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Carcinoma della Mammella: scelte terapeutiche complesse Discussione di un caso clinico: Paziente con comorbidità Giorgio Mustacchi e Marina Bortul Fellow.

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Presentazione sul tema: "Carcinoma della Mammella: scelte terapeutiche complesse Discussione di un caso clinico: Paziente con comorbidità Giorgio Mustacchi e Marina Bortul Fellow."— Transcript della presentazione:

1 Carcinoma della Mammella: scelte terapeutiche complesse Discussione di un caso clinico: Paziente con comorbidità Giorgio Mustacchi e Marina Bortul Fellow up 2009

2 Programma di lavoro Da discutere nellambito dei lavori di gruppo: –Ruolo della chirurgia nella malattia metastatica –Approccio alla paziente con BC HER2+ e comorbidità cardiovascolare –Scelta della terapia endocrina nella paziente con BC ER+ –Rischi e benefici della terapia con AIs (switching vs upfront) –Scelta della terapia endocrina a ripresa di malattia Donna di 56 anni con diabete, ipertensione e CHF Mastectomia per: CLI multifocale (N-, G3, ER+, PR-, HER2-POS) dopo 4 anni sviluppa metastasi epatiche

3 Donna di 56 anni, in menopausa da 5 Diabete di Tipo II (dieta e antidiabetici orali) Ipertensione arteriosa (ACE-Inibitori + diuretici) CHF due anni prima (LVEF 45%) La Paziente Giugno 2003 Mastectomia dx CLI multifocale G3 N neg Ki67 35 % Er 60 % PgR neg HER2 +++

4 La Terapia Adiuvante scelta CMF x 6 TAMOXIFEN LVEF Basale : 45 % Post CMF : 46 % Depressione 2003: no Trastuzumab adiuvante

5 Aprile 2007: Intervallo libero 4 anni Linfonodi sopraclaveari dx Astenia G2 Anoressia G2 Febbricola serotina Metastasi epatiche PS 2 LVEF 40 % Biopsia Linfonodo FISH pos ER 70% PgR Neg

6 Scelta Terapeutica: Docetaxel e Trastuzumab Tempo 0 Dopo 6 cicli

7 Il seguito della storia TTP: 12 mesi – (PD fegato, polmone e N s.cl) PS 2 (dispnea, astenia) 2° linea: –Capecitabina + Trastuzumab PR per 7 mesi (PS1)

8 PD dopo 7 mesi 3° linea di trattamento Non vuole più alopecia Chiede la prospettiva reale 3 linea scelta Letrozole + Trastuzumab SD per 4 mesi

9 La fine della storia PD con decadimento generale Si concorda per BSC Ambulatoriale per 4 mesi ADI 1 mese Decesso in Hospice dopo 1 mese Sopravvivenza Globale : 29 mesi

10 Primo quesito Ha senso fare una biopsia a progressione di malattia? SI NO

11 Secondo Quesito Ruolo della chirurgia nella malattia metastatica Se la metastasi era polmonare ? Oltre linformazione biologica, può la chirurgia dare altro?

12 Terzo Quesito Approccio alla paziente con BC HER2+ e comorbidità cardiovascolare Opportunità di usare Trastuzumab Cardiotossicità di Trastuzumab Scelta dello schema chemioterapico Monitoraggio cardiologico

13 Quarto Quesito Trastuzumab beyond Progression ? Opportunità di usare Trastuzumab Scelta dello schema chemioterapico Monitoraggio cardiologico Alternative attuali al Trastuzumab

14 Quinto Quesito Scelta della terapia endocrina nella paziente con BC HER2+/ER+ Endocrino sensibilità del fenotipo Tipo di Endocrinoterapia

15 Sesto quesito Alternative a Trastuzumab

16 Settimo quesito Trastuzumab o Lapatinib ?

17 Ottavo Quesito Rischi e benefici della terapia con AIs (switching vs upfront) Back from San Antonio 2008 Highlights on Endocrine adjuvant treatment in postmenopausal women

18 Primo quesito Ha senso fare una biopsia a progressione di malattia? SI NO

19 Franco N et al. Proc ASCO 2004;Abstract 539. Perchè la biopsia? Discordance in ER and PR Status Between Primary and Metastatic Breast Cancer: A Meta-Analysis Receptor change ER, n=658 Risk ratio (95% CI) PR, n=418 Risk ratio (95% CI) Positive to negative0.22 ( )0.20 ( ) Negative to positive0.11 ( )0.15 ( ) Total discordance0.29 ( )0.27 ( )

20 Perchè la biopsia? Discordance in HER2 Testing

21 Secondo Quesito Ruolo della chirurgia nella malattia metastatica Se la metastasi era polmonare ? Oltre linformazione biologica, può la chirurgia dare altro?

22 Terzo Quesito Approccio alla paziente con BC HER2+ e comorbidità cardiovascolare Opportunità di usare Trastuzumab Cardiotossicità di Trastuzumab Scelta dello schema chemioterapico Monitoraggio cardiologico

23 NR Months Survival 100% 80% 60% 40% 20% 0% NR PR CR 4 landmark P<.0001, logrank test >12 months Response and survival (Bruzzi, Del Mastro, JNCI 2004)

24 Prognosis of women with Stage IV breast cancer by HER2 status and trastuzumab treatment. S.Dawood et al ASCO 2008 Abs # patients 1782 HER2 Negative 118 HER2 Positive NO Trastuzumab 191 HER2 Positive Trastuzumab

25

26 Clinical benefits of trastuzumab plus taxanes 1 Slamon DJ, et al. N Engl J Med 2001;344:783–92 2 Baselga J. Oncology 2001;61(Suppl. 2):14–21 3 Marty et al. J Clin Oncol. 2005

27 No Difference in OS PolyCT NO better in PFS, ORR PolyCT better toxicity profile due to lower docetaxel dose No Difference in OS PolyCT better in PFS, ORR PolyCT slightly worse toxicity profile Poly vs monochemotherapy

28 Comorbidity is a Key Factor Charlson, J Chron Dis 40:373, 1987

29 Cardiac events Cardiac Dysfunction Outcomes (CREC) H + ACACH + TT Cardiac dysfunction events, n (%)39 (27)11 (8)12 (13)1 (1) NYHA class III/IV heart failure, %16421 Deaths, n4112 MBC4002 Cardiac0100 Pneumonia0010 CREC; Cardiac Review and Evaluation Committee Seidman A et al. J Clin Oncol 2002; 20:

30 Trastuzumab plus chemotherapy in MBC patients - other trials Cardiac Dysfunction Outcomes (CREC) Cardiac disfunctionNYHA Class III-IV CHF StudyTreatmentNo. pts% % H0551g H0552g H0649g H0650 H0659g H0693g H alone H+cisplatinum H alone H other CT Seidman A et al. J Clin Oncol 2002; 20:

31 Francesco Perrone Unità Sperimentazioni Cliniche Istituto Nazionale Tumori di Napoli Cardiosafety with trastuzumab in metastatic breast cancer

32 CHF fromTrastuzumab is not associated with ultrastructural changes Ewer MS et al., JCO 2005, 23:

33 Chia, S. et al. J Clin Oncol; 24: Pegylated Liposomial Doxo + Trastuzumab LVEF over time CHF : 0 Cardiotoxicity Without CHF 10 %

34 Peg Liposomial Doxo + Trastuzumab Efficacy RR % (N = 29)52 Median PFS mos12 Median OS mosnot reached 2 yrs Survival %77 Chia, S. et al. J Clin Oncol; 24: st line M1 BC pts LVEF > 55 % G3 PPE : 30 % G3 Neutropenia : 23 %

35 Italic denotes studies for which the extended paper is not yet in our hand MBC: Trastuzumab + Paclitaxel Cardiotoxicity

36 Italic denotes studies for which the extended paper is not yet in our hand MBC: Trastuzumab + Docetaxel Cardiotoxicity

37 Italic denotes studies for which the extended paper is not yet in our hand MBC: Trastuzumab + Vinorelbine Cardiotoxicity

38 Quarto Quesito Trastuzumab beyond Progression ? Opportunità di usare Trastuzumab Scelta dello schema chemioterapico Monitoraggio cardiologico Alternative attuali al Trastuzumab

39 Two trials evaluating anti-HER-2 therapy after progression to trastuzumab-based chemotherapy TrialStudy design No. ptsRR%Median TTP, mos Median OS, mos X German 1 X+T X GSK 2 X+L NR X, capecitabine; T, trastuzumab; L, lapatinib 1 Von Minckwitz G et al. Proc SABCS 2008, 2 Geyer C et al. New Engl J Med 2006

40 Gelmon et al. Clin Breast Cancer. 2004;5: Similar ORR in first and second Trastuzumab treatment MonotherapyPlus taxane Plus vinorelbineTotal Objective response (CR+PR) (% of patients) 1st regimen2nd regimen (Trastuzumab retreatment) ND Trastuzumab Beyond Progression: Multinational Study of 105 Patients

41 Similar TTP in first and second Trastuzumab treatment Gelmon et al. Clin Breast Cancer. 2004;5:52-58

42 Trastuzumab treatment beyond PD The German experience Jackisch, SABCS 2007

43 Prosecution of trastuzumab influences the outcome more than response does Menard, ASCO metastatic pts registered in the DEMETRA study

44 Continuation of Herceptin prolongs median TTP in the GBG-26 study Time from 1st progression (months) Probability HR=0.69 (2-sided p=0.034; 1-sided p=0.015) 8.2 a 5.6 a Herceptin + Xeloda (n=78) Xeloda (n=78) von Minckwitz, ASCO 2008

45 Continuation of Herceptin probably improves OS in the GBG-26 study a Time from 1st progression (months) Probability HR=0.76 (2-sided p=0.26; 1-sided p=0.13) Herceptin + Xeloda (n=78) Xeloda (n=78) 25.5 a von Minckwitz, ASCO 2008

46 Quinto Quesito Scelta della terapia endocrina nella paziente con BC HER2+/ER+ Endocrino sensibilità del fenotipo Tipo di Endocrinoterapia

47 Metastatic Breast Cancer Hormone Responsiveness

48 ER/PgR HER2 & Tamoxifen DFS in tamoxifen- treated patients Arpino, G. et al. J Natl Cancer Inst 2005;97: ER+/PR+ ER+/PR-

49 Her2+ BetterHer2+ worse Overall 1.44 (1.34 – 1.56) Ellegde 1.21 (0.87 – 1.69) Hayes 1.06 (0.47 – 2.38) Houston 2.07 (1.57 – 2.73) Lipton 1 st 1.42 (1.24 – 1.63) Willsher 1.33 (0.56 – 3.16) Wright 1.54 (0.86 – 3.74) Yamauchi 1.66 (1.05 – 2.64) HER2 and Endocrine Therapy - Metanalysis ER+ Patients (N=1195) Lipton 2 nd 1.40 (1.25 – 1.56) Relative Risk of Treatment Failure (95%CI) p< Test for Heterogeneity: p=0.26

50 De Laurentiis, Clin Cancer Res 2005;11: Tamoxifen in HER2+ Disease

51 Tam vs AI in HER2+ tumors Neoadjuvant setting AuthorNrStudy armsResults subgroup HER2 and ER+ % pts HER2 + Ellis JCO TAM vs Letrozole RR 21% vs 88% P= IMPACT trial BCRT 2004 abs 330TAM vs Anastrozole vs Combination CR 22% vs 58% vs 31% 14

52 Overall 1.42 (1.24 – 1.63) Effect by Type of Therapy Lipton Study (N=566) Her2+ BetterHer2+ worse Letrozole 1.53 (1.24 – 1.88) Tamoxifen 1.34 (1.12 – 1.60) Relative Risk of Treatment Failure (95%CI)

53 TransATAC: adjuvant HT & HER2 Time To Recurrence (Dowsett, SABCS 2008) Actually, endocrine resistance!

54 TanDEM: Response and clinical benefit rates Patients (%) A + H (n=74) A (n=73) A + H (n=103) A (n=104) p=0.026 p=0.018 PR, partial response; SD, stable disease; PD, progressive disease

55 TanDEM: Anastrazole +/- Trastuzumab Progression-free survival A + H No. at risk A Probability Months 95% CI 3.7, , 4.6 p value Median PFS 4.8 months 2.4 months Events Baselga 2006 Luminal B Tumors are quite endocrine-resistant

56 TTP is usually much longer Nabholtz, J. M. et al. J Clin Oncol; 18:

57 Sesto quesito Alternative a Trastuzumab

58 EGF Lapatinib Mechanism of Action Binds to intracellular ATP binding site of EGFR (ErbB-1) and HER2 (ErbB-2) preventing phosphorylation and activation Blocks downstream signaling through homodimers and heterodimers of EGFR (ErbB-1) and HER2 (ErbB-2) Dual blockade of signaling may be more effective than the single-target inhibition provided by agents such as trastuzumab Lapatinib Downstream signaling cascade Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21: ; Konecny et al. Cancer Res. 2006;66:

59 EGF Study Design Progressive, HER2+ MBC or LABC Previously treated with anthracycline, taxane and trastuzumab* No prior capecitabine Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m 2 /d po days 1-14 q 3 wk Capecitabine 2500 mg/m 2 /d po days 1-14 q 3 wk Patients on treatment until progression or unacceptable toxicity, then followed for survival Stratification: Disease sites Stage of disease RANDOMIZERANDOMIZE *Trastuzumab must have been administered for metastatic disease N=528

60 EGF Response Rate - ITT Population Lapatinib + Capecitabine (n=160) Capecitabine (n=161) Complete response1 (< 1%)0 (0%) Partial response35 (22%)23 (14%) Overall response rate* (95% CI) 22.5% ( ) 14.3% ( ) *P-value (Fishers exact, 2-sided) = 0.113

61 EGF Time (weeks) Cumulative Progression-Free Survival, % Progression-Free Survival - ITT Population P-value (log-rank, 1-sided) 73 (45%)45 (28%)Progressed or died 0.48 (0.33, 0.70)Hazard ratio (95% CI) Median PFS, wk No. of pts Capecitabine Lapatinib + capecitabine

62 EGF Mean LVEF at Scheduled Assessments Week 12Week 18 Week 24 Week 36Week 48Week 6Screening Assessment Lapatinib + Capecitabine Capecitabine Mean LVEF (%) n=160 n=108 n=92 n=84 n=67 n=63 n=37 n=26 n=15 n=9 n=7 n=1

63 Trastuzumab plus lapatinib Synergistic drug interactions were observed in HER2- overexpressing cell lines 1 Phase I: MBC, 94% progressed on prior trastuzumab 1CR, 6PRs in 27 patients (26%) 2 Humanized monoclonal antibody directed against HER2 Trastuzumab Lapatinib Dual-specific TK inhibitor against EGFR and HER2 1 Konecny et al. Cancer Res 2006; 2 Storniolo et al. Breast Cancer Res Treat 2005

64 EGF104900: PFS and OS

65 Settimo quesito Trastuzumab o Lapatinib ?

66 HER2 signalling pathway: the role of PTEN HER2 Shc GRB2 PI3K p85 c-myc AKT GSK3 HRG PTEN Ras MAPK Cell survivalCell proliferation HER3 mTOR PI3K p85 IGF-1R

67 The traslational Neoadjuvant Study Jenny Chang, SABCS 2008

68 Low PTEN/PI3KA-mut Jenny Chamg, SABCS 2008

69 Conclusions Jenny Chamg, SABCS 2008

70 PK interaction between Tamoxifen and Lapatinib TAM induces hepatic CYP3A, the primary route of LAP elimination So LAP plasma levels are reduced. This important information may impact in ongoing adjuvant lapatinib studies parameter (units)LAPLAP+TAM Decrease in LAP+TAM vs LAP LAP AUC tau (h*mg/L) 25.2 ( )17.9 ( )0.71 ( ) LAP Cmax (mg/L)1.73 ( )1.20 ( )0.69 ( ) LAP Cmin (mg/L)0.56 ( )0.33 ( )0.58 ( ) Cardoso, SABCS 2008, Poster 2073

71 Trastuzumab and Letrozole

72 Letrozole+Lapatinib in MBC

73 Response Rate (HER2 pos, n=219) S. Johnston, SABCS 2008

74 PFS : HER2 pos pts S. Johnston, SABCS 2008

75 Ottavo Quesito Rischi e benefici della terapia con AIs (switching vs upfront) Back from San Antonio 2008 Highlights on Endocrine adjuvant treatment in postmenopausal women

76 Start AI After 2–3 Years of TAM: Randomization/Analysis Upfront or at Switch Annual recurrence rate (%) Time (years) BIG 1-98 IES, ITA, ARNO/ABCSG TEAM TAM AI Node+ Node– Update of Houghton. J Clin Oncol. 2005;23(16S):24s. Abstract 582; Untch and Jackisch. Onkologie. 2007;30:55. R Randomization R R R

77 Switch metanalysis

78 TAM vs AI

79 5 yrs AI vs TAM (ER+): DFS

80 TAM 2-3 yr AI 2-3 yr

81 Conclusioni DFS : AI > TAM in ogni caso Upfront: + 4 % a 8 anni –effetto presente fino alla fine del trattamento Switch: % a 6 anni –Effetto presente fino a 2-3 anni, poi modesto (???) Buon profilo di sicurezza

82 BIG 1-98

83 BIG 1-98 Study Design

84 BIG 1-98: monotherapy update

85 BIG 1-98: BC Events Tam Let vs Let

86 BIG 1-98: BC Events Let Tam vs Let

87 BIG 1-98 Central Review (Median Follow-up of 51 mo) DFS Benefit of Letrozole Observed Irrespective of PgR or HER2 Status Viale et al. J Clin Oncol. 2007;25:3846; Rasmussen et al. J Clin Oncol. 2007;25(18S):12s. Abstract DFS (%) DFS (%) Years Since Randomization DFS by PgR status DFS by HER2 status NEvents4-y DFS%(SE) PgR-absent tamoxifen (3) PgR-absent letrozole (3) PgR-present tamoxifen (1) PgR-present letrozole (1) NEvents4-y DFS%(SE) HER2- tamoxifen (1) HER2- letrozole (1) HER2+ tamoxifen (5) HER2+ letrozole (4)

88 ABCSG 8 Trial

89 ABCSG 8 Trial : RFS

90 ABCSG 8 Trial : OS

91 The TEAM STUDY

92 TEAM Trial: revised design 2004

93 TEAM: DFS at 2.75 years (ITT)

94 TEAM: Time to Distant Metastases

95 DFS: On-Study Drug and Pre-Switch (96 never treatet pts excluded)

96 TEAM : conclusions

97 Sommario Mustacchi su HT adiuvante in menopausa (2008) Argomento ormai abusato AI > TAM sempre (ma non così tanto) 1 cp Tam 0.40 ; 1 cp AI 5.30 Possibili usi: –AI 5 anni (tutti), TAM AI (ANA,Exe), LET TAM (?) Scelta: in base al profilo di tossicità e dati disponibili Tam rimane accettabile scelta per basso rischio, cardiopatiche, etc etc Tante opzioni possibili = miglior tayloring Se Sequenziale +/- = Upfront, meno tossicità (?) e ½ costo

98 That s not the last song


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