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HOT TOPICS IN BREAST CANCER Chieti, 11 Novembre 2009 OLD AND NEW ANTHRACYCLINES: a still valid option in breast cancer treatment A. Nuzzo U.O. di Oncologia.

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Presentazione sul tema: "HOT TOPICS IN BREAST CANCER Chieti, 11 Novembre 2009 OLD AND NEW ANTHRACYCLINES: a still valid option in breast cancer treatment A. Nuzzo U.O. di Oncologia."— Transcript della presentazione:

1 HOT TOPICS IN BREAST CANCER Chieti, 11 Novembre 2009 OLD AND NEW ANTHRACYCLINES: a still valid option in breast cancer treatment A. Nuzzo U.O. di Oncologia Medica Ospedale Renzetti di Lanciano A. Nuzzo U.O. di Oncologia Medica ASL Lanciano-Vasto

2 Agosto Ho terminato di visitare i pazienti ricoverati e sto rientrando nel mio studio dove mi attende Aurelio Di Marco per illustrarmi le caratteristiche di un nuovo farmaco antitumorale che è stato isolato da Federico Arcamone nei laboratori di Farmitalia. Si chiama Adriamicina……. Bonadonna G, Sursum corda. In: Dallaltra parte Ed. Rizzoli, 2006

3 EBCTCG Meta-analysis Breast cancer mortality Peto R on behalf of the Early Breast Cancer Trialists Collaborative Group (EBCTCG). Presented at SABCS 2007, December 13, San Antonio, TX Death rates (% / year: total – rate in women without recurrence) & logrank analyses Anthr % Taxane 25.9 % % + SE 10-y gain 5.1 % (SE 1.6) Lorank 2p < Years 10-y gain 4.3 % (SE 1.0) Lorank 2p < y gain 4.3 % (SE 1.0) Lorank 2p < Years CMF 31.3 % Anthr % Control 36.4 % CMF 32.2 % Taxanes > Anthra. > CMF > No Chemo.

4 a still valid option in breast cancer treatment? FALSE !!

5 Anthracyclines and Early Breast Cancer: The End of an Era? L. Gianni, Journal of Clinical Oncology 2009 Anthracyclines are a mainstay of adjuvant therapy for breast cancer patients worldwide, but some research data suggest that not all patients benefit. Some of the latest studies suggest that a large majority of patients (70%–80%) might not benefit, Early Breast Cancer can be treated with less toxic but equivalent regimens.

6 1. 1. leucemogene cardiotossiche Le antracicline sono farmaci tossici ?

7 710 donne in premenopausa, pN+ FEC (5FU 600 mg/mq 1° e 8° + EPI 60 mg/mq 1° e 8°, EDX per os 75 mg/mq 1°-14° ) vs CMF classico FU mediano 10 anni Levine MN et al: J Clin Oncol 1998 Randomized trial of intensive cyclophosphamide, epirubicin and fluorouracil chemotherapy compared to cyclophosphamide, emethotrexate and fluorouracil in premenopausal women with node-positive breast cancer. NCI of Canada Clinical Trials Group FEC intensiveCMF per os DFS (§) 52%45% OS62%58% (§) significativo

8 M. Crump et al., J Clinical Oncology 2003 Risk of Acute Leukemia Following Epirubicin-Based Adjuvant Chemotherapy: A Report From the National Cancer Institute of Canada Clinical Trials Group

9 CARDIOTOSSICITA DA ANTRACICLINE: UN PROBLEMA CLINICO EMERGENTE Più lunga sopravvivenza dei pazienti La potenziale guarigione di molti pazienti trattati con antracicline (neoplasie ematologiche, terapia adiuvante del ca. mammario, neoplasie pediatriche) Acquisizione di dati a lungo termine

10 CARDIOTOSSICITA: TIPO I e II TIPO ITIPO II FARMACODOXORUBICINATRASTUZUMAB DOSE CORRELATASINO MECCANISMOSTRESS OSSIDATIVOINIBIZIONE HER-2 DANNO ULTRASTRUTTURA PRESENTEASSENTE REVERSIBILITANOSI RECHALLENGENOPOSSIBILE Ewer MS. JCO 2005;23:

11 …Anthracycline cardiomyopathy is characterized by a dose-dependent progressive decrease in systolic left ventricular function often resulting in CHF. In the adult survivor, it is clinically indistinguishable from CHF due to other causes… Journal of Clinical Oncology, Vol 25, No 25 (September 1), 2007: pp

12 Tossicità cardiaca doxorubicina vs epirubicina Dose Ratio 1:1.7 Mouridsen, Acta Onc 90: 29; AC x 4 AC-Tax TAC x 6 FEC x 3- Doce

13 CARDIOTOSSICITA TARDIVA DA DOXORUBICINA Zambetti M et al, JCO 2001;19, pts CMF (363 pt) CMF + doxorubicina (637: 300 mg/mq) (3 studi di CT adj) CHF nel 0,6% tutte trattate con doxo: 1% Follow up mediano = 14 aa : mortalità per cardiopatia 0,4% 355 paz libere da malattia a 11 aa: alterazioni ECG = 23% alterazioni ecocardio = 34% < LVEF 8% in doxo vs 2% p=.032

14 Felker GM et al. N Engl J Med 2000;342: Years Peripartum Idiopathic ischemic heart disease Due to Due to HIV infection Due to infiltrative myocardial disease Due to doxorubicin therapy Proportion of Patients Surviving Survival According to the Underlying Cause of Cardiomyopathy

15 Doxorubicine liposomaili disponibili Non-pegylated liposomal doxorubicin (MYOCET) Pegylated liposomal doxorubicin (CAELYX ) Doxorubicine-citrate linear polimer Liposomal membrane: egg PC/cholesterol Diameter: 150 nm Doxorubicine-ammonium sulfate gel-like precipitate Liposomal membrane: soy HPC/DSPE/cholesterol Polyethylene glycol surface Diameter: 80 nm

16 van Dalen EC, Michiels EM, Caron HN, Kremer LC.van Dalen EC, Michiels EM, Caron HN, Kremer LC. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev Oct 18;(4):

17 van Dalen EC, Michiels EM, Caron HN, Kremer LC.van Dalen EC, Michiels EM, Caron HN, Kremer LC. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev Oct 18;(4):

18 van Dalen EC, Michiels EM, Caron HN, Kremer LC.van Dalen EC, Michiels EM, Caron HN, Kremer LC. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev Oct 18;(4):

19 Van Dalen et al. Cochrane Database Syst Rev Oct 18;(4): Meta-analisi degli studi di fase III Confronto tra Antracicline rispetto alla Cardiotossicità

20 The Cochrane review Based on the currently available evidence on heart failure, we conclude that in adults with a solid tumour liposomal- encapsulated doxorubicin should be favoured over doxorubicin. Until more evidence becomes available on tumour response and survival in patients treated with liposomal-encapsulated doxorubicin or doxorubicin in equimolar doses, we recommend the use of a higher cumulative liposomal- encapsulated doxorubicin dose as compared to the standard cumulative doxorubicin dose Van Dalen EC et al. The Cochrane Library 2006, Issue 4

21 Quante zampe ha questo elefante? Fattori predittivi ?

22 Fattori predittivi Terapia efficace Riduzione complessiva del 20% del rischio di recidiva Riduzione dello 0% del rischio di recidiva Riduzione del 100% del rischio di recidiva Fattori predittivi ?

23 The effect of genetic variability on drug response in conventional breast cancer treatment. Wiechec E, Hansen LL. Wiechec EHansen LL Eur J Pharmacol Oct 18.

24 Prognosi molecolare MammaPrint® Oncotype DX ……….

25 Criteri di selezione 1) 1) ETA 2) 2) COMORBIDITA 3) 3) LVEF 4) 4) HER-2 5) 5) Topoisomerasi IIα 6) 6) chromosome 17 polysomy (Bartlett et al, SABCS 2008)

26 DOSE CUMULATIVA E RISCHIO DI SCOMPENSO NEI PAZIENTI ANZIANI Swain et al. Cancer. 2003: 97,

27 Identifying Breast Cancer Patients Who Won't Respond to Anthracyclines TOPOISOMERASI II alfa Top II a Fig. 15 depliant Proteina di 170 kdaltonProteina di 170 kdalton Posizione 17 q 21-22Posizione 17 q Riparazione DNA tramite legame covalenteRiparazione DNA tramite legame covalente

28 AMPLIFICAZIONE DELLA TOP II NEL CARCINOMA MAMMARIO AMPLIFICAZIONE DELLA TOP II α NEL CARCINOMA MAMMARIO Co-amplificazione TOP II / HER-2 Co-amplificazione TOP II α / HER-2 35% delle pz con HER-2 amplificato 35% delle pz con HER-2 amplificato (Slamon D, SABCS 2006) (Slamon D, SABCS 2006) 37% delle pz con HER-2 amplificato 37% delle pz con HER-2 amplificato (Tanner M, JCO 2006) (Tanner M, JCO 2006) Amplificazione TOP 2 II / HER-2 non amplificato Amplificazione TOP 2 II α / HER-2 non amplificato 1,7 – 10,3% 1,7 – 10,3% (Knoop AS, JCO 2005) (Knoop AS, JCO 2005)

29 II Amplificazione TOP II α Come fattore predittivo di risposta alle antracicline nel carcinoma della mammella Dal 2002, almeno 6 studi pubblicati hanno dimostrato lassociazione tra amplificazione TOP 2A e miglior outcome - Slamon D, Brest Cancles Treat pz Adiuvante - Tanner M, JCO pz Adiuvante - Knoop AS, JCO pz Adiuvante - Park K, EJC pz Neoadiuvante - Coon JC, Clin Canc Res pz Neoadiuvante - Di Leo A, Clin Canc Res pz Adiuvante Slamon D, SABCS Modificata Slamon D, SABCS Modificata

30 HER2 e antracicline Overall Survival heterogeneity c25 = 5.2, p = 0.39 heterogeneity c25 = 5.5, p = 0.36 Test for interaction chi 2 = 12.0, p < Study HR 95% CI NSABP B NSABP B GUN Milan DBCG-89-D NCIC MA Overall HER2 positive HER2 negative non anthra betteranthra better p < p = A. Gennari SABCS Total p = 0.056

31 The role of topoisomerase II alpha and HER-2 in predicting sensitivity to anthracyclines in breast cancer patients. Oakman C, Moretti E, Galardi F, Santarpia L, Di Leo A Oakman CMoretti EGalardi FSantarpia LDi Leo A Cancer Treat Rev Sep 14. In the search for predictive biomarkers to refine clinical prescription of cytotoxic agents, both HER-2 and topo IIα are under exploration for their potential role in identifying individuals with early breast cancer who may benefit from anthracycline therapy. Whilst recent meta-analyses support a predictive role for HER-2 amplification, it remains unclear whether HER-2 is the critical biomarker or whether it is a surrogate marker for topo IIα alteration, a known drug target of anthracyclines. The major limitation in considering HER-2 as a single marker is heterogeneity within the subgroups of HER-2 positive and HER- 2 negative disease.

32 The role of topoisomerase II alpha and HER-2 in predicting sensitivity to anthracyclines in breast cancer patients. Oakman C, Moretti E, Galardi F, Santarpia L, Di Leo A. Oakman CMoretti EGalardi FSantarpia LDi Leo A Cancer Treat Rev Sep 14. For topo IIα, current data is inconclusive. Issues plaguing this field are technical variability in marker definition, complex regulation pathway of topo IIα and lack of prospective, adequately powered studies. With current evidence, neither HER-2 nor topo IIα gene status can be considered clinically valuable markers for anthracycline benefit.

33 factors associated with responsiveness to the anthracycline-containing regimen amplification of the human epidermal growth-factor receptor type 2 (HER2) gene (K. Pritchard et al, N Engl J Med. 2006). II alterations in the topoisomerase II alpha (TOP II α ) gene (K. Pritchard et al, JNCI 2009) I do not use any of these data to guide my own treatment decision-making K. Pritchard

34 uomo barbuto o donna nuda ? Abbiamo alternative migliori delle antracicline ?

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36 Jones, S. et al. J Clin Oncol; 27: Disease-free survival (DFS) and overall survival (OS) (A) DFS by treatment; (B) DFS by treatment and age; (C) OS by treatment: 1 day; (D) OS by treatment and age

37 Jones, S. et al. J Clin Oncol; 27: Summary of unplanned, exploratory analyses of disease-free survival hazard ratios (HR) and CI

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42 Summing-up Anthracyclines remain a mainstay of EBC and ABC treatment Cardiovascular and leukemogen risk however is not trivial and should not be overlooked Data suggest that only some subgroups may derive specific benefits from anthracyclines (although not conclusive) Available non-anthra-based regimens may help us manage uncertainty while further data accumulate M. de Laurentis, XII AIOM Milano 2009

43 Clodoveo Masciarelli grazie

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