Paziente in et fertile

1
Corso multidisciplinare di aggiornamento sul
carcinoma della mammella
Paziente in età fertile
Angiolo Gadducci Department of Procreative
Medicine, Division of Gynecology and Obstetrics,
University of Pisa
2
Pregnancy in breast cancer (BC) survivors

• BC accounts for more than 30 of all cancers
  diagnosed in women
• 25 of BCs occur before menopause and 15 under
  the age of 45 year
• Over the past decade BC incidence has increased
  by 0.5/year, whereas the death rate decreased
  1.4/year
• The decline in mortality is more remarkable in
  women lt 50 years

3
Pregnancy in BC survivors

• The increasing number of BC survivors will make
  the issues of ovarian dysfunction and
  childbearing ability more and more relevant for
  the quality of life of these pts.
• Coupled with the increased number of women who
  delay first childbirth gt 35 years, the larger use
  of chemotherapy (CT) has resulted in a large
  proportion of BC pts of young age facing in
  fertility

Colleoni, 2002 Oktay 2005 Thewes 2005
4
Pregnancy in BC survivors

• Ovarian function after chemotherapy
• Protective role of Gn-RHa against ovarian damage
  by chemotherapy
• Prognosis of BC survivors who have a pregnancy
• Obstetric outcome after cancer treatment

5
Ovarian dysfunction after CT

• Ovarian damage depends on
• Patient age
• Specific drugs
• Total dose administered

6
Ovarian damage after CT
CT apoptosis of pregranulosa cells of
primordial follicles ? depletion of primordial
storage at birth at puberty at
menopause N ovocytes In normal ovary 2.000.000
200.000 400
7
Ovarian damage after CT
Ovarian toxicity Drugs High
Alkylating agents (CTX,
L-PAM, nitrogen mustard) Moderate
CDDP, DOX, TAX Mild or no
MTX, 5-FU, VCR, ACT-D, BLEO
Feldman 1989
8
Ovarian dysfunction after CT

• Age and alkylating agent dose are the most
  important predictive factors for CT-related
  amenorrhoea in
• women receiving neoadjuvant CT with HD-IFO
  HD-MTX DOX CDDP for osteosarcoma of the
  extremities Longhi 2003
• women receiving CT for BC Bines 1996,
  Collicchio 1998

• The total dose of CTX needed to induce
  amenorrhoea in a woman aged 40 is 4-times less
  the equivalent dose in a 20-year old one
  Shanin, 1998

9
CT-induced amenorrhoea in BC
Authors Regimen
Amenorrhoea rate Goldrisch 1990
CMF lt 40 yrs 61

gt 40 yrs 95
Valagussa 1993 CMF DOX lt 30 yrs
4 36-40 yrs 50

41-45 yrs 86
gt 46 yrs 100 Minton 2002 CMF
lt 40 yrs 21-70 gt 40 yrs
40-100
10
CT-induced amenorrhoea in BC pts
Authors Regimen
Amenorrhoea rate Bines 1996 CMF
69 AC (DOX CTX) 34 Levine
1998 CMF 43 FEC (EPIDOX
CTX 5-FU) 51
11
CT-induced amenorrhoea in BC pts
Authors pts Regimen
Amenorrhoea rate Hortobagy 1986 796
DOX-based CT 59 Age
(years) lt 30 0 30-39
33 40-49 96
12
Incidence of CT-induced, long-term amenorrhoea
in BC pts aged lt 40 yrs after adjuvant
anthracycline and taxane

• To assess the incidence of long-term amenorrhoea
  (gt 12 months) in 166 premenopausal BC pts lt 40
  yrs after adjuvant anthracycline and taxane-based
  CT
• All pts had regular pretreatment menses
• 25 (15) pts developed long-term amenorrhoea
• 141 (85) pts resumed menstruation
• Significant association between age and
  amenorrhoea, with older women being at higher
  risk (p lt 0.01)

Fornier, 2005
13
Incidence of CT-induced amenorrhoea in BC pts
treated with adjuvant DOX CTX (AC) followed
by a taxane (T)

• To assess the incidence of amenorrhoea in 191
  premenopausal pts aged lt 50 yrs after adjuvant AC
  T
• Amenorrhoea 95 CI OR (95 CI)
• AC T 64 55-72 1.9 (1.0-3.5)
• AC 55 43-66 p 0.05
• 40 of pts lt 40 years resumed menstruation,
  whereas the amenorrhoea was more likely to be
  irreversible in older women.
• The addition of T did not change the
  reversibility rate.

Tham, 2007
14
Pregnancy in BC survivors

• Ovarian function after chemotherapy
• Protective role of Gn-RHa against ovarian damage
  by chemotherapy
• Prognosis of BC survivors who have a pregnancy
• Obstetric outcome after cancer treatment

15
Gn-RH agonists (Gn-RHa) as protective agents
against CT-induced ovarian dysfunction
D-TRP6Gn-RH follicle loss in
CTX-treated rats Bokser 1990
Gn-Rha appear to protect the ovaries against the
CT-induced damage in women with different
malignancies Blumenfeld 1996, 2002, 2003
Recchia 2001
16
Prevention of irreversible CT-induced ovarian
damage in young women with lymphoma by a Gn-RH
A in parallel to CT
D-TRP6Gn-RH Pts Ovulation and cyclic
menses 3-8 months after CT completion
yes 16 15
(93.7) no 18 7
(38.8)

p0.017
Blumenfeld , 1996
17
Gn-RH A added to adjuvant CT protect ovarian
function in young women with early BC

• Study population 13 pts (26-39 years) received
  adjuvant AC, AC/T, CAF, DOX T/CMF plus
  leuprolide
• All pts became amenorrhoic by the 2nd cycle of
  CT.
• Menses resumed in all pts within 12 months of
  completion of CT with a mean time of 4-20 months
  (2-12 months)

Fox 2001
18
Gn-RH A added to adjuvant CT protect ovarian
function in young women with early BC

• Study population 100 premenopausal high-risk,
  early BC pts who received Gn-RH A as ovarian
  protection during adjuvant CT (CMF 26 pts,
  anthracycline-based regimens 74 pts)
• After a median follow-up of 75 months
• normal menses all pts lt 40 yrs,
• 56 of pts gt 40 yrs
• 3 pregnancies were observed (2 normal
  deliveries, 1 voluntary abortion)
• Projected 10-y DFS 76
• Projected 10-y OS 91

Recchia, 2006
19
Pregnancy in BC survivors

• Ovarian function after chemotherapy
• Protective role of Gn-RHa against ovarian damage
  by chemotherapy
• Prognosis of BC survivors who have a pregnancy
• Obstetric outcome after cancer treatment

20
Prognosis of pts who had a pregnancy after BC
Study group Control group Years pts
at risk survivors pts at risk
survivors after pregnancy lt 1 32 75 64
61 1 32 75 61 59 2 32 75 59 58 3 3
2 75 49 61 4 32 75 35 49 gt
5 29 72 23 26
Cooper and Butterfield, 1970
21
Prognosis of pts who had a pregnancy after BC
Authors pts who had a pregnancy
pts who had no pregnancy
n. 10-year S n. 10-year
S Mignot 1986 68 75 136
78 Ariel 1989 30 N- 77 600 N-
70 16 N 56
360 N 53 Petrek 1991 22 N-
77 103 N- 75
34 N 25 63 N
41 Sankila 1994 91 92
471 60 Gelber 2001 94 85 188
74
22
Prognosis of pts who had a pregnancy after BC
von Schoultz 2.119 BC women aged lt 50 years
at diagnosis 1995 50 had a
pregnancy after BC HR of distant
metastasis 0.48 (p0.14) Kroman 1997 5725
BC women aged lt 45 years at diagnosis
173 had a
pregnancy after BC RR of death 0.55 (95
CI 0.28-1.06)
23
Prognosis of pts who had a pregnancy after BC
n Deaths RR 95 CI No subsequent
pregnancy 265 34 1.0 reference Any subsequent
pregnancy 53 5 0.8 0.3-2.3
Velentgas, 1999
24
Prognosis of pts who had a pregnancy after BC

• Study population 370 pts lt 35 yrs treated with
  adjuvant CT at the MD Anderson Cancer Center
  Houston
• 47 (13) had at least one pregnancy
• Pts who became pregnant tended to have
• Earlier stage (stage I/II 80 vs 73)
• Fewer N (lt4 87 vs 52)
• More ER- (69 vs 58)
• Younger age (lt 30 yrs 57 vs 32)

Blaklely, 2004
25
Prognosis of pts who had a pregnancy after BC
n 5-y RFS HR 95 CI No subsequent
pregnancy 323 49 Any subsequent
pregnancy 47 82 0.70 0-25-1.95
Blaklely, 2004
26
Prognosis of pts who had a pregnancy after BC
Study population in 1982-2000, 2539 women aged
15-44 years in Western Australia had a
BC 123 (5) of these had at least one pregnancy
after their diagnosis COX
Model Variable HR 95 CI p value Age 0.97 0.
96-0.99 lt0.001 N 2.61 2.17-3.13 lt0.001 Subse
quent pregnancy 0.59 0.37-0.95 0.030
Ives, 2007
27
Prognosis of pts who had a pregnancy after BC
Study population in 1982-2000, 2539 women aged
15-44 years in Western Australia had a
BC 123 (5) of these had at least one pregnancy
after their diagnosis COX Model Time to
subsequent pregnancy HR 95 CI p value 6
months 2.20 0.14-35.42 0.579 6-24
months 0.45 0.16-1.28 0.135 gt 24
months 0.48 0.27-0.83 0.009
Ives, 2007
28
Effect of subsequent pregnancy on BC prognosis
Selection bias pts who subsequently conceive
are generally those ones with more favourable
prognostic features ("healthy mother"
effect) Foetal antigen (Ag) hypothesis BC and
foetal cells share common Ag during
pregnancy foetal Ag can elicit an immune
response against micrometastases.
Sankila, 1994
Janerich, 1994 Botelho, 1998 Averette 1999
29
Pregnancy in BC survivors

• Ovarian function after chemotherapy
• Protective role of Gn-Rha against ovarian damage
  by chemotherapy
• Prognosis of BC survivors who have a pregnancy
• Obstetric outcome after cancer treatment

30
Pregnancy and BC
Only 7 of fertile women go on to conceive
following BC Clinical data on health
status of their offspring are very limited
31
Pregnancy outcome in BC survivors

• Total pregnancies 87 in 53 women
• Single live birth 41 (47.1)
• Multiple births 1 (1.1)
• Still births 0
• Miscarriage 21 (24.1)
• Ectopic pregnancy 1 (1.1)
• Induced abortion 20 (22.9)
• Ongoing pregnancy 3 (3.4)
• vs 18 in controls

Valengtas,1999
32
Pregnancy outcome in BC survivors

• Total pregnancies 47
• Full term delivery 32 (68)
• Elective abortion 10 (21)
• Miscarriage 4 (9)
• Preterm delivery 1 (2)

Blakely, 2004
33
Pregnancy outcome after CT in chilbearing aged
women
Study population 16 pts treated with CT for
ovarian cancer (3), mole (1), vaginal cancer
(1), BC (4), lymphoma (4), lung cancer (1),
melanoma (1), osteosarcoma (1) 21 pregnancy
18 normal infants 1 newborn with a minor
foot abnormality 1 miscarriage 1 ongoing
pregnancy Minime interval between treatment and
pregnancy 32 months (range 3-140) Caesarian
sections 7 (35) Newborn weight 2900-4020 g
Durrieu, 2004
34
Pregnancy outcome in BC survivors
123 BC women had a pregnancy Live babies 66
(54) Miscarriage 15 (12) Termination 42
(34) Still births 0 Ectopic pregnancy 0 2
preterms deliveries
Ives, 2007
35
Pregnancy and BC
No increased incidence of Prematurity
Stillbirth Congenital
malformations Slightly increased incidence of
miscarriage Reichman 1994, Valentgas 1999,
Moore 2000, Puckridge 2003, Blakely 2004, Durrie
2004 Park 2006
36
Pregnancy among long-term survivors of acute
leukemia a second nationwide survey
A Japanese nationwide survey of 336 long-term
survivors of acute leukaemia 89 (50 female
pts and 39 spouses of male pts) had 117
pregnancies during their first remission
Obstetric outcome Abortion
8
Living child
109 ? 2 minor anomalies All children
(age range 2 mos-20 yrs) were in good health
Kavamura, 1998
37
Pregnancy outcome in pts treated for
Hodgkins disease
Study population 94 Hodgkins disease
survivors (43 females, 51 males) attempted
conception 35 females and 25 partners of male
pts had 84 pregnancies Obstetric
outcome Spontaneous abortion 3

Elective abortion
11 Stillborn
2 Live child
68 (no increase in
congenital anomalies)
Aisner, 1993
38
Fertility after conservative surgery and CT for
MOGCT
Study population 70 DG, 99 NDG 138 (81) women
had fertility sparing-surgery and 81 received
CT Obstetric outcome 20 CT-treated pts
12 CT-untreated pts 55 conceptions 40
pregnancies at term 9 miscarriages 6
terminations
Zanetta et al, 2001
39
Fertility after conservative surgery and CT for
MOGCT
1/14 conceptions of CT-untreated pts 4/55
malformation 3/41 conceptions of CT treated
pts Miscarriage rate (11) in the expected
range of general population Malformation
rate (7.2) slightly higher compared with
general population
Zanetta et al, 2001
40
Conclusions

• Most important factors in determining the risk of
  CT-induced amenorrhea age and cumulative dose of
  cytotoxic drugs (alkylating agents)
• Gn-RHa appear to protect the ovaries against
  CT-induced damage

41
Conclusions

• BC survivors who became pregnant are a
  self-selecting group of women with a better
  prognosis (healthy mother effect)
• Pregnancy is a realistic option for some BC
  survivors and is nor detrimental for mother or
  her offspring.

42
Conclusions

• Available data failed to detect a significant
  deleterious effect of prior CT exposure on the
  obstetric outcome of subsequent pregnancies
• A prospective multicenter survey is warranted to
  investigate the long-term effects of CT on the
  offspring of cancer survivors

43
Paola
44
Paola ha 36 anni
Paola insegna. Per molti anni solo supplenze,
poi 3 anni fa è diventata di ruolo. E ha scoperto
che lo stipendio rimaneva da fame Il marito,
Luca, ha 37 anni. E impiegato di banca, da 12
anni. Quattro anni fa è stato promosso ed è
salito di livello. Sono sposati da 11
anni. Hanno preferito non avere figli. I soldi
erano davvero pochi, il lavoro di lei saltuario
e le famiglie di entrambi non navigano nelloro e
non possono tanto aiutarli. Ma da 2-3 anni le
cose vanno un po meglio... Paola ha smesso di
prendere la pillola
Ma figli non ne sono ancora arrivati.
45
Paola è andata dal ginecologo
P. A leggere i giornali e sentire la TV ci sono
tante cose che si possono fare per aver
figli Gin. Certo, ci sono tante cose che si
possono fare ma prima dobbiamo fare un po di
esami
Le sembra giusto, quel ginecologo le piace
Mammografia bilaterale nulla da segnalare a
sinistra. A destra, al QSE, addensamento nodulare
a margini spiculati, diametro massimo 20 mm.
Distorsione strutturale del parenchima
circostante. Il quadro è compatibile con lesione
eteroplasica della mammella. Necessario
approfondimento citologico e/o bioptico. Che
brutte parole
Ma lei era andata per avere un figlio
46
Quel ginecologo non le piace più, ma ci è tornata
Il nodulo non si palpava bene, il seno di Paola è
giovane e si sente. Lo ha controllato anche con
leco e poi le ha fatto un agoaspirato. Dopo un
paio di giorni è arrivato il referto. Positivo
per cellule maligne. Gin. Si. Purtroppo lesame
citologico che abbiamo fatto ha confermato il
sospetto che cera alla mammografia P. Ho il
cancro?!
Gin. (che brutto mestiere che tocca
fare!) Si, ma questo vuol dire poco se non lo
togliamo e non vediamo comè non si può dire
molto potrebbe non essere tanto cattivo non è
il momento di disperarsi ci sono delle cose
importanti da fare, anche per capire meglio
Ma lei voleva solo avere un figlio
47
Lha operata
La stadiazione era negativa. Le condizioni
generali ottime (Paola è giovane e tutto le
funziona bene). Una quadrantectomia. Ha fatto il
linfonodo sentinella (ndr è bravo sto
ginecologo!) Era positivo allesame estemporaneo
Le ha tolto i linfonodi del primo livello.
Diagnosi istologica carcinoma duttale
infiltrante di diametro di 1.8 cm, scarsamente
differenziato con presenza di metastasi in 2 dei
10 linfonodi asportati (2/10).
48
pT1 N1 M0 G3 ER 80 PgR neg HER2 IHC.
Paola e Luca nello studio delloncologo
medico P. Che significano quelle sigle e quei
numeri? Non ci capisco niente Il mio ginecologo
ha detto che dovevo venire qui da lei
49
Loncologo di Paola è bravo
Si aggiorna.
Va allAIOM. Sempre. Va allASCO. Quasi
sempre. Va allESMO. Non proprio tutti gli
anni. ESO almeno un corso allanno
50
Loncologo di Paola è bravo
Si aggiorna.
Va allAIOM. Sempre. Va allASCO. Quasi sempre
questanno forse no. Va allESMO. Non proprio
tutti gli anni. ESO almeno un corso allanno
SU QUESTO E UN PO CONFUSO
51
Loncologo di Paola oggi è a Roma
Riassumendo 36 anni, nessuna patologia
concomitante Quadrantectomia QSE dx per CDI, 18
mm, N 2/10 pT1 N1 M0 G3 ER 80 PgR neg HER2
IHC P. Dottore, è brutto? cosaltro dovrò
fare? mi cadranno i capelli? ah,
dimenticavo, io volevo avere un figlio