Cancer Treatment Reviews xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
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 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 b
a r t i c l e
i n f o
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
a b s t r a c t 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 pregnancy. Multi-TKIs are of particular concern given their potential interference with other vital physiological 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 counseling 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 particularly 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 complications 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 ⇑ 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: [email protected] (H.A. Azim Jr.).
Administration (FDA) as class D, indicating that they are contraindicated 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 trimester 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 trimesters [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 represent 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 gestation 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.
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
2
M. Lambertini et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx
Period of implantaon
Period of organogenesis
Period of fetal development
CHEMOTHERAPY
High risk of death and spontaneous aboron
Major congenital malformaons (around 20%)
Relave increase in obstetric and fetal complicaons.
MONOCLONAL ANTIBODY
Possible high risk of spontaneous aboron
No major congenital malformaons expected
TYROSINE KINASE INHIBITORS
Possible high risk of death and spontaneous aboron
Possible occurrence of major congenital malformaons
Possible obstetric and fetal complicaons. Limited clinical data
ATRA
Possible high risk of death and spontaneous aboron
Possible occurrence of major congenital malformaons
Possible occurrence of adverse events. Available data does not suggest increase in toxicity over chemotherapy alone
IFN-α
No apparent increase in risk of fetal death and spontaneous aboron
No major congenital malformaons expected
No major adverse events expected.
Specific “on-target” effects Example: - Trastuzumab: oligohydramnios - Rituximab: B-cell depleon
Fig. 1. Key differences between chemotherapy and different classes of targeted agents in terms of their expected toxicity during pregnancy.
fetal exposure [9]. This is not the case with small molecules like tyrosine kinase inhibitors (TKIs), which similar to chemotherapy can cross the placenta throughout the pregnancy period. On the other hand, targeted agents are by definition ‘‘targeted’’ against different tumor-related molecular aberrations, which in some instances could also have a physiological role in fetal development. Hence, each family of agents with specific ‘‘target’’ could have very specific pregnancy-related adverse events secondary to their ontarget effect. In this review, we provide a critical evaluation and discuss the available preclinical and clinical data dealing with the use of targeted agents in managing cancer during pregnancy. We will discuss how to counsel pregnant patients requiring treatment with targeted therapy and how to deal with patients who become accidentally pregnant while receiving any of these compounds.
Anti-HER2 agents Trastuzumab Trastuzumab is a humanized recombinant IgG1 monoclonal antibody that is approved in managing patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer [10]. It is considered one of the most important agents in the history of managing breast cancer, having resulted in significant improvement in survival both in the early and advanced settings when added to chemotherapy without considerably increasing chemotherapy-related toxicity [11–13]. Given the relative rarity of gastric cancer in women in the childbearing period, the focus here will be on women diagnosed with HER2-positive
breast cancer during pregnancy and whether trastuzumab could be considered in these patients. The HER2 pathway is involved in fetal organogenesis, as it plays a vital role in normal cardiac and neural development (Table 1) [14]. Moreover, HER2 seems to be involved in the early conception and implantation phases [15]. To date, no embryolethal or fetotoxic effects have been reported in laboratory animal studies with the use of trastuzumab [7]. In humans, around 34 breast cancer patients exposed to trastuzumab during pregnancy have been reported [16,17]. In only 5 cases, trastuzumab was ‘‘intentionally’’ started during the second or third trimester for pregnant patients with metastatic HER2positive breast cancer [17]. Chemotherapy was given in all cases except one; two with paclitaxel, one with docetaxel and one with vinorelbine [17]. All cases were complicated with oligohydramnios resulting in preterm delivery. All babies were alive at the time of reporting but at least two had respiratory distress and renal failure at delivery [17]. All the remaining cases (n = 29) became accidentally pregnant on trastuzumab, thus being exposed during the first trimester [16,17]. The largest report came from the HERA trial in which 16 patients became pregnant while receiving adjuvant trastuzumab [16]. A total of 4 patients (25%) experienced spontaneous abortion. Of those who elected to continue pregnancy, trastuzumab was stopped once pregnancy was confirmed, and all delivered at term with no pregnancy complications or fetal malformations [16]. None of these cases developed oligohydramnios [16]. On the other hand, sporadic case reports on patients who elected to continue trastuzumab and pregnancy (n = 8) showed what appears to be a high risk of oligohydramnios (n = 5), preterm delivery (n = 4) and neonatal deaths (n = 4) [17]. Of note, no congenital
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
3
M. Lambertini et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx Table 1 Key preclinical/clinical findings on the use of targeted agents in pregnant cancer patients, and possible clinical implications. Agents
Key preclinical findings
Key clinical findings
Use during pregnancy
Target physiological role in fetus
Placental studies
Fetotoxic studies
1st trimester
2nd and 3rd trimesters
HER2 involved in cardiac and neural development, early conception and implantation phases HER2 involved in cardiac and neural development, early conception and implantation phases CD20 important in the function of human lymphocytes
Crosses placenta
No embryo-toxicity nor teratogenicity
No congenital malformations
Oligohydramnios, preterm delivery and neonatal deaths
Not to use
No data available
No data available
No data available
Not to use
Crosses placenta
Bcr-abl tyrosine kinase, PDFGRa and other TKs play key role during organogenesis
Crosses placenta
Cytopenia and B-cell depletion at birth with no reported complications and recovering within days-few months No adverse events
To use with caution
Imatinib
ATRA
RAR plays key role in fetal development
Crosses placenta
IFN-a
Pleiotropic cytokine involved in embryonic development and implantation phase
Limited placental transfer
No embryo-lethal, teratogenic or body weight changes effects. B-cell depletion during organogenesis Embryo-toxicity and teratogenicity when administered during organogenesis (particularly skeletal system defects) Embryo-toxicity and teratogenicity when administered during organogenesis Increased abortion rate at higher doses than those used in humans; no teratogenic effects
No congenital malformations with lapatinib (only 1 case available) No congenital malformations
Erlotinib/ gefitinib
EGFR involved in various stages of embryonic development, placental function and early conception and implantation phases VEGF involved in vasculogenesis and angiogenesis of the placenta and in normal fetal development VEGF involved in vasculogenesis and angiogenesis of the placenta and in normal fetal development Bcr-abl tyrosine kinase, PDFGRa and other TKs play key role during organogenesis BRAF involved in cardio-faciocutaneous development
Cross placenta
Embryo-toxicity, teratogenicity and abortion when administered during organogenesis
No data available
Embryo-toxicity and teratogenicity (particularly skeletal system defects)
Dosedependent placental transfer
Trastuzumab
Other antiHER2 agents Rituximab
Sunitinib/ sorafenib
Bevacizumab
Dasatinib/ nilotinib Vemurafenib
Major malformations (skeletal defects with or without urogenital malformations)
To use with caution
No major complications
To use with caution
No adverse events
To use throughout pregnancy
No adverse events (only 2 cases available)
Not to use
No data available
No data available
Not to use
Embryo-toxicity and teratogenicity (particularly skeletal system defects)
No data available
No data available
Not to use
Cross placenta
Embryo-toxicity and teratogenicity
Spontaneous Abortion
No adverse events
Not to use
Crosses placenta
No data available
No data available
Only 1 case available
Not to use
Induced and spontaneous abortions but no congenital malformations One infant born with major malformations but with also imatinib exposure during the 1st trimester No congenital malformations (only 3 cases available)
HER2 = human epidermal growth factor receptor 2; PDGFR a = platelet-derived growth factor receptors a; TKs = tyrosine kinases; RAR = retinoic acid receptor; ATRA = alltrans retinoic acid; IFN-a = interferon-a; EGFR = epidermal growth factor receptor; VEGF = vascular endothelial growth factor.
malformations were reported in any of the neonates that were exposed to trastuzumab in utero despite first trimester exposure [17]. Two main observations could be made from the limited available data on trastuzumab exposure during pregnancy. First, high number of cases developed oligohydramnios, but only in those who received the drug beyond the first trimester. Second, none of the babies exposed to trastuzumab during the period of organogenesis (i.e. first trimester) developed congenital malformations. Both observations are not in line with the published experience with chemotherapy. This is probably secondary to the different structure of trastuzumab being a monoclonal antibody and hence its early crossing through the placenta appears to be limited. On the other hand, it is targeted against the HER2 oncogene, which is also expressed on the fetal kidney. Trastuzumab-related fetal renal impairment, causing deregulation of fetal urine production and amniotic fluid reabsorption, could explain why oligohydramnios was observed in patients exposed to trastuzumab during pregnancy [18,19]. Such association was rarely reported in patients
exposed to chemotherapy during pregnancy arguing that targeted agents are likely to produce ‘‘on-target’’ effects secondary to their administration during pregnancy. However, it should be noted that sporadic case reports are always a subject of publication bias and hence it is hard to estimate the actual risk of developing oligohydramnios secondary to trastuzumab exposure. We encourage physicians caring for cancer patients who were exposed to trastuzumab during pregnancy to register their patients in the ongoing MotHER study (NCT00833963), which collects prospective information on all women exposed to any HER2-targeted agents during pregnancy. This will help to better understand their potential toxicity when given in a pregnant woman. To translate this information to counseling patients in daily practice, elective administration of trastuzumab should be avoided during pregnancy. Chemotherapy can be started and trastuzumab can be postponed until delivery, whether in the early or advanced setting [3]. Importantly, women of childbearing potential and considered for maintenance therapy with trastuzumab should be advised for active contraception. As trastuzumab does not
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
4
M. Lambertini et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx
adversely affect fertility, pregnancy can occur while on maintenance therapy. Yet in those patients who become accidentally pregnant on trastuzumab, it does not appear that brief exposure during the first trimester would increase pregnancy or fetal risk. Hence, it is reasonable to consider stopping the medication and allowing pregnancy to continue. Of note, none of the patients or babies experienced cardiac dysfunction secondary to trastuzumab exposure during pregnancy. Nevertheless, cardiac evaluation of the mother during pregnancy as well as the fetus is warranted. Other anti-HER2 agents Apart from trastuzumab, a number of HER2-targeted agents, namely lapatinib, pertuzumab and T-DM1, are approved for the treatment of metastatic HER2 positive breast cancer [10]. To date, no cases have been reported for pertuzumab or T-DM1 exposure during pregnancy, while one case was exposed to lapatinib during pregnancy. Pertuzumab is currently approved in combination with trastuzumab and docetaxel in managing metastatic HER2-positive disease. Hence, from a clinical perspective, a similar approach like that of trastuzumab would apply for pertuzumab as it is not approved for use without trastuzumab. To our knowledge, no formal embryofetal, peri- or post-natal toxicology studies were performed on T-DM1, which is an antibody drug conjugate, composed of trastuzumab connected to a cytoctoxic agent, emtansine. It is a large molecule; hence its transfer via the placenta and its toxic effects are expected to mimic that of trastuzumab. Hence, until further data are available, it should not be considered in pregnant patients. Lapatinib is a dual TKI of the epidermal growth factor receptor (EGFR) and of HER2; both playing an important physiological role in fetal development [14,20,21]. Lapatinib, being a small TKI is expected to cross the placenta throughout the pregnancy. In humans, only one case of lapatinib exposure during pregnancy has been reported [22]. This woman had metastatic disease and became accidentally pregnant on lapatinib, which was stopped around week 14 of gestation with no pregnancy complications or fetal malformations reported [22]. The lack of fetal toxicity in the single reported case does not indicate the safety of drug, which should also be avoided during pregnancy. Rituximab Rituximab is a chimeric murine/human IgG1 monoclonal antibody targeting the CD20 antigen present on the surface of normal and malignant B-lymphocytes. Rituximab has revolutionized the management of B-cell lymphomas, and hence is a current standard of care [10]. Furthermore, rituximab is approved for the treatment of chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide or chlorambucil, and for other non-malignant conditions [10]. In humans, placental transfer of rituximab has been documented. In a case report on rituximab exposure during pregnancy, the cord blood serum level of the monoclonal antibody at delivery was three times the level of rituximab in the maternal circulation [23]. In another case, despite the last dose of rituximab was administered two months prior to delivery, a similar concentration of the drug was detected in maternal and newborn serum at birth [24]. In both cases, the newborns experienced a complete depletion of B-cells at birth, but with a recovery to normal levels within 4 months [23,24]. The largest analysis to date comes from Chakravarty et al., which included both maternal and paternal exposure to rituximab before or during pregnancy [25]. Of those, only 21 women were exposed to rituximab during pregnancy and had known pregnancy outcome. Around 50% of these women were treated for lymphomas while the remaining were treated for autoimmune disorders. All
except two were treated after the period of organogenesis. No neonatal or congenital malformations were reported; yet a striking observation is a neonatal cytopenia, even among those who were delivered at term. In this report, 7 out of 11 full term babies had cytopenia at delivery but no reports on complications secondary to cytopenia were reported [25]. Importantly, cytopenia recovered within days or few months after delivery, with no reported complications [25]. Other sporadic case reports on rituximab exposure during pregnancy also noted transient B-cell depletion at birth. A recent large multi-centric retrospective study on managing lymphoma during pregnancy did not show a difference in pregnancy complications or risk of malformations between patients treated with rituximab in combination with standard chemotherapy (n = 13, mainly CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]) or chemotherapy alone (n = 77) [26]. Few case reports were published on accidental pregnancy on maintenance rituximab with normal fetal outcome. Similar to trastuzumab, rituximab is a large molecule and hence exposure during the first trimester is unlikely to have an adverse effect on fetal organogenesis. Yet, it is important to use active contraception in women undergoing maintenance therapy with this agent, which is becoming an increasing approach in nowadays practice. Our interpretation of data favors the use of rituximab for pregnant patients with B-cell lymphomas [3]. The potential maternal benefits of rituximab in terms of disease control and overall survival appear to outweigh the relatively limited fetal risk secondary to in utero exposure to rituximab. Nonetheless, patients and physicians need to bear in mind the potential risk of neonatal and postneonatal cytopenia and the possible consequences particularly the increased risk of infection. Imatinib Imatinib is a TKI targeting the bcr-abl tyrosine kinase, a mutant constitutive tyro sine kinase created by the t(9;22) balanced translocation (i.e. the Philadelphia chromosome) [27]. Imatinib inhibits other tyrosine kinases including non-mutated abl, ARG (abl-related gene), c-kit (the stem cell factor receptor), c-FMS (the colonystimulating factor 1 receptor), platelet-derived growth factor receptors (PDGFR) a and b, and others [27]. Imatinib is approved for the management of Philadelphia chromosome positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST), both being classically diagnosed in elderly population [10]. Imatinib is also used in managing Philadelphia chromosome positive acute lymphoblastic leukemia (ALL), chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, myelodysplastic/ myeloproliferative neoplasms and systemic mastocytosis [10]. Placental transfer of imatinib to the fetus has been documented in humans [28,29]. In the two case reports by Russell and colleagues, imatinib concentration in maternal and umbilical cord blood were 886 and 0–157 ng/mL, respectively [28]. In the case report by Ali et al., imatinib concentration at delivery (16 h after a maternal dose of imatinib) in maternal, umbilical cord and infant peripheral blood were 1562, 338 and 478 ng/mL, respectively [29]. The day after delivery, infant peripheral blood concentration of imatinib decreased to 183.5 ng/mL [29]. In animal studies, imatinib was found to induce embryotoxicity and teratogenicity when administered during organogenesis. When administered at doses similar to those used in humans, it can induce total fetal loss and post-implantation loss [7]. Skeletal system defects were the most common malformations developed with the use of imatinib during the first trimester [7]. It has been hypothesized that the occurrence of these malformations may be due to the inhibitory effect of imatinib on PDFGRa that play an important role during organogenesis [30]. In humans, several reports have been published on pregnancy outcomes following imatinib exposure during gestation.
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
M. Lambertini et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx
All major malformations occurred in fetuses exposed during the first trimester. An early report by Pye and colleagues investigating the pregnancy and fetal outcomes of 180 women exposed to imatinib during pregnancy, showed the occurrence of fetal abnormalities in 12 pregnancies with drug exposure during the first trimester [31]. Out of those, there were 8 live births, 1 stillbirth, and 3 terminations. Major malformations consisted of skeletal defects with or without urogenital malformations [31]. The rate of major malformations following exposure to imatinib in the first trimester is around 11%, while no major or minor malformations were observed in infants with in utero exposure to imatinib in the second and/or third trimesters only [7]. For this reason, imatinib exposure during the first trimester should be completely avoided. This is rather in line with preclinical data suggesting teratogenic effects secondary to imatinib exposure particularly skeletal alterations. As expected, first trimester exposure is also associated with high rate of spontaneous abortion. According to the recent report from the National Toxicology Program of the US Department of Health and Human Services, out of 157 pregnancies reported in literature to have been exposed to imatinib during pregnancy, 19 (12.1%) experienced spontaneous abortion, which ranks the highest among other anticancer agents, according to this report [7]. This is probably due to the fact that most of these pregnancies (n = 151) were exposed during the first trimester, secondary to patients becoming accidentally pregnant while undergoing treatment with imatinib. This underscores the need to use active contraception in patients undergoing treatment with imatinib. On the other hand, fewer patients received imatinib electively during second or third trimester with no major or minor malformations reported [7]. Thus, the use of imatinib in the second and/or third trimesters could be a valid approach albeit safety data are rather limited and based on less than 10 patients. Hence solid conclusions cannot be drawn. All-trans retinoic acid (ATRA) ATRA (or tretinoin) is the carboxylic acid form of vitamin A and is indicated for the treatment of acute promyelocytic leukemia (APL) [10]. Placental transfer of ATRA can occur in humans. This compound has been reported to have extensive placental transport but a relatively short half-life [32,33]. In animal experiments, ATRA showed to have embryolethal and teratogenic effects: particularly, it can induce soft-tissue and skeletal alterations (e.g. cranio-facial defects) but also malformations of the central nervous system leading to behavioral dysfunctions [34,35]. The rate of major malformations among all ATRA-exposed offspring is 4% (1/26 live born infants) [7]. The only malformation described was a Potter syndrome (i.e. bilateral renal agenesis and oligohydramnios). However, it was diagnosed prior to the third trimester when administration of ATRA was started and thus it cannot be attributable to ATRA [36]. Chelghoum and colleagues reported two induced abortions and one spontaneous abortion following first-trimester exposure to ATRA but in patients concurrently treated also with daunorubicin and cytarabine [37]. In three infants with in utero exposure to ATRA in the second and third trimesters, an abnormal cardiac function was reported, arrhythmia in two cases and dilation of the right atrium and ventricle in one infant [33,38,39]. Hence, in our opinion, current evidence does not discourage the use of ATRA following the first trimester in pregnant patients with APL.
5
Immune related agents: interferon-a (IFN-a) IFN-a is a pleiotropic cytokine, which is used in the treatment of patients with melanoma, CML, lymphoma, hairy cell leukemia and AIDS-related Kaposi sarcoma in addition to other non-malignant conditions, although generally not as first-line treatment [10]. In humans, IFN-a does not cross the placental barrier in significant amounts [40,41]. No IFN-a was detectable in fetal blood and amniotic fluid in the two HIV-seropositive pregnant women reported by Pons and colleagues treated with IFN-a during the 2nd trimester of pregnancy [40]. In the two cases reported by Haggstrom et al., IFN-a concentration in the babies were
Contents lists available at ScienceDirect
Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv
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 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 b
a r t i c l e
i n f o
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
a b s t r a c t 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 pregnancy. Multi-TKIs are of particular concern given their potential interference with other vital physiological 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 counseling 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 particularly 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 complications 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 ⇑ 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: [email protected] (H.A. Azim Jr.).
Administration (FDA) as class D, indicating that they are contraindicated 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 trimester 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 trimesters [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 represent 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 gestation 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.
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
2
M. Lambertini et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx
Period of implantaon
Period of organogenesis
Period of fetal development
CHEMOTHERAPY
High risk of death and spontaneous aboron
Major congenital malformaons (around 20%)
Relave increase in obstetric and fetal complicaons.
MONOCLONAL ANTIBODY
Possible high risk of spontaneous aboron
No major congenital malformaons expected
TYROSINE KINASE INHIBITORS
Possible high risk of death and spontaneous aboron
Possible occurrence of major congenital malformaons
Possible obstetric and fetal complicaons. Limited clinical data
ATRA
Possible high risk of death and spontaneous aboron
Possible occurrence of major congenital malformaons
Possible occurrence of adverse events. Available data does not suggest increase in toxicity over chemotherapy alone
IFN-α
No apparent increase in risk of fetal death and spontaneous aboron
No major congenital malformaons expected
No major adverse events expected.
Specific “on-target” effects Example: - Trastuzumab: oligohydramnios - Rituximab: B-cell depleon
Fig. 1. Key differences between chemotherapy and different classes of targeted agents in terms of their expected toxicity during pregnancy.
fetal exposure [9]. This is not the case with small molecules like tyrosine kinase inhibitors (TKIs), which similar to chemotherapy can cross the placenta throughout the pregnancy period. On the other hand, targeted agents are by definition ‘‘targeted’’ against different tumor-related molecular aberrations, which in some instances could also have a physiological role in fetal development. Hence, each family of agents with specific ‘‘target’’ could have very specific pregnancy-related adverse events secondary to their ontarget effect. In this review, we provide a critical evaluation and discuss the available preclinical and clinical data dealing with the use of targeted agents in managing cancer during pregnancy. We will discuss how to counsel pregnant patients requiring treatment with targeted therapy and how to deal with patients who become accidentally pregnant while receiving any of these compounds.
Anti-HER2 agents Trastuzumab Trastuzumab is a humanized recombinant IgG1 monoclonal antibody that is approved in managing patients with human epidermal growth factor receptor 2 (HER2)-positive breast and gastric cancer [10]. It is considered one of the most important agents in the history of managing breast cancer, having resulted in significant improvement in survival both in the early and advanced settings when added to chemotherapy without considerably increasing chemotherapy-related toxicity [11–13]. Given the relative rarity of gastric cancer in women in the childbearing period, the focus here will be on women diagnosed with HER2-positive
breast cancer during pregnancy and whether trastuzumab could be considered in these patients. The HER2 pathway is involved in fetal organogenesis, as it plays a vital role in normal cardiac and neural development (Table 1) [14]. Moreover, HER2 seems to be involved in the early conception and implantation phases [15]. To date, no embryolethal or fetotoxic effects have been reported in laboratory animal studies with the use of trastuzumab [7]. In humans, around 34 breast cancer patients exposed to trastuzumab during pregnancy have been reported [16,17]. In only 5 cases, trastuzumab was ‘‘intentionally’’ started during the second or third trimester for pregnant patients with metastatic HER2positive breast cancer [17]. Chemotherapy was given in all cases except one; two with paclitaxel, one with docetaxel and one with vinorelbine [17]. All cases were complicated with oligohydramnios resulting in preterm delivery. All babies were alive at the time of reporting but at least two had respiratory distress and renal failure at delivery [17]. All the remaining cases (n = 29) became accidentally pregnant on trastuzumab, thus being exposed during the first trimester [16,17]. The largest report came from the HERA trial in which 16 patients became pregnant while receiving adjuvant trastuzumab [16]. A total of 4 patients (25%) experienced spontaneous abortion. Of those who elected to continue pregnancy, trastuzumab was stopped once pregnancy was confirmed, and all delivered at term with no pregnancy complications or fetal malformations [16]. None of these cases developed oligohydramnios [16]. On the other hand, sporadic case reports on patients who elected to continue trastuzumab and pregnancy (n = 8) showed what appears to be a high risk of oligohydramnios (n = 5), preterm delivery (n = 4) and neonatal deaths (n = 4) [17]. Of note, no congenital
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
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M. Lambertini et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx Table 1 Key preclinical/clinical findings on the use of targeted agents in pregnant cancer patients, and possible clinical implications. Agents
Key preclinical findings
Key clinical findings
Use during pregnancy
Target physiological role in fetus
Placental studies
Fetotoxic studies
1st trimester
2nd and 3rd trimesters
HER2 involved in cardiac and neural development, early conception and implantation phases HER2 involved in cardiac and neural development, early conception and implantation phases CD20 important in the function of human lymphocytes
Crosses placenta
No embryo-toxicity nor teratogenicity
No congenital malformations
Oligohydramnios, preterm delivery and neonatal deaths
Not to use
No data available
No data available
No data available
Not to use
Crosses placenta
Bcr-abl tyrosine kinase, PDFGRa and other TKs play key role during organogenesis
Crosses placenta
Cytopenia and B-cell depletion at birth with no reported complications and recovering within days-few months No adverse events
To use with caution
Imatinib
ATRA
RAR plays key role in fetal development
Crosses placenta
IFN-a
Pleiotropic cytokine involved in embryonic development and implantation phase
Limited placental transfer
No embryo-lethal, teratogenic or body weight changes effects. B-cell depletion during organogenesis Embryo-toxicity and teratogenicity when administered during organogenesis (particularly skeletal system defects) Embryo-toxicity and teratogenicity when administered during organogenesis Increased abortion rate at higher doses than those used in humans; no teratogenic effects
No congenital malformations with lapatinib (only 1 case available) No congenital malformations
Erlotinib/ gefitinib
EGFR involved in various stages of embryonic development, placental function and early conception and implantation phases VEGF involved in vasculogenesis and angiogenesis of the placenta and in normal fetal development VEGF involved in vasculogenesis and angiogenesis of the placenta and in normal fetal development Bcr-abl tyrosine kinase, PDFGRa and other TKs play key role during organogenesis BRAF involved in cardio-faciocutaneous development
Cross placenta
Embryo-toxicity, teratogenicity and abortion when administered during organogenesis
No data available
Embryo-toxicity and teratogenicity (particularly skeletal system defects)
Dosedependent placental transfer
Trastuzumab
Other antiHER2 agents Rituximab
Sunitinib/ sorafenib
Bevacizumab
Dasatinib/ nilotinib Vemurafenib
Major malformations (skeletal defects with or without urogenital malformations)
To use with caution
No major complications
To use with caution
No adverse events
To use throughout pregnancy
No adverse events (only 2 cases available)
Not to use
No data available
No data available
Not to use
Embryo-toxicity and teratogenicity (particularly skeletal system defects)
No data available
No data available
Not to use
Cross placenta
Embryo-toxicity and teratogenicity
Spontaneous Abortion
No adverse events
Not to use
Crosses placenta
No data available
No data available
Only 1 case available
Not to use
Induced and spontaneous abortions but no congenital malformations One infant born with major malformations but with also imatinib exposure during the 1st trimester No congenital malformations (only 3 cases available)
HER2 = human epidermal growth factor receptor 2; PDGFR a = platelet-derived growth factor receptors a; TKs = tyrosine kinases; RAR = retinoic acid receptor; ATRA = alltrans retinoic acid; IFN-a = interferon-a; EGFR = epidermal growth factor receptor; VEGF = vascular endothelial growth factor.
malformations were reported in any of the neonates that were exposed to trastuzumab in utero despite first trimester exposure [17]. Two main observations could be made from the limited available data on trastuzumab exposure during pregnancy. First, high number of cases developed oligohydramnios, but only in those who received the drug beyond the first trimester. Second, none of the babies exposed to trastuzumab during the period of organogenesis (i.e. first trimester) developed congenital malformations. Both observations are not in line with the published experience with chemotherapy. This is probably secondary to the different structure of trastuzumab being a monoclonal antibody and hence its early crossing through the placenta appears to be limited. On the other hand, it is targeted against the HER2 oncogene, which is also expressed on the fetal kidney. Trastuzumab-related fetal renal impairment, causing deregulation of fetal urine production and amniotic fluid reabsorption, could explain why oligohydramnios was observed in patients exposed to trastuzumab during pregnancy [18,19]. Such association was rarely reported in patients
exposed to chemotherapy during pregnancy arguing that targeted agents are likely to produce ‘‘on-target’’ effects secondary to their administration during pregnancy. However, it should be noted that sporadic case reports are always a subject of publication bias and hence it is hard to estimate the actual risk of developing oligohydramnios secondary to trastuzumab exposure. We encourage physicians caring for cancer patients who were exposed to trastuzumab during pregnancy to register their patients in the ongoing MotHER study (NCT00833963), which collects prospective information on all women exposed to any HER2-targeted agents during pregnancy. This will help to better understand their potential toxicity when given in a pregnant woman. To translate this information to counseling patients in daily practice, elective administration of trastuzumab should be avoided during pregnancy. Chemotherapy can be started and trastuzumab can be postponed until delivery, whether in the early or advanced setting [3]. Importantly, women of childbearing potential and considered for maintenance therapy with trastuzumab should be advised for active contraception. As trastuzumab does not
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
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M. Lambertini et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx
adversely affect fertility, pregnancy can occur while on maintenance therapy. Yet in those patients who become accidentally pregnant on trastuzumab, it does not appear that brief exposure during the first trimester would increase pregnancy or fetal risk. Hence, it is reasonable to consider stopping the medication and allowing pregnancy to continue. Of note, none of the patients or babies experienced cardiac dysfunction secondary to trastuzumab exposure during pregnancy. Nevertheless, cardiac evaluation of the mother during pregnancy as well as the fetus is warranted. Other anti-HER2 agents Apart from trastuzumab, a number of HER2-targeted agents, namely lapatinib, pertuzumab and T-DM1, are approved for the treatment of metastatic HER2 positive breast cancer [10]. To date, no cases have been reported for pertuzumab or T-DM1 exposure during pregnancy, while one case was exposed to lapatinib during pregnancy. Pertuzumab is currently approved in combination with trastuzumab and docetaxel in managing metastatic HER2-positive disease. Hence, from a clinical perspective, a similar approach like that of trastuzumab would apply for pertuzumab as it is not approved for use without trastuzumab. To our knowledge, no formal embryofetal, peri- or post-natal toxicology studies were performed on T-DM1, which is an antibody drug conjugate, composed of trastuzumab connected to a cytoctoxic agent, emtansine. It is a large molecule; hence its transfer via the placenta and its toxic effects are expected to mimic that of trastuzumab. Hence, until further data are available, it should not be considered in pregnant patients. Lapatinib is a dual TKI of the epidermal growth factor receptor (EGFR) and of HER2; both playing an important physiological role in fetal development [14,20,21]. Lapatinib, being a small TKI is expected to cross the placenta throughout the pregnancy. In humans, only one case of lapatinib exposure during pregnancy has been reported [22]. This woman had metastatic disease and became accidentally pregnant on lapatinib, which was stopped around week 14 of gestation with no pregnancy complications or fetal malformations reported [22]. The lack of fetal toxicity in the single reported case does not indicate the safety of drug, which should also be avoided during pregnancy. Rituximab Rituximab is a chimeric murine/human IgG1 monoclonal antibody targeting the CD20 antigen present on the surface of normal and malignant B-lymphocytes. Rituximab has revolutionized the management of B-cell lymphomas, and hence is a current standard of care [10]. Furthermore, rituximab is approved for the treatment of chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide or chlorambucil, and for other non-malignant conditions [10]. In humans, placental transfer of rituximab has been documented. In a case report on rituximab exposure during pregnancy, the cord blood serum level of the monoclonal antibody at delivery was three times the level of rituximab in the maternal circulation [23]. In another case, despite the last dose of rituximab was administered two months prior to delivery, a similar concentration of the drug was detected in maternal and newborn serum at birth [24]. In both cases, the newborns experienced a complete depletion of B-cells at birth, but with a recovery to normal levels within 4 months [23,24]. The largest analysis to date comes from Chakravarty et al., which included both maternal and paternal exposure to rituximab before or during pregnancy [25]. Of those, only 21 women were exposed to rituximab during pregnancy and had known pregnancy outcome. Around 50% of these women were treated for lymphomas while the remaining were treated for autoimmune disorders. All
except two were treated after the period of organogenesis. No neonatal or congenital malformations were reported; yet a striking observation is a neonatal cytopenia, even among those who were delivered at term. In this report, 7 out of 11 full term babies had cytopenia at delivery but no reports on complications secondary to cytopenia were reported [25]. Importantly, cytopenia recovered within days or few months after delivery, with no reported complications [25]. Other sporadic case reports on rituximab exposure during pregnancy also noted transient B-cell depletion at birth. A recent large multi-centric retrospective study on managing lymphoma during pregnancy did not show a difference in pregnancy complications or risk of malformations between patients treated with rituximab in combination with standard chemotherapy (n = 13, mainly CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]) or chemotherapy alone (n = 77) [26]. Few case reports were published on accidental pregnancy on maintenance rituximab with normal fetal outcome. Similar to trastuzumab, rituximab is a large molecule and hence exposure during the first trimester is unlikely to have an adverse effect on fetal organogenesis. Yet, it is important to use active contraception in women undergoing maintenance therapy with this agent, which is becoming an increasing approach in nowadays practice. Our interpretation of data favors the use of rituximab for pregnant patients with B-cell lymphomas [3]. The potential maternal benefits of rituximab in terms of disease control and overall survival appear to outweigh the relatively limited fetal risk secondary to in utero exposure to rituximab. Nonetheless, patients and physicians need to bear in mind the potential risk of neonatal and postneonatal cytopenia and the possible consequences particularly the increased risk of infection. Imatinib Imatinib is a TKI targeting the bcr-abl tyrosine kinase, a mutant constitutive tyro sine kinase created by the t(9;22) balanced translocation (i.e. the Philadelphia chromosome) [27]. Imatinib inhibits other tyrosine kinases including non-mutated abl, ARG (abl-related gene), c-kit (the stem cell factor receptor), c-FMS (the colonystimulating factor 1 receptor), platelet-derived growth factor receptors (PDGFR) a and b, and others [27]. Imatinib is approved for the management of Philadelphia chromosome positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST), both being classically diagnosed in elderly population [10]. Imatinib is also used in managing Philadelphia chromosome positive acute lymphoblastic leukemia (ALL), chronic eosinophilic leukemia, dermatofibrosarcoma protuberans, myelodysplastic/ myeloproliferative neoplasms and systemic mastocytosis [10]. Placental transfer of imatinib to the fetus has been documented in humans [28,29]. In the two case reports by Russell and colleagues, imatinib concentration in maternal and umbilical cord blood were 886 and 0–157 ng/mL, respectively [28]. In the case report by Ali et al., imatinib concentration at delivery (16 h after a maternal dose of imatinib) in maternal, umbilical cord and infant peripheral blood were 1562, 338 and 478 ng/mL, respectively [29]. The day after delivery, infant peripheral blood concentration of imatinib decreased to 183.5 ng/mL [29]. In animal studies, imatinib was found to induce embryotoxicity and teratogenicity when administered during organogenesis. When administered at doses similar to those used in humans, it can induce total fetal loss and post-implantation loss [7]. Skeletal system defects were the most common malformations developed with the use of imatinib during the first trimester [7]. It has been hypothesized that the occurrence of these malformations may be due to the inhibitory effect of imatinib on PDFGRa that play an important role during organogenesis [30]. In humans, several reports have been published on pregnancy outcomes following imatinib exposure during gestation.
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
M. Lambertini et al. / Cancer Treatment Reviews xxx (2015) xxx–xxx
All major malformations occurred in fetuses exposed during the first trimester. An early report by Pye and colleagues investigating the pregnancy and fetal outcomes of 180 women exposed to imatinib during pregnancy, showed the occurrence of fetal abnormalities in 12 pregnancies with drug exposure during the first trimester [31]. Out of those, there were 8 live births, 1 stillbirth, and 3 terminations. Major malformations consisted of skeletal defects with or without urogenital malformations [31]. The rate of major malformations following exposure to imatinib in the first trimester is around 11%, while no major or minor malformations were observed in infants with in utero exposure to imatinib in the second and/or third trimesters only [7]. For this reason, imatinib exposure during the first trimester should be completely avoided. This is rather in line with preclinical data suggesting teratogenic effects secondary to imatinib exposure particularly skeletal alterations. As expected, first trimester exposure is also associated with high rate of spontaneous abortion. According to the recent report from the National Toxicology Program of the US Department of Health and Human Services, out of 157 pregnancies reported in literature to have been exposed to imatinib during pregnancy, 19 (12.1%) experienced spontaneous abortion, which ranks the highest among other anticancer agents, according to this report [7]. This is probably due to the fact that most of these pregnancies (n = 151) were exposed during the first trimester, secondary to patients becoming accidentally pregnant while undergoing treatment with imatinib. This underscores the need to use active contraception in patients undergoing treatment with imatinib. On the other hand, fewer patients received imatinib electively during second or third trimester with no major or minor malformations reported [7]. Thus, the use of imatinib in the second and/or third trimesters could be a valid approach albeit safety data are rather limited and based on less than 10 patients. Hence solid conclusions cannot be drawn. All-trans retinoic acid (ATRA) ATRA (or tretinoin) is the carboxylic acid form of vitamin A and is indicated for the treatment of acute promyelocytic leukemia (APL) [10]. Placental transfer of ATRA can occur in humans. This compound has been reported to have extensive placental transport but a relatively short half-life [32,33]. In animal experiments, ATRA showed to have embryolethal and teratogenic effects: particularly, it can induce soft-tissue and skeletal alterations (e.g. cranio-facial defects) but also malformations of the central nervous system leading to behavioral dysfunctions [34,35]. The rate of major malformations among all ATRA-exposed offspring is 4% (1/26 live born infants) [7]. The only malformation described was a Potter syndrome (i.e. bilateral renal agenesis and oligohydramnios). However, it was diagnosed prior to the third trimester when administration of ATRA was started and thus it cannot be attributable to ATRA [36]. Chelghoum and colleagues reported two induced abortions and one spontaneous abortion following first-trimester exposure to ATRA but in patients concurrently treated also with daunorubicin and cytarabine [37]. In three infants with in utero exposure to ATRA in the second and third trimesters, an abnormal cardiac function was reported, arrhythmia in two cases and dilation of the right atrium and ventricle in one infant [33,38,39]. Hence, in our opinion, current evidence does not discourage the use of ATRA following the first trimester in pregnant patients with APL.
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Immune related agents: interferon-a (IFN-a) IFN-a is a pleiotropic cytokine, which is used in the treatment of patients with melanoma, CML, lymphoma, hairy cell leukemia and AIDS-related Kaposi sarcoma in addition to other non-malignant conditions, although generally not as first-line treatment [10]. In humans, IFN-a does not cross the placental barrier in significant amounts [40,41]. No IFN-a was detectable in fetal blood and amniotic fluid in the two HIV-seropositive pregnant women reported by Pons and colleagues treated with IFN-a during the 2nd trimester of pregnancy [40]. In the two cases reported by Haggstrom et al., IFN-a concentration in the babies were
