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Cancer treatment during pregnancy: from fetal safety to maternal efficacy

Periodic Reporting for period 3 - CRADLE (Cancer treatment during pregnancy: from fetal safety to maternal efficacy)

Reporting period: 2018-10-01 to 2020-03-31

The evolution in drug regulation of the last 50 years has left pregnant women and their fetuses orphaned. This is particularly problematic for cancer during pregnancy, which raises a difficult and conflicting medical ethical decision process and which has recently become increasingly frequent. In 2012 we published the first prospective study indicating that antenatal exposure to cancer treatment can overall be considered safe. Building on this proof of concept, the current proposal wants to take a groundbreaking step towards developing a standard of care for cancer during pregnancy by addressing –in an integrated fashion- the challenges at the level of the fetus, the mother and the fetomaternal barrier. At the core of this proposal lies an international registry of pregnant women with cancer, along with a registry of their children, and biobanks of maternal, placental, cord blood and tumoral tissues. Research track ‘child’ aims to deliver robust evidence of fetal safety. Research track ‘mother’ aims to address the emerging concerns in the oncological management of the mother, and specifically, the possible distinct biology of pregnancy-associated breast cancer, the most frequent cancer type in pregnancy. The research approach includes large-scale clinical follow-up studies along with laboratory studies on patient biomaterials, including pharmacological investigations and RNA-sequencing studies. Complementary to these studies is research track ‘placenta’ in which cutting-edge models of human placental research are used to address the poorly understood physiological basis of the placental barrier function in this specific situation. This ambitious program will rely on a multidisciplinary team of experts.

This project aims to establish groundbreaking progress towards a standard of care for cancer in pregnancy by addressing –in an integrated fashion- the remaining concerns of antenatal exposure to chemotherapy for the fetus, the emerging concerns for the efficacy of the oncological management for the mother, and the poorly understood physiological basis of the placental barrier in this specific context. We defined 5 major objectives, corresponding to 5 distinct research programs.
1. We will use the growing registry of children within INCIP to deliver robust prospective evidence on the risk profile of antenatal exposure to chemotherapy for fetal cardiac and neuropsychological development.
2. Using the INCIP patient registry we will define the epidemiology of chemotherapy-associated IUGR. We will study the pathophysiology through a prospective study on biomaterials of chemotherapy-treated pregnant patients from INCIP, supported by investigations in an experimental setting.
3. Using prospective clinical studies in pregnant cancer patients from INCIP we will study the currently existing concerns with regards to staging, chemotherapy and psycho-emotional guidance during pregnancy.
4. Using cutting-edge models of human placental research we will characterize the dynamics of transplacental passage of the 4 most commonly used chemotherapeutics in pregnancy, as well as the underlying mechanisms of efflux transport and drug metabolism.
5. Using a two-phase retrospective/prospective study involving large-scale RNA-sequencing studies of tumor tissue from INCIP breast cancer patients, we will determine whether PP-BC exhibits a specific molecular signature with prognostic relevance.
1. We are using the growing registry of children within INCIP to deliver robust prospective evidence on the risk profile of antenatal exposure to chemotherapy for fetal cardiac and neuropsychological development.
This is a multicenter prospective follow-up of children identified through the INCIP registry. The study is ongoing.
Results have been published in:
-Vandenbroucke T. et al in NEJM 2015 and
-Vandenbroucke T et al.in The Lancet Child and Adolescent Health 2017.
We concluded: Neonatal and long-term safety data are important indicators for patients and clinicians when considering cancer treatment during pregnancy. When this knowledge is not available, the likelihood of
termination of pregnancy, delay of maternal treatment, or induction of preterm delivery is high. By contrast, when outcome data are available and discussed with the patient, an informed decision to continue the pregnancy and treat the
maternal cancer is much more likely to be made. Overall, the available evidence suggests that exposure to chemotherapy in the second and third trimesters is not detrimental to fetal life. However, the most important risks of exposure
are those of small for gestational age and preterm birth, which is associated with an increased risk of neurocognitive dysfunction. Moreover, hearing loss in the child has been reported after cisplatin administration during pregnancy.
Chemotherapy administered during the first trimester of pregnancy is associated with an increased risk of congenital malformations and is therefore contraindicated.
2. Using the INCIP patient registry we will define the epidemiology of chemotherapy-associated Intra Uterine Growth Rrestriction. We will study the pathophysiology through a prospective study on biomaterials of chemotherapy-treated
pregnant patients from INCIP, supported by investigations in an experimental setting.
Results have been published in:
- de Haan J. et al in Lancet Oncol 2018.
We concluded: Management of cancer in pregnancy has importantly changed over 20 years: For the period 1996-2016, an increase of cancer treatment during pregnancy was found, while the incidence of iatrogenic
prematurity decreased. However, patients with antenatal chemotherapy exposure may have an increased risk to develop pregnancy related complications, specifically small for gestational age and NICU admission. Involvement of
hospitals with obstetrical high care units in the management of these patients is recommended.
- Verheecke M et al. in Placenta 2018:
We concluded the following: A substantial percentage of children in utero exposed to chemotherapy (21%) are smaller at birth. Reasons for this are by far unexplored. This article published by our group , shows that there's
some DNA-damage present at the maternal side of the placenta caused by chemotherapy, which can be related to fetal growth restriction. The fetal side of the placenta seems to be protected from this potential damage.
On February 2nd 2018, one of our PhD students defended her doctoral thesis at KU Leuven, promoted by F. Amant: Exploring the pathophysiologic mechanisms of prenatal exposure to cancer treatment on the fetal growth and
cardiac function.
3. Using prospective clinical studies in pregnant cancer patients from INCIP we will study the currently existing concerns with regards to staging, chemotherapy and psycho-emotional guidance during pregnancy.
Staging: We concluded that WB-DWI/MRI is feasible for single-step non-invasive staging of cancer during pregnancy with additional value for conventional imaging procedures. Han S et al. in Eur Radiol. 2018.
Psycho-emotional guidance: We concluded that Women and partners using internalizing coping strategies deal with the highest levels of distress and may benefit from additional
psychosocial support. Vandenbroucke T et al in Psycho-oncology 2017.
4. Using cutting-edge models of human placental
Not only may the scientific deliverables of this proposal constitute a major step forward to the well-being of both mother and fetus in a pregnancy complicated by cancer, the methodological approach may also provide critical impetus to further research in this field.