Pregnancy-associated breast cancer (PABC) is breast cancer (BC) diagnosed during pregnancy, in the first postpartum year, or at any time during lactation, although it occurs most frequently during the first year after the pregnancy. PABC occurs in 15 to 35 per 100,000 deliveries in the United States or one per 1,000 pregnancies yearly. However, its incidence appears to be increasing due in part to an overall increase in BC incidence and an increase in the age at conception. Given the risk to both mother and child, the question has been asked whether it is possible to personalize the diagnosis and treatment of BC during pregnancy.

PABC is more often associated with hereditary mutations in risk genes compared with older women and is often diagnosed at a more advanced stage. While pregnancy is generally protective against BC over the course of a woman’s lifespan, it also increases the risk of BC in the period following the pregnancy, with the greatest risk within the first 6 years post pregnancy.

Changes in hormonal levels, which include an increase in estrogen levels during pregnancy and lactation, can contribute to the development of more severe disease and metastases. Other factors that affect prognosis include immunological changes, inflammation, delay in diagnosis, and pregnancy-associated plasma protein A.

Less differentiated, infiltrating ductal adenocarcinoma is more common in PABC and may contribute to the presence of more advanced disease at diagnosis. Other noticeable differences in PABC and other BCs include the presence of more frequent mutations of the mucin gene family, mismatch repair deficiencies, nonsilent mutations, and a decreased expression of estrogen and progesterone receptor expression, but not HER2 expression.

Among the precision-medicine tools that may be employed in PABC are blood-based biomarkers, such as circulating tumor cells, which are released from primary tumors and can help determine the risk of metastases, exosomes, and circulating tumor DNA (also known as liquid biopsy). Genomic instability and epigenetic modification can contribute to outcome variability. Unfortunately, in pregnant women, standard, BC-specific immunohistochemical targets (e.g., HER2), targets derived from genomic analysis (e.g., phosphatidyl kinase 3, gene mutation of the estrogen receptor 1), pathologist-identified targets (e.g., tumor infiltrating lymphocytes), and molecular targets (e.g., Kirsten Rat Sarcoma viral oncogene homolog, murine sarcoma viral oncogene homolog B1, and EGFR [epidermal growth factor receptor]) cannot be utilized due to lack of information in this population.

The diagnosis of PABC can be confirmed with the use of mammography (although changes in breast tissue and risk to the fetus are a concern), ultrasound, and needle biopsy; gadolinium-enhanced MRI should be avoided. Staging of PABC can be challenging due to the inability to utilize CT scanning, and bone scans and may be left until after delivery.

PABC is more often associated with a genetic predisposition secondary to the presence of BRCA1 and/or BRCA2 (breast cancer antigen 1/ 2). Other genes that may increase risk of PABC are under investigation and include partner and localizer of BRCA2, checkpoint kinase 2, and cadherin 1, type 1.

A treatment plan should be in place at the time of delivery. Women with PABC should be treated with the same evidence-based medicine that guides treatment of nonpregnant women. However, treatment options vary depending on trimester and are divided into conception to the first 4 weeks, 4 to 14 weeks, 14 to 28 weeks, and 28 weeks to delivery.

During the first trimester (i.e., from conception through 14 weeks), surgery is associated with a 1% to 2% increased risk of miscarriage and with premature delivery in the second and third trimesters. Radiotherapy has been associated with gross malformations, microcephaly, mental and growth retardation, sterility, and secondary malignancies in the mother and is contraindicated. While there is not enough information to support the use of gamma knife stereotactic radiosurgery during the first trimester, it is thought to be safe during the second and third trimesters.

Chemotherapy poses great risks to the developing fetus with severe fetal malformations and increased risk of miscarriage in the later part of the first trimester, and growth retardation, low birth weights, preterm labor, and myelosuppression when administered during the second and third trimesters. However, agents that may be safer during pregnancy include doxorubicin, cyclophosphamide, taxanes (especially paclitaxel), platinum therapy, and anthracyclines, but data are limited. Chemotherapy should not be administered in the 3 to 4 weeks preceding delivery to prevent myelosuppression in the baby. Anti-HER2 treatment in women with HER2-positive BC does not seem to affect the fetus during the first trimester but can lead to oligohydramnios or anhydramnios in the second and third trimesters and are relatively contraindicated. Hormonal therapy (e.g., tamoxifen, aromatase inhibitors, luteinizing hormone-releasing hormone agonists) poses a risk of miscarriage or malformation during the first trimester.

Data are lacking for later trimesters, but these agents are contraindicated during pregnancy. Immunotherapy (i.e., programmed death-1 and programmed death ligand-1 modulators) increases the risk of miscarriage during the first trimester and has been associated with premature delivery and stillbirth in the second and third trimesters.

Antivascular endothelial growth factor/antivascular EGFR biologicals are associated with intrauterine growth restriction in the fetus and preeclampsia in the mother during the later trimesters; early on, they can lead to miscarriage, vascular malformation throughout the fetus, and skeletal malformations. Data are lacking on the effect of poly ADP ribose polymerase inhibitors on the developing fetus. Supportive care with antiemetics or colony-stimulating factors is generally safe. The exception is long-term dexamethasone, which should be avoided due to both maternal and fetal harm.

There are also pharmacokinetic and pharmacodynamic changes that must be taken into consideration since pregnancy leads to a 40% to 60% increase in plasma volume. A decrease in plasma albumin can interfere with the pharmacokinetics of taxanes. Alterations in estrogen levels, changes in drug clearance, metabolism, third spacing secondary to the amniotic sac, and alterations in fetal P-glycoprotein have all been observed during pregnancy, but their impact on treatment of PABC remains unclear.

Postponement of treatment until after delivery depends on tumor type with greater risk for metastases associated with triple-negative BC than with hormone-dependent BC. Breastfeeding should be discouraged in all women.

Iatrogenic prematurity can lead to long-term complications and should be avoided. Ultrasound and Doppler flowmetry should be used to monitor the fetus. Despite all of these concerns about treatment of PABC, infant outcomes have been favorable with no effect on early childhood development. However, long-term follow up of these children is needed. Termination of the pregnancy remains controversial. Early studies have not shown an improvement in outcome in PABC with pregnancy termination.

The future of precision medicine in the management of PABC may lie in evaluating the unique RNA and DNA tumor code and using genome testing or next-generation sequencing in assessing prognosis and identifying viable treatment options.

Pharmacists may not often encounter women with PABC; however, it is important for them to have an understanding of the risk versus the benefit of treatment in this patient population.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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