A prenatal genetic counselor’s take on the IDENTIFY trial

By Samantha Montgomery, MS CGC

Non-reportable or abnormal NIPT (non invasive prenatal testing, also called non invasive prenatal screening or cell free DNA screening) results can occur for a variety of reasons. For my prenatal colleagues, you are likely aware that unfortunately sometimes the answer can be maternal malignancy. For my GC colleagues who have not worked in the prenatal space in recent years, you might be surprised to hear about this phenomenon and how it impacts our patients.  Obtaining a sample that contains cell free DNA from both the pregnant person and the placenta unlocks the potential for quite a few complications. These cases are often something we learn in graduate school, but unless you actually get one of these results in your inbox or in a referral, the idea of counseling a pregnant patient about possibly having cancer may seem foreign and daunting. This is especially challenging because we lack formal guidance and recommendations for care. Early case series suggested that patients with highly unusual cell free DNA results had 20 to 44% chance for malignancy, but with a wide range of estimates based on little data and no specific body systems to target, next steps were difficult. Some of these patients may have other non cancerous tumors, such as fibroids, or other benign explanations, while some do actually represent the 1 in every 1,000 pregnant people who have cancer. 

“Preliminary data from the IDENTIFY trial presented by Dr. Bianchi at ACMG showed that NIPT results with sub-chromosomal and/or whole chromosome copy number gains and losses across three or more chromosomes was seen as a highly sensitive and specific biomarker for maternal malignancy.”

The first time I saw a patient for this indication I happened to have a second year GC student with me in clinic. So we tackled the case prep together and spoke with the performing lab about their findings. Non reportable NIPT results that are suspicious for maternal malignancy often show multiple chromosome abnormalities inconsistent with a viable pregnancy. Lab transparency in recent years has provided additional insight about which non reportable NIPT results need close attention; however, that information is reliant on a single dataset from the labs themselves. Broader, more comprehensive information about these cases is needed and luckily for prenatal GCs Dr. Diana Bianchi at the National Institutes of Health (NIH) has been working to fill the gap. 

If you recently attended the American College of Medical Genetics meeting in Toronto, Canada this spring you had an opportunity to hear from Dr. Diana Bianchi herself about some of their preliminary findings from the NIH IDENTIFY trial (Incidental Detection of Maternal Neoplasia Through Non-Invasive Cell-Free DNA Analysis, a Natural history Study).  The IDENTIFY trial is currently available for individuals who are 18 years and older who have received abnormal or non reportable NIPT results, had follow up ultrasound or diagnostic testing that indicate normal fetal assessment, and are currently pregnant or up to two years postpartum.

The IDENTIFY trial involves a trip to the NIH Clinical Center in Maryland. The trial includes free evaluations, cost of travel for the participant and one support person as well as hotel reimbursement. Evaluations include a full body MRI (safe for both participant and fetus), physical exam, blood and stool samples, possible Pap smear, survey assessing emotional well-being, and ultimately a list of possible diagnoses and treatment options. Participants may be followed for up to 5 years and asked to provide copies of local medical records and possible request to return to the NIH for in person assessment in one year if indicated for reevaluation.  

Preliminary data from the IDENTIFY trial presented by Dr. Bianchi at ACMG showed that NIPT results with sub-chromosomal and/or whole chromosome copy number gains and losses across three or more chromosomes was seen as a highly sensitive and specific biomarker for maternal malignancy. It was emphasized that patients with this NIPT pattern should undergo further evaluation and pregnancy alone is not a reason to delay assessment.  The most common cancers identified in the study were Hodgkin Lymphoma, Non-Hodgkin lymphoma, colorectal and breast cancer, in that order.  Physical examination and standard laboratory tests (such as serum tumor markers and fecal occult blood) were not as sensitive and specific in their ability to detect occult malignancies as was whole body MRI. 

Although the current financial burden seems to be lifted by the IDENTIFY trial funds covering their screening recommendations, there are still barriers participants must face that can be a deterrent for follow up. For my patient in particular, she declined traveling to Maryland during her already high risk pregnancy and she opted to try and obtain her MRI locally. Sadly, as expected, insurance denied coverage for MRI in a presumably healthy and asymptomatic individual. My patient ultimately elected to forgo assessment until after delivery. At the time, she expressed concern about the stresses of travel and rigorous assessment and feared it would exacerbate her underlying stress and anxiety in pregnancy. For other patients, they may not have the ability to take additional time off work for such a trip, as prenatal care appointments may often take up what little time off they have, if any. 

Beyond tackling the logistics of such assessments, many patients will have psychosocial needs we must address. Consistent with recently published NIH findings regarding patient perspectives, my patient’s primary concern focused on fetal health and wellbeing.  At the time, this response came as a surprise to me and my student. The performing NIPT lab had expressed anecdotally that a majority of these results were later confirmed malignancies and we had shared that insight with our patient.  After contracting and thorough discussion of her complex pregnancy and fertility history, it became clear that her main worry was about the health of her child and her own health and wellbeing was put on the back burner. That day the patient was visibly relieved by her normal anatomy scan as well as our reassurance that our worries didn’t lie with the fetal health but in fact her own health. The patient did reach out after delivery to confirm the process for seeking care with the NIH so we hope she made it to Maryland in the end and was ultimately able to receive the care she needed. 

Many prenatal genetic counselors are looking forward to the upcoming publication from the IDENTIFY study. I hope the insight it provides gives clear guidance on how we can best serve this niche patient population and allows us to fight for coverage of necessary screening tests. If you or a colleague need to refer a patient to the NIH for the IDENTIFY study, please contact genetic counselor, Amy Turriff, information linked out below. 

https://www.genome.gov/Clinical-Research/Current-NHGRI-Clinical-Studies/IDENTIFY-Study 

Clinical Trials Number: NCT04049604

Samantha Montgomery, MS, CGC
Pronouns: she/her/hers
Certified Genetic Counselor & Clinical Instructor
Department of Obstetrics, Gynecology, and Reproductive Sciences 
UTHealth | The University of Texas Health Science Center at Houston  
McGovern Medical School

References:

Bianchi, D. W., Chudova, D., Sehnert, A. J., Bhatt, S., Murray, K., Prosen, T. L., . . . Halks-Miller, M. (2015). Noninvasive prenatal testing and incidental detection of occult maternal malignancies. JAMA, 314(2), 162. PMID: 26168314

Carlson LM et al (2018)  Maternal Malignancy Evaluation After Discordant Cell-Free DNA Results.  Obstet Gynecol, 131, 3, 464-468. PMID: 29420407 PMCID: PMC5823781

Rink BD, Stevens BK, Mary E Norton ME (2022) Incidental Detection of Maternal Malignancy by Fetal Cell-Free DNA Screening. Obstet Gynecol. 140(1):121-131. PMID: 35849469

Snyder HS, Curnow, Bhat S, Bianchi DW (2016) Follow-up of multiple aneuploidies and single monosomies detected by noninvasive prenatal testing: implications for management and counseling. Prenatal Diagnosis 2016, 36, 203–209.PMID: 26785403 PMCID: PMC5067681

Turriff A, Miner SA, Annunziata CM, Bianchi DW. Patients' perspectives on prenatal screening results that suggest maternal cancer: A qualitative analysis. Prenat Diagn. 2023 Aug;43(9):1101-1109. doi: 10.1002/pd.6406. Epub 2023 Jul 21. PMID: 37409892; PMCID: PMC10530532.