Obstetrics and Gynecology

Breast cancer in pregnancy

Breast Cancer in pregnancy, PABC, pregnancy associated breast cancer

1. What every clinician should know

Taking care of the pregnant women with breast cancer is not without considerable apprehension. Unlike many women with chronic medical conditions who embark on a pregnancy, women with breast cancer face extreme and contrasting feelings from the joy of bringing new life to the fear of death. These women will need to consider therapeutic options, establish priorities and weigh the effects of treatment on the fetus. These anxieties are further compounded by the lack of information about the safety of treatment regimens. Although the objective is to cure the mother and deliver a healthy baby, conflicts in achieving these outcomes simultaneously may dictate difficult ethical decisions. Delaying therapy to the mother may impair cure while treatment may potentially affect the fetus.

Pregnancy associated breast cancer (PABC) is defined as breast cancer diagnosed during pregnancy or within a year of delivery. In the United States more than 5,000 women annually are diagnosed with PABC. The incidence is approximately 1/1000 to 3:10,000. A Swedish cohort study found an increase in PABC from 16/100,000 in the 1960s to 37.4/100,000 in 1990. This increase is likely attributed to postponement in childbearing. This study also confirmed that diagnosis of breast cancer during pregnancy and lactation is delayed.

Of all women diagnosed with breast cancer 0.2-3.8% will be pregnant or postpartum. Only 5% of women with breast cancer are age under 40; of these 10% will be pregnant. The median age at diagnosis of PABC is 33 years; the median gestational age at diagnosis is 21 weeks. The predominant histology is invasive ductal carcinomas, which are high grade tumors, and lymph vascular invasion is common. Most tumors are hormone independent (75% are progesterone negative, 66% estrogen negative). Approximately 65-95% of these women are diagnosed stage II-III.

2. Diagnosis and differential diagnosis

Making the diagnosis

Most commonly, PABC are self-discovered by the patient. They may report a new painless induration or palpable mass, sometimes associated with nipple discharge. The delay in diagnosis that occurs for PABC translates to the diagnosis of more advanced disease and worse outcome. If we assume a doubling rate of 130 days, a two-month delay increases the risk of metastasis by 1.7% and a six-month delay increases the risk of metastasis by 5%. Multiple factors are associated with this delay including: physiologic changes of the breast that may hinder breast examination (increase in volume, water content, parenchymal density and palpable nodularity), low index of suspicion by the physician, a focus on the pregnancy and delay in ordering diagnostic tests.

Furthermore, there are limited data on diagnostic imaging procedures during pregnancy. Mammography is the most extensively studied procedure during pregnancy. Although safe, its efficacy is limited. Retrospective studies on self-breast examination report a sensitivity of 78%, positive predictive value of 73% and negative predictive value of 87%. The radiation exposure to the fetus in a bilateral two-view digital mammogram is less than 0.03 μGy. Using lead apron shields decreases that dose up to 50%. This dose is exponentially lower than that associated with teratogenesis.

In contrast, breast ultrasound is not only safe but has reported sensitivities and negative predictive values of 100%.

Therefore breast sonogram should be the first line for workup of a palpable mass in a pregnant or lactating women that persists for longer than 2 weeks. The most appropriate indication for breast MRI during pregnancy remains controversial.

Ultimately, diagnosis is made with core needle biopsy or excision biopsy if needed to rule out invasive disease. The pathologist should be aware that the patient is pregnant to avoid false positive results related to pregnancy changes suggesting atypia. Reports of risk of breast fistula formation may be overstated. A recent publication of 52 excisional and/or core biopsies reported no complications. Biopsy tissue with evidence of carcinoma should be evaluated for receptors as in non-pregnant women including estrogen, progesterone and human epidermal growth factor (HER-2)

Treatment options should be individualized after appropriate staging is performed. To minimize radiation risk to the fetus the evaluation should include the most common sites of metastasis and biopsies in areas suspicious for metastasis. The workup should include:

  1. Chest X-ray (with abdominal shield).

  2. Liver ultrasound (or MRI).

  3. Screening non-contrast MRI of the thoracic-lumbar spine.

  4. Complete metabolic panel and complete blood count.

  5. Consideration of maternal echocardiogram if anthracycline base chemotherapy will be given.

A multi-disciplinary team that includes medical and radiation oncologists, breast surgeons, maternal-fetal medicine, neonatology, psychologist/psychiatrist, nutritionist and in selective scenarios medical ethicists are recommended.

3. Management

Treatment should not be delayed, and should be tailored to be as similar to that used in a non-pregnant women as possible. Considerations should include gestational age at diagnosis, tumor staging, and patient's preference. Recommendations of treatment algorithms are based on expert opinion drawn from case series, as well as retrospective and some prospective studies.

If the diagnosis is made during the first trimester and the lesion is large or inoperable, waiting until a gestational age of 12-14 weeks to initiate systemic chemotherapy followed by surgery either prior to or after delivery is recommended. Radiotherapy and/or hormonal therapy are usually administered after delivery.

If the lesion is operable consultation with a breast surgeon is recommended to plan surgery. In general, breast surgery can be safely performed during all trimesters. The most common surgery is mastectomy. Breast conserving surgery with axillary lymph node dissection can be performed. The role of lymph node mapping has not been fully evaluated during pregnancy. The radiation exposure of tenechtion is approximately 4.3 mGy. Counseling should include discussion about the background risk of miscarriage during the first trimester.

Guidelines for monitoring the fetus should follow institutional protocols. The operative team should be familiar with the physiologic changes of pregnancy that may complicate anesthetic and surgical procedure; these include delayed gastric emptying, decreased functional residual capacity of the lung, decreased serum cholinesterase activity, and increased cardiac output. Recommendations should include maternal preoxygenation, use of antacids, rapid sequence induction with cricoid pressure, and maternal positioning to avoid vena cava compression and maternal hypotension.

If the patient is diagnosed between 12-34 weeks of gestation and the lesion is locally advanced (T3, T4) or is a large operable lesion, administration of primary systemic chemotherapy is indicated followed by surgery that may be postponed until after delivery. Late preterm delivery may be indicated to better time patient treatment including surgery, radiotherapy and hormonal therapy ( if indicated). In our practice we individualize each patient treatment regimen.

Chemotherapy is rarely administered past 34 weeks of gestation. This is to avoid the potential risk of maternal/ fetal anemia, neutropenia as well as infection. If the patient is diagnosed between 12-34 weeks of gestation and the lesion is operable, then surgery is recommended followed by stage appropriate adjuvant systemic chemotherapy, with timing of delivery dependent on gestational age. Radiotherapy and hormonal therapy (if indicated) follow post-delivery. If delivery is recommended prior to 34 completed weeks of gestation, then consideration for administration of corticosteroids per current guidelines is suggested. In women with recurrent or aggressive disease, preterm delivery may be indicated to optimize maternal therapy.

Chemotherapy

There are limited data on the pharmacokinetics of chemotherapeutic agents in pregnant women. Physiologic changes during pregnancy may influence the pharmacology of antineoplastics agents due to the increased maternal plasma volume, enhanced renal excretion, altered plasma protein binding, third-space of amniotic fluid, and altered GI absorption and entero-hepatic circulation.

Chemotherapy regimen may include:

  1. fluorouracyl and doxirubicin/epirubicin + cyclophosphamide.

  2. doxirubucin/epirubicin + cyclophosphamide + taxane (paclitacel or docetaxel).

Epirubicin in combination with other chemotherapeutic agents has been associated with neonatal death; therefore, doxirubicin may be the preferred agent. The first prospective trial using a standardized regimen included 24 women. This protocol included treatment after the first trimester in an outpatient setting utilizing combination chemotherapy with cyclophsphamide ( 500 mg/ m2) intravenously (iv) on day 1, doxorubicin (50 mg/m2) by continous infusion over 72 hours and fluorouracil (500 mg/m2) iv on days 1 and 4 via a central venous catheter administered every 21-28 days for up to 6 cycles.

The mean gestational age at delivery was 38 weeks of gestation. There were no reported congenital anomalies or fetal growth restriction. Associated complications included preterm birth, transient tachypnea of the newborn and transient neonatal leukopenia. A more recent voluntary registry that included 130 women with breast cancer during pregnancy of whom 104 received chemotherapy reported a congenital malformation rate of 3.8% which is similar to the general population.

Another series of 29 women treated with doxorubicin and cyclophosphamide reported no complications except one case of preeclampsia and one case of fetal growth restriction. Other series confirm no serious adverse morbidity to mothers and their neonates, although some have reported lower gestational age at delivery, which may be iatrogenic.

There are limited data on human placental transfer of chemotherapy agents. In the baboon model, assessment of transplacental transfer of doxorubicin, epirubicin and paclitaxel has revealed that drug concentrations were much lower in fetal blood than in maternal blood concentration (7.3%, 4% and 1.4%, respectively). The risk of teratogenesis has been reported to be as high as 17% if chemotherapeutics are administered in the first trimester of pregnancy and therefore administration of these agents is contraindicated in this gestational time period. Although transtuzumab is the standard of care for those with Her-2 overexpression its use during pregnancy has been associated with oligohydramnios and anhydramnios, and therefore its use during pregnancy cannot be recommended.

Antepartum

In general prenatal care in women with breast cancer is not managed differently than in other pregnant women except for heightened surveillance for possible complications and side effects from treatment modalities. Prior to any treatment the fetus should be evaluated for appropriate dating, anatomical survey and growth. Maternal comorbidities should be identified; in particular, risk for anemia, aymptomatic bacteuria, preterm labor and preeclampsia.

Appropriate immunizations should be administered if possible prior to chemotherapy. Anemia should be evaluated and treated accordingly to etiology. Psychosocial counseling is essential and an integral component of antenatal care in this group of women, as anxiety and depression are not uncommon. Fetal antenatal testing in cases of fetal growth restriction should be initiated as clinically indicated.

Intrapartum

Timing of delivery should optimize maternal treatment while avoiding iatrogenic fetal morbidity due to prematurity. Although delivery at 39 weeks of gestation is associated with lower neonatal complications, this may be associated with less than optimal treatment strategies for the mother. A women may recieve the last cycle of chemotherapy at 33-35 weeks of gestation and therefore may experience a delay in treatment of several weeks if delivery occurs at 39 weeks. In such cases, earlier delivery may be elected.

Cesarean delivery should be reserved for obstetrical indications. Delivery should be performed in a setting where neonatology services are available. The placenta should be sent for pathological examination to evaluate for potential metastasis.

Postpartum

In women requiring chemotherapy postpartum, breastfeeding is contraindicated. Although breast engorgement does seem to be a rare event in women receiving chemotherapy (due to decrease in milk production), breast binding is suggested. If available donor bank milk should be offered.

There is a need for reliable contraception in this group of women to avoid the potential of first trimester exposure to chemotherapy. Endocrine therapy with tamoxifen as been associated with spontaneous miscarriages and fetal malformations as high as 20%. Future pregnancies are not contraindicated but preconception counseling is advised. In women under 35 years of age, future pregnancies following treatment of breast cancer is not associated with an increased risk of recurrence or death.

Women who have received bisphosphonates should delay pregnancy for at least 6 months to a year due to slow release of these agents back into the circulation and potential risk of teratogenesis in the fetus.

4. Complications

Complications as a consequence of the condition

Patients undergoing chemotherapy may present with side effects such as anemia, neutropenia and febrile neutropenia. Pregnancies are at risk for preterm labor, oligohydramnios and intrauterine growth restriction.

Strategies to lower the risk of complications include:

  1. Institute supportive care for nausea, diarrhea and mucositis.

  2. Surveillance of central lines for infection, thrombosis.

  3. Serial evaluation of blood count, liver and renal tests.

  4. Monitoring of treatment response.

  5. Dietary evaluation.

  6. Serial sonogram for fetal growth.

Complications as a consequence of management

Flurouracyl toxicity may include myelosuppression, mucositis and diarrhea. Hand-foot syndrome may include numbness, tingling and nail/skin changes. Cyclophosphamide may induce myelosuppression. Doxorubicin can cause myelosuppression, and acute or chronic cardiotoxicity.

Although erytropoetin has been used in pregnant women to treat anemia, the 2008 Food and Drug administration issued a black box warning on epoetin alfa and darbepoetin alfa due to reported shortened overall survival and time to disease progression in patients with advanced breast cancer. Thus, at the present time these agents cannot be recommended. The use of granulocyte colony stimulating factor to treat and prevent febrile neutropenia should be considered.

If growth restriction is identified, modification of chemotherapy regimen may be warranted. Attempts should be made to avoid maternal and fetal hematologic suppression at the time of delivery. In some clinical scenarios such as fetal growth restriction, preterm labor or preeclampsia oncologic treatment may be delayed .

5. Prognosis and outcome

Prognosis for pregnancy outcome

The prognosis in general is worse when compared to non-pregnant women. Factors that contribute to the worsening prognosis include: delay in diagnosis with more advanced disease as well as delay in treatment and young maternal age (women under 40 years). When compared stage by stage, women with PABC have similar prognosis to those with non - PABC. A large single institutional retrospective study in women under 35 years of age, which included 104 women with PABC and 564 with non-PABC, studied the rates of local recurrence, distant metastasis and overall survival.

Median follow up was 100 months. Outcomes were similar between the group of women. The overall 5-year survival in women with negative nodes is 85% and 37% with positive nodes. Although termination of pregnancy may be an option for some women -- in particular women with advanced disease in the first trimester -- termination of pregnancy does not routinely improve outcomes.

Impact on long-term outcomes

Although metastasis to the placenta has been reported in approproximately 60 cases, no case of cancer transmission to the fetus has been documented. Data are limited in the long-term outcome of fetuses exposed to chemotherapy. A prospective cohort of 25 women who received neoadjuvant chemotherapy reported no significant short term complications for the majority of the children. Similar findings have been reported in other national registries. The longest follow-up of neonates exposed to chemotherapy in utero was from a study in which the median follow up was 18.7 years (range 6-29 years); in this study, no significant abnormalities in anatomic, psychological or learning disorders was found.

6. What is the evidence for specific management and treatment recommendations

Berry, Dl., Theriault, RL, Holmes, FA. "Management of Breast Cancer During Pregnancy using a standardized protocol". J Clinical Oncology . vol. 17. 1999. pp. 855-61.

(First prospective clinical trial on a cohort of 24 women treated with a standardized chemotherapy for breast cancer. Reported complications included preterm delivery, low birth weight and transient leukopenia.)

Amant, F, von Minkwitz, G, Han, SN. "Prognosis of women with primary breast cancer diagnosed during pregnancy: results from an international collaborative study". J Clin Oncol, Jul. vol. 31. 10. pp. 2532-9.

(This is a large report on 311 women diagnosed with breast cancer and treated during pregnancy. Data was obtained from muti-national cancer registries. Details on patients characteristics, staging and treatment were reported. Outcomes including overall survival, disease-free survival were then compared to non-pregnant women with breast cancer from the same registries.)

Loibl, S, von Minckwitz, G, Gwyn, K. "Breast Carcinoma during pregnancy. International Recommendations from a Expert Meeting". Cancer . vol. 106. pp. 237-43.

S, Han, SN, von Mindckwitz, G. "Treatment of breast cancer during pregnancy: an observational study". Lancet Oncol. vol. 13. 2012. pp. 887-96.

Hahn, KME, Johnson, PH, Gordon, N. "Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero". Cancer . vol. 107 . 2006. pp. 1210-25.

(Large prospective cohort of 52 women treated during pregnancy using a standardized protocol. Study reports on the presentation, treatment and short term follow of children exposed to chemotherapy in utero.)

Cardonic, E, Dougherty, R, Grana, G. "Breast cancer during pregnancy: Maternal and fetal outcome". J Cancer . vol. 16. 2010. pp. 76-82.

(Report from a voluntary registry that included 130 malignancies during pregnancy, of which 103 had primary breast cancer.)

Aviles, A, Neri, N. "Hematologic malignancies and pregnancy: A final report of 84 children who received chemotherapy in utero". Clin Lymphoma. vol. 2. 2001. pp. 173-7.

(Authors reports on 84 children exposed to chemotherapy in utero and observed no significant abnormalities in the cardiac, neurologic, physical, psychological or learning disorders with a median follow up of 18.7 years (range 6-29 years.)

Van Calsteren, K, Verbesselt, R, Beijnen, J. "Transplacental transfer of antracyclines, vinblastine, and 4-hydroxy-cyclophosphamide in the baboon model". Gynecologic Oncology. vol. 600. 2010. pp. 594.

(In this study both fetal and maternal samples were obtained in nine baboons to determine the transplacental transfer of several chemotherapy agent. The study reported on the limited transplacental passage and fetal exposure.)

Beadle, BM, Woodard, WA, Middleton, LP. "The impact of pregnancy on breast cancer outcomes in women 35 years or less". Cancer. vol. 115. 2009. pp. 1174-84.

(This is a large (668 women) retrospective single institution cohort on all women under 35 years of age treated for breast cancer from 1973-2006. Rates of locoregional recurrence, distant metastasis and overall survival were compared between PABC and non- PABC. Outcomes were similar between groups. PABC women presented with more advance stage of the disease, suggesting that delay in diagnosis and treatment impacted on their prognosis.)

Litton, JK, Theriault, RL. "Breast Cancer and Pregnancy: Current concepts in Diagnosis and Treatment". The oncologist. vol. 15. 2010. pp. 1238-47.

(Large registry of women (447) with pregnancy associated breast cancer from seven European countries. Registry include retrospective as well as prospective cases since 2003. Primary outcome was fetal health for up to 4 weeks after delivery. Outcome non-clinical significant birth weight and gestational age at delivery in women exposed to chemotherapy during pregnancy.
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