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Cancer treatment during pregnancy: from fetal safety to maternal efficacy

Periodic Reporting for period 4 - CRADLE (Cancer treatment during pregnancy: from fetal safety to maternal efficacy)

Reporting period: 2020-04-01 to 2021-03-31

This project entirely addressed better care for pregnant women with cancer.
Our studies show that children antenatally exposed to cancer treatment and in particular to chemotherapy, show a normal performance. Importantly, the subset of children whose mother died due to the cancer, have a lower verbal IQ that needs more attention. These findings are overall very reassuring and allow us to continue to treat these patients while preserving the pregnancy. Our studies provide tools to physicians to diagnose and determine the dissemination of the cancer in pregnant women. We also define characteristics of the couple that refer to a need for psycho-emotional support. Nevertheless, we show that chemotherapy during pregnancy crosses the placenta and can affect intrauterine growth in certain conditions. Follow up of these patients in centers with a high-risk obstetric unit is therefore strongly adviced. Finally, we show the importance of awareness around breast cancer in the postpartum period and the importance of early detection since these cancers have a higher tendency to fatal recurrences.
1.NEUROPSYCHOLOGIC&CARDIAC DEVELOPMENT AFTER ANTENATAL EXPOSURE TO CHEMO:
Our data show increased risk for prematurity, small for gestational age and need for Neonatal Intensive Care Unit admission when children are antenatally exposed to chemotherapy. This short term risk underscores the importance of care by dedicated specialists in a multidisciplinary setting. But after a longer follow up of 6 years, these children perform within normal ranges and do not encounter particular medical problems. Interestingly, exposed children had a lower verbal IQ, especially when their mother died. We hypothesise that a lower attention to these children in a stressfull situation contributes to this observation. Our studies provide a tool to parents or fathers to avoid this verbal backlog. A sub-analysis in 6-year-old exposed children suggested more difficulties to modulate emotions and behavior. This observation is subclinical since parents did not report on this in particular.
Also, we applied event-related potentials to evaluate the development of executive functioning. Prenatal chemo exposure and prematurity were found to affect neurocognitive processes of conflict monitoring and suggest that cancer and/or chemotherapy during pregnancy might impact neurodevelopment of the child.
We also used multimodal Magnetic Resonance imaging of the brain to assess structural and functional brain development of children born to cancer-complicated pregnancies. Cancer during pregnancy was associated with local differences in grey and white matter structure. While platinum derivatives showed an increased impact on gyrification of the left superior temporal gyrus, chemotherapy during pregnancy in general was not associated with a worse outcome.
So overall, despite mainly subtle alterations, they are mainly subclinical and should not be a reason to change our policy to preserve pregnancies and treat cancer during pregnancy.

2.INTRA UTERINE GROWTH RESTRICTION
21% of children in utero exposed to chemo are smaller at birth. The observed DNA-damage at the maternal side of the placenta caused by chemo may be linked to this growth restriction. Interestingly, the fetal side of the placenta seems to be protected from this damage. The study was continued to evaluate histologic abnormalities linked to this growth restriction. Studying placental histologic changes in context of chemo-induced growth restriction is challenging because of chemo combinations. To disentangle the effect of multiple drug use, we complemented clinical studies with use of non-cancer pregnant mouse model exposed to different single agent chemo treatments during late pregnancy and controls. The obtained maternal and fetal tissues are now analyzed by immunohistochemistry and high-resolution contrast-enhanced microComputedTomography and will soon be published when they results are final.

REGISTRY
Our research team enlarged the international network to 73 hospitals in 27 countries that contribute to 2478 registered patients at this moment. This unique setting contributed to an analysis of data of 1170 patients that show that cancer in pregnancy management importantly changed over the years: cancer treatment (especially chemotherapy) in pregnancy increased, while incidence of iatrogenic prematurity decreased over the last 20 years. Patients with antenatal chemo exposure may have increased risk to develop pregnancy related complications, specifically a risk for smaller babies and admission to the neonatal intensive care. We recommend hospitals with obstetrical high care units in the management of these patients. Our data also clarify that the pregnancy duration after which chemotherapy does not induce congenital malformations is 12 weeks.

3.CANCER STAGING & TREATMENT DURING PREGNANCY:

Our studies addressed some crucial steps in the staging and management of cancer during pregnancy.
We can conclude that whole body diffusion weighted Magnetic Resonance imaging is feasible and safe for single-step non-invasive staging of cancer during pregnancy with additional value for conventional imaging procedures. Also the sentinel lymph node biopsy procedure in breast cancer patients is safe for both the mother and child. When chemotherapy is planned, our observed pregnancy-induced chemodilution do not directly warrant dose adjustments for the studied drugs. The prognosis in cervical cancer, hematological cancers and breast cancer is not affected by this chemodilution and this is very reassuring. But at the same time we found that women and partners using internalizing coping strategies deal with the highest levels of distress and may benefit from additional psychosocial support.

4.TRANSPLACENTAL PASSAGE
Based on the assessment of multiple quality control measurements, the described method of a closed human ex-vivo placenta perfusion model was validated. The success rate (38%) was more than twice the success rate reported in literature (15%).

5.POSTPARTUM BREAST CANCER:
Our studies have shown that women with breast cancer diagnosed in the postpartum period, have a higher chance for fatal recurrences. A large-scale transcriptome and immunohistochemistry descriptive analysis in tumor specimens of the breast cancer cohorts, investigates whether human postpartum breast cancer displays unique molecular and immunological features that explain this observation. Final results are expected in December 2021.
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. Our data support cancer treatment of mothers and preserve the pregnancy but also provide tools on how to tackle the challenges associated with this approach.
CRADLE