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Adjuvante Systeemtherapie Borstkanker

Niewe standard in adjuvante therapie borstkanker. Adjuvante Systeemtherapie Borstkanker. Patrick Neven et al. MBC & Gyn Oncol UZ-Leuven. VVOG Gent 2006. Age-specific incidence of breast cancer in women, Flanders, 1997-2001. Clemmensen’s hook. Source: Vlaams Kankerregistratienetwerk, VLK.

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Adjuvante Systeemtherapie Borstkanker

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  1. Niewe standard in adjuvante therapie borstkanker Adjuvante SysteemtherapieBorstkanker Patrick Neven et al. MBC & Gyn Oncol UZ-Leuven VVOG Gent 2006

  2. Age-specific incidence of breast cancer in women, Flanders, 1997-2001 Clemmensen’s hook Source: Vlaams Kankerregistratienetwerk, VLK

  3. Breast cancer is a “heterogenous” disease Allred score 0 Modified Quick score: Score van 0 tot 5: proportie + cellen Score van 0 tot 3: intensiteit + cellen ------------------------------------------------- Sum is modified Quick score Allred score 4 ER IHC HER-2 IHC FISH Allred score 8

  4. Breast Cancers UZ-Leuven 2000-2005Clinically Heterogeneous (n=2368) • ER-PR-HER-2- 9.2% • ER-PR-HER-2+ 4.3% • ER+PR+HER-2- 69.9% • ER+PR+/-HER-2+/- 16.6%

  5. Borstkanker algemeen ADJUVANTE therapie • Bij diagnose: • Vroegtijdig borstkanker: 90% • Lokaal gevorderd borstkanker: 8% • Gemetastaseerd borstkanker: 2% • Metastasering: uiteindelijk 30-40% NEO-ADJUVANTE therapie

  6. 1. New standards in adjuvant breast cancer 2.UZ-Leuven Beleid

  7. Adjuvant Treatment Predictive factors ER / PgR qualitative + quantitative Certain Uncertain Independent ER+ / PgR + ER+/- PgR ER- / PgR- Grading Nodal Status Menopausal Status HER-2/neu VI (angioinvasion) endocrine treatment chemohormonal treatment chemotherapy HER-2 Prognostic factors NPI

  8. ER+ HT vs CTHT:UZ-LeuvenRisk & Endocrine Responsiveness * Menopausal status

  9. New standards in adjuvant breast cancer Adjuvant Hormonotherapy

  10. Pre- & Postmenopausal Five years of tamoxifen 15 Years of Follow-Up EBCTCG Lancet 1995 EBCTCG Lancet 2005

  11. Adjuvante Therapie Borstkanker New Standards: Clinical Practice and Questions 1. Premenopausal women: Tamoxifen 5 years Is HT enough? Role of Ovarian Suppression? 2. Postmenopausal women: Tamoxifen 5 years AIs challenging 5 years of adj. Tamoxifen Extended therapy

  12. Premenopausal ER-positive breast cancer: Do we always need CT? Best HT vs Best CT EBCTCG: YES but… 3 yrs HT 6X FEC 50 FASG 06 Premenopausal and node positive: 7 years follow-up Roché et al. Ann Oncol 2006; Augustus

  13. Premenopausal ER-positive breast cancer: Do we need CT? UZ-Leuven: July 2006 All ER+ cases adj. CT + 3w later Tamoxifen (INT 100) Only HT: Low risk ~ Age, Grade, Size, N, ERPR, HER-2 & VI [pN0] + [ER+PR+HER-2-] + [VI-] + ≥ 35 years: pT1-2 Gr 1 pT1 Gr 1-2 pT1a-b Gr 1-3 Avoid CT? Ongoing Trials Yes, CT adds up to HT in most premenopausal women

  14. Premenopausal ER-positive breast cancer: Do we add ovarian suppression (OS) to Tam? Tam + OS vs Tam?Controversial Evidence Adj INT-0101: Did not answer Q. ABC trial: Negative trial ZIPP: Positive trial CT-amenorrhea: Positive (age, indirect) M+ Meta-anal.: Positive trial

  15. Premenopausal breast cancer: Adjuvant anti-estrogen therapy UZ-Leuven5 years tamoxifen alone is standard Place of OS? * If pregnancy wanted Discuss: Option &TEXT

  16. Postmenopausal ER+ breast cancer Why tamoxifen still has a future ? Postmenopausal women AIs challenging 5 years of adjuvant tamoxifen

  17. CTHT vs HT Postmenopausal ER-positive breast cancer: Do we need CT? EBCTCG Yes, CT adds up to HT in some postmenopausal women

  18. Aromatase InhibitorsChallenging Tamoxifen E • ReduceEstrogen • Aromatase • Inhibitors ER E • Block Estrogen • SERMs • (Tamoxifen)

  19. Letrozole BIG 1.98 5y Adjuvant trials tamoxifen vs aromatase inhibitors Randomization S U R G E R Y Tamoxifen No treatment ATAC HR=0.87 Anastrozole HR=0.81 S U R G E R Y HR=0.60 ARNO S U R G E R Y Exemestane HR=0.68 IES Letrozole HR=0.58 MA.17 Tamoxifen Placebo 10y

  20. Postmenopausal WomenAIs challenging 5y tamoxifen NIH, NCCN, St.-Gallen adjuvant guidelines ASCO Technology Assessment [2005] St. Gallen International Expert Consensus • Treatment by risk categories [Ann Oncology 2005] The use of AIs What is relevant for the individual patient?

  21. Results of Trials: Tam vs AIs „Average outcome: AIs > Tam“ Distant metastases AI: ‘All’ need it ↔ Only ‘some’ [0.8% - 4%] need it Predictive Factors; AIs vs Tam ER/PR levels, PR-, HER-2+, ?Oncotype DX Prognostic Factors: AIs vs Tam  PR-, Node positive,HER-2+, GGI Survival benefit is limited: Efficacy vs Toxicity Cost [X6]

  22. Tamoxifen vs AIs: UZ-LeuvenRisk & Endocrine Responsiveness Grade 2 lesions (55%of all ER+PR+)

  23. Co-Morbidity & Side effects Endometrial polyp Arthralgia

  24. Prevention of osteoporose and fractures

  25. Side effects of tamoxifen versus AIs ATAC BIG IES * Significance at a p<0.05 level

  26. Extended Adjuvant Use:Na 5 jaar tamoxifen nog 2-3j Letrozole vermindert mortaliteit bij vrouwen met ER-positieve, node positieve borstkanker Wat na 5 jaar tamoxifen?

  27. New standards in adjuvant breast cancer Adjuvant Chemotherapy

  28. Nut van adjuvante chemotherapie:Lancet overview 2005 <50y: breast cancer mortality 50-69y: breast cancer mortality OS Lancet 365:1687-717

  29. Is adjuvante therapie nuttig bij ouderen?  leeftijd op zich is geen rede om chemotherapie achterwege te laten

  30. Heeft adjuvante chemotherapie nut bij hormoongevoelige tumoren? 50-69y: breast cancer recurrence ER poor 50-69y: breast cancer recurrence ER positive DFS OS  antwoord: JA maar absolute winst is kleiner

  31. Balans effect - neveneffect Hoog risico patient Laag risico patient Acute nevenwerkingen 1% hartfalen 0.2-0.4% acute leukemie Acute nevenwerkingen 1% hartfalen 0.2-0.4% acute leukemie 5-15% absolute winst in 10j overleving 0.5-5% absolute winst in 10j overleving

  32. Overzicht • Adjuvante chemotherapie • CMF • Anthracyclines: FEC, CEF, AC, … • Taxanes • dose dense chemotherapie • Adjuvant herceptin • Neo-adjuvante chemotherapie • Guidelines UZ Leuven

  33. CMF CMF vs anthracyclines OS Lancet 365:1687-717

  34. Anthracyclines Optimale dosis anthracycline? • FASG: 565 pt, N+, HR- FE50C q3w x 6 vs FE100C q3w x 6 • DFS (5j): 54.8% vs 66.3 %* • OS (5j): 65.3 % vs 77%* • significant meer tox: stomatitis, nausea en braken, 7 pt FE100C met febriele neutropenie  dosisintensiteit = belangrijk !! French Adjuvant Study Group. JCO 2001; 19: 602.

  35. Taxanes: Ph III trials Taxanes

  36. Pooled analysis of 9 adjuvant taxane trials Bria et al. Cancer. 2006 106: 2337

  37. Taxanes

  38. Dose dense Studie UZ Leuven-St-Augustinus

  39. Taxanes Taxanes: besluit • Efficienter dan niet taxane bevattende chemotherapie • Nieuwe standaard bij high risk tumoren. • Bijkomend voordeel vooral N+ (terugbetaling in België); quid N-? • Nevenwerkingen: anders, wel minder long term nevenwerkingen. • combinatie vs sequentiëel? • Paclitaxel vs Docetaxel?

  40. Herceptin Herceptin adjuvant trials -HERA trial: standard adjuvant chemo  H (1-2j) vs nil -NSABP-31 trial: ACP  H 1y vs nil -NCCTG 9831: ACP with H concomittant, sequential, or nil -FinHER: Doc vs vinorelbine + H vs nil  FEC -BCIRG 006: ACD; ACDH; DCH (C: carbopl)

  41. Herceptin DISEASE-FREE SURVIVAL 1-yearHerceptin Patients (%) 100 80 Observation 60 2-yearDFS 40 Events HR 95% CI p value 127 85.8 0.43, 0.67 <0.001 0.54 127 20 220 77.4 220 0 24 6 0 12 18 Months from randomisation 1694 1172 885 532 No. at risk 268 224 1693 1108 767 445 Median follow-up: 1 yearHR, hazard ratio; CI, confidence interval

  42. Overzicht • Adjuvante chemotherapie • CMF • Anthracyclines: FEC, CEF, AC, … • Taxanes • dose dense chemotherapie • Adjuvant herceptin • Neo-adjuvante chemotherapie • Guidelines UZ Leuven

  43. BSMO trial with neoadjuvant Docetaxel-capecitabine-herceptin

  44. Overzicht • Adjuvante chemotherapie • CMF • Anthracyclines: FEC, CEF, AC, … • Taxanes • dose dense chemotherapie • Adjuvant herceptin • Neo-adjuvante chemotherapie • Guidelines UZ Leuven

  45. +/- Chemotherapy < 35 yrs > 35 yrs “Tailored therapy“ Menstruation Amenorrhea LHRH + TAM TEXT Hormone level postmeno Hormone level premeno TAM of SOFT TAM of SOFT TAM Conclusion I Premenopausal patientswith ER+ breast cancer Endocrine treatment =

  46. Conclusion II Postmenopausal patients with ER+ breast cancer • Tamoxifen 20mg for 5 years • Mostly Switch if any of the 5 criteria fulfilled • Extended if N+ and already 5 years • Special attention: PR- & HER-2+ AIs look like competitors for tamoxifen but we may have to wait another 10 years to find out.M Baum in Breast Cancer Research 2002

  47. Guidelines: UZ leuvenWelke adjuvante chemotherapie? • Standaard: Indien CT nodig!! • Bij lymfeklier positieve tumoren: 3x FEC100  3x taxotere100 • Andere: 6 x FE100C • Indien cardiale contraindicatie voor anthracyclines: • Bij lymfeklier positieve tumoren: 4x taxotere-cyclophosphamide • Andere: 6 x CMF • Her2 pos: Herceptin 1j adjuvant na beeindigen CT

  48. Guidelines: UZ leuvenOpmerkingen • Start CT 4 tot 6 w na heelkunde (ifv wondheling). • Nooit radiotherapie en anthracyclines concomittant! Start radiotherapie na recuperatie hematoxiciteit (bvb na 3w) • Tamoxifen steeds 3w na laatste CT; quid aromatase-I? • Patiënten  70j: individueel te bekijken.

  49. Guidelines: UZ leuvenNeo-adjuvante chemotherapie • Her2 pos: trial Taxotere-Xeloda + Herceptin • Her2 neg: 3 x FE100C  3 x taxotere 100 • Alternatief 4 x AC  4 x Taxotere 100 • Zo contra-indicatie anthracyclines, voorkeur Taxotere 100 • Zo leeftijd ≥70j (of jonger, postmenopauzaal én unfit voor chemo) én sterk positieve hormoonreceptoren: • Tamoxifen (of aromatase remmer in compassionate use) 4 à 6 maanden tot beste respons • Bij Her2 positieve tumoren eerder aromatase remmer (compassionate use) overwegen • Zo geen respons op hormoontherapie: overweeg chemotherapie (adriamycine of Taxotere monotherapie)

  50. Toekomst • Bij wie kan chemotherapie achterwege gelaten worden? • MINDACT trial • Integratie van nieuwe ‘biological therapies’: angiogenese remmers, receptor tyrosine kinase inhibitors, … • fulvestrant • bevacizumab adjuvant • lapatinib adjuvant

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