New study highlights risks of anti-ERBB2 cancer drugs during pregnancy

While the treatment of breast cancer does not change with pregnancy status unless absolutely necessary, the health of the fetus must be carefully considered while deciding on the choice of therapy.

Study: Treatments during pregnancy targeting ERBB2 and outcomes of pregnant individuals and newborns. Image Credit: fizkes / Shutterstock.com

The safety and efficacy of anti-ERBB2 inhibitors

In a critical new study, researchers found that the use of anti-ERBB2 inhibitors is associated with significant and specific harms to the pregnancy and fetus. These drugs include trastuzumab, pertuzumab, and lapatinib.

Currently, trastuzumab is contraindicated in pregnancy due to the high risk of oligohydramnios and anhydramnios, as well as the lack of data on other fetal outcomes. Likewise, these restrictions apply to other anti-ERBB2 agents due to the lack of evidence of their safety in pregnancy.

Nevertheless, breast tumors that are ERBB2-positive and hormone receptor-negative are primarily treated with anti-ERBB2 agents as a result of their historical efficacy. Since the use of these agents in pregnancy is dependent on the expectation of greater maternal benefit as compared to fetal harm, extensive studies are required to confirm their safety during pregnancy.

To obtain this type of data, the current study published in JAMA Network Open utilized the World Health Organization (WHO) VigiBase, which collects information on adverse drug reactions in the form of case reports throughout the world beginning in 1967. Since maternal and fetal outcomes following exposure to drugs contraindicated in pregnancy, including anti-cancer drugs, are expected to be reported to VigiBase, the researchers expected to find information that could be analyzed for this purpose.

This study aimed to determine the likelihood of maternal or fetal complications with ERBB2 antagonists compared to other antineoplastic agents.

What did the study show?

The researchers conducted a case-control study, which included over 3,500 cases with cancer complicating pregnancy who were treated for the condition with an anti-cancer drug during pregnancy. These patients were then categorized into anti-ERBB2 recipients and those who received other drugs, which comprised about 330 and 3,200 cases, respectively.

The mean participant age in the anti-ERBB2 group was about 31 years, with nearly half of patients from the United States. Most were being treated for breast cancer. The most commonly used drug was trastuzumab, with about 20 each receiving trastuzumab-emtansine or lapatinib, while 55 were on pertuzumab.

Over 50% of exposures in the anti-ERBB2 group were to anti-ERBB2 monotherapy, with most patients only using drugs in this category. The remaining 50% of patients were prescribed molecular-targeted therapies.

Chronic myeloid leukemia (CML) was slightly more common than breast cancer at 30% and 23%, respectively. About one in seven reports on the use of anti-ERBB2 drugs during pregnancy dated to 2009 or before, as compared to about 10% for other anti-cancer drugs.

Most reports in either group contained information on adverse outcomes in pregnancy, as well as for the fetus or newborn, at 61% and 56% in the anti-ERBB2 and other drug categories, respectively. This corroborates findings from earlier studies.

Oligohydramnios were reported in about 25% of exposures, whereas preterm birth was reported in over one in seven cases. Intrauterine growth restriction (IUGR) was reported in 10% of cases.

Respiratory diseases in the newborn and spontaneous miscarriage accounted for about 7% of exposures. Only a single complication was reported in each case, with only five exceptions.

The likelihood of oligohydramnios in the anti-ERBB2 group was about 18-fold higher than in other drug recipients. The same trend was observed to a lesser extent for respiratory tract disorders at birth or kidney failure during the newborn period, both of which were increased by nine-fold in children born to anti-ERBB2 recipients as compared to those on other drugs.

These findings demonstrate the role of ERBB2 in the development of the lung, skin, intestine, and kidneys during intrauterine life.

Fetal kidney failure, leading to oligohydramnios, and subsequently to pulmonary hypoplasia and neonatal respiratory disorders, has been described in a Potter sequence.”

For the trastuzumab-emtansine combination alone, the likelihood of cardiovascular defects was five-fold higher, while fetuses exposed to tapatinib were at an eight-fold increased risk for IUGR.

What are the implications?

[The current study is], to our knowledge, the largest reported series of cases of maternofetal exposure to anti-ERBB2 therapy during pregnancy.”

The use of anti-ERBB2 agents for cancers during pregnancy is associated with specific and significant adverse outcomes for the pregnancy and fetus, including congenital disabilities and IUGR, as compared to the use of other anti-cancer drugs. The association of lapatinib and trastuzumab-emtansine with teratogenicity should lead to their contraindication during pregnancy.

If oligohydramnios is identified during anti-ERBB2 therapy during pregnancy, careful monitoring and the withdrawal of these agents is recommended, despite their valuable role in preventing severe disease in hormone receptor-negative breast cancers in pregnant women.  

This approach demands a thorough investigation to ascertain its safety, and dedicated research must be pursued to confirm the validity of this strategy.”

Additional studies are needed to confirm these toxicity findings, especially as VigiBase has an intrinsic variability in the quality of its data from multiple sources.