Publications by authors named "Liesbeth Lenaerts"

15 Publications

  • Page 1 of 1

Non-invasive prenatal testing suggesting a maternal malignancy: What do we tell the prospective parents in Belgium?

Prenat Diagn 2021 Aug 17. Epub 2021 Aug 17.

Department of Development and Regeneration, Division Woman and Child, Clinical Department Obstetrics and Gynaecology, University Hospital Leuven, KULeuven, Leuven, Belgium.

Cancer is diagnosed in one in 1000 to 1500 pregnancies. Most frequently encountered malignancies during pregnancy are breast cancer, hematological cancer, cervical cancer and malignant melanoma. Maternal cancer is associated with an increased risk of IUGR and preterm labor, especially in patients with systemic disease or those receiving chemotherapy during pregnancy, requiring a high-risk obstetrical follow-up. Fetal aneuploidy screening by non-invasive prenatal testing (NIPT) can lead to the incidental identification of copy number alterations derived from non-fetal cell-free DNA (cfDNA), as seen in certain cases of maternal malignancy. The identification of tumor-derived cfDNA requires further clinical, biochemical, radiographic and histological investigations to confirm the diagnosis. In such cases, reliable risk estimation for fetal trisomy 21, 18 and 13 is impossible. Therefore, invasive testing should be offered when ultrasonographic screening reveals an increased risk for chromosomal anomalies, or when a more accurate test is desired. When the fetal karyotype is normal, long term implications for the fetus refer to the consequences of the maternal disease and treatment during pregnancy. This manuscript addresses parental questions when NIPT suggests a maternal malignancy. Based on current evidence and our own experience, a clinical management scheme in a multidisciplinary setting is proposed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.6031DOI Listing
August 2021

Breast cancer diagnosed in the post-weaning period is indicative for a poor outcome.

Eur J Cancer 2021 Sep 27;155:13-24. Epub 2021 Jul 27.

Department of Oncology, Laboratory of Gynecological Oncology, KU Leuven, Leuven, Belgium; Department of Gynecology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Department of Gynecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium; Department of Gynecological Oncology, Amsterdam University Medical Centers, Amsterdam, the Netherlands. Electronic address:

Background: In young women, a breast cancer diagnosis after childbirth increases the risk for metastasis and death. Studies in rodents suggest that post-weaning mammary gland involution contributes to the poor prognosis of postpartum breast cancers. However, this association has not been investigated in humans, mainly because of missing information on the patient's lactation status at diagnosis.

Patients And Methods: Clinicopathological data of 1180 young women with primary invasive breast cancer, diagnosed within 2 years postpartum (PP-BC), during pregnancy (Pr-BC), or nulliparous (NP-BC), were collected. For PP-BC patients, breastfeeding history was retrieved to differentiate breast cancers identified during lactation (PP-BC) from those diagnosed post-weaning (PP-BC). Differences in prognostic parameters, first site of distant metastasis, and risks for metastasis and death were determined between patient groups.

Results: Cox proportional hazard models pointed to a twofold increased the risk of metastasis and death in PP-BC patients compared with PP-BC (hazard ratio [HR] 2.1 [P = 0.021] and 2.9 [P = 0.004]), Pr-BC (HR 2.1 [P<0.001] and 2.3 [P<0.001]) and NP-BC (HR 2.1 [P<0.001] and 2.0 [P<0.001]) patients. Prognosis was poorest for PP-BC patients who did not breastfeed or only for ≤ 3 months before diagnosis. This could not fully be attributed to differences in standard prognostic characteristics. In addition, PP-BC tumours showed a 3- to 8-fold increased risk to metastasise to the liver, yet this did not correlate with the poor outcome of this patient cohort.

Conclusions: Breast cancer diagnosed shortly after weaning specifically adds to the poor prognosis in women diagnosed with PP-BC. Apart from the importance of an increased awareness, these data show that detailed lactation data need to be registered when breast cancer outcome in young women is investigated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejca.2021.06.009DOI Listing
September 2021

Novel next-generation sequencing-based methodologies to characterize the mutational consequences of (prenatal) chemotherapy exposure in noncancerous tissue.

Curr Opin Oncol 2021 Sep;33(5):476-484

Department of Oncology.

Purpose Of Review: Although chemotherapeutics are considered as genotoxins for decades, their exact mutagenic impact on the genome of cancerous and normal cells of cancer patients was unknown for a long time. However, this knowledge is necessary to understand the long-term side effects of chemotherapy. A particular condition represents pregnant cancer patients being treated with chemotherapy. Since certain chemotherapeutics can cross the placenta, concerns exist about possible mutational effects on the fetus' genome with potential long-term health consequences.

Recent Findings: Recent advances of next-generation sequencing (NGS) techniques have opened possibilities to explore the exact mutational footprint of chemotherapies in healthy tissue from treated cancer patients. However, the ultra-low frequency of chemotherapy-induced mutations, introduction of technical artefacts, and inaccessibility of normal tissue has posed important limitations. This review discusses five state-of-the-art approaches that were recently designed to overcome these drawbacks.

Summary: Results of the latest investigations give valuable insights into the genome-wide genotoxicity profile of frequently applied chemotherapies, with most of these drugs being associated with a signature of random base substitutions and small indels. Though these findings still might be limited to extrapolate to healthy tissue, they pave the way for studies on the origin of long-term chemotherapy-related adverse health effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/CCO.0000000000000755DOI Listing
September 2021

Comprehensive genome-wide analysis of routine non-invasive test data allows cancer prediction: A single-center retrospective analysis of over 85,000 pregnancies.

EClinicalMedicine 2021 May 13;35:100856. Epub 2021 May 13.

Department of Oncology, KU Leuven, Herestraat 49, Leuven, Belgium.

Background: Implausible false positive results in non-invasive prenatal testing (NIPT) have been occasionally associated with the detection of occult maternal malignancies. Hence, there is a need for approaches allowing accurate prediction of whether the NIPT result is pointing to an underlying malignancy, as well as for organized programs ensuring efficient downstream clinical management of these cases.

Methods: Using a data set of 88,294 NIPT performed at University Hospital Leuven (Belgium) between November 2013 and March 2020, we retrospectively evaluated the positive predictive value (PPV) of our NIPT approach for cancer detection. In this approach, whole-genome cell-free DNA (cfDNA) data from NIPT were scrutinized for the presence of (sub)chromosomal copy number alterations (CNAs) predictive for a malignancy, using an unbiased NIPT analysis pipeline coined GIPSeq. For suspected cases, the presence of a maternal cancer was evaluated via subsequent multidisciplinary clinical follow-up examinations. The cancer-specificity of the identified CNAs in cfDNA was assessed through genetic analyses of a tumor biopsy.

Findings: Fifteen women without a cancer history were identified with a GIPSeq result suggestive of a malignant process. Their cfDNA profiles showed either genome-wide aberrations or a single trisomy 8. Upon clinical examinations, a solid or hematological cancer was identified in 4 and 7 cases, respectively. Three women were identified as having a clonal mosaicism. For one case no underlying condition was found. These numbers add to a PPV of 73%. Based on this experience, we presented a multidisciplinary care path for efficient clinical management of these cases.

Interpretation: The presented approach for analysing NIPT results has a high PPV, yet unknown sensitivity, for detecting asymptomatic malignancies upon routine NIPT. Given the complexity of diagnosing a pregnant woman with cancer, clinical follow-up should occur in a well-designed multidisciplinary setting, such as via the care model that we presented here.

Funding: This work was supported by Research Foundation Flanders and KU Leuven funding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eclinm.2021.100856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138727PMC
May 2021

The MNK1/2-eIF4E Axis Supports Immune Suppression and Metastasis in Postpartum Breast Cancer.

Cancer Res 2021 Jul 11;81(14):3876-3889. Epub 2021 May 11.

Department of Physiology, Faculty of Medicine, McGill University, Montréal, Québec, Canada.

Breast cancer diagnosed within 10 years following childbirth is defined as postpartum breast cancer (PPBC) and is highly metastatic. Interactions between immune cells and other stromal cells within the involuting mammary gland are fundamental in facilitating an aggressive tumor phenotype. The MNK1/2-eIF4E axis promotes translation of prometastatic mRNAs in tumor cells, but its role in modulating the function of nontumor cells in the PPBC microenvironment has not been explored. Here, we used a combination of PPBC models and assays to study the effects of inactivation of the MNK1/2-eIF4E axis on the protumor function of select cells of the tumor microenvironment. PPBC mice deficient for phospho-eIF4E (eIF4E) were protected against lung metastasis and exhibited differences in the tumor and lung immune microenvironment compared with wild-type mice. Moreover, the expression of fibroblast-derived IL33, an alarmin known to induce invasion, was repressed upon MNK1/2-eIF4E axis inhibition. Imaging mass cytometry on PPBC and non-PPBC patient samples indicated that human PPBC contains phospho-eIF4E high-expressing tumor cells and CD8 T cells displaying markers of an activated dysfunctional phenotype. Finally, inhibition of MNK1/2 combined with anti-PD-1 therapy blocked lung metastasis of PPBC. These findings implicate the involvement of the MNK1/2-eIF4E axis during PPBC metastasis and suggest a promising immunomodulatory route to enhance the efficacy of immunotherapy by blocking phospho-eIF4E. SIGNIFICANCE: This study investigates the MNK1/2-eIF4E signaling axis in tumor and stromal cells in metastatic breast cancer and reveals that MNK1/2 inhibition suppresses metastasis and sensitizes tumors to anti-PD-1 immunotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1158/0008-5472.CAN-20-3143DOI Listing
July 2021

Postpartum breast cancer: mechanisms underlying its worse prognosis, treatment implications, and fertility preservation.

Int J Gynecol Cancer 2021 03;31(3):412-422

Department of Oncology, KU Leuven University Hospitals Leuven Gasthuisberg Campus, Leuven, Flanders, Belgium

Breast cancers that occur in young women up to 5 to 10 years' postpartum are associated with an increased risk for metastasis and death compared with breast cancers diagnosed in young, premenopausal women during or outside pregnancy. Given the trend to delay childbearing, this frequency is expected to increase. The (immuno)biology of postpartum breast cancer is poorly understood and, hence, it is unknown why postpartum breast cancer has an enhanced risk for metastasis or how it should be effectively targeted for improved survival. The poorer prognosis of women diagnosed within 10 years of a completed pregnancy is most often contributed to the effects of mammary gland involution. We will discuss the most recent data and mechanistic insights of the most important processes associated with involution and their role in the adverse effects of a postpartum diagnosis. We will also look into the effect of lactation on breast cancer outcome after diagnosis. In addition, we will discuss the available treatment strategies that are currently being used to treat postpartum breast cancer, keeping in mind the importance of fertility preservation in this group of young women. These additional insights might offer potential therapeutic options for the improved treatment of women with this specific condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/ijgc-2020-002072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925817PMC
March 2021

Management of pregnancy in women with cancer.

Int J Gynecol Cancer 2021 03;31(3):314-322

Department of Gynecology, Antoni van Leeuwenhoek Nederlands Kanker Instituut, Amsterdam, The Netherlands

As the incidence of cancer in pregnancy has been increasing in recent decades, more specialists are confronted with a complex oncologic-obstetric decision-making process. With the establishment of (inter)national registries, including the International Network on Cancer, Infertility and Pregnancy, and an increasing number of smaller cohort studies, more evidence on the management of cancer during pregnancy is available. As fetal, neonatal, and short-term pediatric outcomes after cancer treatment are reassuring, more women receive treatment during pregnancy. Prenatal treatment should adhere to standard treatment as much as possible to optimize maternal prognosis, always taking into account fetal well-being. In order to guarantee the optimal treatment for both mother and child, a multidisciplinary team of specialists with expertise should be involved. Apart from oncologic treatment, a well-considered obstetric and perinatal management plan discussed with the future parents is crucial. Results of non-invasive prenatal testing are inconclusive in women with cancer and alternatives for prenatal anomaly screening should be used. Especially in women treated with chemotherapy, serial ultrasounds are strongly recommended to follow-up fetal growth and cervical length. After birth, a neonatal assessment allows the identification of any cancer or treatment-related adverse events. In addition, placental histologic examination aims to assess the fetal risk of metastasis, especially in women with malignant melanoma or metastatic disease. Breastfeeding is discouraged when systemic treatment needs to be continued after birth. At least a 3-week interval between the last treatment and nursing is recommended to prevent any treatment-induced neonatal effects from most non-platinum chemotherapeutic agents.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/ijgc-2020-001776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925815PMC
March 2021

Breast Cancer Detection and Treatment Monitoring Using a Noninvasive Prenatal Testing Platform: Utility in Pregnant and Nonpregnant Populations.

Clin Chem 2020 11;66(11):1414-1423

Department of Oncology, Laboratory of Gynecological Oncology, KU Leuven, Leuven, Belgium.

Background: Numerous publications have reported the incidental detection of occult malignancies upon routine noninvasive prenatal testing (NIPT). However, these studies were not designed to evaluate the NIPT performance for cancer detection.

Methods: We investigated the sensitivity of a genome-wide NIPT pipeline, called GIPSeq, for detecting cancer-specific copy number alterations (CNAs) in plasma tumor DNA (ctDNA) of patients with breast cancer. To assess whether a pregnancy itself, with fetal cell-free DNA (cfDNA) in the maternal circulation, might influence the detection of ctDNA, results were compared in pregnant (n = 25) and nonpregnant (n = 25) cancer patients. Furthermore, the ability of GIPSeq to monitor treatment response was assessed.

Results: Overall GIPSeq sensitivity for detecting cancer-specific CNAs in plasma cfDNA was 26%. Fifteen percent of detected cases were asymptomatic at the time of blood sampling. GIPSeq sensitivity mainly depended on the tumor stage. Also, triple negative breast cancers (TNBC) were more frequently identified compared to hormone-positive or HER2-enriched tumors. This might be due to the presence of high-level gains and losses of cfDNA or high ctDNA loads in plasma of TNBC. Although higher GIPSeq sensitivity was noted in pregnant (36%) than in nonpregnant women (16%), the limited sample size prohibits a definite conclusion. Finally, GIPSeq profiling of cfDNA during therapy allowed monitoring of early treatment response.

Conclusions: The results underscore the potential of NIPT-based tests, analyzing CNAs in plasma cfDNA in a genome-wide and unbiased fashion for breast cancer detection, cancer subtyping and treatment monitoring in a pregnant and nonpregnant target population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/clinchem/hvaa196DOI Listing
November 2020

Noninvasive prenatal testing detected acute myeloid leukemia in paucisymptomatic pregnant patient.

Clin Case Rep 2020 Oct 20;8(10):1924-1927. Epub 2020 Jun 20.

Center for Human Genetics University Hospitals Leuven Leuven Belgium.

To the authors' best knowledge, this is the first report of acute myeloid leukemia (AML) detected by noninvasive prenatal testing. This was an aggressive case that otherwise would have been difficult to characterize due to disadvantages of "gold-standard" techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccr3.3027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562837PMC
October 2020

Noninvasive Prenatal Testing and Detection of Occult Maternal Malignancies.

Clin Chem 2019 12 11;65(12):1484-1486. Epub 2019 Oct 11.

Department of Human Genetics, KU Leuven, Leuven, Belgium;

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1373/clinchem.2019.306548DOI Listing
December 2019

Detection of incipient tumours by screening of circulating plasma DNA: hype or hope?

Acta Clin Belg 2020 Feb 3;75(1):9-18. Epub 2019 Oct 3.

Department of Human Genetics, KU Leuven, Leuven, Belgium.

The last half-decade has been marked by a rapid expansion of research efforts in the field of so-called liquid biopsies, thereby investigating the potential of blood-derived cell-free tumour DNA (ctDNA) markers for application in clinical oncological management. The analysis of cfDNA appears to be particularly attractive for therapy monitoring purposes, while in terms of early cancer diagnosis and screening the potentials are just starting to be explored. Challenges, both of biological and technical nature, need to be addressed. One such challenge is to overcome the low levels of ctDNA in the circulation, intrinsic to many early-stage cancers. Here, we give an overview of the features of ctDNA and the approaches that are currently being applied with the ultimate aim to detect tumours in a presymptomatic stage. Although many studies report encouraging results, further technical development and larger studies are warranted before application of ctDNA analysis may find its place in clinic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/17843286.2019.1671653DOI Listing
February 2020

Interaction between mouse adenovirus type 1 and cell surface heparan sulfate proteoglycans.

PLoS One 2012 7;7(2):e31454. Epub 2012 Feb 7.

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.

Application of human adenovirus type 5 (Ad5) derived vectors for cancer gene therapy has been limited by the poor cell surface expression, on some tumor cell types, of the primary Ad5 receptor, the coxsackie-adenovirus-receptor (CAR), as well as the accumulation of Ad5 in the liver following interaction with blood coagulation factor X (FX) and subsequent tethering of the FX-Ad5 complex to heparan sulfate proteoglycan (HSPG) on liver cells. As an alternative vector, mouse adenovirus type 1 (MAV-1) is particularly attractive, since this non-human adenovirus displays pronounced endothelial cell tropism and does not use CAR as a cellular attachment receptor. We here demonstrate that MAV-1 uses cell surface heparan sulfate proteoglycans (HSPGs) as primary cellular attachment receptor. Direct binding of MAV-1 to heparan sulfate-coated plates proved to be markedly more efficient compared to that of Ad5. Experiments with modified heparins revealed that the interaction of MAV-1 to HSPGs depends on their N-sulfation and, to a lesser extent, 6-O-sulfation rate. Whereas the interaction between Ad5 and HSPGs was enhanced by FX, this was not the case for MAV-1. A slot blot assay demonstrated the ability of MAV-1 to directly interact with FX, although the amount of FX complexed to MAV-1 was much lower than observed for Ad5. Analysis of the binding of MAV-1 and Ad5 to the NCI-60 panel of different human tumor cell lines revealed the preference of MAV-1 for ovarian carcinoma cells. Together, the data presented here enlarge our insight into the HSPG receptor usage of MAV-1 and support the development of an MAV-1-derived gene vector for human cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031454PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274534PMC
July 2012

Mouse adenovirus type 1 and human adenovirus type 5 differ in endothelial cell tropism and liver targeting.

J Gene Med 2009 Feb;11(2):119-27

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.

Background: For adenovirus vectors derived from human serotype 5 (Ad5), the efficiency and safety after intravascular delivery is hindered by their sequestration in nontarget tissues, predominantly the liver. The latter is largely dictated by adenovirus binding to blood coagulation zymogens. In addition, several target cells, such as endothelial and smooth muscle cells, are difficult to transduce by Ad5 due to the low expression of the primary coxsackie-adenovirus receptor (CAR). Therefore, alternative adenovirus serotypes are being explored.

Methods: In the present study, we assessed the tropism of mouse adenovirus type 1 (MAV-1), a nonhuman adenovirus for which cellular attachment is CAR-independent.

Results: The typical replication of MAV-1 in endothelial cells as observed in vivo was not reflected in elevated attachment to primary and continuous endothelial cells in cell culture. Remarkably, MAV-1 displayed a higher affinity for primary human smooth muscle cells than recombinant Ad5 (rAd5). Attachment of MAV-1 to human and mouse cells of hepatocyte origin was not altered by physiological concentrations of human coagulation factor XI (FXI) or the vitamin K-dependent FIX, FX and FVII. By contrast, attachment of Ad5-derived vectors was enhanced at least eight-fold by FX. Using surface plasmon resonance, MAV-1 was shown to directly associate with human FX and murine FX and FIX but, opposite to rAd5, this interaction did not lead to enhanced cellular attachment. In intravenously injected severe combined immunodeficiency mice, distribution of MAV-1 to the liver was markedly lower than that observed with rAd5.

Conclusions: Our data on the tropism of MAV-1 suggest that this virus may find utility in the field of gene therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgm.1283DOI Listing
February 2009

Clinical features and treatment of adenovirus infections.

Rev Med Virol 2008 Nov-Dec;18(6):357-74

Division of Virology and Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium.

Adenoviruses (Ads) are common opportunistic pathogens that are rarely associated with severe clinical symptoms in healthy individuals. In contrast, in patients with compromised immunity, Ad infections often result in disseminated and potentially life-threatening disease. Among these are AIDS patients, individuals with hereditary immunodeficiencies and recipients of solid organ or haematopoietic stem cell transplants (HSCT) who receive immunosuppressive therapy. The latter account for the largest number of severe Ad infections. There is currently no formally approved antiviral therapy for the treatment of severe Ad keratoconjunctivitis and life-threatening Ad infections in immunocompromised patients. Here we update current knowledge on Ad biology, the clinical features observed in different patient groups and specific immune responses towards Ad infections. In addition, we review current and future treatment options, including: (i) the antiviral drugs cidofovir, ribavirin and new investigational compounds, as evaluated in the clinic or in relevant animal models, as well as (ii) novel immunotherapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/rmv.589DOI Listing
December 2008
-->