Il tumore mammario nelle giovani donne

Lucia Del MastroSS Sviluppo Terapie Innovative

12 maggio 2012

IRCCS Azienda Ospedaliera Universitaria San Martino – IST Istituto Nazionale per la Ricerca sul Cancro

4.5% in donne 20-39 anni = 6.400

Breast cancer - Incidence in Italy

2010– Breast cancer incidence age 20-84: 37947

• Rate: 165/100.000

– Breast cancer incidence age 20-39: 1788 (4%)• Rate: 25/100.000

http://www.tumori.net/it/banca_dati

• Baseline risk assessment– Prognostic factors

• Age• T size• N• Histologic grade• HER2• ER (?)

• Expected benefit of therapy– Predictive factors

• ER -> endocrine therapy

• HER2 -> Trastuzumab

Chemotherapy benefit: no reliable predictive factors

Adjuvant therapy decision making

Age less than 35 years:a cut-off for defining young age-onset

breast cancer

Han et al; Breast Cancer Res Treat (2010)

Aggressive Clinico-Pathologic Features of

Breast Cancer in Young Women

• Women < 35 yrs of age, have higher % of ER and PR negative breast tumors and LVI (p < 0.001) compared to those aged 35 – 50 years

• Differences in T size, nodal and Her2 status have been less clear across studies

Adami et al. NEJM 1986.El Saghir et al. BMC 2006.Holli et al. Eur J Cancer 1997.Colleoni et al. Ann Oncol 2002.Anders et al. JCO 2008.Albain et al. JNCI 1994.

Kroman et al, BMJ 2000

Factors influencing the effect of age on prognosis

Adj chemotherapy and outcome according to age (1)

Aebi et al Lancet 2000

Adj chemotherapy and outcome according to age (2)

Goldhirsch et al. J Natl Cancer Inst Monogr 2001

RELATIVE RISK OF RELAPSE AND 5-YEAR DISEASE-FREE SURVIVAL IN ER-POSITIVE AND ER-NEGATIVE DISEASE

Breast cancer in young women: specific clinical issues

• Risk of hereditary breast cancer• Optimal endocrine treatment• Fertility/pregnancy issues

Hereditary breast cancer • Estimate the likelihood that BRCA1-2 mutation is present• BRCA1 (cr.17)/BRCA2 (cr.13)

– High penetrance: 45-84% lifetime risk of BC. Increased risk of contralateral BC (up to 60%). 11-62% lifetime risk of ovarian cancer

• BRCA1– More likely triple negative– BRCA1 mutation: 11-28% of patients with triple negative BC– Triple negative BC at age <= 40 y: BRCA1 mutation in 11-47%

• Management of patients with BRCA1/2 mutations– Consider bilteral risk reduction mastectomy– Consider bilateral risk reduction salpingo-oophorectomy after

completion of childbearing

Breast cancer in young women: specific clinical issues

• Risk of hereditary breast cancer• Optimal endocrine treatment• Fertility/pregnancy issues

Breast cancer in young women: specific clinical issues

• Risk of hereditary breast cancer• Optimal endocrine treatment• Fertility/pregnancy issues

Copyright © American Society of Clinical Oncology

Petrek, J. A. et al. J Clin Oncol; 24:1045-1051 2006

Fig 2. Bleeding after chemotherapy by patient age

Early menopause by age- < 35 y: 10%- 35-40 y: 50%- >40 y: 85%

Acute ovarian failure underestimates age specific reproductive impairment for young women ‐undergoing chemotherapy for cancer

Cancerpages n/a-n/a, 17 AUG 2011 DOI: 10.1002/cncr.26403http://onlinelibrary.wiley.com/doi/10.1002/cncr.26403/full#fig1

Ovarian function/fertility preservation options in breast cancer patients

Intervention Definition Fertility preservation

Preservation of ovarian function

Embryo cryopreservation

Harvesting eggs,IVF, embryo criopreservation

+? Small case series

no

Oocyte cryopreservation

Harvesting and freezing of

unfertilized eggs

? Small case series, case reports; 2% live

birth per thawed oocyte

no

Ovarian cryopreservation and transplantation

Freezing of ovarian

tissueand reimplantation

? Only 2 live birth reported

? Limited life span of

ovarian tissue

Ovarian suppression with GnRH analogs or antagonists

GnRH given before and

during CT to protect ovaries

? Normal pregnancies reported

(3-8%)

yes

Modified from Lee; JCO 2006

Gonadotropin releasing hormone (GnRH) analogs or antagonists

Role in preventing chemotherapy-induced

menopause in breast cancer patients

Copyright ©2007 AlphaMed Press

Blumenfeld, Z. Oncologist 2007;12:1044-1054

Figure 1. A suggested pathophysiologic mechanism of chemotherapy-induced gonadotoxicity

2. Decrease in uteroOvarian perfusion

3. Activation of GnRHReceptors-> decreasedApoptosis

4. Protection of undiffe-rentiated germ line Stem Cells

Risk of CT-induced menopause w/o LH-Rha protection

STUDY CT+LHRHa CT alone HR 95% CL

PROMISE GIM-6 11\139 31\121 0.25 0,12 – 0,52

GBG 37 ZORO 9\30 13\30 0.56 0,19 – 1,62

MUNSTER 3\26 2\21 1.24 0,19 – 8,19

BADAWY 4\39 26\39 0.06 0,02 – 0,19

SVERRISDOTTIR 41\51 38\43 0.54 0,17 – 1,72

DEMEESTERE 9\45 7\39 1.14 0,38 – 3,42

BEHRINGER 1\10 3\9 0.22 0,02 – 2,67

TOTAL 78\340 120\302 0.46 0,3 - 0,72

LHRHa better LHRHa worse

Long-term outcomesCT alone

N=133

CT + Triptorelin

N=148

Pregnancies 1 3

Cancer recurrences 13 14

Deaths 3 8

Meta-analisi di 7 studi sulle stimolazioni per crioconservazione di ovociti e/o embrioni:

Totale cicli di stimolazione 226

5 studi su 7 hanno riportato i dati dello scongelamento

Totale cicli di scongelamento 20 (sia embrioni che ovociti)

Gravidanze 13

What women want

• From March 2010 to march 2012– 28 patients <= 40 yrs treated at IST-Genoa were

offered strategies for fertility/ovarian function preservation

– Oocyte cryopreservation• 3/28 accepted : 11.0%

– GnRHa temporary ovarian suppression• 25/28 accepted : 89.0%

Ca mammario: gravidanza e fertilità. Protocollo interaziendale per la gestione clinica e per la ricerca applicata

IST S.S. Senologia Chirurgica S.C. Oncologia Medica A S.C. Diagnostica per immagini

IRCCS Giannina Gaslini Dipartimento Ostetrico

Neonatale Ospedale S. Martino

Centro di Fisiopatologia della Riproduzione umana dell’UO di Clinica Ostetricia e Ginecologia.

by L. Del Mastro and G. Canavesehttp://clinicaltrials.istge.it/ist/prefer