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CONTROVERSIES IN ADJUVANT ENDOCRINE THERAPY AROMATASE INHIBITORS

CONTROVERSIES IN ADJUVANT ENDOCRINE THERAPY AROMATASE INHIBITORS. JAMES F BISHOP MD PROFESSOR OF CANCER MEDICINE, UNIVERSITY OF SYDNEY DIRECTOR, SYDNEY CANCER CENTRE ROYAL PRINCE ALFRED HOSPITAL, SYDNEY. 3 RD GENERATION AROMATASE INHIBITORS.

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CONTROVERSIES IN ADJUVANT ENDOCRINE THERAPY AROMATASE INHIBITORS

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  1. CONTROVERSIES IN ADJUVANT ENDOCRINE THERAPYAROMATASE INHIBITORS JAMES F BISHOP MD PROFESSOR OF CANCER MEDICINE, UNIVERSITY OF SYDNEY DIRECTOR, SYDNEY CANCER CENTRE ROYAL PRINCE ALFRED HOSPITAL, SYDNEY

  2. 3RD GENERATION AROMATASE INHIBITORS • Aromatase convert androgens to low level estrogen in PM women • AI suppress estrogen levels to 1-10% pre-treatment levels with Letrozole > Anastrozole* • Inadequate data in pre-menstrual women with hormone combination with LHRH analogue • * J Clin Oncol 20:751, 2002

  3. AROMATASE INHIBITORS IN MBC • All AI superior or equivalent to megestrol acetate as second line for efficacy and toxicity • Anastrozole and Letrozole superior or equivalent to TAM for efficacy (TTP) and toxicity (fewer TE events) • Exemestane vs TAM ongoing phase III trial

  4. LESSONS FROM THE OVERVIEW IMPACT OF TAMOXIFEN (5 YEARS) VS NONE Reduction In Annual Odds Age (Years) Lancet 351:1451, 1998

  5. NSABP B-24: TAMOXIFEN RISK REDUCTION * At 74 mos median follow up Fisher et al Lancet 353:1993, 1999

  6. LESSONS FROM THE OVERVIEW OVARIAN ABLATION < 50 YEARS Reduction In Annual Odds Effect less in the presence of chemotherapy Lancet 348:1189, 1998

  7. 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)

  8. ATAC TRIAL – STUDY ENDPOINTS • Primary Endpoints • Disease-free survival •  Loco regional or distant recurrence, new primary breast cancer, or death from any cause • Safety/Tolerability • Secondary Endpoints • Incidence of new breast (contralateral) primaries • Time to distant recurrence • Survival (data will be mature in ~ 2 years) • Hormone receptor-positive population (protocol-defined sub-group)

  9. PATIENT CHARACTERISTICS Tamoxifen(n=3116) Combination(n=3125) Anastrozole(n=3125) Mean age (years) 64.1 64.1 64.3 Mean weight (kg) 70.8 71.1 71.3 Receptor status (%) Positive 83.7 83.3 84.0 Negative 7.4 8.0 6.9 Other 8.9 8.7 9.1 Primary treatment (%) Mastectomy 47.8 47.3 48.1 Axillary surgery 95.5 95.7 95.2 Radiotherapy 63.3 62.5 62.0 Chemotherapy 22.3 20.8 20.8 Prior tamoxifen 1.6 1.7 1.7

  10. HR 95.2% CI p-value AN vs TAM 0.83 0.71–0.96 0.0129 Comb vs TAM 1.02 0.88–1.18 0.7718 0 6 12 18 24 30 36 42 KAPLAN–MEIER CURVES OF DISEASE-FREE SURVIVAL IN ITT POPULATION 100 95 Anastrozole Tamoxifen 90 Combination Proportion event free (%) Proportion event free (%) 85 80 0 Time to event (months) Time to event (months) Curves truncated at 42 months

  11. 100 95 Anastrozole Tamoxifen 90 Combination Proportion event free (%) 85 HR 95.2% CI p-value AN vs TAM 0.78 0.65–0.93 0.0054 Comb vs TAM 1.02 0.87–1.21 0.7786 80 0 0 6 12 18 24 30 36 42 Time to event (months) KAPLAN–MEIER CURVES OF DISEASE-FREE SURVIVAL IN RECEPTOR-POSITIVE POPULATION Curves truncated at 42 months

  12. ANALYSIS OF THE INCIDENCE OF NEW (CONTRALATERAL) BREAST PRIMARIES 100 Anastrozole Tamoxifen 99 Combination Proportion without CL BCa (%) OR 95% CI p-value AN vs TAM 0.42 0.22–0.79 0.0068 Comb vs TAM 0.84 0.51–1.40 0.5132 98 0 0 6 12 18 24 30 36 42 Time to first contralateral new primary (months)

  13. SIGNIFICANT DIFFERENCE IN PRE-DEFINED ADVERSE EVENTS In favour of anastrozole In favour 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

  14. ASCO TECHNOLOGICAL REPORT 2002 • AIM: • To define whether adjuvant AI should have broad based use in conventional practice • METHODOLOGY: • Panel of experts • Computerised searches of Medline/ASCO Jan 2002 • 3 companies invited to provide unpublished data

  15. ASCO TECHNOLOGICAL REPORT 2002 IMPLICATIONS OF THE ATAC TRIAL • EVIDENCE: • Long term adverse effects of TAM but not AI are known. Some concern about adverse bone effects • Absolute differences in DFS are small, currently 2.02% • 5 years of TAM need to see full benefit but reported at 33 mos FU • No reported differences in survival • Optimal duration of AI not addressed in this trial • Possible optimal sequence of TAM and AI not addressed • ATAC trial data not yet peer reviewed

  16. ASCO TECHNOLOGICAL REPORT 2002 IMPLICATIONS OF THE ATAC TRIAL • PANEL CONSENSUS: • ATAC trial is preliminary • 5 years of TAM remains standard of care • Need for longer FU and other trial results

  17. ASCO TECHNOLOGICAL REPORT 2002 ARE ALL AROMATASE INHIBITORS EQUIVALENT? • EVIDENCE: • Confined discussion to third generation anastrozole, Letrozole and Exemestane which may be equivalent in MBC • Quoted RCT in 713 MBC Anastrozole vs Letrozole showing equivalence in TTP, response duration * • Ongoing trials which will compare AI • PANEL CONSENSUS: • Only adjuvant data is with Anastrozole • If AI to be used in an adjuvant setting should be Anastrozole • * Rose et al ASCO 2002

  18. ASCO TECHNOLOGICAL REPORT 2002 WOMEN ALREADY ON ADJUVANT TAM • EVIDENCE: • Study of TAM vs TAM -> aminoglutethimide * with superiority for sequential arm • PANEL CONSENSUS: • No data supporting substitution of TAM for AI • Intolerable SE from TAM, AI could be considered but unproven • * Boccardo et al J Clin Oncol 19:4201, 2001.

  19. ASCO TECHNOLOGICAL REPORT 2002 SHOULD AI BE GIVEN AFTER 5 YEARS OF TAM • EVIDENCE: • No data • PANEL CONSENSUS: • After TAM for 5 years should not receive AI unless in a trial

  20. ASCO TECHNOLOGICAL REPORT 2002 DURATION OF ADJUVANT AI • EVIDENCE: • No trials • ATAC trial current report with FU 33 mos • PANEL CONSENSUS: • Patients receiving adjuvant AI should receive 2-3 years • Review as more data is available

  21. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS IN PRE-MENOPAUSAL • EVIDENCE: • AI no established role in pre-menopausal women • MBC trials with LHRH + AI show activity • PANEL CONSENSUS: • AI alone is contra-indicated in pre-menopausal women • Adjuvant Zoladex or oophorectomy plus AI not been reported

  22. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS AFTER CT INDUCED AMENORRHEA • EVIDENCE: • Resumption of ovarian function frequently occurs especially in younger women • Such resumption would render AI ineffective • PANEL CONSENSUS: • Cautioned against use of AI in this setting because of the substantial probability of resumption of ovarian function

  23. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS IN DCIS • EVIDENCE: • Reduction in contralateral cancers in Anastrozole arm of ATAC • No data on DCIS • PANEL CONSENSUS: • Women with DCIS should not receive AI outside a clinical trial

  24. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS IN CHEMO-PREVENTION • EVIDENCE: • TAM remains the only agent tested and approved by the FDA • Reduction in contralateral breast cancer in Anastrozole arm of ATAC is insufficient evidence • PANEL CONSENSUS: • Women with increased risk of breast cancer should not receive AI to reduce risk outside a clinical trial

  25. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS IN ER NEGATIVE CANCERS • EVIDENCE: • Overwhelming evidence that adjuvant hormone therapy is effective only in ER positive patients • No contradictory data with AI • PANEL CONSENSUS: • Women with ER negative cancers should not receive AI as adjuvant therapy

  26. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS IN HER-2 POSITIVE CANCERS • EVIDENCE: • Conflicting studies some suggest TAM is less beneficial in HER-2 positive cancers • Many studies have methodological flaws • NIH consensus conference recommended all ER positive patients receive TAM regardless of HER-2 status

  27. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS IN HER-2 POSITIVE CANCERS OPR ErbB-1 +/or Breast Erb-2 Positive Sparing Surgery TAM 4mos 41% 21% 21% Letrozole 4mos 60% 86% 41% ER +/OR PR Positive R Ellis et al: J Clin Oncol 19:3808, 2001.

  28. IRESSA RESTORES TAM SENSITIVITY IN HER-2 OVEREXPRESSING TUMOURS • MCF-7/HER2 overexpressing cells • Given estrogen, TAM estrogren deprivation + Iressa • Iressa restored TAM sensitivity • Massarweh: ASCO #130:2002.

  29. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS IN HER-2 POSITIVE CASES • PANEL CONSENSUS: • Recommendation against use of HER-2 studies to make decisions about adjuvant hormone therapy • Clinical data to support use of HER-2 status are inadequate

  30. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS WHEN TAM IS CONTRAINDICATED • EVIDENCE: • TAM is associated with increased risk of thrombo-embolic and cerebrovascular disease • PANEL CONSENSUS: • Reasonable to use adjuvant AI with a relative or absolute contraindication to TAM • Recommend careful consideration of the significance of the contraindication given the proven benefits with TAM

  31. ASCO TECHNOLOGICAL REPORT 2002 AROMATASE INHIBITORS FOR INVASIVE BREAST CANCER WHILE ON TAM OR RALOXIFEN • EVIDENCE: • In MBC AI are effective following progression on TAM • Role of AI following Raloxifen unknown • Evidence of cross resistance between Raloxifen and TAM suggesting TAM may be ineffective after Raloxifen • PANEL CONSENSUS: • Reasonable to use adjuvant AI although data are poor

  32. ADJUVANT ANASTROZOLE TRIALS

  33. ADJUVANT LETROZOLE TRIALS

  34. ADJUVANT EXEMESTANE TRIALS Total target accrual for all adjuvant AI trials 40,811 women

  35. ASCO TECHNOLOGICAL REPORT 2002 SUMMARY OF ROLE OF ADJUVANT AI • ATAC Trial – not yet • Are all AI the same – Anastrozole now • If now on TAM – no • After 5 years of TAM – no • Duration of AI – don’t know • In pre-menopausal – no • After CT amenorrhoea – watch out!

  36. ASCO TECHNOLOGICAL REPORT 2002 SUMMARY OF ROLE OF ADJUVANT AI • 8. DCIS – no • 9. Chemo-prevention – no • 10. ER/PR negative cancers – definitely no! • HER-2 positive cancers – no, but who knows • Women where TAM contraindicated – maybe • New invasive cancers after chemo-prevention - OK

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