breast cancer and pregnancy -...

BREAST CANCER AND PREGNANCY

F. Cardoso, MDDirector, Breast Unit, Champalimaud Clinical Center, Lisbon, Portugal

ESO Breast Cancer Program CoordinatorESMO Board of Directors & NR Committee Chair

EORTC Breast Group Past-Chair

www.abc-lisbon.org

DISCLOSURES

Consultant/Ad Board:

Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi-Sankyo,

Eisai, GE Oncology, Genentech, GlaxoSmithKline, Macrogenics,

Merck-Sharp, Merus BV, Mylan, Mundipharma, Novartis, Pfizer,

Pierre-Fabre, Roche, Sanofi, Seattle Genetics, Teva

PREGNANCY AFTER BREAST CANCER

SAFE?

• Same risk of recurrence and death• Even in Luminal Breast Cancers

YES

death/recurrenceNon PregnantPregnantStudy

reduced874333Azim et al (2013)

reduced9718Cordoba et al (2011)

reduced181451244Azim et al (2011) – M/A

reduced130511089Valachis et al (2010) – M/A

reduced2416123Ives et al( 2007)

reduced9865371Kroman et al (2008)

No difference32347Blakely et al (2004)

reduced2775438Mueller et al (2003)

reduced18894Gelber et al (2001)


Differences in DFS between the pregnant group and matched non-

pregnant group

Azim H A et al. JCO 2013;31:73-79

SUPPORTIVE CARE

Pregnancy after breast cancer should not be discouraged even inpatients with HR positive disease, although all available data havelimitations.


Prospective data from a global clinical trial are being collected (POSITIVE Trial).

• What is the ideal interval between ET interruption and pregnancy?

• When is it considered safe to interrupt ET?

• What is the impact of different ETs in fertility?

Tamoxifen

Ovarian Function Suppression

Open questions


1 + CT

StopET 2

Up to 2 years’ break to allow

conception, delivery ±breast feeding

Follow-up

Screening/eligibility:

Patients with ER+early breast cancer

≥ 18 and ≤42 years at enrollment

Completing 18-30 months of ET (SERMs alone, GnRH analogue + SERM or AIs) 1

Pregnancy desire

0

ENROLLMENT

3

3 months

wash out

24 mos

ET resumption

to complete 5

(-10) yrs

10 yrs2 No more than 1 month prior enroll.

Translational research

Ovarian function evaluation

Uterine evaluation

Genomic evaluation of primary breast tumor

Circulating tumor DNA (ctDNA)

POSITIVE STUDY“The Baby Trial”

Psycho-oncology companion – psychological distress, fertility concerns, decisional conflict

BREAST CANCER DURING PREGNANCY

RARE BUT RISING

Eibye S et al; Obstet Gynecol 2013

Melanoma20.9%

Cervix CA20.3%

Breast CA 20.2%

Stensheim et al, JCO 2009

Epidemiology

Courtesy F. Peccatori

Berry DL et al, JCO 1999

EPIDEMIOLOGY

1/3.000 pregnancies, 5-10% breast cancer < 40 y/o


Possible causes: Increasing age at pregnancy


Possible causes: Increasing incidence of breast cancer in young women


Incidence

✓ Possible absolute increase, at least in some countries

✓ Probable relative increase in countries with high percentage of young women

✓ Relative increase in countries where HRT dependent postmenopausal breast cancer is decreasing (e.g. US)


Matching variables (1 case: 2 controls)

Age (±2 years)

Year of surgery (±2 years)

pT (1a vs. 1b vs. 1c vs. 2 vs. 3 vs. X)

# of positive nodes (0 vs. 1-3 vs. 4-9 vs. 10+)

Neoadjuvant chemotherapy (Yes vs. No)

Azim HA Jr et al; Acta Oncol 2012

Pregnant CasesN = 65

ControlsN = 130

Age (years)

< 3535-39≥ 40

20 (30.8)33 (50.8)12 (18.5)

41 (31.5)61 (46.9)28 (21.5)

Median 36 (28-47) 36 (28-47)

Year of Surgery

1996 - 20032004 - 20052006 - 20082009 - 2010

16 (24.6)20 (30.8)16 (24.6)13 (20.0)

37 (28.5)35 (26.9)36 (27.7)22 (16.9)

Median 2005 2005

pT

1a-b1c23X

5 (7.6)21 (32.3)31 (47.7)6 (9.2)2 (3.1)

10 (7.6)42 (32.3)62 (47.7)12 (9.2)4 (3.1)

pN

pN0pN1pN2pN3pNx

28 (43.1)19 (29.2)10 (15.4)6 (9.2)2 (3.1)

56 (43.1)38 (29.2)20 (15.4)12 (9.2)4 (3.1)


Clinical characteristics


Estrogen Receptor

PresentAbsent

43 (66.1)22 (33.9)

98 (75.4)32 (24.6)

0.175

ProgesteronReceptor

PresentAbsent

42 (64.6)23 (35.4)

87 (66.9)43 (33.1)

0.748

Grade123

4 (7.5)18 (34.0)31 (58.5)

4 (3.6)43 (39.1)63 (57.3)

0.503

Ki-67 %< 20≥ 20

18 (28.6)45 (71.4)

30 (23.4)98 (76.6)

0.442

Her2/neuNegative Positive

54 (83.1)11 (16.9)

103 (81.1)24 (18.9)

0.737

Perivascular Invasion

Absent Present

31 (47.7)34 (52.3)

70 (55.1)57 (44.9)

0.330

Molecular subtypes

Luminal ALuminal BHer2/NeuTriple Negative

8 (12.3)37 (56.9)6 (9.2)

14 (21.5)

13 (10.3)82 (65.1)4 (3.2)

27 (21.4)

0.306

ControlsN = 130

p


Pregnant CasesN = 65

Biological characteristics: no major differences

ControlsN = 130


Chi-square: p=0.68

Basal Luminal-A Luminal-B HER2


Molecular subtypes (IHC): similar distribution


Azim HA Jr et al; Endocrine Rel Cancer 2014Courtesy F. Peccatori

SRC Gene Module

p=0.004

β-Catenin Gene Module

p=0.019

Gene expression profile in several cancer related genes (Affimetrix)

IGFR1 Gene Module

p=0.032

PDL1 GenePD1 Gene

p=0.015p=0.014


...but the same happens in normal (mouse) breast during pregnancy

SRC Gene Module

β-Catenin Gene Module

PD1 Gene

p=0.001p=0.035

p=0.008

IGF1 Gene Module

p=0.004


TILS ≥50%Pregnant: 2/86 patients (2.3%)Non-pregnant: 11/116 (9.6%), p<0.001 Courtesy F. Peccatori

MAIN MESSAGE

TREATMENT MUST BE PERFORMED IN A SPECIALISED CENTER BY AN EXPERIENT

MULTIDISCIPLINARY TEAM!

Managing Breast Cancer during Pregnancy

FIRST QUESTION:TO CONTINUE OR TO STOP THE PREGNANCY?

• Only when diagnosis happens very early (first trimester) this hypothesis needs consideration

• However, this is always a parents decision (independently of the time of pregnancy)

• NO IMPACT ON PROGNOSIS



INTERRUPTING THE PREGANCY DOESN’T ADD ANYBENEFIT TOTHE MOTHER


1st QUESTION:To Continue or To Stop the Pregnancy?

If the decision is to continue pregnancy:

1st MAIN MESSAGE:

AVOID PREMATURE DELIVERY!

2nd MAIN MESSAGE:

TREAT AS YOU WOULD IN A NON-PREGNANT CASE (only few exceptions: ET, anti-HER2)


ULTRASSOUND: YESMRI WITHOUT CONTRAST

MAMMOGRAPHY: IF INDISPENSABLERX: YES BUT PREFERABLE AFTER DELIVERY

BONE SCAN, CTs, PETs: NO

2nd QUESTION:Which type of exams can you perform during pregnancy?


SURGERY: YESCHEMOTHERAPY: YES

RADIOTHERAPY: Yes, with protection but preferable after deliveryHormonal and biological treatments: NO

3th QUESTION:Which type of treatments are possible during pregnancy?



• Breast Conservative Surgery is possible and preferable. Identical indications as in non-pregnant women.

• Sentinel node biopsy is feasible but without using blue dye. Radioisotope dosing should be the minimum possible.

SURGERY

No difference in the surgical approach of breast cancer during pregnancy, but:

- careful anesthesiological evaluation- fetal monitoring, when appropriate

SURGERY

Pic

ture

co

urt

esy

of

Pro

f F

Am

ant


Lymphatic mapping

Dosimetry studies in non-pregnant women:10 MBq fetal exposure < 0.1 mGy

SNB with radioactivelymphatic mapping is safe !

Gentilini O et al, Ann Oncol 2004;15:1348ff

Sentinel node sampling during pregnancy is safe


Breast reconstruction during pregnancy is safe

• Usually contra-indicated

• Associated to serious adverse impact on the fetus

• Wait until after delivery (no problem with the needed time)

RADIOTHERAPY


SYSTEMIC TREATMENTS: crucial importance of GESTACIONAL AGE


1st TRIMESTER – Risk of malformations is 20%

Cardonick E & Iacobucci; Lancet Oncol 2004

The placenta

CHEMOTHERAPY DURING PREGNANCY


SYSTEMIC TREATMENT: CHEMOTHERAPY

Number of patients

drug in the fetus (n) % drug in the fetus

Doxorubicin 15 6 7.5 ± 3.2

Epirubicina 11 8 4.0 ± 1.6

Paclitaxel 11 7 1.4 ± 0.8

Docetaxel 9 0 0

Ciclofosfamide 4 3 25.1 ± 6.3

Carboplatin 7 7 57.5 ± 14.2

PLACENTAL ROLE!

van Calsteren et al; Acta Obstet Gynecol 2011van Calsteren et al; Gynecol Oncol 2011

PACLITAXELEPIRUBICIN

Loibl et al; Lancet Oncol 2012

Chemotherapy effects on pregnancy and fetus

Loibl et al; Lancet Oncol 2012

Chemotherapy effects on newborns

CHEMOTHERAPY RECOMMENDATIONS

• MDT team (including also obstetrics and neonatalogy)

• Treat as similiar as possible to a non pregant patien

• Prefer sequential CT (less toxic, identical efficacy) e.g. EC-Paclitaxel weekly or Paclitaxel weekly – EC

• Dosing according to real weight (not excluding the baby)

• Support measures (ex: antiemetics yes; no growth factors)

• Pregnancy Surveillance: Ultrasound after each cycle of CT


SYSTEMIC TREATMENT: HORMONAL THERAPY

NO!

HIGH RISK OF MALFORMATIONS!

SYSTEMIC TREATMENT: TRASTUZUMAB

NO!

HIGH RISK OF MALFORMATIONS! (anidramnios)Specially in the 2nd e 3rd trimester (different from other drugs)


LHRHa + AROMATASE INHIBITORS

- No data

TAMOXIFEN

- 90 cases on file (Lancet 1993)

- Labia minor coalescence and clitoris hypertrophy in 2 cases(Lancet 1997)

- Goldenhar syndrome in 1 case (JAMA 1994)

Hormonal treatment during pregnancy


FcR mediated placental transfer after first trimester

Fetal kidney:HER 2 +++

OLIGOHYDRAMNYOS

ANHYDRAMNYOS

Azim H et al, Nat Rev Clin Oncol 2009

Trastuzumab during pregnancy


- 18 cases

- Oligo-anhydramnios in 11/18 cases

- Neonatal death in 4/11 cases (respiratory and renal failure due to premature delivery)

- Increased risk with prolonged administration

TRASTUZUMAB CONTRAINDICATED !

Trastuzumab during pregnancy


MOTHER PROGNOSIS (Young women!)

Pregnant cases (n=311) Controls (n=865)

http://www.jco.org/current.shtml

Median follow up: 51 months

p-value: 0.0339

DFS

p-value: 0.0499

OS

Pregnant cases (n=65)

Controls (n=120)

Prognosis (DFS & OS)

Azim HA Jr et al; Acta Oncol 2012Courtesy F. Peccatori

Lancet Oncol 2012; 13: 256–64

CHILD LONG TERM EFFECTS

Fetal exposure to chemotherapy was not associated with increased

CNS morbidity….compared with the general population.

CHILD LONG TERM EFFECTS

• Long term cognitive function is related with date of delivery but not with the number of CT cycles

• Each additional pregnancy month is associated to a rise of 11.6 points in the Intelligence Coefficient Scale

MAIN MESSAGE:

AVOID PREMATURE DELIVERY!

NEED FOR MORE INFORMATION: EUROPEAN REGISTRIES

Registry for breast cancer

during pregnancy

GBG-29

BIG 02-03

www. germanbreastgroup.de/pregnancy

With support of the BANSS-Foundation

BREAST CANCER DURING PREGNANCY: CONCLUSIONS


SUPPORTIVE CARE


Treatment of patients with breast cancer during pregnancy shouldbe decided on an individual basis according to internationalguidelines within an expert multidisciplinary team, expanded toinclude obstetricians and perinatologists, and according topatients' preferences.

breast cancer and pregnancy -...

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