching Tamoxifen Tamoxifen IES Exemestane Tamoxifen Adapted from EBCTCG. Lancet 1998;352:930-942

  15. Randomisation Randomisation Randomisation Anastrozole meta analysis Median follow-up time 30 months Switch analysis Tamoxifen (n=490) 2 years’ prior tamoxifen (n=979) ARNO 95 Anastrozole (n=489) Tamoxifen (n=1282) 2 years’ prior tamoxifen (n=2579) ABCSG 8 Anastrozole (n=1297) 3-2 years Tamoxifen (n=225) 2-3 years’ prior tamoxifen (n=448) ITA 3-2 years Anastrozole (n=223) 0 5 Time (years) SABCS 2005, Jonat W.

  16. Meta-Analysis: Anastrozole improves overall survival (ITT population)Median follow-up time 30 months % patientsalive 100 90 80 70 HR 0.71 [95% CI 0.52-0.98] p=0.038 60 0 0 1 2 3 4 5 6 7 Time to death (years) At risk: Anastrozole 2009 1544 1189 820 530 274 105 10 Tamoxifen 1997 1535 1172 825 506 267 89 11 *Zero point = after 2 years’ Tamoxifen treatment SABCS 2005, Jonat W.

  17. ARNO 95: Anastrozole improves overall survival Median follow-up time 30.1 months Kaufmann M, ASCO 2006 presentation

  18. ITT ER+ / unknown 100 100 90 90 80 80 70 70 E = 222 / 2352 E = 210 / 2286 60 60 50 50 Women alive % T = 261 / 2372 40 40 T = 251 / 2306 30 30 20 20 10 10 0 0 1 2 3 4 5 1 2 3 4 5 Time since randomisation (years) Time since randomisation (years) HR=0.85 (95% CI: 0.71-1.02) Log-rank test: p=0.08) HR=0.83 (95% CI: 0.69-1.00) Log-rank test: p=0.05) IES: Exemestane improves overall survivalMedian follow-up time 58 months Coombes RC et al. ASCO 2006.

  19. Patients Newly Diagnosed (2 years of Tamoxifen followed by 3 years AI) Recurrence rate/year(%) 16 12 8 Node +ve 4 Node -ve 0 0 2 4 6 8 10 Randomisation Time (years) Tamoxifen ABCSG 8 Tamoxifen Anastrozole ProspectiveSequencing Exemestane TEAM II currently no data Tamoxifen Exemestane letrozole Tamoxifen BIG 1-98 currently no data Tamoxifen Letrozole Adapted from EBCTCG. Lancet 1998;352:930-942

  20. Primary surgery Tamoxifen Anastrozole (2 years) (3 years) ABCSG 8 trial structure Tamoxifen (5 years) to start R a n d o m I z a t I o n within 6 weeks of surgery Switching period Sequencing period SABCS 2005, Jakesz R.

  21. ABCSG 8:Event-free survival following surgeryMedian follow-up 54.6 months 100 95 Year 1&2 After Switch: Year 3+ No significantdifference in first 2 years HR 1.194 p=0.5185 Significantdifference in favour of switch HR 0.628 p=0.0097 90 85 Event-Free Survival (%) TOTAL 80 No significantbenefit for sequence over 5yrs Tamoxifen HR 0.761 p=0.0683 75 70 0 12 24 36 48 60 72 Switch randomisation T→A Sequence randomisation T Time since surgery (months) 98.3% 94.4% 98.0% 92.9%

  22. Why this difference? • switching strategy trials: patients who have completed an initial period of tamoxifen treatment without recurrence are randomised to continue tamoxifen or switch to an AI • sequencing strategy trials: patients are randomised before adjuvant treatment to receive either tamoxifen alone for 5 years, or a sequence of tamoxifen followed by an AI • the resulting data relate to different patient populations, Switching study patient populations are by default enriched with patients who respond well to endocrine therapy by excluding patients who have had an early recurrence despite tamoxifen treatment Curr Med Res Opin 2006; 22(8): 1575-1585

  23. Patients Newly Diagnosed (2 years of AI followed by 3 years Tamoxifen) letrozole Tamoxifen Tamoxifen letrozole Recurrence rate/year(%) 16 12 8 Node +ve 4 Node -ve 0 0 2 4 6 8 10 Time (years) Randomisation Prospective Sequencing BIG 1-98 currently no data Adapted from EBCTCG. Lancet 1998;352:930-942

  24. Patients who have completed5 years’ Tamoxifen Recurrence rate/year(%) 16 12 8 Node +ve 4 Node -ve 0 0 2 4 6 8 10 Time (years) Randomisation Tamoxifen Placebo MA 17 Extendedadjuvant Tamoxifen Letrozole Tamoxifen No treatment ABCSG 6a Anastrozole Tamoxifen Adapted from EBCTCG. Lancet 1998;352:930-942

  25. 100 80 60 p-value = 0.04 Overall Survival (%) 40 20 Letrozole Placebo 0 0 10 20 30 40 50 60 Months MA17: overall survival Node +Median follow-up time 30 months Zero point = after 5 years’ Tamoxifen treatment Goss P et al. J Nat Cancer Institute 2005, Vol 97, No17

  26. Recurrence-freepatients(%) 100 75 HR 0.64 p=0.0477 50 25 Anastrozole No treatment 0 84 0 12 24 36 48 60 72 Time (months) ABCSG 6a: Recurrence-free survival for loco-regional, contralateral and distant metastatic diseaseMedian follow-up time 60 months Zero point = after 5 years’ Tamoxifen treatment Jakesz R. ASCO 2005

  27. How to choose an AI strategy? • In the absence of trial data comparing the different AI strategy, currently the best we can do is to develop model using the available data • Such models exist: • Punglia et al, J Clin Oncol 2005 • Cuzick et al, Br J Cancer 2006

  28. Punglia et al model • Punglia’s model indicates that a switching strategy provide modest benefits compared with adjuvant AI monotherapy. • However, this model was limited in that it used a mix of endpoints from different trials (disease-free survival and time to recurrence), and assumed different carryover effects for tamoxifen and AIs • Furthermore, this model did not take fluctuating rates of recurrence into account, and consequently, there is scope for improvement upon it Curr Med Res Opin 2006; 22(8): 1575-1585

  29. Cuzick et al model • Another recently-published model of the available data provides an alternative explanation for the more favourable HR from switching trials compared with initial adjuvant trials. • The ‘Deep’ model constructed by Cuzick et al. incorporates the phenomenon of phenotypic receptor remodelling during tamoxifen therapy and predicts a consistent benefit in terms of recurrence for patients receiving primary AI therapy to at least 10 years of follow-up Curr Med Res Opin 2006; 22(8): 1575-1585

  30. Take home messages (1) • Every treatment strategy investigated to date shows significant benefits associated with receiving an AI compared with tamoxifen for the adjuvant treatment of hormone receptor-positive early breast cancer in postmenopausal women • We can therefore conclude not only that newly-diagnosed patients should receive an AI, but also that patients currently receiving adjuvant tamoxifen should consider switching to an AI Curr Med Res Opin 2006; 22(8): 1575-1585

  31. Take home messages (2) • A direct comparison of 5 years of AI therapy with switching from tamoxifen to an AI after 2-3 years is not yet available • Modelling of current data suggests that primary AI therapy is more effective than a switching regimen over a follow-up of at least 10 years Curr Med Res Opin 2006; 22(8): 1575-1585

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