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Pregnancy-associated Breast CancerNeed for Indian Registry?
Dr. Jyoti Bajpai
Associate Professor, Medical Oncology
Tata Memorial Hospital, Mumbai, India.
Overview
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Malignancies in pregnancy- Focus on PABC
Diagnosis of PABC
Available treatment options
Chemotherapy in PABC
Chemotherapeutic agents used in cancer during pregnancy
Concerns with Chemotherapy treatment in PABC
Management of PABC: evidence from NCCN guidelines
Post partum care
Need for Indian-specific registry for PABC
Common malignancies seen in pregnancy
European registry of Cancer during pregnancy (n=503)
data from September 20111
11%
7%
Breast
6%
3%
Haematologic
10%
42%
Skin
Cervical
Brain
5%
Ovarian
16%
Other
Unknown
• Cancer is diagnosed in one in every 1000–2000 pregnancies, with 2500–5000 new
cases in Europe each year2
• Approximately 0.2% to 2.6% of all breast cancers occur during pregnancy3,4
1. European Registry of Cancer during pregnancy Loibl et al.
Lancet Oncol. 2012;13(9):887-96.
2. Wallack et al. Curr Probl Cancer.1983;7:1-58.
3. Lethaby et al. Int J Cancer.1996; 67:751-5.
Incidence of tumor types in pregnant
women
Malignancy
Incidence (per number of gestations)
Malignant melanoma
Breast carcinoma
1:1000-10,000
1:3000-1:10,000
Carcinoma of the cervix
1:2000-10,000
Lymphoma
1:1000-1:6000
Leukemia
1:75,000-1:100,000
Ovarian cancer
1:10,000-1:100,000
Colon cancer
1:13,000
Pentheroudakis et al. Ann Oncol. 2010;21 Suppl 5:v266-73.
Pregnancy-associated breast cancer (PABC)
Definition
PABC is defined as breast malignancies
diagnosed/occurring during gestation or till one year
postpartum
Pregnancy-associated breast cancer
(PABC)
Breast cancer diagnosed during pregnancy is rare but increasing1
PABC is often diagnosed at an advanced stage and its prognosis is inferior
compared to non-PABC2
1 incidence per 3,000 to 10,000 pregnancy3, other studies report from 2.3 to
40 per 100 000 deliveries4
The incidence is lower (0.7% in India)5 in developing countries as the age of the
mother at delivery is younger
1. Keyser et al. Rev Obstet Gynecol. 2012;5:94-9.
2. Padmagirison et al. The Obstetrician & Gynaecologist
2010;12:186-92.
3. White. Surg Gynecol Obstet 1955;100:661-6.
4. Andersson et al. Obstet Gynecol 2009;114:568-72.
5. Gogia et al. Indian J Cancer 2014;51:167-9.
Incidence
Incidence of PABC has been increasing as evident from large registry study that
included four million deliveries over five decades1
37.4
15
12
30
20
16
Incidence of PABC per
100000 deliveries
Incidence of PABC per
100000 deliveries
40
16
10
10.6
8
4
2.4
0
0
1963
2002
Overall
incidence
Andersson et al. Obstet Gynecol 2009;114:568–72.
First year after Second year
delivery
after delivery
Reasons for increased incidence of PABC
Delaying of childbearing to a later age1,2
Increasing incidence of cancer with age2
Increasing number of premenopausal women diagnosed with
breast cancer1,2
Better detection and increasing awareness1
1. Ulery et al. J Midwifery Womens Health. 2009;54(5):357-63.
2. Keleher et al. J Am Coll Surg. 2002;194(1):54-64.
Cellular microenvironment leading to
breast tumor progression
Polyak K. Cancer Cell. 2006;9(3):151-3.
Causes of breast
lump in pregnancy
Risk factors
Hormonal1,2
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•
•
•
Abscess 5
Early menarche
late menopause
parity
breastfeeding
Galactocoele
1
1,3
Reproductive
1 Focal lobular hyperplasiaGenetic
• late age at first 2 Lactating adenoma
pregnancy
Causes
• use
of oral
• BRCA1 and BRCA2
contraceptive
mutations
• hormone
replacement 3 Ectopic breast tissue
4
therapy
1. Narod et al. Nat Rev Cancer. 2004/09/03 ed. 2004;4(9):665–76. 3. Narod S. Nature reviews. Cancer [Internet]. 2002;2(2):113–23.
2. Russo ethttp://www.sah.org.au/assets/files/PDFs/GP%20Conf%20Presentations/Breast%20Cancer%20in%20Pregnancy.pdf
al. The breast journal [Internet]. 2001;7(5):278–91.
Clinical presentation
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A lump in or near the breast or in the underarm area
A change in the size or shape of the breast
A dimple or puckering in the skin of the breast
A nipple turned inward into the breast
Fluid, other than breast milk, from the nipple, especially if
it's bloody
• Scaly, red, or swollen skin on the breast, nipple, or areola
• Dimples in the breast that look like the skin of an orange,
called peau d’orange
http://www.cancer.gov/cancertopics/pdq/treatment/breast-cancer-and-pregnancy/Patient/page1
Causes of delayed diagnosis
• Imaging diagnosis is difficult due to pregnancy-induced breast
changes, such as engorgement1,2
• Self-examination is difficult and is not performed frequently2
• Young women are not potential candidates for screening test3
• Patients reluctant to biopsy during pregnancy3
Diagnosis delayed by one month increases axillary lymph node
metastasis by approximately 0.9% to 1.8%4
1. Yu et al. Obstet Gynecol Sci. 2013;56(3):143-59.
2. Fuentes-Alburo et al. Breast Cancer Res Treat 2000;64:250.
3. Chiechi et al. Minerva Ginecol 1998;50:301-4.
4. Nettleton et al. Obstet Gynecol 1996;87:414-8.
Increased rates of mortality among women
with PABC
To investigate the
mortality in women
with PABC in relation
to when the tumor was
detected (during
pregnancy) and by
time since diagnosis,
compared with women
with non-PABC
Population-based
cohort study in
15,721 Swedish
women with
PABC
PABCs definition: as malignancies
diagnosed within 9 months before the delivery
date (during pregnancy) or within 2 years after
delivery
Non-PABC definition: Breast cancers occurring
outside this time window
Johansson et al. Cancer Epidemiol Biomarkers Prev. 2011 Sep;20(9):1865-72.
Measures:
Mortality rates
and Hazard Ratios
in patients with
PABC compared
to Non-PABC
Mortality rates in women with PABC by
time since diagnosis
Increased mortality among women with PABC which peaked around 2 years after
diagnosis. Mortality increase was most pronounced in women diagnosed shortly after
delivery indicating
poor prognosis
.
Overview
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•
•
•
•
•
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•
•
Malignancies in pregnancy- Focus on PABC
Diagnosis of PABC
Available treatment options
Chemotherapy in PABC
Chemotherapeutic agents used in cancer during pregnancy
Concerns with Chemotherapy treatment in PABC
Management of PABC: evidence from NCCN guidelines
Post partum care
Need for Indian-specific registry for PABC
Physical
examination
Diagnosis
Includes inspection and palpation of breast
Inspect for lumps, asymmetry, or skin dimpling
Palpated to evaluate texture and detection of masses
Physical examination
Imaging modality of choice to assess a breast lump or localised change in
breast consistency
Ultrasound
Can be safely used in pregnancy
Sensitivity and specificity unaltered by pregnancy
Ultrasound exam
Used to rule out multicentricity and contralateral disease
Sensitivity of approximately 86% during pregnancy
Mammogram
The foetal radiation exposure from mammography with abdominal
Mammogram
shielding is low (0.004 Gy)
MRI
Preferred over ultrasonography for hepatic and bone metastases
MRI Technically difficult after 20 weeks as required to lie face down
Increased blood flow to breasts will decrease sensitivity and specificity
Associated with risks of heating and cavitation to the fetus
BiopsyCore biopsy is the preferred procedure
Biopsy
Fine needle aspiration is unreliable due to possibility of false positive
diagnosis of malignancies and should not be preferred
Barton et al. JAMA 1999;282:1270-80.
Kulshrestha M. Journal of South Asian Federation Obstetrics and Gynecology. 2011;3:1-5.
Diagnostic work-up
Breast mass palpated
Breast ultrasound
Benign
Suspicious
Mammogram ± fine
needle aspiration
Keyser et al. Rev Obstet Gynecol. 2012;5(2):94-9.
Staging studies
• Should be tailored to minimize fetal exposure to radiations
Pulmonary metastasis
• Chest radiographs with abdominal shielding
Liver metastases
• Liver Ultrasound
Bony metastasis
• Skeletal survey via MRI or a modified bone scan
Central nervous system symptoms
• MRI of the brain
1. Keyser et al. Rev Obstet Gynecol. 2012;5(2):94-9.
2. Cardonick E. Int J Womens Health. 2014;6:935-43.
Overview
•
•
•
•
•
•
•
•
•
Malignancies in pregnancy- Focus on PABC
Diagnosis of PABC
Available treatment options
Chemotherapy in PABC
Chemotherapeutic agents used in cancer during pregnancy
Concerns with Chemotherapy treatment in PABC
Management of PABC: evidence from NCCN guidelines
Post partum care
Need for Indian-specific registry for PABC
Factors affecting treatment plan and prognosis
Gestational age at diagnosis of cancer
Staging of tumor
Biology of tumor
Type of breast cancer
Age of the fetus
Hormonal receptor status
Involvement of lymph nodes
Whether there are signs or symptoms
Patient’s general health
1. Kulshrestha M. Journal of South Asian Federation Obstetrics and Gynecology. 2011;3:1-5.
2. http://www.cancer.gov/cancertopics/pdq/treatment/breast-cancer-and-pregnancy/Patient/page1
Treatment options
Chemo therapy
Surgery
Radiation therapy
Targeted therapy
Hormonal therapy
Surgery
• Surgical resection is the mainstay of treatment for early
breast cancer diagnosed during pregnancy1,2
• Modified radical mastectomy is standard of care in 1st and
2nd trimester of pregnancy3
• Breast-conserving surgery (lumpectomy with lymph node
dissection) should be preferred in the 2nd and 3rd trimester1,2
• Surgery can be performed in all trimesters with minimal risk
for the foetus (particularly after the 12th week of gestation) 3
• 1st and 2nd Trimester  Mastectomy
• 3rd Trimester 
<2cm  Lumpectomy
>2cm  Mastectomy
1. Pentheroudakis et al. Ann Oncol 2010;21:v266-73.
Version 2.2012.
2. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. 3. Zagouri et al. J Thorac Dis. 2013 Jun;5 Suppl 1:S62-7.
Radiotherapy
• Not recommended during pregnancy owing to its teratogenic
effects on the fetus
• In patients diagnosed in late 1st and 2nd trimester of pregnancy,
consider delaying radiotherapy to the postpartum period 1
• However, evidence from literature suggests that a conservative
estimate of the lifetime risk of radiation induced by fetal
exposure to 0.01 Gy is about 1 in 1700 cases2
• So based on theoretical assumptions and few experiences, it
may be assumed that radiotherapy is relatively safe only during
the 1st and 2nd trimester of pregnancy1,3
1. Amant et al. Eur J Cancer. 2010 Dec;46(18):3158-68.
2. Kal et al. Lancet Oncol 2005;6(5): 328-33.
3. Toesca et al. Gynecol Surg. 2014;11(4):279-284.
Hormone therapy
• Most PABC are hormone receptor negative
• Tamoxifen is contraindicated in pregnancy due to its
–
–
–
–
–
affects on growing embryonic tissues,
associated with miscarriage
preterm labor
genital tract anomalies
congenital disorders like Goldenhar syndrome, ambiguous genitalia,
Pierre Robin sequence
• If indicated, hormonal therapy can be started after delivery
and after completion of chemotherapy
1. Amant et al. Eur J Cancer. 2010;46(18):3158-68.
2. Cullins et al. JAMA 1994;271:1905-6.
3. Cunha et al. Hum Pathol 1987;18:1132-43.
4. Isaacs et al. Gynecol Oncol 2001;80:405-8.
5. Tewari et al. Lancet 1997;350:183.
6. Braems et al. Oncologist 2011;16:1547-51.
Targeted therapy
• Trastuzumab- not recommended
– High incidence of oligohydramnios and abnormal implantation1
• Lapatinib- not recommended
– Evidence of massive trans-placental transfer2,3,4
• Bevacizumab- not recommended
– Unclear mode of action2,3,4
• Rituximab- not recommended
– Transient neonatal lymphopenia24
• Imatinib- not recommended
– Associated with low birth weight and premature delivery 4
• Erlotinib- not recommended
– Due to lack of data, not advised during gestation 4
1. Azim et al. Expert Rev Clin Immunol 2010;6:821-6.
2. http://www.nccn.com
3. Zagouri et al. Breast Cancer Res Treat 2013;137:349-57.
4. Pentheroudakis et al. Ann Oncol 2010;21:v266-73.
Termination of pregnancy
• No survival benefit with termination of the pregnancy
• Evidence also suggests improved survival for patients who
continued their pregnancies compared to those who
terminated
• However there exists bias of lower risk patients continuing
versus those with more active disease choosing to terminate
• Therapeutic abortion may be preferred in
– women with advanced-stage disease
– patients insisting on breast conservation therapy,
– whom a significant delay of this treatment would jeopardize
maternal health
Cardonick E. Int J Womens Health. 2014;6:935-43.
Overview
•
•
•
•
•
•
•
•
•
Malignancies in pregnancy- Focus on PABC
Diagnosis of PABC
Available treatment options
Chemotherapy in PABC
Chemotherapeutic agents used in cancer during pregnancy
Concerns with Chemotherapy treatment in PABC
Management of PABC: evidence from NCCN guidelines
Post partum care
Need for Indian-specific registry for PABC
Chemotherapy
• Delaying chemotherapy until
after delivery may be
reasonable in some cases
• Contraindicated due to possible
damage to organogenesis
• The estimated risk of fetal
malformations is up to 17%
• Most multi-drug protocols
may be administered without
increased risk for severe
malformations
• Certain chemotherapy
regimens can be relatively
safely administered
The risk of congenital malformations drops
from 10-20% in first trimester to 1.3% in the
third trimester of pregnancy
1. Ring et al. J Clin Oncol 2005;23:4192-7.
2. Azim et al. Cancer Treat Rev 2010;36:101-9.
3. Loibl et al. Cancer 2006;106:237-46.
4. McGrath et al. Ther Adv Med Oncol. 2011 Mar;3(2):73-83.
Overview
•
•
•
•
•
•
•
•
•
Malignancies in pregnancy- Focus on PABC
Diagnosis of PABC
Available treatment options
Chemotherapy in PABC
Chemotherapeutic agents used in cancer during pregnancy
Concerns with Chemotherapy treatment in PABC
Management of PABC: evidence from NCCN guidelines
Post partum care
Need for Indian-specific registry for PABC
Chemotherapeutic agents
Alkylating agents
Platinum compounds
Antimetabolites
Chemotherapeutic
agents
Antitumor antibiotics
Targeted agents
Antitumor
antibiotics
Molecularly
targeted
agents
Platinum
compounds
Antimetabolites
Alkylating
agents
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Methotrexate
Tyrosine
kinase
Cyclophosphamide
5-fluorouracil
inhibitor
Dacarbazine
Cisplatin
Aminopterin
Bleomycin
Imatinib
Ifosfamide,
carboplatin
Cytarabine
monoclonal
antibody,
Mechlorethamine
Tioguanine
rituximab
Procarbazine
Mercaptopurine
Topoisomerases
Anthracyclines
Plant alkaloids & taxanes
Doxorubicin, daunorubicin,
epirubicin, idarubicin, and
mitoxantrone
Paclitaxel, docetaxel,
etoposide, vinblastine, and
vincristine
SGOC Clinical Practice Guidelines,. J Obstet Gynaecol Can 2013;35(3):263–278
Anthracyclines
Drug
Findings
Comment
Doxorubicin
•
Normal outcomes during the second and
third trimesters1
•
Can be used in the second
and third trimesters
Epirubicin
•
No congenital malformations during the
second and third trimesters2
•
Can be used in the second
and third trimesters
Idarubicin
•
Normal pregnancy outcome during the
first trimester3
•
Caution should be exercised
Mitoxantrone
•
Normal delivery during the third
trimester and no congenital
malformations4
•
Can be used in the second
and third trimesters
1. Van Calsteren et al. Acta Obstet Gynecol Scand
2010;89:1338–45.
2. Ring et al. J Clin Oncol 2005;23:4192–7.
3. Niedermeier et al. Pharmacotherapy 2005;25:1134–40.
4. Karimi-Zarchi et al. Arch Gynecol Obstet 2008;277:75–8.
Plant alkaloids and Taxanes
Drug
Findings
Comment
Paclitaxel
•
Delivery of healthy infant with no
congenital malformations1
•
Use with caution during second
and third trimesters
Docetaxel
•
Evidence of cerebral ventriculomegaly
during early stages of pregnancy2
•
Appears to be safe in the
second and third trimesters.
Etoposide
•
Do not cause any congenital
malformations during the second and
third trimesters3,4,5
•
•
Only limited experience
Appears to be safe in the
second and third trimesters
Vinblastine
•
Infants with malformations in the
second and third trimesters3
•
To be used with caution
Vincristine
•
Does not increase risk for
malformation during the second and
third trimesters3
•
Can be used in the second and
third trimesters
1. Gonzalez-Angulo et al. Clin Breast Cancer 2004;5(4):317–9.
2. Mir et al. Ann Oncol 2010;21:425–33.
Overview
•
•
•
•
•
•
•
•
•
Malignancies in pregnancy- Focus on PABC
Diagnosis of PABC
Available treatment options
Chemotherapy in PABC
Chemotherapeutic agents used in cancer during pregnancy
Concerns with Chemotherapy treatment in PABC
Management of PABC: evidence from NCCN guidelines
Post partum care
Need for Indian-specific registry for PABC
Concerns with Chemotherapy
Maternal effects
Fetal effects
Altered drug clearance
Nucleic acid synthesis, microtubule
function, cell division rate
Delayed elimination of agents such
as methotrexate
Potential to cross the placenta
Difficult to predict the appropriate
dose
Sontaneous abortions, fetal death,
and major congenital malformations
Increase maternal and fetal toxicity
Eyes, ears, teeth-palate, genitalia,
hematopoietic system, and CNS
remain vulnerable
Ring et al. Ann Oncol 2005;16(12):1855-60.
Infants exposed to chemotherapy in utero had
a lower birthweight
To determine whether
treatment for breast
cancer during pregnancy
is safe for both mother
and child
447 Patients with
a primary
diagnosis of early
breast cancer
during pregnancy
48% women received chemotherapy during
pregnancy with a median of four cycles
• 178 received an anthracycline,
• 15 received cyclophosphamide,
methotrexate, and fluorouracil,
• 14 received a taxane.
Loibl S, et al. Lancet Oncol. 2012;13(9):887-96.
Primary endpoint
was fetal health
for up to 4 weeks
after delivery
Overview
•
•
•
•
•
•
•
•
•
Malignancies in pregnancy- Focus on PABC
Diagnosis of PABC
Available treatment options
Chemotherapy in PABC
Chemotherapeutic agents used in cancer during pregnancy
Concerns with Chemotherapy treatment in PABC
Management of PABC: evidence from NCCN guidelines
Post partum care
Need for Indian-specific registry for PABC
NCCN treatment guidelines
Trimester
First
Second/early
third
Third
Primary Treatment
Adjuvant Treatment
Mastectomy + Axillary staging
Adjuvant chemotherapy can
begin in second trimester
Mastectomy or Breast conserving surgery +
Axillary staging
Or
Neoadjuvant chemotherapy + mastectomy or
Breast conserving surgery + Axillary staging
post partum
Adjuvant chemotherapy ±
adjuvant radiotherapy and/or
endocrine therapy post partum
Mastectomy or Breast conserving surgery +
Axillary staging
Adjuvant chemotherapy ±
adjuvant radiotherapy and/or
endocrine therapy post partum
NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 2.2012.
Clinical algorithm for
Management of PABC
Breast lump in pregnancy
Breast imaging; Core Biopsy; Staging investigations (with precautions)
< 12 weeks of gestation
> 12 weeks of gestation
Avoid Chemotherapy
Consider mastectomy since
radiation may be delayed
until after delivery
Termination of pregnancy
can be consider in very
poor ECOG PS and/or very
poor prognosis patients to
be discussed with patient
Operable
Locally advanced
Mastectomy or BCS
SNB or Axillary sampling or
clearance
Neo-adjuvant chemotherapy
Adjuvant chemotherapy
Delivery at 35-37 weeks of
gestation
Measures to attain fetal
maturity
Radiation therapy and/or
Targeted Therapy
Bajpai J et al. Pregnancy and Breast Cancer in Oncology Gold Standard. Chapter 18 2014;327-344
Overview
•
•
•
•
•
•
•
•
•
Malignancies in pregnancy- Focus on PABC
Diagnosis of PABC
Available treatment options
Chemotherapy in PABC
Chemotherapeutic agents used in cancer during pregnancy
Concerns with Chemotherapy treatment in PABC
Management of PABC: evidence from NCCN guidelines
Post partum care
Need for Indian-specific registry for PABC
Lactation
• As a rule, women on cancer chemotherapy after delivery should
not be breastfeeding as neither short-term nor long-term safety
has been established
• Mother can discontinue, or temporarily interrupt, breast-feeding if
the risk is perceived to be high
• Cancer chemotherapy schedules may allow breastfeeding women
to store their own milk for near-future use
• Women on chemotherapy should perceive the importance of
breastfeeding and the risks associated with it differently from
women taking non-cancer related medications
• Given the nature of the maternal diseases in question, risk-benefit
assessment of breastfeeding during maternal chemotherapy
needs to be carefully individualized
Gideon Koren SGOC Clinical Practice Guideliens. J Obstet Gynaecol Can 2013;35(3):263–78.
Overview
•
•
•
•
•
•
•
•
•
Malignancies in pregnancy- Focus on PABC
Diagnosis of PABC
Available treatment options
Chemotherapy in PABC
Chemotherapeutic agents used in cancer during pregnancy
Concerns with Chemotherapy treatment in PABC
Management of PABC: evidence from NCCN guidelines
Post partum care
Need for Indian-specific registry for PABC
Rationale for nation-wide registry for
PABC in India
• Indian data is largely lacking and pattern of care is varied and
often substandard
• Varied treatment policies followed across the country
• Required to adopt a uniform consensus
• Need of nationwide registry to collate data on Incidence and
treatment patterns and outcomes of PABC in India
–
–
–
–
Etiology
Staging
Frequency of biomarkers
Treatment pattern and outcome (both maternal and foetal)
• Widen the scope to develop treatment algorithm or build national
consensus statement
Take home messages
Investigations involving ionizing radiation
should be avoided unless absolutely
necessary
PABC needs multi-disciplinary
management
1
Standard chemotherapeutic drugs can be
used safely, especially in the 2nd or 3rd
trimesters.
Targeted therapy and hormonal therapy
should be deferred until after delivery.
2
Surgery can be planned safely in all three
trimester depending upon the local stage
and patient’s wishes.
Breast conservation should be avoided in
the first trimester of pregnancy
3
4
The oncological outcome is similar to non
pregnant women and is dependent on
tumour biology and stage of the disease
rather than pregnancy
Radiation therapy is best deferred until
after delivery
5
Bajpai J et al. Pregnancy and Breast Cancer in Oncology Gold Standard. Chapter 18 2014;327-
6