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

Da discutere nell’ambito dei lavori di gruppo: Programma di lavoro 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 Da discutere nell’ambito 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

La Paziente Giugno 2003 Mastectomia dx CLI multifocale G3 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%) Giugno 2003 Mastectomia dx CLI multifocale G3 N neg Ki67 35 % Er 60 % PgR neg HER2 +++

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

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

Scelta Terapeutica: Docetaxel e Trastuzumab Tempo 0 Dopo 6 cicli

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)

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

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

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

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

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

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

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

Sesto quesito Alternative a Trastuzumab

Settimo quesito Trastuzumab o Lapatinib ?

Endocrine adjuvant treatment in postmenopausal women 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

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

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 Positive to negative 0.22 (0.17-0.30) 0.20 (0.12-0.33) Negative to positive 0.11 (0.06-0.22) 0.15 (0.08-0.28) Total discordance 0.29 (0.18-0.47) 0.27 (0.20-0.36) Franco N et al. Proc ASCO 2004;Abstract 539.

Perchè la biopsia? Discordance in HER2 Testing

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

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

Response and survival P<.0001, logrank test 100% 80% 60% Survival PR >12 months 16.2 28.8 40% CR NR NR 20% si 0% 4 landmark 12 24 36 48 60 Months P<.0001, logrank test (Bruzzi, Del Mastro, JNCI 2004)

Prognosis of women with Stage IV breast cancer by HER2 status and trastuzumab treatment. S.Dawood et al ASCO 2008 Abs #1018 2091 patients 1782 HER2 Negative 118 HER2 Positive NO Trastuzumab 191 HER2 Positive Trastuzumab Trastuzumab è l’unica terapia HER2-specifica ad aver dimostrato un aumento della sopravvivenza nelle donne come terapia di elezione per carcinoma mammario metastatico 24

La presenza di un netto vantaggio in termini di sopravvivenza a favore di trastuzumab, indipendentemente dalla CT di associazione, ne sottolinea l’utilità che nasce dallo sfruttamento di un meccanismo d’azione nuovo, indipendente e sinergico a quello di altre terapie consolidate. 25

Clinical benefits of trastuzumab plus taxanes L’associazione Trastuzumab e taxano è il fondamento terapeutico per il trattamento di elezione in donne con carcinoma metastatico HER2-positivo 1Slamon DJ, et al. N Engl J Med 2001;344:783–92 2Baselga J. Oncology 2001;61(Suppl. 2):14–21 3Marty et al. J Clin Oncol. 2005 26

Poly vs monochemotherapy 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 27

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

Cardiac events Cardiac Dysfunction Outcomes (CREC) H + AC AC H + T T Cardiac dysfunction events, n (%) 39 (27) 11 (8) 12 (13) 1 (1) NYHA class III/IV heart failure, % 16 4 2 1 Deaths, n MBC Cardiac Pneumonia Come parte del processo per ottenere la registrazione del trastuzumab per il trattatmento del carcinoma mammario metastatico CREC; Cardiac Review and Evaluation Committee Seidman A et al. J Clin Oncol 2002; 20: 1215-1221

Trastuzumab plus chemotherapy in MBC patients - other trials Cardiac Dysfunction Outcomes (CREC) Cardiac disfunction NYHA Class III-IV CHF Study Treatment No. pts % H0551g H0552g H0649g H0650 H0659g H0693g H alone H+cisplatinum H  other CT 3 1 11 16 15 7 5 6 4 2 8 10 Seidman A et al. J Clin Oncol 2002; 20: 1215-1221

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

CHF fromTrastuzumab is not associated with ultrastructural changes Ewer MS et al., JCO 2005, 23: 7820-7826

Pegylated Liposomial Doxo + Trastuzumab LVEF over time CHF : 0 Cardiotoxicity Without CHF 10 % Chia, S. et al. J Clin Oncol; 24:2773-2778 2006

Peg Liposomial Doxo + Trastuzumab Efficacy RR % (N = 29) 52 Median PFS mos 12 Median OS mos not reached 2 yrs Survival % 77 30 1st line M1 BC pts LVEF > 55 % G3 PPE : 30 % G3 Neutropenia : 23 % Chia, S. et al. J Clin Oncol; 24:2773-2778 2006

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

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

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

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

Two trials evaluating anti-HER-2 therapy after progression to trastuzumab-based chemotherapy Study design No. pts RR% Median TTP, mos Median OS, mos X 78 27 5.6 20.4 German1 X+T 48 8.2 25.5 161 17 4.4 13.7 GSK2 X+L 160 29 8.4 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

Trastuzumab Beyond Progression: Multinational Study of 105 Patients Monotherapy Plus taxane Plus vinorelbine Total 45 40 35 30 25 20 15 10 5 Objective response (CR+PR) (% of patients) 1 mono 41% 2 mono 36% 1 + tax 38% 2 + tax 38% 1 total 39% 2 total 32% 21pts risposto al secondo regime, di questi, 9 non avevano risposto al primo regime ND 1st regimen 2nd regimen (Trastuzumab retreatment) Similar ORR in first and second Trastuzumab treatment Gelmon et al. Clin Breast Cancer. 2004;5:52-58.

Trastuzumab Beyond Progression: Multinational Study of 105 Patients 1st line monotherapy: n 27 TTP 23wks 2° line monotherapy: n 10 TTP 30.5wks 1° line +tax : n 45 TTP 24wks 1° line +vnr : n 0 2° line +tax : n 20 TTP 24wks 2° line + vnr : n 33 TTP 26 wks Similar TTP in first and second Trastuzumab treatment Gelmon et al. Clin Breast Cancer. 2004;5:52-58

Trastuzumab treatment beyond PD The German experience Jackisch, SABCS 2007

440 metastatic pts registered in the DEMETRA study Prosecution of trastuzumab influences the outcome more than response does 440 metastatic pts registered in the DEMETRA study Menard, ASCO 2008

Continuation of Herceptin prolongs median TTP in the GBG-26 study Herceptin + Xeloda (n=78) Xeloda (n=78) Probability + 1.0 + + + HR=0.69 (2-sided p=0.034; 1-sided p=0.015) 0.8 + + + + + 0.6 + + 0.4 + + + + + + + + 0.2 + Reference von Minckwitz G et al. J Clin Oncol (Meeting Abstracts) 2008; 26: abs 1025. 5.6a 8.2a + + + 0.0 10 20 30 40 Time from 1st progression (months) 74 77 40 55 15 29 8 12 5 4 3 3 2 1 1 1 1 1 von Minckwitz , ASCO 2008 44

Continuation of Herceptin probably improves OS in the GBG-26 study Herceptin + Xeloda (n=78) Xeloda (n=78) Probability + + 1.0 + + + + + + + + + + + + + + + + + + + + HR=0.76 (2-sided p=0.26; 1-sided p=0.13) + + + + + + + 0.8 + + + + + + + + + + + + + + + + 0.6 + + + + + + + + + + + + + + + + + + 0.4 + + + + + + + + 0.2 Reference von Minckwitz G et al. J Clin Oncol (Meeting Abstracts) 2008; 26: abs 1025. + + + + 20.4a 25.5a 0.0 10 20 30 40 Time from 1st progression (months) 74 77 66 68 50 59 33 47 21 27 10 15 8 6 3 1 2 1 von Minckwitz , ASCO 2008 45

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

Metastatic Breast Cancer Hormone Responsiveness ER, estrogen receptor; PgR, progesterone receptor. Over the subsequent hundred years, a great deal has been learned about the biology of breast cancer; specifically, endocrine-responsive cancer, which is defined by the presence of hormone receptors or steroid hormone receptors (ie, the estrogen and progesterone receptors). A patient with ER- and progesterone receptor (PgR)–negative disease is unlikely to respond to any sort of endocrine approach to therapy, whereas any level of expression of estrogen and/or progesterone receptors results in a substantial likelihood of responding to antihormone therapy. 47

ER/PgR HER2 & Tamoxifen DFS in tamoxifen-treated patients ER+/PR+ ER+/PR- ER+/PR+ ER+/PR- Arpino, G. et al. J Natl Cancer Inst 2005;97:1254-1261

HER2 and Endocrine Therapy - Metanalysis ER+ Patients (N=1195)  Her2+ Better Her2+ worse  Relative Risk of Treatment Failure (95%CI) Ellegde 1.21 (0.87 – 1.69) Hayes 1.06 (0.47 – 2.38) Houston 2.07 (1.57 – 2.73) Lipton 1st 1.42 (1.24 – 1.63) Lipton 2nd 1.40 (1.25 – 1.56) Willsher 1.33 (0.56 – 3.16) Wright 1.54 (0.86 – 3.74) Yamauchi 1.66 (1.05 – 2.64) Overall 1.44 (1.34 – 1.56) p<0.00001 Test for Heterogeneity: p=0.26

Tamoxifen in HER2+ Disease De Laurentiis, Clin Cancer Res 2005;11:4741-4748

Tam vs AI in HER2+ tumors Neoadjuvant setting Author Nr Study arms Results subgroup HER2 and ER+ % pts HER2 + Ellis JCO 2001 250 TAM vs Letrozole RR 21% vs 88% P=0.0004 14 IMPACT trial BCRT 2004 abs 330 Anastrozole Combination CR 22% 58% 31%

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

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

TanDEM: Response and clinical benefit rates A + H (n=74) A (n=73) A + H (n=103) A (n=104) p=0.026 Patients (%) p=0.018 43 17 28 7 PR, partial response; SD, stable disease; PD, progressive disease

TanDEM: Anastrazole +/- Trastuzumab Progression-free survival Probability 1.0 0.8 0.6 0.4 0.2 5 10 15 20 25 30 35 40 45 50 55 60 Months 95% CI 3.7, 7.0 2.0, 4.6 p value 0.0016 Median PFS 4.8 months 2.4 months Events 87 99 Luminal B Tumors are quite endocrine-resistant No. at risk A + H 103 48 31 17 14 13 11 9 4 1 1 A 104 36 22 9 5 4 2 1 Baselga 2006

TTP is usually much longer Nabholtz, J. M. et al. J Clin Oncol; 18:3758-3767 2000

Sesto quesito Alternative a Trastuzumab

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 1+1 2+2 1+2 As a dual-kinase inhibitor with specificity for both ErbB1 and ErbB2, lapatinib can block signaling through homodimers composed of either of these receptors.1,2 In theory, lapatinib may also be able to inhibit or decrease signaling through other heterodimer combinations, such as ErbB2/ErbB3. 1. Rusnak DW, Lackey K, Affleck K, et al. The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumor-derived cell lines in vitro and in vivo. Mol Cancer Ther 2001; 1:85-94. Xia W, Mullin RJ, Keith BR, et al. Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erk1/2 and AKT pathways. Oncogene 2002; 21:6255-63. Konecny GE, Pegram MD, Venkatesan N, et al. Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells. Cancer Res. 2006;66:1630-1639. Downstream signaling cascade Rusnak et al. Mol Cancer Ther 2001;1:85-94; Xia et al. Oncogene 2002;21:6255-6263; Konecny et al. Cancer Res. 2006;66:1630-1639

Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk Study Design Progressive, HER2+ MBC or LABC Previously treated with anthracycline, taxane and trastuzumab* No prior capecitabine R A N D O M I Z E Lapatinib 1250 mg po qd continuously + Capecitabine 2000 mg/m2/d po days 1-14 q 3 wk Capecitabine 2500 mg/m2/d po days 1-14 q 3 wk Stratification: Disease sites Stage of disease Patients on treatment until progression or unacceptable toxicity, then followed for survival N=528 *Trastuzumab must have been administered for metastatic disease

Response Rate - ITT Population Lapatinib + Capecitabine (n=160) Capecitabine (n=161) Complete response 1 (< 1%) 0 (0%) Partial response 35 (22%) 23 (14%) Overall response rate* (95% CI) 22.5% (16.3 - 29.8) 14.3% (9.3 - 20.7) *P-value (Fisher’s exact, 2-sided) = 0.113

Progression-Free Survival - ITT Population Lapatinib + capecitabine 100 Cumulative Progression-Free Survival, % Capecitabine 90 No. of pts 160 161 Progressed or died 45 (28%) 73 (45%) 80 Median PFS, wk 36.9 17.9 70 Hazard ratio (95% CI) 0.48 (0.33, 0.70) P-value (log-rank, 1-sided) 0.000045 60 50 40 30 20 10 10 20 30 40 50 60 70 Time (weeks)

Mean LVEF at Scheduled Assessments 80 Lapatinib + Capecitabine Capecitabine 75 70 65 Mean LVEF (%) 60 55 n=160 n=160 n=108 n=92 n=84 n=67 n=63 n=37 n=37 n=26 n=15 n=9 n=7 n=1 50 Screening Week 6 Week 12 Week 18 Week 24 Week 36 Week 48 Assessment

Trastuzumab plus lapatinib Synergistic drug interactions were observed in HER2-overexpressing cell lines1 Phase I: MBC, 94% progressed on prior trastuzumab 1CR, 6PRs in 27 patients (26%)2 Trastuzumab Humanized monoclonal antibody directed against HER2 Dual-specific TK inhibitor against EGFR and HER2 Lapatinib 1Konecny et al. Cancer Res 2006; 2 Storniolo et al. Breast Cancer Res Treat 2005 63

EGF104900: PFS and OS L’aggiunta di Trastuzumab a lapatinib ha migliorato significativamente il tempo mediano di sopravvivenza libera da progressione rispetto al solo lapatinib (2.8 vs 1.0 mesi; p= 0.008) e aumentato il tasso di risposta complessiva (10.3% vs 6.9%; p= 0.46) e la sopravvivenza complessiva (mediana 11.9 vs 9.0 mesi; p= 0.106) 64

Settimo quesito Trastuzumab o Lapatinib ?

HER2 signalling pathway: the role of PTEN PI3K p85 IGF-1R HRG GRB2 Ras PI3K p85 Shc PTEN A large-scale RNA interference screen to discover genes involved in trastuzumab resistance in breast cancer identified only PTEN as a modulator of drug sensitivity. Oncogenic mutants of PIK3CA (activator of the same pathway and frequently mutated in breast cancer) also conferred resistance to trastuzumab in cell culture. In a cohort of 55 breast cancer patients, activation of the PI3K pathway, as judged by the presence of oncogenic PIK3CA mutations or low PTEN expression, was associated with poor prognosis after trastuzumab therapy, and the combined analysis of PTEN and PIK3CA identified twice as many patients at increased risk for progression compared to PTEN alone. Thus, assessment of PI3K pathway activation may provide a biomarker to identify patients unlikely to respond to trastuzumab-based therapy. from Berns et al, Cancer Cell 2007, 12: 395 AKT MAPK mTOR GSK3 c-myc Cell survival Cell proliferation

The traslational Neoadjuvant Study Jenny Chang, SABCS 2008

Low PTEN/PI3KA-mut Jenny Chamg, SABCS 2008

Conclusions Jenny Chamg, SABCS 2008

PK interaction between Tamoxifen and Lapatinib parameter (units) LAP LAP+TAM Decrease in LAP+TAM vs LAP LAP AUC tau (h*mg/L) 25.2 (16.3-39.0) 17.9 (12.8-24.9) 0.71 (0.64-0.79) LAP Cmax (mg/L) 1.73 (1.26-2.38) 1.20 (0.91-1.59) 0.69 (0.62-0.78) LAP Cmin (mg/L) 0.56 (0.32-0.99) 0.33 (0.22-0.48) 0.58 (0.47-0.72) 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 Cardoso, SABCS 2008, Poster 2073

Trastuzumab and Letrozole

Letrozole+Lapatinib in MBC

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

PFS : HER2 pos pts S. Johnston, SABCS 2008

Endocrine adjuvant treatment in postmenopausal women 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

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

Switch metanalysis

TAM vs AI

5 yrs AI vs TAM (ER+): DFS

TAM 2-3 yr  AI 2-3 yr

Conclusioni DFS : AI > TAM in ogni caso Upfront: + 4 % a 8 anni effetto presente fino alla fine del trattamento Switch: + 3.5 % a 6 anni Effetto presente fino a 2-3 anni, poi modesto (???) Buon profilo di sicurezza

BIG 1-98

BIG 1-98 Study Design

BIG 1-98: monotherapy update

BIG 1-98: BC Events TamLet vs Let

BIG 1-98: BC Events LetTam vs Let

Years Since Randomization Years Since Randomization BIG 1-98 Central Review (Median Follow-up of 51 mo) DFS Benefit of Letrozole Observed Irrespective of PgR or HER2 Status DFS by PgR status DFS by HER2 status 100 DFS (%) 90 80 70 60 50 40 30 20 10 1 2 3 4 5 DFS (%) 100 90 80 70 60 50 40 30 20 10 1 2 3 4 5 Material evaluable for 74% (3650/4922) of pts randomized to monotherapy arms Kaplan-Meier analyses limited to 3533 pts with tumors confirmed to express ER (1.7% were determined to be ER-absent upon central assessment) Conclusions: Low expression of PgR and overexpression of HER2 were associated with poorer outcome The benefit, in terms of DFS, of LET over TAM was observed in all patients irrespective of the tumor PgR or HER2 status In women with ER+ tumors, PgR and HER2 status do not appear to be selection criteria for treatment with LET vs TAM Years Since Randomization Years Since Randomization N Events 4-y DFS% (SE) PgR-absent tamoxifen 185 41 79 (3) PgR-absent letrozole 191 37 81 PgR-present tamoxifen 1553 228 86 (1) PgR-present letrozole 1580 167 90 N Events 4-y DFS% (SE) HER2- tamoxifen 1646 240 86 (1) HER2- letrozole 1647 178 90 HER2+ tamoxifen 105 32 70 (5) HER2+ letrozole 134 28 79 (4) Viale et al. J Clin Oncol. 2007;25:3846; Rasmussen et al. J Clin Oncol. 2007;25(18S):12s. Abstract 538. 87

ABCSG 8 Trial

ABCSG 8 Trial : RFS

ABCSG 8 Trial : OS

The TEAM STUDY

TEAM Trial: revised design 2004

TEAM: DFS at 2.75 years (ITT)

TEAM: Time to Distant Metastases

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

TEAM : conclusions

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

That ‘s not the last song