ࡱ> zat2d)`&NȔ( ( / 0DTimes New Romanttқ 0DArialNew Romanttқ 0" DWingdingsRomanttқ 00DTahomagsRomanttқ 0"@DGill Sans MTanttқ 0"PDSymbolns MTanttқ 0`DArial Blackanttқ 0"@ .  @n?" dd@  @@`` z` +S  Q<  >6= $>x9T     G   ( - GGGG>I  >< $\      I$ Q< C6< $=<<<y9S  (+        $#   MB  J U     = 6H  99EG LP QRSTV #] c deghlmotuv#wx%yz {'   )># !+ (((   %# 7      ,r$t2d)`&NȔi AA1? ff333f3@42d2d  0ppppU pp ,:ʚ;ģ8ʚ;<4!d!d@ x 0@<4dddd@ x 0@<4dddd@ x 0@pDg4OdOdlu 0Xp po0___PPT10 pp`___PPT9B/ 0&? 5O =_3ADVANCES IN THE HORMONAL TREATMENT OF BREAST CANCER4&TURKISH-HELENIC ESMO COURSE 1-4 DECEMBER 2005- iSTANBUL P1nar Saip University of 0stanbul, Institute of Oncology Department of Medical Oncology $PFN3Advances in the Hormonal Treatment of Breast Cancer4fProper selection of endocrine responsive disease Adjuvant endocrine therapy for early stage breast cancer premenapausal postmenapausal Neoadjuvant endocrine therapy in post menapausal women Endocrine treatment for advanced disease premenapausal postmenapausal 6kMbMgg91Proper selection of endocrine responsive disease 2$Who are really endocrine responsive?%^HR  positive disease is heterogeneous disease0A subset of HR+ patients can expect a relatively large benefit with CT, another group of patients may obtain little or no benefit Not all HR+ disease responds to endocrine therapy Consentration of HR varies among breast carcinomas Increased concentration of steroid hormone receptors is associated with increased effectiveness of endocrine therapies mortality reduction with TMX 23% for low consentration 36% for high consentration *c-`HR  positive disease is heterogeneous disease 1 Presence of PR improves the benefit from adjuvant TAM treatment ATAC (anastrozol vs tamoxifen) ER+, PR+ HR: 0.82 ER+, PR- HR: 0.48 (e84There is an inverse relationship between PR and HER254 HER 2 + ER+ PR+ 8.2% ER+ PR- 29.5% This inverse relationship may in part be explained by PR levels in breast cancer cells being down regulated by the growth factors VQZZ.ZZ/ZZ550!Relationship between ER and HER 2" At presentation ER+ , HER2 - 70% ER+, HER2 + 10% ER-, HER2 + 10% ER-, HER2 - 10% In HER 2+ population the proportions of ER+ and ER- tumor are about equal The level of ER is lower in ER+ HER2+ cases than in ER+ HER2- . The biology and clinical behavior of ER+ HER2+ tumors may in part be explained by their lower ER expression $PP3$Prediction of response to tamoxifen %RThere is tamoxifen resistance in ER+, HER2+ tumors Ovarian Ablation +TAM is more effective in premenapausal patients Aromatase inhibitors are more effective in postmenapausal women response rate (HER2+) letrozole %88 TAM %213 SS;tA Multigene assay to predict recurrence of tamoxifene treated, nod (-) breast cancer Paik et al NEJM 2004;351: 2817uuuTo determine whether the results of RT-PCR of prospectively selected genes (16) would correlate with distant recurrence and response to Tam . (NSABP-B14) A mathematical algorithm RS was developed based on expression levels of these genes Patients categorised as low, intermediate and high risk according to their RT-PCR profiles Kaplan Meier estimates of the rate of distant recurrence at 10 years according to RS risk categories Risk category percentage of patients rate of distant recurrence Low 51 6.8 (4.0-9.6) Intermediate 22 14.3(8.3-20.3) High 27 30.5(23.6-37.4) The rate in the low risk group was significantly lower than the high risk group <0.001TIP_PIW5xMultivariate Cox analysisVariable p value HR(95%CI) without RS Age at surgery 0.004 0.57(0.39-0.83) Clinical tumor size 0.06 1.44(0.99-2.11) With RS Age at surgery 0.08 0.71(0.48-1.05) Tm size 0.23 1.26 (0.86-1.86) Recurrence score <0.001 3.21 (2.23-4.61) FA .rPaik et al ASCO 2005 DFS at 10 years Benefit of TAM placebo TAM absolute relative p % % % % Low 85.9 93.1 7.2 51% .04 Intermediate 62.2 79.5 17.3 46 .02 High 68.7 70.3 1.6 5 .82  ;5 ST GALLEN CONSENSUS MEETING 2005!{ RATHER THAN THE EARLIER RISK ASSESSMENT APPROACH, ENDOCRINE RESPONSIVENESS OF THE DISEASE BECAME THE MAIN CONSIDERATION.|62005 St Gallen 474FEATURES OF UNCERTAINITY TO ENDOCRINE RESPONSIVENESS5LOW LEVELS OF STEROID HORMON RECEPTORS LACK OF PROGESTERONE RECEPTORS OVEREXPRESSED OR AMPLIFIED HER2 HIGH NUMBER OF LYMPH NODES HIGH TUMOR LEVELS OF UROKINASE-TYPE PLASMINOGEN ACTIVATOR INCREASED PROLIFERATION MARKERS V) ADVANCES IN ADJUVANT ENDOCRINE THERAPY *eSystemic adjuvant endocrine treatment for early breast cancer significantly reduces recurrence and mortality 15 years after treatment(EBCTCG) meta-analysis 194 randomised trials up to 1995- 144,939 women trials n death Tamoxifen 1-2 yrs vs none 44 33.209 13914 5 yrs vs none 12 15017 4071 Ovarian A/S Ablation vs none 15 6506 3006 Suppresion vs none 6 4807 832 1tReduction after 15 years; breast ca p mortality p recurrence Tamoxifen 5 yrs 11.8 <.00001 9.2 <.00001 vs none, ER+ Ovarian A/S vs 4.3 .0001 3.2 .004 none<<<T   GOvarian supression/ablation Alone as an Alternative to Chemotherapy: "HG$*ZEBRA ( J Cancer 2003;39:1711) IBCSG VIII (J Nat C Inst 2003;95:1833) Scottish (Breast 2002;11:419) TABLE (Anticancer Res 2002;22:2325) !OA/OS alone vs Chemotherapy (CMF)""!  !OA/OS + Tamoxifen vs chemotherapy"?ABCSG Jakesz JCO 2002;20:4621 GROCTA Boccardo JCO 2000;18:2718 @ ;Ovarian ablation/supression + Tamoxifen vs chemotherapy (1)<<;  "*Chemotherapy vs CT OA TAM+$ ($ INT 0101 Davidson Proc ASCO; 2003; 22:15 France Arriagada Proc ASCO 2003;22:4 Mam-1 GOCSI Bianco Proc ASCO 2001;20,20 IBCSG 11-93 IBCSG The Breast 2001;10:130 5 Ovarian ablation/supression after chemotherapy (2)66"( `Study Treatment Disease characteristics Result in terms of OS France CT (any) Nod+/- No difference CT (any) +OA(RT/ medical Mam-1 CMF Node+, ER +/- G+Tam>CT GOCSI A CMF p=0.04 (n=466) CMF G+ Tam (2Y) A CMF G+ Tam (2Y) IBCGS AC X 4 +OA(G,S,RT)+Tam(5Y) Nod+, ER+ No difference 11-93 OA (G, S, RT) + Tam (5Y) INT-0101 CAF Nod +, ER+ CAF + G = CAF N: 1504 CAF + G (5 Y) CAF + G + Tam > CAF +G CAF+G +Tam p<0.01 dfs l " dP " !  'H "  Conclusions "Ovarian function supression plus tamoxifen is at least as effective as chemotherapy The current contravery remains in patients who continue to menstruate after CT whether the additon of OS improves the results compared to tam alone The role of AI in premenapausal women is not known yet. #:Questions in the onging trials SOFT: PERCHE TEXT M$Endocrine responsive St Gallen 2005 %Risk Premenapausal Postmenapausal Low risk Tam or Nil Tam or AI or Nil or OFS Intermediate Tam (OFS) (CT),or Tam or CT Tam (OFS),or AI,or Tam alone,or CT Tam or OFS CT AI High CT Tam or CT Tam or CT Tam+ OFS,or CT AI CT (AI + OFS) 2Z"\  I N-Endocrine response uncertain St Gallen 2005 .Risk Premenapausal Postmenapausal Low risk Tam or Nil Tam or AI or Nil or GnRHA Intermediate CT Tam (OFS),or CT AI,or Tam OFS (CT),or CT Tam CT AI +OFS OFS Switch High CT Tam or CT AI or CT Tam+ OFS,or CT Tam CT (AI + OFS) SwitchLPPPPP\ D  fCAdvances in the adjuvant hormonal treatment of postmenapausal womenDZUpfront Aromatase inhibitors Switching aromatase inhibitors Extended aromatase inhibitors[!Results of the ATAC trial after 5 years adjuvant treatment -Upfront AI $KIB*  ,#( Disease-free survival (ITT* population)")$($ ) %!Overall survival (ITT population)""$ " 4Benefits of switching postmenopausal women with hormone-sensitive early breast cancer to anastrozole after 2 years adjuvant tamoxifen: Combined results from 3,224 women enrolled in the ABCSG Trial 8 and the ARNO 95 trialjAustrian Breast & Colorectal Cancer Study Group (ABCSG) and the German Adjuvant Breast Cancer Group (GABG)kPk6Switching trial ABCSG 8  ARNO 95: Combined analysis trial structureE#"58Event-free survival [oIntergroup exemestane study-IES: 50% nod-, 80%HR+, n:4742 median follow up 30.6 months swithcing trial "p$Lp\:Intergroup exemestane study ";9;'/Extended AI trial letrozol vs placebo -MA 174  (8MA.17 Results: Disease-Free Survival (Primary End Point)99 9 )MA.17 Results: Overall Survival **MA.17 Results: Subanalysis of Nodal Status&    1Letrozole is effective regardless of nodal status22 2 DABest ajuvant endocrine treatment strategy in postmenapausal womenB#lUnanswered QuestionsWhat is the best strategy? How long should we use? Will the AI-associated benefit long lasting? In which patients should we use (erbB1/2+, NOD+, PR- )?? Is it beneficial in premenapausal women with LHRHa Will it translate into a long term survival gain? Z$mOngoing trials  5 year TMX 5 year Letrozol 2-3 y letrozol + 2-3 y TMX 2-3 y TMX + 2-3y Letrozol 5 y1l TMX + 5 y1l plasebo 5 y1l TMX + 5 y EXE 5 y TMX 5 y EXE P J z3 'pASCO Technology assessment on the use of AIs as adjuvant therapy for postmenapausal women with HR+ breast cancer: Status report 2004tOnly one trial MA17 showed survival benefit in node positive patients The others show a clear and consistent improvement in disease free survival. Panel believes that optimal adjuvant hormonal treament for a postmenapausal women with HR+ disease should include an AI either as initial therapy or after treament withTAM. Risks and benefits of AIs should be considered uuuY Advances  %In the neoadjuvant hormonal treatment&ZNeoadjuvant phase III trialsDP024:Response rates and HER &  ~ letrozole Tamoxifen p HER + 15/17 4/19 0.0004 ER + (88%) (21%) HER - 55/101 42/100 0.0780 ER + (54%) (42%) !A0`.`d      (* (h"Advances in the hormonal treatment#Advanced Disease)ijLHRH Agonist + Tamoxifen in Pre-/perimenopausal Women with Advanced Breast Cancer: An EORTC Meta-analysis kTThe combination of LHRH agonist + tamoxifen is superior to LHRH agonist alone in the treatment of advanced breast cancer in hormone-sensitive pre-/perimenopausal women @P*j__Fulvestrant vs anastrozole after first line TAM US and rest , Randomized, Double-blind 2 trialsB/ a.Fulvestrant vs anastrozole Time to Progressionk.Fulvestrant vs anastrozole Time to Progression3vFulvestrant vs TAM first line Median follow up 14.5 TTP 6.8 (FUL) 8.3 (TAM) HR+ patients TTP 8.2 and 8.3 month RR 31.6% and 33.9% NO DIFFERENCE JCO 2004; 22,16054A 8Endocrine therapy in Advanced Breast Cancer: Conclusions'FThe efficacy of LHRH agonists in advanced disease is enhanced by the addition of tamoxifen in premenapausal women Aromatase inhibitors are the first line endocrine treatment option in postmenapausal women. 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