In Brief | Oncology | Screening

Prenatal cfDNA Testing: A Valuable Diagnostic Approach for Maternal Cancer Screening

This article is a review of recent studies originally published in NEJM, 4 December,2024. It does not represent the original research, nor is it intended to replace the original research. Access the full Disclaimer Information.

Cell-free DNA (cfDNA) is fragmented DNA which is released into the bloodstream during cell death. It's concentration varies depending on factors such as tissue damage, cancer, and inflammation. Liquid biopsies using cfDNA have become a significant area of research, with plasma cfDNA serving as a potential blood marker for various diseases.¹

 cfDNA sequencing is a widely used technique for screening fetal aneuploidy, such as Down syndrome, during pregnancy. As a collateral benefit, it has also been found to incidentally detect signs of maternal cancer, particularly when sequencing results are unusual or nonreportable. 

While this incidental discovery is becoming increasingly recognised, there is insufficient data to establish clear DNA-sequencing patterns or biomarkers that would identify pregnant individuals at higher risk for cancer. 

Moreover, there is limited understanding of the most appropriate follow-up procedures for these cases, making further research crucial.


Study Purpose

The study aimed to investigate the potential of cfDNA-sequencing results, specifically when unusual or non-reportable, as indicators of undiagnosed cancer in pregnant and post-partum individuals. 

The primary goal was to assess the presence of occult cancer in these participants following a thorough cancer screening protocol. 

The secondary objective was to evaluate the performance of different diagnostic tools, including whole-body MRI, physical exams, laboratory tests, and cfDNA sequencing, to determine the best approach for identifying cancer in this population.

Study Methodology

The study was conducted in North America.

Pregnant or postpartum participants who were asymptomatic but who had received unusual or non-reportable cfDNA sequencing results were selected. 

The screening protocol included rapid whole-body MRI, which is known for its ability to detect occult cancers; laboratory tests and standardised cfDNA sequencing conducted using a genome-wide platform. 

The primary endpoint was to confirm cancer after initial screening, while secondary analyses focused on assessing the sensitivity, specificity, and overall performance of the diagnostic tests used in the screening.

Findings

Of 107 participants in the study, 52 (48.6%) were found to have cancer, indicating a significant rate of undiagnosed cancer in individuals with unusual or non-reportable cfDNA sequencing results.

MRI: The sensitivity of whole-body MRI in detecting occult cancers was 98.0%, with a specificity of 88.5%. 

Physical exams and laboratory tests were found to have limited utility in detecting cancer in this cohort. These traditional diagnostic methods did not contribute significantly to identifying individuals who had cancer, highlighting the need for more sensitive and advanced screening methods.

cfDNA sequencing revealed that 49 participants had specific patterns of copy-number gains and losses across multiple chromosomes (≥3), which was strongly associated with the presence of cancer. 95.9% of participants with this pattern had cancer.

In contrast, participants who had cfDNA sequencing patterns showing only chromosomal gains (multiple trisomies) or losses (monosomies) were more likely to have non-malignant conditions, such as fibroids. 

This distinction suggests that certain cfDNA patterns can help differentiate between malignant and non-malignant conditions.

Discussion
 

Maternal cancers often present without clear symptoms, complicating early detection and intervention. Traditional diagnostic methods, such as physical examinations and standard laboratory tests, have shown limited effectiveness in identifying these cancers during pregnancy. This underscores the urgent need for precise and sensitive tools to detect maternal cancers at earlier, more treatable stages.

Whole-body MRI demonstrated high sensitivity in detecting hidden malignancies in this cohort, highlighting its potential as a critical diagnostic tool for pregnant individuals. 

Additionally, the study revealed that atypical cfDNA sequencing patterns, originally designed for foetal aneuploidy screening, could serve as markers for maternal cancer. Specific patterns, particularly those indicating multiple chromosomal abnormalities, were strongly associated with malignancies, offering a path to differentiate between malignant and benign conditions like fibroids.


Conclusion

The study results support the hypothesis that unusual or non-reportable cfDNA sequencing patterns can serve as early indicators of occult cancer in pregnant individuals, even when they are asymptomatic. Nearly half (48.6%) of the pregnant individuals included in the study who had unusual or nonreportable cfDNA sequencing results had undiagnosed cancer, suggesting that cfDNA sequencing could be a promising tool for early detection of maternal cancers. 

These findings suggest a paradigm shift in prenatal screening, extending its scope beyond foetal aneuploidy to include maternal cancer detection. Integrating cfDNA sequencing into routine prenatal care could revolutionise maternal healthcare by enabling early cancer detection, improving outcomes, and saving lives. This research paves the way for broader adoption of genomic technologies in prenatal care, advancing both maternal and foetal health.

Access the original study
 

Turriff AE et al. Prenatal cfDNA sequencing and incidental detection of maternal cancer. New England Journal of Medicine DOI: 10.1056/NEJMoa2401029

Additional References

1. Gong, Y., Dou, L., Zhou, X., & Zhang, Y. (2022). Bioinformatics analysis methods for cell-free DNA. Computers in Biology and Medicine, 143, 105283. https://doi.org/10.1016/j.compbiomed.2022.105283
 

2. Desai, V. B., Wright, J. D., Schwartz, P. E., et al. (2018). Occult Gynecologic Cancer in Women Undergoing Hysterectomy or Myomectomy for Benign Indications. Obstetrics and gynecology, 131(4), 642–651. https://doi.org/10.1097/AOG.0000000000002521

3. Finestone, E., & Wishnia, J. (2022). Estimating the burden of cancer in South Africa. SA Journal of Oncology, 6(1). https://hdl.handle.net/10520/ejc-sajo_v6_i0_a220

4. Ismail, S. (2021). Radioguided occult lesion localisation (ROLL) as a diagnostic and therapeutic procedure: Clinical review at a single tertiary hospital in South Africa [Master's thesis, Cape Peninsula University of Technology]. Cape Peninsula University of Technology Institutional Repository. https://etd.cput.ac.za/handle/20.500.11838/3618

5. Zhang D, Zhai J, Li L, Wu Y, Ma F, Xu B. Prognostic Factors and a Model for Occult Breast Cancer: A Population-Based Cohort Study. J Clin Med. 2022 Nov 17;11(22):6804. doi: 10.3390/jcm11226804. PMID: 36431280; PMCID: PMC9698700

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