
==== Front
Lancet Reg Health Eur
Lancet Reg Health Eur
The Lancet Regional Health - Europe
2666-7762
Elsevier

S2666-7762(24)00212-6
10.1016/j.lanepe.2024.101045
101045
Comment
Incidental findings in NIPT show potential for detecting hematological malignancies
van Kemenade Folkert J. f.vankemenade@erasmusmc.nl

Dept of Pathology, Erasmus MC Univ Med Center, PO Box 2024, 3000 CA, Rotterdam, Netherlands
30 8 2024
10 2024
30 8 2024
45 10104513 8 2024
15 8 2024
© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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pmcThe non-invasive pregnancy test (NIPT) is a screening test of cell free fetal DNA in blood samples in order to detect potential abnormalities in early pregnancy. It is offered in the Netherlands to all pregnant women since April 2023. In the default version, it tests for three chromosomal abnormalities (aneuploidies) in 21, 18 and 13. Yet, women can opt in for a genome wide test, that enlarges the test for all maternal autosomes. Prior to implementation of NIPT in the Netherlands, a large implementation trial (Trident-2) had been conducted to gather information on, among other things, the frequency of unexpected findings in the mother's autosomes, such as malignancies.1 Importantly, in this trial, 11 out of 56,818 (0.015%) women with placental and maternal cfDNA testing received results of complex abnormal-NIPT profiles, pointing to possible malignancies of which five women were confirmed with hematological malignancies.1

Were these findings representative of all malignancies in the tested (pregnant) population? To answer this question, in this issue of The Lancet Regional Health – Eurupe, Heesterbeek and colleagues2 decided to do a ‘reverse approach’ i.e. helped by the International Network on Cancer, Infertility and Pregnancy (INCIP) database. This database registers pregnancy associated cancers in several countries, the Netherlands included.3,4 Over a 4-year period (2017–2021), during which the Trident-2 trial was conducted, they found 143 Dutch cases. In 67 cases there was a match with a Trident-2 participant.2 Two participants were excluded from this study, because these women had already cancer diagnosed during the NITP test, leaving 65 women. Of these 65 women 54 women had a solid tumour and 11 women a hematological malignancy. Which results did the NIPT show in these women?

Authors did the analysis a bit more uniform than in the Trident-2 study, i.e. using the Wisecondor pipeline and the Maastricht criteria. This, interestingly, led 2 results with ‘normal’ in the Trident-2 to be revised to ‘suspicious or mildly suspicious for malignancy’.5 Authors found that 16 out of 65 (24.6%) had a NIPT result malignant suspicious and 49 (75.4%) women had a normal NIPT result.

The test did clearly better for circulating tumors than for solid tumors: 10 out of 11 hematological cancers had malignancy suspicious-NIPT result. Only one hematological case (diagnosed after the pregnancy) was missed i.e. reported as a normal NIPT result. For solid tumors, the NIPT test was much less informative: only five out of 54 cases with a solid tumour had a malignancy suspicious-NIPT result and four out of these patients had advanced cancer staged III or IV. Authors could explain these results by pointing out that the NIPT test is largely based on the leukocytes in the blood, reflecting stem cell abnormalities, thus making detection of hematological malignancies easier. In addition, authors found a shorter time interval in patients with a malignancy suspicious-NIPT, compared to the group with a non-suspicious-NIPT results. In summary, the NIPT showed a promising performance for hematological malignancies, but did poorly for solid tumors (see Fig. 1).Fig. 1 Piecharts (left panel) shows overall number of matched women in the INCIP database with NIPT test results in the Trident-2 study, viz. ‘suscipicious malignancy’ (orange) vs normal result (blue). Almost 25% of women with cancer were detected. The smaller piecharts on the right show distribution for hematological malignancies (upper right panel) and other (solid) malignancies (lower right panel) respectively.

Can this result be translated to deliverance of NIPT test results on maternal autosomes, if opted-in for? First of all, not all malignancies are registered in the INCIP database, so we are not sure where findings can be extrapolated to the Dutch pregnant population. In the Trident-2 detected malignancies, almost 50% were hematological malignancies, while in the INCIP group, the hematological malignancies had a lower percentage. Authors point out that the distribution of tumours was comparable in the NIPT group vs the non NIPT group in the INCIP database. But, even if results were representative for pregnant women with a malignancy, can we consider reporting unexpected findings in case of hematological malignancies? Not yet, we need more information about the reproducibility of the pipeline outside a research context, information about the limits of the test for hematological malignancies, such as sensitivity and specificity, and, most importantly, an evaluation of the potential benefits and harms for the women in case of disclosing results. Does a quickened workup allow for better prognosis or a less harmful treatment? Can we avoid increasing inequity in case reporting unexpected findings? Authors rightly avoid claiming that a malignancy score in a NIPT test is ready for implementation, but the results are worthy of further exploration whether in case of disclosure of suspected hematological malignancies, benefits will outweigh harms.

Declaration of interests

No conflicts of interests to disclose.
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References

1 van der Meij K.R.M. Sistermans E.A. Macville M.V.E. TRIDENT-2: national implementation of genome-wide non-invasive prenatal testing as a first-tier screening test in the Netherlands Am J Hum Genet 105 6 2019 1091 1101 31708118
2 Heesterbeek C.J. Tjan-Heijnen V.C. Heimovaara J.H. Prenatal cell-free DNA testing of women with pregnancy-associated cancer: a retrospective cross-sectional study Lancet Reg Health Eur 45 2024 10.1016/j.lanepe.2024.101024
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