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Cecilia Nisticò Dipartimento di Oncologia Medica Oncologia Medica C Direttore: Prof. E. Terzoli

Ritmi circadiani e qualità di vita: actigrafia e uovi orizzonti nel carcinoma della mammella. Mediterranean Scholl of Oncology. Endocrinoterapia adiuvante del carcinoma nel 2008. Cecilia Nisticò Dipartimento di Oncologia Medica Oncologia Medica C Direttore: Prof. E. Terzoli

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Cecilia Nisticò Dipartimento di Oncologia Medica Oncologia Medica C Direttore: Prof. E. Terzoli

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  1. Ritmi circadiani e qualità di vita: actigrafia e uovi orizzonti nel carcinoma della mammella Mediterranean Scholl of Oncology Endocrinoterapia adiuvante del carcinoma nel 2008 Cecilia Nisticò Dipartimento di Oncologia Medica Oncologia Medica C Direttore: Prof. E. Terzoli IRE - Istituto Nazionale Tumori Regina Elena Roma Roma, 28 Novembre 2008

  2. Breast Cancer Treatment • Final Outcomes: • Adjuvant setting • Treatment Goal:to Cure • Advanced Disease • Treatment Goal:to Care

  3. Adjuvant Therapy- Early Breast Cancer - • Chemotherapy • Endocrine therapy • Biologic targeted therapy • Bisphosphonates • Organ specific therapy

  4. Adj HT Screening Adj CTX Recent decrease in UK and USA breast cancer mortality at ages 35­69 years Modified from Peto et al. Lancet 355:1822, 2000

  5. 13% 18% 25% 30% 12% 15% !

  6. Benefits from Adjuvant Systemic Therapy • It is estimated that • Optimal chemotherapy would reduce annual odds of recurrence by about 50%-60% • Optimal endocrine therapy would reduce annual odds of recurrence by about 60%-70% • Trastuzumab would reduce annual odds of recurrence by 45%-55% • Zoledronic acid would reduce odds of recurrence by about 36% • Reductions in odds of mortality are somewhat more modest because of competing causes of death

  7. Benefits from Adjuvant Systemic Therapy • Benefits of endocrine therapy are restricted to ER +/or PgR+ tumors • Can we predict response to individual endocrine agents? • Optimal endocrine therapy would reduce annual odds of recurrence by about 60%-70% • Sequential administration of chemotherapy followed by endocrine therapy provides optimal benefit for the overall group • Can we identify patients in this group who do not benefit from the addition of chemotherapy?

  8. Davidson N, ASCO 2007

  9. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 15-Year Reductions in Recurrence and Disease-Specific Mortality • Meta-analysis of 194 randomized trials • Meta-analysis of 144,939 women EBCTCG. Lancet. 2005;365:1687-17.

  10. EFFICACY OF ADJUVANT TAM 5 YEARS, ER +/UNKNOWN EBCTCG, Lancet 2005;365:1687-17

  11. Polychemotherapy versustamoxifen-treated ER+ disease, for entry age <50: 5-year probabilities of recurrence (ER+ includes 12% ER unknown) Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Lancet 2005; 365: 1687–1717 EBCTCG Overview (2005)

  12. Davidson N, ASCO 2007

  13. Davidson N, ASCO 2007

  14. Davidson N, ASCO 2007

  15. Davidson N, ASCO 2007

  16. 5 yrs

  17. Davidson N, ASCO 2007

  18. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 15-Year Reductions in Recurrence and Disease-Specific Mortality • Meta-analysis of 194 randomized trials • Meta-analysis of 144,939 women EBCTCG. Lancet. 2005;365:1687-17.

  19. EBCTCG. Lancet. 2005;365:1687-1717. EBCTCG Overview (2005)

  20. Ovarian function suppression (OFS) was accepted as analternative where tamoxifen was contraindicated. Retrospective subset analysis suggeststhatwomenyounger than 40 yearsseemed to benefit from the addition ofgoserelin to CMF.

  21. Retrospective subset analysis suggeststhatwomenyounger than 40 yearsseemed to benefit from the addition ofgoserelin to CAF. J Clin Oncol 2005;23:5973-82

  22. Davidson N, ASCO 2007

  23. TAM standard all pts • TAM for 5 yrs • Chemo + TAM better than whatever alone • OS beneficial in youger pts continuing to menstruate after chemo or TAM • Optimal LHRH duration uncertain • AIs in Meno after chemo: caution! • No data of AIs + LHRH vs TAM (RCTs ongoing)

  24. AIs & TAM: mechanism of action

  25. Hormonal Adjuvant Treatment Strategies in Early Breast Cancer “Up-Front” R Tamoxifen Aromatase Inhibitors 5 years “Extended Switch” Placebo R Tamoxifen Aromatase Inhibitors 10 years “Early Switch” Tamoxifen R Tamox. Arom. Inhibitors 2-3 years 3-2 years

  26. RCTs – AIs Adjuvant BC

  27. Adjuvant Aromatase Inhibitors

  28. Aromatase Inhibitors Adjuvant Trials. Distant metastases

  29. At risk: A 2618 2540 2448 2355 2268 2014 830 T 2598 2516 2398 2304 2189 1932 774 ATAC: recurrences* before 2.5 years (HR+ patients) 25 HR+ A 282 T 370 HR 0.74 95% CI (0.64–0.87) p-value 0.0002 Patients (%) 20 15 ‘Arimidex’ (A) 10 Tamoxifen (T) 5 0 0 1 2 3 4 5 6 Follow-up time (years) * Censoring non-BC deaths before recurrence

  30. p<0.0001 Hot flushes p<0.0001 Vaginal bleeding p<0.0001 Vaginal discharge Endometrial cancer p=0.02 Ischemic cerebrovascular events p=0.03 Venous thromboembolic events p=0.0004 Deep venous thromboembolic events p=0.02 p<0.0001 Joint symptoms p<0.0001 Total fractures Pre-defined adverse events*: ATACMedian follow-up 68 months Anastrozole Tamoxifen 0 10 20 30 40 50 Incidence (%) * Other Pre-defined AE’s with NO significant differences seen between groups: Ischemic Cardiovascular Disease, Cataracts, Nausea & Vomiting, Mood Disturbances, Fatigue ATAC Trialists’ Group. Lancet 2005;365:60-62

  31. ATAC 100 mo.: SAEs: on and off treatment (Number – safety population) 4 Endometrial cancer 12 1 12 Myocardial infarction 33 26 28 34 375 Fracture episodes* 234 146 143 On treatment Off treatment Serious adverse event Anastrozole Tamoxifen Anastrozole Tamoxifen Treatment-related 153 284 49 57 Cerebrovascular accident 34 22 20 20 *A fracture episode comprised one or more fractures on the same day based on adverse events and serious adverse event reports

  32. Predefined adverse eventsat any time on treatment or any severity Anastrozole (N = 3092) Tamoxifen (N = 3094) Hot flushes Nausea and vomiting Fatigue / tiredness (asthenia) Mood disturbances Musculo-skeletal disorders Vaginal bleeding Vaginal discharge Ischaemic cardiovascular disease Ischaemic cerebrovascular event Venous thromboembolic events Deep venous thromboembolic events CataractsCarpal tunnel syndrome† 1102 (35.6) 394 (12.7) 578 (18.7) 599 (19.4) 1104 (35.7) 167 (5.4) 110 (3.6) 130 (4.2) 64 (2.1) 87 (2.8) 48 (1.6) 189 (6.1) 79 (2.5) 1263 (40.8) 358 (12.4) 544 (17.6) 555 (17.9) 915 (29.6) 319 (10.3) 409 (13.2) 106 (3.4) 91 (2.9) 141 (4.6) 75 (2.4) 218 (7.0) 22 (0.7) †included as a non-predefined adverse event of interest

  33. Deaths according to treatment group (ITT population) No. patients (%) Cause of death Total deaths Deaths after recurrence Deaths without recurrence Cardiovascular Cerebrovascular Second primary non-breast cancer Other Anastrozole(n = 3125) 629 (20) 350 (11) 279 (9) 67 (2) 25 (1) 84 (3) 103 (3) Tamoxifen(n = 3116) 624 (20) 382 (12) 242 (8) 66 (2) 29 (1) 60 (2) 87 (3)

  34. Fracture episode rates throughout the study 4 Annual fracture episode rates (%) Anastrozole (A)Tamoxifen (T) 3 2 1 0 0 1 2 3 4 5 6 7 8 9 Time since randomization (years) At risk: A T 2984 2976 2859 2824 2745 2699 2640 2572 2496 2419 2306 2208 2077 2000 1713 1645 702 659

  35. ATAC 100:benefits continue and detrimental effects decline after treatment cessation Time to recurrence Fracture episode rates 4 Patients (%) 30 Annual fracture episode rates (%) Tamoxifen (T) Anastrozole (A) Tamoxifen (T) Anastrozole (A) 25 21.8% 3 20 2 15 12.5% 17.0% 10 1 9.7% 5 Absolutedifference 2.8% 4.8% 0 0 0 1 2 3 4 5 6 7 8 9 0 1 2 3 4 5 6 7 8 9 Follow-up time (years) Time since randomisation (years)

  36. 5-year difference (L-T) = -3.4% (SE 1.2) Cuminc p=0.0002 BIG 1-98: cumulative incidence of breast cancer relapse Proportion failing(%) 20 13.6% 15 Tamoxifen (T) Letrozole (L) 8.1% 10 10.2% 5 6.2% 0 0 1 2 3 4 5 Time since randomisation (years) SE = standard error Thürlimann B et al. The Breast 2005;14:S3, abs S4

  37. BIG 1-98 DFS by Local Pathological Assessment 0.81 All patients (n=8010) 0.84 ER+ / PgR+ (n=5055) 0.83 ER+ / PgR- (n=1631) 0.72 ER+ / PgR unk (n=1154) 0.5 0.75 1.0 1.25 1.5 Favors L Favors T Hazard Ratio (L:T)

  38. “Endometrial events” :Tamoxifen vs Aromatase Inhibitor

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