Breast Cancer in Pregnancy back from St.Gallen 2013

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1 Breast Cancer in Pregnancy back from St.Gallen 2013 Giovanni Giardina Oncologia Medica Varese

2 Epidemiology * Breast cancer is the most common malignancy occuring during pregnancy. * It has been estimated that up to 3.8% of breast cancer may be diagnosed in women who are pregnant. (median age yrs; median gestational age ws) * Approximately, 1 in pregnancies is associated with cancer A. Frederic, EJC,2010

3 * The incidence is expected to increase further with the rising trend of delaying childbirth to later in life. * There is generally limited experience in treating this clinical setting of breast cancer and the management presents a considerable challenge, mandating changes in approach to the diagnosis, staging and planning of locoregional and systemic therapies. S, McGrath, Ther.Adv.Med.Oncol.,2011

4 The diagnosis may be difficult due to pregnancy related physiological changes of the breast. Average delay from the first symptoms ranges from 1 to 2 months. Delay of diagnosis by 1 month may increase the risk of nodal involvement by 0.9%.

5 Diagnosis Similar to non-pregnant women, the diagnosis is based on * clinical examination * mammography * ultrasound * magnetic resonance imaging * cito-histology

6 Staging Procedures Staging procedures, including radiology, should always be executed if they are likely to change therapeutic decisions. Thereshold related deterministic radiation effects, such as mental retardation and organ malformations, only arise above a dose of Gy.

7 Possibilità terapeutiche CHIRURGIA CHEMIOTERAPIA RADIOTERAPIA da definire in funzione del periodo di gestazione >>>> in modo interdisciplinare e con la paziente

8 CHEMOTHERAPY adjuvant/neoadjuvant * MATERNAL PHYSIOLOGY decreased plasma albumin/increases other proteins will alter drug-protein binding amniotic fluid (pharmacological third space) may be delayed the drug elimination

9 * FETAL DEVELOPEMENT Organogenesis takes place during the first 10 weeks p-glycoprotein expressed in the human placenta may reduce fetal exposure to sevaral antineoplastic agents Ring et al. 2005

10 In general, insults during the first trimester can result in major malformations. Once organogenesis is complete, such malfomations are unlikely.. BUT Chemotherapy after the first trimester is not without risk as the foetus still needs to grow and mature. (central nervous system and gonads) H.A. AZIM, The Breast,2011

11 RECOMANDATION of an international consensus meeting (EJC,46,2010) Regimens that could be used in the (neo)adjuvant setting: * FEC / EC / FAC / AC / Taxanes (non-dna damaging / very low transfer rate) * weekly Epirubicin (fetal safety data / insufficient efficacy data) F.Peccatori et al. 2009

12 Study n pts Regimen weeks at weeks at birth congenital start delivery weight anomalies Cardonick 130 AC/FAC 20.4+/ / /- 4 cases 2010 FEC/ADM 1075 pyloric stenosis VNR/TAX pul-artery fistula encephalopathy hemangioma Hahn 57 FAC 23(11-34) 37(29-42) cases 2006 ( ) down s syndrome ureter. reflux club foot Peccatori 20 EpiADM w 19(16-30) 35(28-40) -- 1 case 2009 ADM based polycyst. kidney Azim 26 ADM based 2 trim. 35(28-40) -- 1 case 2008 polycist. kidney Ring 28 AC/EC 20(15-33) 37(30-40) 3000 nil 2005 Ther. Advances Med. Oncol. 2011

13 Given the potential fetal toxicity of Methotrexate CMF should not be used The Panel concludes that whilst the long term outcome of children exposed in utero to Chemotherapy is poorly documented, the evailable evidence is reassuring with regard to outcome and Chemotherapy should not be withheld for fetal reasons in the second and third trimester of pregnancy.

14 OTHER AGENTS TRASTUZUMAB is not recommended oligo/anhydramnios neonatal deaths (4 cases) secondary to respiratory and renal failure TAMOXIFEN is not recommended various birth defects delaying hormonal treatment, if indicated, after delivery/chemotherapy will not reduce efficacy

15 LAPATINIB is not a standard tratment for early BC its use during pregnancy cannot be recommended (massive transplacental transfer; concerns regarding the use of anti-her2 agents) BEVACIZUMAB its mode of action would strongly caution against using it during pregnancy

16 SUPPORTIVE THERAPY Metoclopramide, Alizapride, 5-HT antagonists, NK1 antagonists, G-CSF and Erythropoietin are SAFE Methylpredisolone or Hydrocortisone is preferred over Dexa/Betamethasone (repeted courses of 12 mg betamethasone for lung maturation have higher rates of attention problems and cerebral palsy in more children at the age of 2)

17 IMPORTANT ISSUES Before starting staging and treatment : an US of the foetus should be performed Before every cycle of chemotherapy : an evaluation of fetal morphology, growth and wellbeing must be carried out by US and, if indicated with Doppler including the peak systolic velocity of the middle cerebral artery

18 Chemotherapy should not be administred : after 35 weeks (spontaneous labour, risk of neutropaenia at the time of delivery, limited capacity to metabolise and eliminate drugs due to liver and renal immaturity) Chemotherapy can be restarted when needed after delivery 1 week only is needed (uncomplicated cesarean)

19 Although placental metastasis in breast cancer are rare : * the placenta should be analysed histopathologically In absence of safety data : * breastfeeding shortly after chemotherapy is not recommended. * primary inhibition of milk production is needed because especially lipophylic agents as taxanes can accumulate in the milk

20 TAKE HOME MESSAGES * Efficient treatment of BC during pregnancy is possible * Diagnostic procedures/staging imaging/chemotherapy are feseable but should be discussed by a multidisciplinary team with sufficient expertise (distant disease staging can be postponed after delivery)

21 *Chemotherapy can be administred during the second and third trimester. Although preliminary data indicate that the serum levels of cytotoxic drugs are lower during pregnancy, standard dosages based on actual heigh and weight should be used

22 * Trastuzumab and Tamoxifen should be avoided * If possible, delivery should not be induced before the 37 week * In recent studies, no significant reduction in RFS and OS has been seen with termination of pregnancy * Several studies have indicated that the prognosis for pregnant patients may not be worse than for age and stage-matched nonpregnant controls

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24 The Panel recommends a plan of care that integrates the physical and emotional well being of the mother with the health of the foetus Referral to an experienced multidisciplinary team, including neonatal, perinatal, obstetrical, breast surgical and oncological care is recommended

25 CASO CLINICO

26 C.A. 35 anni *anamnesi familiare negativa *nessuna patologia di rilievo *1 gravidanza a termine a 32 anni Dicembre 2011, in corso di controllo ginecologico si rileva nodulo QSE Sx

27 Esegue ECOGRAFIA che conferma nodulo con aspetti di malignità FNAC = C 5 ER 45% PgR-vo

28 Dopo discussione con la paziente e marito QUADRANTECTOMIA SE Sx + BLNS Es. Istologico: Carcinoma duttale, G 3 ER 95% PgR 2% Ki67 29% p53 2% HER2-vo (FDA 1+) inv. vascolare: assente Stadio TNM: pt1c (1.2cm) pn0sn (0/3) M0 (non eseguita Scinti ossea)

29 Si era alla 15 settimana di gravidanza QUALE TERAPIA ADIUVANTE??? * rischio di recidiva locale (indicazione x RT) * rischio di recidiva a distanza (indicazione x Chemio-Endocrino)

30 ADJUVANT on line RISCHIO DI MORTE a 10 anni senza terapia 14% con OT beneficio 3.9 con CHT 5.3 CHT + OT 7.7 RISCHIO DI RICADUTA senza terapia 33% con OT beneficio 11.3 con CHT 14.4 CHT + 0T 21.0

31 In paziente non gravida Si proporrebbe : * EC x 4 (durata: 12 sett.) * RADIOTERAPIA (60 Gy; 6 sett.) * ENDOCRINOTERAPIA completa (LH-RHa da subito e Tamoxifene)

32 NELLA NOSTRA PAZIENTE * ENDOCRINOTERAPIA non proponibile!!! * CHEMIOTERAPIA fattibile nel 2 /3 trimestre * RADIOTERAPIA non fattibile nel 3 trimestre

33 RADIOTERAPIA subito?? inizio alla 16 /17 settimana durata 6 settimane (fine a 22 /23 settimana = nel 2 trimestre) ERA POSSIBILE!!!!

34 CHEMIOTERAPIA subito?? inizio alla 18 settimana con EpiADM settimanale x 16 (fine alla 34 settimana) POTEVA andare bene!!!! e dopo il parto: RT e inizio di OT

35 NULLA Avrebbe comportato dilazionare la terapia adiuvante di 5 mesi, scelta non ottimale in termini di riduzione del rischio per la madre

36 QUALE CHEMIOTERAPIA Adjuvant on line senza T Antra Antra (mono) (based) OS 10aa 86% 91% 91% DFS 10aa 67% 80% 81%

37 QUINDI, si poteva proporre (ragionevolmente) a 4 settimane da intervento (18 settimana; 2 trimestre) CHEMIOTERAPIA con EC x 4 oppure EpiADM settimanale x 16 arrivando così alla 30 o 34 settimana e poi RT + OT dopo il parto (naturale o indotto alla 36 /37 settimana

38 La paziente ha eseguito 16 settimane di Chemioterapia ben tollerata, eccetto episodio di Neuropenia G4 E stata monitorata settimanalmente dai Colleghi Ginecologi

39 Il 1 agosto 2012 è nato Matteo che sta crescendo vivo e vegeto La pz ha eseguito Radioterapia e avviato terapia Endocrina completa con LHRHa e Tamoxifene che continuerà per 5 anni

40 European Task Forse on Cancer in Pregnancy German Breast Group European Society of Gynecological Oncology (

41 Centro Multidisciplinare di Senologia - Varese

42 G R A Z I E per l attenzione