Hot Topic Targeted agents for cancer treatment during pregnancy Matteo Lambertini a , Fedro A. Peccatori b , Hatem A. Azim Jr. c,⇑ a Department of Medical Oncology, UO Oncologia Medica 2, IRCCS AOU San Martino-IST, Genoa, Italy b Fertility and Procreation Unit, Gynecologic Oncology Department, European Institute of Oncology, Milan, Italy c BrEAST Data Centre, Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium article info Article history: Received 25 February 2015 Accepted 6 March 2015 Available online xxxx Keywords: Cancer during pregnancy Targeted agents Biological agents Monoclonal antibodies Tyrosine kinase inhibitors Malformation Abortion Safety abstract The last decade has witnessed important advances in the field of managing cancer during pregnancy. However, still limited data is available on the safety of administering targeted agents in pregnant cancer patients. Given the increasing use of targeted agents in clinical practice, it is becoming vital to properly understand how far they can be used in a pregnant patient without compromising the outcome of the fetus. Unlike chemotherapy, monoclonal antibodies are large molecules that require active transport via the placenta to reach the fetus. On the other hand, similarly to chemotherapy, small molecules like tyrosine kinase inhibitors (TKIs) can cross the placenta throughout the pregnancy period. The majority of targeted agents have worrying preclinical data discouraging their use during preg- nancy. Multi-TKIs are of particular concern given their potential interference with other vital physiologi- cal functions that could be necessary in fetal development. Yet this does not mean that all targeted agents should be avoided completely during pregnancy. The current review provides a critical evaluation on all targeted agents that are currently in clinical use and provides a guide in order to help clinicians counsel- ing their pregnant cancer patients. Ó 2015 Elsevier Ltd. All rights reserved. Introduction The last decade has witnessed important advances in the field of managing cancer during pregnancy [1–3]. Several groups have published large prospective and retrospective studies looking into the safety of administering chemotherapy during pregnancy par- ticularly doxorubicin/epirubicin-based regimens and to a lesser extent taxanes [4–6]. Available data suggest that chemotherapy is associated with an increased risk of congenital malformations when administered during the first trimester, reaching up to 20% [7]. Yet the risk of malformations appears to be comparable to that of the general population when chemotherapy is started from the 14th week of gestation onwards, albeit pregnancy-related com- plications are relatively higher compared to untreated patients [7]. Nevertheless, if patients are managed in referral centers with specific expertise in the field, neonatal outcome are usually satisfactory [3]. Conversely, limited data are available on the safety of administering targeted agents in pregnant cancer patients. Most of these compounds are labeled by the Food and Drug Administration (FDA) as class D, indicating that they are con- traindicated during pregnancy. However, in the majority of cases, this is based on limited preclinical data. Given the increasing use of targeted agents in clinical practice, with some playing a pivotal role in improving patient survival, it is becoming increasingly important to properly understand whether these compounds can be used in pregnant patients without compromising fetal outcome. Adopting the rule of thumb of chemotherapy – avoiding first trime- ster exposure and starting therapy with second trimester – is not always valid for two folds. First, such ‘‘rule’’ has not even proven to apply for all chemotherapeutics, with some cytotoxics (e.g. idarubicin), showing increased fetal morbidity and pregnancy complications even with exposure during the second and third tri- mesters [8]. Second, targeted agents have different structure, metabolism and pharmacokinetics than chemotherapy and hence their pattern of adverse events and safety in the pregnancy setting could be completely different (Fig. 1). Another important point is that targeted agents do not repre- sent a homogenous group of drugs. On one hand, biological agents such as monoclonal antibodies are large molecules that require active transport via the placenta to reach the fetus [9]. It has been shown that this does not take place before the 14th week of gesta- tion suggesting that exposure to monoclonal antibodies during the first trimester of pregnancy is unlikely to be associated with high http://dx.doi.org/10.1016/j.ctrv.2015.03.001 0305-7372/Ó 2015 Elsevier Ltd. All rights reserved. ⇑ Corresponding author at: BrEAST Data Centre, Department of Medicine, Institut Jules Bordet, Boulevard de Waterloo, 121, 1000 Brussels, Belgium. Tel.: +32 (0)2 541 3854; fax: +32 (0)2 541 3477. E-mail address: hatem.azim@bordet.be (H.A. Azim Jr.). Cancer Treatment Reviews xxx (2015) xxx–xxx Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv Please cite this article in press as: Lambertini M et al. Targeted agents for cancer treatment during pregnancy. Cancer Treat Rev (2015), http://dx.doi.org/ 10.1016/j.ctrv.2015.03.001