Clinical Decision Making in the Management of Breast Cancer Diagnosed During Pregnancy: A Review and Case Series Analysis

Abstract

Purpose:

To highlight the various options available for the management of breast cancer diagnosed during pregnancy by describing the investigations, treatment, and outcomes in relation to these women.

Methods:

This is a narrative review of the literature to describe the issues related to pregnancy and obstetric management in patients with breast cancer. It incorporates a description of six cases of women (aged 29–39 years) with a first-time diagnosis of breast cancer during pregnancy to illustrate a number of issues that need to be considered during different trimesters.

Results:

Of the six cases, two were diagnosed in each pregnancy trimester. A painless breast mass was the presenting symptom in five cases (83%). In all cases, breast ultrasound was the primary diagnostic imaging procedure. Chest X-ray was performed in 3 (50%) and computed tomography in 2 (33%). A core needle biopsy was performed in all cases, and sentinel lymph node biopsy in 3 (50%) cases. Four women had grade 3 tumor; five had estrogen receptor-positive tumors. Four women had breast surgery during pregnancy. Five women gave birth after the induction of labor and/or cesarean section. In all six cases, a multidisciplinary team was involved in the delivery of health care.

Conclusion:

Regular breast examinations are needed for all pregnant woman during prenatal visits. Breast ultrasonography should be offered if a breast lump or other symptoms are detected. Breast surgery can be safely performed during all pregnancy trimesters, and some systemic therapeutic agents can be administered safely in the second and third trimesters.

Introduction

Breast cancer is one of the most common malignancies diagnosed in women during pregnancy, with an incidence in Australia of 23 per 100,000 pregnancies.¹ The most common presenting symptom is a painless breast lump.² This can present diagnostic difficulties, as normal physiological changes during pregnancy can lead to the development of benign transient lumps in the breast of a pregnant woman, thereby masking breast cancer symptoms.^2–4 This problem is compounded by physician reluctance to request imaging studies during pregnancy using ionizing radiation such as mammography, to avoid potential harm to the conceptus.⁵ This is despite published evidence that mammography is relatively safe during pregnancy, and that with proper shielding, the fetus is exposed to a negligible radiation dose.^4,6 Together, these factors can lead to delays, resulting in breast cancer diagnosis in pregnant women at a more advanced stage compared with nonpregnant women.²

Despite concerns about the adverse effects of chemotherapeutic agents on fetal well-being, in many cases of cancer in pregnancy, use of these agents cannot be delayed until the postpartum period.⁷ Recent studies demonstrate that a cancer diagnosis during pregnancy is not an absolute indication for termination of pregnancy and that fetal exposure to chemotherapy after the first trimester is not associated with major complications or congenital anomalies.^8–10

Preterm birth is a significant adverse outcome associated with breast cancer diagnosed during pregnancy. A recent European population-based study found that the preterm birth rate among women with any type of cancer was 48%, with the majority of preterm birth (88%) being iatrogenic. For women in the study diagnosed with breast cancer, 50% delivered preterm.¹⁰

We aim at highlighting the various options available for the management of breast cancer diagnosed during pregnancy by reviewing the literature and describing the investigations, treatment, and outcomes for six selected cases.

Methods

A narrative review of the literature is presented that includes the most relevant published studies and guidelines on the management of breast cancer during pregnancy. In addition, six cases of women with breast cancer diagnosed during pregnancy are described to illustrate current management practices implemented in Australia and New Zealand. These cases were identified from a population-wide epidemiological study of all women diagnosed with breast cancer during pregnancy in Australia and New Zealand between January 2013 and June 2014. This study utilized the Australasian Maternity Surveillance System (AMOSS), a hospital-based surveillance and research system of serious and rare conditions in pregnancy, with data coordinators in nearly 300 Australian and New Zealand maternity units. Ethics approval was granted by multiple ethics committees across Australia, including the New South Wales Population and Health Services Research Ethics Committee (HREC/09/CIPHS/21).¹¹ The process of data collection for AMOSS has been described in a previous publication.¹²

Case reports

The median age of the six cases of women diagnosed with breast cancer during pregnancy was 34.5 (29–39) years. Two women were diagnosed in each pregnancy trimester. A painless breast mass was the presenting symptom in five cases (83%). In all cases, breast ultrasound was the primary diagnostic imaging procedure followed by mammogram in three cases (50%) (Table 1). Chest X-ray was performed in 3 (50%) and computed tomography (CT) in 2 (33%). Core needle biopsy (CNB) was performed in all cases and sentinel lymph node biopsy (SLNB) in 3 (50%) cases. Four women had grade 3 (high) tumor, and five had estrogen receptor-positive tumors (Table 2). Four women had breast surgery during pregnancy. Five women gave birth after the induction of labor and/or cesarean section (CS) (Table 3). Three babies were born preterm, and none of the six babies had congenital malformations or experienced major complications at birth (Table 4). In all our cases, a multidisciplinary team was involved in the care of the women with the teams' members, including an obstetrician, maternal–fetal medicine specialist, breast cancer surgeon, medical oncologist, radiation oncologist, anesthetist, and a breast care nurse.

Table 1.

Diagnostic Procedures

Case	Age group, years	Gestation at diagnosis, weeks	CXR	Breast US	Mammogram	Nuclear medicine	CT chest/abdomen	Histological diagnosis	Lymph node biopsy procedures
1	30–34	4	No	Yes	Yes	Bone scan	Yes	CNB	SLNB and AC
2	35–39	8	No	Yes	No	No	No	CNB	SLNB and AC
3	35–39	15	Yes	Yes	Yes	No	No	CNB	AC
4	30–34	17	Yes	Yes	Yes	VQ scan	No	CNB	AC
5	25–29	33	No	Yes	No	No	No	CNB	Not known
6	35–39	38	Yes	Yes	No	Bone scan	Yes	CNB	SLNB

AC, axillary clearance; CNB, core needle biopsy; CT, computed tomography; CXR, chest X-ray; SLNB, sentinel lymph node biopsy; US, ultrasound; VQ, ventilation–perfusion lung scan.

Table 2.

Tumor Characteristics

Case	Maximum tumor diameter, mm	Tumor grade	Lymphovascular invasion	Estrogen receptor status	Progesterone receptor status	Her2 status	Lymph nodes with cancer
1	40	High	No	Positive	Positive	Negative	15
2	9	Low	No	Positive	Positive	Negative	0
3	35	High	Not known	Positive	Positive	Positive	10
4	40	High	Yes	Positive	Negative	Negative	2
5	Not known	High	Not known	Negative	Positive	Positive	—
6	8	Intermediate	No	Positive	Positive	Negative	15

Table 3.

Obstetric and Cancer Management During Pregnancy

Case	Labor induction/reason	CS/indication	Breast surgery	Chemotherapy	Prenatal corticosteroids	Lactation suppression
1	No	No	Breast conservation	Yes	No	No
2	Yes/postdate	Yes/poor progress in labor and nonreassuring FHR trace	Mastectomy	No	No	No
3	No	Yes/maternal request	Mastectomy	Yes	Yes	No
4	No	Yes/previous CS and maternal request	Breast conservation	Yes	Yes	Yes
5	Yes/breast cancer management	No	Delayed until end of pregnancy	No	Yes	Yes
6	No	Yes/breast cancer management	Delayed until end of pregnancy	No	No	No

CS, cesarean section; FHR, fetal heart rate.

Table 4.

Perinatal Outcome

Case	Gestational age at birth, weeks	Gender	Birthweight, ^a g	5 minutes Apgar score	Major infant complications	Congenital malformations	Resuscitation	Respiratory support	Admission to NICU/SCN
1	36	Female	2801	9	No	No	No	No	No
2	40	Female	3225	9	No	No	No	No	No
3	34	Female	2315	9	No	No	No	No	Yes
4	38	Female	2750	9	No	No	No	No	No
5	35	Female	2578	9	No	No	No	No	No
6	38	Male	3540	9	No	No	No	No	No

None of the babies was small for gestation.

NICU, neonatal intensive care unit; SCN, special care nursery.

Trimester 1

Case 1

A gravida 3 para 2 woman was diagnosed with grade 3, hormone receptor-positive breast cancer at 4 weeks' gestation. Bone scan and CT were performed, which showed no distant metastases. Breast conservation surgery and axillary lymph node clearance was performed at 5 weeks' gestation. Adjuvant systemic therapy (doxorubicin, cyclophosphamide followed by paclitaxel) commenced at 13 weeks' gestation. The last dose was given at 36 weeks' gestation, and spontaneous rupture of membranes occurred shortly after.

Case 2

A primigravid woman presented with a painless mass discovered on examination at 8 weeks' gestation. This grade 1 cancer was confirmed by breast ultrasound and CNB. She underwent a mastectomy and SLNB 6 weeks after diagnosis. Chemotherapy and radiotherapy were not recommended. Labor was induced at 40 weeks' gestation. Due to the slow progress of labor and a nonreassuring fetal heart rate trace, the baby was delivered by CS.

Trimester 2

Case 3

A gravida 2 para 0 woman reported a unilateral breast lump associated with breast erythema 2 weeks before CNB confirmed an inflammatory malignancy at 15 weeks' gestation. Neoadjuvant chemotherapy (doxorubicin and cyclophosphamide) was initiated at 18 weeks' gestation, with the last dose administered at 26 weeks' gestation. Mastectomy and axillary clearance were performed at 29 weeks' gestation, and pathology confirmed residual 35 mm of grade 3 tumor with 10 out of 20 lymph nodes involved. A CS was scheduled at 35 weeks' gestation at maternal request. Radiotherapy was delayed until after birth, and chemotherapy continued postpartum. The baby was born preterm and admitted to the special care nursery due to the preterm birth and low birthweight.

Case 4

A gravida 3 para 2 woman, with one prior CS, presented with a nontender breast lump. Diagnostic procedures and tumor characteristics are shown in Tables 2 and 4. Wide local excision and axillary node dissection was performed 8 days after diagnosis, with 2 of the 25 removed lymph nodes containing tumor deposits. Adjuvant chemotherapy was initiated at 23 weeks' gestation (doxorubicin, cyclophosphamide). The last dose of chemotherapy was administered at 31 weeks' gestation. The woman received Paclitaxel postpartum, and the treatment ended 13 weeks after giving birth. Radiotherapy to the breast was then performed.

Trimester 3

Case 5

A primigravid woman presented with a breast lump and nipple retraction for 5 weeks. Surgery, systemic therapy, and radiotherapy were delayed until the end of pregnancy. Labor was induced 2 weeks after diagnosis, at 35 weeks' gestation to initiate breast cancer management. The woman delivered a healthy infant by an unassisted vaginal birth. The total hospital stay for the woman was 6 days, after which she was transferred to another hospital to commence neoadjuvant chemotherapy.

Case 6

A gravida 4 para 1 woman experienced a painless breast lump for 8 weeks. The CNB confirmed a unilateral grade 2 tumor at 38 weeks' gestation. Two days after the pathological diagnosis, the woman delivered a healthy infant by planned CS. Four cycles of neoadjuvant chemotherapy commenced 4 days after delivery.

Discussion

These six cases highlight the complexity and differences in the management of breast cancer diagnosed during pregnancy based on gestational age and cancer stage.

In keeping with the literature, the main presenting symptom in our cases (cases 2–6) was a painless breast lump.^2,13 Detecting breast lump during pregnancy may be difficult due to the physiological changes.^2,4 Therefore, there is a need to examine every pregnant woman for breast lumps during antenatal visits.

Ultrasonography

Irrespective of the timing of diagnosis, breast ultrasonography represented the primary diagnostic imaging modality in all cases (Table 1). This result is reassuring, as data from recent studies reinforce the effectiveness of breast ultrasonography in detecting breast cancers during pregnancy.¹⁴ The literature showed breast ultrasound to be highly sensitive in detecting a malignant breast mass during pregnancy and lactation, with sensitivity varying from 74% to 100%.^5,15,16 Further, current guidelines of the American College of Obstetricians and Gynecologists (ACOG) recommend the use of ultrasound as the primary breast imaging modality during pregnancy as it carries a low fetal risk.¹⁷ However, it is recommended that ultrasound be used with the lowest possible acoustic output level.¹⁷

Imaging utilizing ionizing radiation

Ionizing radiation can affect the fetus in two ways: “deterministic effects” are dose-dependent and associated with damage to a number of cells potentially leading to organ failure. Clinically significant deterministic effects are not expected to occur at a dose lower than 100 mGy.¹⁸ In contrast, “stochastic effects” are random (not dose dependent) and associated with damage to a single cell, which can cause carcinogenesis.^6,18

Four of our cases were exposed to at least one ionizing radiation imaging technique (mammography, chest X-ray, CT scan) at varying stages of pregnancy. All these women delivered babies without major complications or congenital malformations.

Mammography was used in three (50%) of our cases: one case in the first trimester and two other cases in the second trimester (Table 1). Although some women and health care providers hold concerns about the use of mammography during pregnancy, it carries a low risk to the fetus.⁵ Previous studies report that mammography appears safe at any time during pregnancy and lactation.^4,6 The published data show that exposure of the fetus to ionizing radiation from mammography is 0.001–0.01 mGy and, with lead shielding, this exposure can be reduced by half.^17,19 The sensitivity of mammography in detecting breast cancer during pregnancy, however, varies with studies reporting a sensitivity of 78%–90%.^4,5 This variability in diagnostic sensitivity is probably due to the high breast tissue density during pregnancy and lactation, which may affect image interpretation.²⁰

Apart from CT scans of the pelvis, the dosages used in all imaging with ionizing radiation techniques fall well below the deterministic effects threshold, and therefore, they can be considered safe during pregnancy.²⁰ Two of our cases underwent CT scans. One woman was diagnosed in the first trimester and the other in the third trimester, but the actual date of the scan is unknown in either case. Nonetheless, ACOG recommendations concerning the use of diagnostic imaging do permit CT scans during pregnancy.¹⁷ The CT scans do entail high radiation exposure; however, their use as an imaging procedure during pregnancy increased annually by 25% from 1997 to 2006.^6,17 This increase is underpinned by the use of a low-exposure technique, which can reduce the fetal exposure dose to <35 mGy for a single-phase scan of the pelvis.^6,17,20 However, although pelvic CT would usually be part of staging for breast cancer, it is not recommended to include the pelvis in staging CT scanning during any stage of pregnancy. Ultrasound can be used as an alternative to CT scanning for abdominal and pelvic staging.²¹

Nuclear medicine

Although the literature on nuclear medicine imaging during pregnancy is sparse, its use may be considered when other diagnostic modalities are inconclusive.²⁰ In situations where magnetic resonance imaging (MRI) is inconclusive in evaluating bone metastases in pregnant women, the use of bone scintigraphy may be considered. For both bone scintigraphy and positron emission tomography scans in pregnancy, exposure of the fetus to radiation associated with the intravenous administration of tracers should be limited. This can be achieved by the use of intravenous hydration along with bladder catheters to prevent the accumulation of the tracer.²⁰ In our series, it was used in three cases (two had a bone scan, and one had a ventilation-perfusion lung scan [VQ scan]). However, MRI without gadolinium may be a better alternative to bone scan in cancer staging in cases where metastases are suspected.²²

Biopsy

All our cases underwent CNB for pathological diagnosis. These results reflect the decline in the use of fine needle aspiration (FNA) in favor of CNB, which is now considered the standard pathology diagnostic method for breast lesions.^2,23,24 Results from a recent meta-analysis show that the pooled sensitivity of CNB is superior to that of FNA (87% vs. 74%) and that the specificity is similar (98% vs. 96%).²³

Surgery

In our cohort, the four women diagnosed with breast cancer in the first and second trimesters underwent breast surgery during pregnancy. The existing literature and practice guidelines state that breast surgery can be performed safely in all pregnancy trimesters.^5,25

Axillary clearance and/or SLNB procedures were offered to five of our cases (Table 1). The SLNB is used to assess lymph node involvement in patients diagnosed with breast cancer.²⁰ The standard SLNB procedure involves the injection of a ^99mtechnetium (^99mTc)–sulfur colloid and blue dye (isosulfan blue) interstitially into the breast.²⁶ Performing SLNB during pregnancy is controversial due to the potential for radiation exposure to the conceptus and anaphylactic reaction to the blue dye. The ACOG concluded that the use of ^99mTc for sentinel node mapping during pregnancy is considered safe, as conceptus exposure to radiation is low (<5 mGy) and the half-life of the isotope is short (6 hours).¹⁷ Similarly, the Royal College of Obstetricians and Gynaecologists (RCOG) state that uterine radiation from radioisotope scintigraphy is minimal.²⁵ In contrast, the American Society of Clinical Oncology (ASCO) clinical practice guideline update in 2016 recommended that SLNB should not be performed during pregnancy due to insufficient evidence relating to its impact on the fetus.²⁷ This is despite recent studies suggesting that the use of ^99mTc or patent blue SLNB during pregnancy appears safe.^28,29 In a large study, Han and colleagues found that in pregnant women the recurrence rate from SLNB is low compared with the recurrence rate in axillary lymph node dissection.²⁹ The SLNB was performed in three of our cases: two in the first trimester and one in the third trimester, with no significant complications or congenital malformations. However, our data do not include information about whether ^99mTc or blue dye or both was used.

Chemotherapy

Three cases received chemotherapy during pregnancy. In one case, the diagnosis was confirmed at <5 weeks' gestation, but chemotherapy was delayed until the end of the first trimester. In the two other cases, the diagnosis was confirmed during the second trimester. These practices are consistent with the literature and RCOG guidelines that indicate that the use of chemotherapeutic agents (anthracycline and taxane) in the second and third trimesters is not associated with significant adverse perinatal outcomes, for example, perinatal deaths or major congenital malformations.^8,25,30,31 We noted that if the diagnosis was confirmed in the first and second trimester rather than the late third trimester, the women were more likely to receive chemotherapy during pregnancy, depending on the tumor grade.

Tamoxifen and trastuzumab

Five women had estrogen receptor-positive tumors (Table 2). For one woman, systemic therapy was not recommended during pregnancy, whereas in another, the decision was made to delay all therapy until after birth as she had been diagnosed in the third trimester. The other three women received chemotherapy without Tamoxifen while pregnant. Tamoxifen is linked to congenital malformations in the fetus and is not recommended for use during pregnancy.²¹

Two women had HER2-positive tumors (Table 2). One of these women was diagnosed in the third trimester, and so systemic therapy was delayed until after birth. The other received Doxorubicin and Cyclophosphamide without Trastuzumab. Trastuzumab, a monoclonal antibody that antagonizes HER2 receptors, is associated with perinatal morbidity, for example, pulmonary hypoplasia, and renal impairment^32–34 and, as with Tamoxifen, treatment should be delayed until after delivery.

Management approach

A multidisciplinary management approach was utilized in all cases. The multidisciplinary team, which may include an obstetrician, surgeon, oncologist, radiation oncologist, and neonatologist, as well as support from specialist nurses and allied health, is essential for the management of women diagnosed with breast cancer during pregnancy and for the safety of the fetus.^22,35

Timing of delivery and perinatal outcomes

Preterm birth is the main adverse perinatal outcome in women diagnosed with breast cancer during pregnancy, with the majority being planned preterm births. In our series, three women were delivered preterm. Of those, two women delivered by induction of labor/CS without an obstetric indication. When planning an early induction of labor or CS, the maternal risk of postponing chemotherapy versus the risk of preterm birth should be considered.⁹

When a diagnosis of breast cancer occurs in the first trimester, immediate delivery is not an option, and if chemotherapy is indicated, it cannot be delayed until after birth. In this case, clinicians will have to decide whether to commence treatment in the second trimester (as in case 1) or terminate the pregnancy. There is no evidence that termination of pregnancy per se improves maternal outcome, and any decision to terminate should consider the woman's will and the stage of cancer at the time of diagnosis.² In case 2, the diagnosis was made at 8 weeks' gestation, and the woman had a mastectomy without further treatment during pregnancy. The pregnancy was allowed to proceed to 40 weeks' gestation. The decision regarding whether to deliver early term (37–38 weeks) versus full term should balance the benefits and risks to both the mother and her baby, that is, the need to commence cancer treatment as soon as practicable versus the increased risk of adverse perinatal outcomes as well as poorer long-term cognitive outcomes associated with early term delivery.^36–38

On the other hand, if the diagnosis occurs in the second trimester, the balance between the risks of treatment and investigation options and baby outcomes need to be considered. Similar to diagnoses that occur in the first trimester, it is too early to deliver the baby, but as gestation has reached the second trimester clinicians may initiate chemotherapy. Case 3 highlights the complexity around cancer management in trimester 2. The women received chemotherapy and had a mastectomy and axillary clearance. Although she could have been allowed to continue chemotherapy and deliver at term (as the baby had already been exposed to chemotherapy), CS was performed at 34 weeks' gestation in response to the woman's request due to her concerns about relapse.

When the diagnosis occurs in the third trimester, it is preferable to deliver the baby as close as possible to 37 weeks' gestation and commence cancer treatment postpartum.

Women who are expected to deliver preterm are given corticosteroids prenatally to stimulate fetal lung maturation and thus reduce the risk of respiratory distress syndrome (RDS).^39,40 Prenatal corticosteroids were administered in three cases, of whom two delivered preterm at 34 and 35 weeks' gestation. The optimal timing for antenatal corticosteroid administration is 24 hours to 7 days before the predicted delivery.⁴⁰ The ACOG recommended that a single course of betamethasone be administered between 34 and 36 (+ 6 days) weeks' gestation to women at risk of preterm delivery within 1 week, providing that they have not received a previous dose of corticosteroids.⁴¹ Prenatal corticosteroids administration in women with predicted birth before 34 weeks can reduce the RDS risk.³⁹

Conclusion

The management of breast cancer diagnosed during pregnancy requires a multidisciplinary team who have expertise in oncology, breast surgery, and maternal–fetal medicine and neonatology to provide optimal care and support from diagnosis, during birth and treatment. This approach can optimize outcomes for mother and child. For every pregnant woman, breast examination should regularly be performed at the prenatal visits, and breast ultrasonography should be offered if a breast lump or other symptom is detected. Breast surgery can be performed during all pregnancy trimesters, and chemotherapy can be administered in the second and third trimesters.

Footnotes

Acknowledgments

The authors acknowledge the support of AMOSS data collectors and participating sites across Australia and New Zealand.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This research is supported by an Australian Government Research Training Program.

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