In an ongoing Incidental Detection of Maternal Neoplasia through Noninvasive Cell-free DNA Analysis (IDENTIFY) study, using a standardised cell-free DNA (cfDNA)-sequencing and cancer-screening protocol, a group of US researchers detected cancer in 48.6% of participants who initially received nonreportable or unusual cfDNA-sequencing results from 12 commercial laboratories in North America. All the participants had received prenatal screening results that suggested the presence of an occult cancer.
The cohort is not representative of the general pregnant population. The results support the use of whole-body magnetic resonance imaging (MRI) in the evaluation of pregnant persons who receive prenatal cfDNA-sequencing results suggestive of cancer. Further investigation of cfDNA-sequencing patterns would help to identify the subgroup of persons with nonreportable results who might have cancer according to Dr. Diana W. Bianchi of the US National Institutes of Health in Bethesda, MD, US, and colleagues, who published the findings on 4 December 2024 in The New England Journal of Medicine.
The authors wrote in the background that sequencing of circulating cfDNA in the plasma of pregnant persons has had a substantial effect on prenatal screening for foetal aneuploidy. Worldwide, such sequencing has resulted in a 50-70% reduction in invasive diagnostic procedures, such as amniocentesis.
Retrospective studies from large commercial or national laboratories have shown an association between unusual sequencing results, such as multiple aneuploidies or an autosomal monosomy, and cancer in pregnant persons. During a typical pregnancy, circulating cfDNA derives from the placenta and the haematopoietic system of the pregnant person. If a tumour is present in the pregnant person, the tumour can also shed cfDNA into the circulation, which distorts the expected ratios for a euploid or aneuploid foetus.
There is currently insufficient evidence to inform subsequent management after pregnant persons receive nonreportable or unusual sequencing results. Additional data are needed to understand the ability of cfDNA sequencing to detect cancer in pregnant persons and to determine how to evaluate persons who receive results that might indicate cancer.
The goals of the IDENTIFY study are to identify DNA-sequencing patterns and other biomarkers that could identify the subgroup of asymptomatic persons who might have cancer and determine the best approach for the diagnostic work-up of pregnant persons who receive these results.
In this ongoing study, the study team performed cancer screening in pregnant or postpartum persons who did not perceive signs or symptoms of cancer but received unusual clinical cfDNA-sequencing results or results that were nonreportable (e.g. the foetal aneuploidy status could not be assessed) from one of 12 different commercial laboratories in North America.
The study team used an uniform cancer-screening protocol including rapid whole-body MRI, laboratory tests, and standardised cfDNA sequencing for research purposes with the use of a genome-wide platform. The primary outcome was the presence of cancer in participants after the initial cancer-screening evaluation. Secondary analyses included test performance.
Cancer was present in 52 of the 107 participants in the initial cohort (48.6%). The sensitivity and specificity of whole-body MRI in detecting occult cancer were 98.0% and 88.5%, respectively. Physical examination and laboratory tests were of limited use in identifying participants with cancer.
Research sequencing showed that 49 participants had a combination of copy-number gains and losses across multiple (≥3) chromosomes; cancer was present in 47 of the participants (95.9%) with this sequencing pattern. Sequencing patterns of cfDNA in which there were only chromosomal gains (multiple trisomies) or only chromosomal losses (one or more monosomies) were found in participants with non-malignant conditions, such as fibroids.
The authors commented that medical history, participant-reported symptoms, physical examination, and laboratory tests were of limited use in identifying which participants had cancer or its location. Pregnancy or the absence of overt symptoms are not reasons to delay imaging. Whole-body MRI was safe, efficient, and the most effective method for detecting cancer. The percentage of false positive results of whole-body MRI screening was 11.5% (95% confidence interval 4.4 to 23.4), which is considerably lower than that reported in other high-risk patient populations screened with whole-body MRI. The effectiveness of cfDNA sequencing in identifying patients with an existing cancer probably explains this lower percentage of false positive results.
The median time between participants’ initial clinical sequencing and their cancer-screening evaluation was 9.6 weeks (range, 2.0 to 114.6). Factors contributing to delays in referral to the IDENTIFY study included confusion about the clinical significance of the initial sequencing results, a decision by providers to perform repeat sequencing, a decision by participants or providers to pursue foetal diagnostic testing before maternal follow-up, and ambivalence of the participant about pursuing cancer screening.
The importance of prompt cancer screening in patients who receive cfDNA-sequencing results suggestive of maternal cancer is highlighted by the five participants in this study who had stage II or III solid tumours identified and the six participants with stage IV cancers with limited metastatic involvement who were eligible for potentially curative treatment.
In an accompanied editorial, Dr. Neeta L. Vora of the Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, University of North Carolina at Chapel Hill wrote that widespread education is needed for both obstetrical providers and oncologists regarding the possibility that cfDNA screening can identify cancer in pregnant persons. Laboratories that perform cfDNA screening should alert clinicians if there are genomic aberrations suggestive of maternal cancer and should develop guidelines to determine whether such aberrations should be reported along with an acknowledgment that false positive and false negative results can occur. Whole-body MRI is not often ordered by obstetrical providers or covered by insurance.
Until these issues are addressed, obstetrical providers should consider working in a multidisciplinary team with specialists in oncology, radiology, maternal foetal medicine, and reproductive genetics to develop workflows for pregnant patients who receive cfDNA results that might indicate cancer according to the editorialist.
The study was supported by grants from the National Institutes of Health Intramural Research Programs.
References
- Turriff AE, Annunziata CM, Malayeri AA, et al. Prenatal cfDNA Sequencing and Incidental Detection of Maternal Cancer. N Engl J Med 2024;391:2123-32.
- Vora NL. Cell-free DNA Screening and Maternal Cancer. N Engl J Med 2024;391:2168-2169.