Breast Cancer in Pregnancy - "back from St.Gallen 2013" Giovanni Giardina

Breast Cancer in
   Pregnancy
“back from St.Gallen 2013”

            Giovanni Giardina
           Oncologia Medica – Varese

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 33-34 yrs; median gestational age 17-25 ws)

* Approximately, 1 in 3000 – 3500 pregnancies is
  associated with cancer

                                   A. Frederic, EJC,2010

* 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

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%.

Diagnosis

Similar to non-pregnant women, the diagnosis
is based on

     * clinical examination
      * mammography
         * ultrasound
            * magnetic resonance imaging
               * cito-histology

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
0.1-0.2 Gy.

Possibilità terapeutiche

              CHIRURGIA
               CHEMIOTERAPIA
                RADIOTERAPIA

da definire in funzione del periodo di gestazione
>>>> in modo interdisciplinare e con la paziente

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

* 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

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

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

Study       n° pts   Regimen     weeks at      weeks at        birth        congenital
                                 start         delivery        weight       anomalies

Cardonick    130     AC/FAC      20.4+/- 5.4   35.8+/-1.9      2836+/-      4 cases
  2010               FEC/ADM                                   1075        pyloric stenosis
                     VNR/TAX                                               pul-artery fistula
                                                                           encephalopathy
                                                                           hemangioma

Hahn          57     FAC         23(11-34)     37(29-42)        2890        3 cases
 2006                                                        (1389-3977)    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

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.

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

LAPATINIB is not a standard tratment for early BC

       its use during pregnancy cannot be recommended
       (massive transplacental transfer; concerns regar-
         ding the use of anti-HER2 agents)

BEVACIZUMAB

        its mode of action would strongly caution against
        using it during pregnancy

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)

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

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)

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

TAKE HOME MESSAGES

* Efficient treatment of BC during pregnancy is possible

* Diagnostic procedures/Staging imaging/Chemotherapy
  are feseable but should be discussed by a multidisci-
  plinary team with sufficient expertise
  (distant disease staging can be postponed after delivery)

*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

* 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

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

CASO CLINICO

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

Esegue ECOGRAFIA che conferma nodulo
con aspetti di malignità

           FNAC = C 5
           ER 45% PgR-vo

Dopo discussione con la paziente e marito

  19.01.2012   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)

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)

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

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)

NELLA NOSTRA PAZIENTE

* ENDOCRINOTERAPIA
      non proponibile !!!

* CHEMIOTERAPIA
      fattibile nel 2°/3° trimestre

* RADIOTERAPIA
       non fattibile nel 3° trimestre

RADIOTERAPIA subito ??

      inizio alla 16°/17° settimana

        durata 6 settimane
    (fine a 22°/23° settimana = nel 2° trimestre)

             ERA POSSIBILE !!!!

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

NULLA

Avrebbe comportato dilazionare la terapia
adiuvante di 5 mesi,

   …… scelta non “ottimale”
      in termini di riduzione del rischio
      per la madre

QUALE CHEMIOTERAPIA

Adjuvant on line

              senza T    Antra     Antra
                         (mono)   (based)

 OS 10aa           86%     91%      91%
 DFS 10aa          67%     80%      81%

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

La paziente ha eseguito 16 settimane di
Chemioterapia ben tollerata,
eccetto episodio di Neuropenia G4

E’ stata monitorata settimanalmente dai
Colleghi Ginecologi

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

European Task Forse on Cancer in Pregnancy

         German Breast Group
European Society of Gynecological Oncology

       (www.cancerinpregnancy.org)

Centro Multidisciplinare di Senologia - Varese

GRAZIE
per l’attenzione