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.

HOT TOPICS IN BREAST CANCERChieti, 11 Novembre 2009

OLD AND NEW ANTHRACYCLINES: OLD AND NEW ANTHRACYCLINES:

a still valid option in breast cancer a still valid option in breast cancer

treatmenttreatment

A. NuzzoU.O. di Oncologia Medica

Ospedale Renzetti di LancianoA. Nuzzo

U.O. di Oncologia Medica

ASL Lanciano-Vasto

“Agosto 1968. 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: “Dall’altra parte” Ed. Rizzoli, 2006

EBCTCG Meta-analysis 2005-EBCTCG Meta-analysis 2005-0606

Breast cancer mortalityBreast cancer mortality

Peto R on behalf of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Presented at SABCS 2007, December 13, 2007. San Antonio, TX.

10

0 5 10 0 5 10 0 5 10

50

0

40

30

20

Death rates (% / year: total – rate in women without recurrence) & logrank analyses

Anthr.31.0%

Taxane25.9%

%+ SE

10-y gain 5.1% (SE 1.6)Lorank 2p < 0.00001

15.3

12.8

Years

10-y gain 4.3% (SE 1.0)Lorank 2p < 0.00003

10-y gain 4.3% (SE 1.0)Lorank 2p < 0.00001

YearsYears

CMF31.3%

Anthr.27.0%

Control36.4%

CMF32.2%

20.5

17.8

19.9

16.5

Taxanes > Anthra. > CMF > No Chemo.

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

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.

1. leucemogene2. cardiotossiche

Le antracicline sono farmaci tossici ?

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 intensive

CMF per os

DFS (§) 52% 45%OS 62% 58%

(§) significativo

M. Crump et al., J Clinical Oncology 2003

Risk of Acute Leukemia Following Risk of Acute Leukemia Following Epirubicin-Based Adjuvant Chemotherapy: Epirubicin-Based Adjuvant Chemotherapy:

A Report From the National Cancer Institute of Canada A Report From the National Cancer Institute of Canada

Clinical Trials GroupClinical Trials Group

CARDIOTOSSICITA’ DA CARDIOTOSSICITA’ DA ANTRACICLINE: UN PROBLEMA ANTRACICLINE: UN PROBLEMA

CLINICO EMERGENTECLINICO 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

CARDIOTOSSICITA’: TIPO I e II

TIPO I TIPO IIFARMACO DOXORUBICINA TRASTUZUMAB

DOSE CORRELATA

SI NO

MECCANISMO STRESS OSSIDATIVO

INIBIZIONE HER-2

DANNO ULTRASTRUTTU

RA

PRESENTE ASSENTE

REVERSIBILITA’ NO SI

RECHALLENGE NO POSSIBILE

Ewer MS. JCO 2005;23:2900-2902

“…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. 3991-4008

Tossicità cardiaca doxorubicina vs epirubicina

Dose RatioDose Ratio1:1.71:1.7

Mouridsen, Acta Onc ’90: 29; 257-85

AC x 4AC-Tax

TAC x 6

FEC x 3- Doce

CARDIOTOSSICITA’ TARDIVA DA DOXORUBICINA

Zambetti M et al, JCO 2001;19,37-43

1000 ptsCMF (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

Felker GM et al. N Engl J Med 2000;342:1077-84

1.00

0.75

0.50

0.25

0.000 5 10 15

Years

Peripartum

Idiopathic

ischemic heart diseaseDue to

Due to HIV infection

Due to infiltrative myocardial disease

Due to doxorubicin therapy

Pro

po

rtio

n o

f P

atie

nts

Su

rviv

ing

Survival According to the Underlying Cause of

Cardiomyopathy

Doxorubicine liposomaili disponibiliDoxorubicine 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

van Dalen EC, Michiels EM, Caron HN, Kremer LC. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev. 2006 Oct 18;(4):

van Dalen EC, Michiels EM, Caron HN, Kremer LC. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev. 2006 Oct 18;(4):

van Dalen EC, Michiels EM, Caron HN, Kremer LC. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev. 2006 Oct 18;(4):

Van Dalen et al. Cochrane Database Syst Rev. 2006 Oct 18;(4):

Meta-analisi degli studi di fase III Confronto tra Antracicline rispetto alla

Cardiotossicità

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

Quante zampe ha questo elefante?

Fattori predittivi ?

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 ?

The effect of genetic variability on drug

response in conventional breast cancer treatment.

Wiechec E, Hansen LL.

Eur J Pharmacol. 2009 Oct 18.

Prognosi molecolare

MammaPrint® Oncotype DX ……….

Criteri di selezioneCriteri di selezione

1) ETA’2) COMORBIDITA’3) LVEF4) HER-25) Topoisomerasi IIα6) chromosome 17 polysomy

(Bartlett et al, SABCS 2008)

DOSE CUMULATIVA E RISCHIO DI SCOMPENSO NEI PAZIENTI ANZIANI

Swain et al. Cancer. 2003: 97, 2869-2879

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 21-22

• Riparazione DNA tramite Riparazione DNA tramite legame covalentelegame covalente

AMPLIFICAZIONE DELLA TOP II AMPLIFICAZIONE DELLA TOP II α NEL CARCINOMA MAMMARIONEL CARCINOMA MAMMARIO

Co-amplificazione TOP II Co-amplificazione TOP II α / HER-2/ HER-2 35% delle pz con HER-2 amplificato35% delle pz con HER-2 amplificato (Slamon D, SABCS 2006)(Slamon D, SABCS 2006)

37% delle pz con HER-2 amplificato37% delle pz con HER-2 amplificato (Tanner M, JCO 2006)(Tanner M, JCO 2006)

Amplificazione TOP 2 II Amplificazione TOP 2 II α / HER-2 non / HER-2 non amplificatoamplificato 1,7 – 10,3%1,7 – 10,3% (Knoop AS, JCO 2005)(Knoop AS, JCO 2005)

Amplificazione TOP II II αCome fattore predittivo di risposta alle antracicline nel carcinoma Come fattore predittivo di risposta alle antracicline nel carcinoma

della mammelladella mammella

Dal 2002, almeno 6 studi pubblicati hanno dimostrato Dal 2002, almeno 6 studi pubblicati hanno dimostrato l’associazione tra amplificazione TOP 2A e miglior outcomel’associazione tra amplificazione TOP 2A e miglior outcome

- Slamon D, Brest Cancles Treat 2006Slamon D, Brest Cancles Treat 2006 2990 pz Adiuvante2990 pz Adiuvante

- Tanner M, JCO 2006Tanner M, JCO 2006 525 pz 525 pz Adiuvante Adiuvante

- Knoop AS, JCO 2005Knoop AS, JCO 2005 825 pz 825 pz Adiuvante Adiuvante

- Park K, EJC 2003Park K, EJC 2003 188 pz 188 pz Neoadiuvante Neoadiuvante

- Coon JC, Clin Canc Res 2002Coon JC, Clin Canc Res 2002 35 pz 35 pz Neoadiuvante Neoadiuvante

- Di Leo A, Clin Canc Res 2002Di Leo A, Clin Canc Res 2002 354 pz 354 pz Adiuvante Adiuvante

Slamon D, SABCS 2006 - ModificataSlamon D, SABCS 2006 - Modificata

HER2 e antraciclineOverall Survival

heterogeneity c25 = 5.2, p = 0.39heterogeneity c25 = 5.5, p = 0.36

Test for interaction chi2 = 12.0, p < 0.001

Study HR 95% CI0.47 - 0.92

0.69 - 1.18 0.66 0.90 NSABP B11

0.63 - 1.060.88 - 1.30

0.821.07 NSABP B15

0.27 - 2.690.85 - 3.15

0.85 1.64 GUN 3

0.32 - 1.160.89 - 1.79

0.611.26 Milan

0.50 - 1.050.59 - 1.13

0.730.82DBCG-89-D

0.42 - 1.010.80 - 1.40

0.651.06 NCIC MA-5

0.62 - 0.850.92 - 1.16

0.73 1.03

Overall

HER2 positive HER2 negative

non anthra betteranthra better

0.6 1 2 50.4

p < 0.0001

p = 0.86

0.9

A. Gennari SABCS 2006

0.83 - 1.000.91Total p = 0.056

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

Cancer Treat Rev. 2009 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.

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.

Cancer Treat Rev. 2009 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.

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).

alterations in the topoisomerase II alpha (TOP II 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

uomo barbuto o donna nuda ?

Abbiamo alternative migliori delle antracicline ?

Jones, S. et al. J Clin Oncol; 27:1177-1183 2009

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

Jones, S. et al. J Clin Oncol; 27:1177-1183 2009

Summary of unplanned, exploratory analyses of disease-free survival hazard ratios (HR) and CI

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

Clo

doveo M

asc

iare

lli

graziegrazie