Natural history and evaluation of abnormal or nonreportable NIPT results and its association with maternal neoplasia

异常或不可报告的 NIPT 结果的自然史和评估及其与母体肿瘤的关联

• 批准号: 10920214
• 负责人: Diana Bianchi
• 金额: $ 7.16万
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10920214
• 关键词: Admission activity; Adrenocortical carcinoma; Algorithms; Amniocentesis; Aneuploidy; Asian; Awareness; Benign; Biochemistry; Biocompatible Materials; Bioethics; Biological; Black race; Blood; California; Canada; Case Study; Chorionic Villi Sampling; Chromosomes; Circulation; Clinical; Clinical Management; Clinical Oncology; Code; Confusion; Counseling; DNA; DNA Sequence; DNA analysis; DNA sequencing; Data; Detection; Diagnosis; Diagnostic; Diagnostic tests; Discipline of obstetrics; Doctor of Philosophy; Eligibility Determination; Enrollment; Evaluation; Fetus; Finding by Cause; Genomics; Guidelines; Hematopoiesis; Hematopoietic System; Hispanic; Hospitals; Image; Incidence; Incidental Findings; Individual; Institutional Review Boards; International; Interview; Journals; Karyotype; Laboratories; Lymphoma; Malignant Neoplasms; Maps; Medical; Medical Oncologist; Mosaicism; Natural History; Neonatal; Neoplasms; Not Hispanic or Latino; Outcome; Pacific Islander; Participant; Patau' s syndrome; Patients; Peer Review; Perinatal; Persons; Physicians; Placenta; Plasma; Positive Test Result; Postpartum Period; Predictive Value; Pregnancy; Pregnant Women; Prenatal care; Protocols documentation; Provider; Proxy; Published Comment; Publishing; Race; Reporting; Research Personnel; Retrospective Studies; Risk; Sampling; Screening Result; Serum; Solid Neoplasm; Stress; Test Result; Testing; Time; Twin Multiple Birth; Ultrasonography; United States; United States National Institutes of Health; Uterine Fibroids; Voice; Woman; Work; Writing; acronyms; cancer risk; care providers; cell free DNA; cell free fetal DNA; circulating DNA; clinical care; clinical center; clinical diagnosis; clinical sequencing; continuing medical education; design; experience; fetal; follow-up; lectures; meetings; multidisciplinary; neoplastic cell; obstetric care; outreach; participant enrollment; pregnant; prenatal; prenatal testing; programs; provider communication; rare cancer; reference genome; research clinical testing; screening; symposium; ultrasound

In the twelve years since it became clinically available, noninvasive screening for fetal aneuploidy by sequencing cell-free (cf) DNA fragments that circulate in maternal blood has disrupted established global paradigms for prenatal care. In general, these tests work by mapping sequenced DNA fragments and determining if there are excess or reduced copy numbers compared to a reference genome. Commercial laboratories in the United States each have their own proprietary analytic algorithms. Around 1% of the time, a non-reportable test result is generated that is due to either technical issues (such as insufficient DNA or low fetal fraction in the sample) or biological issues (such as a twin demise or confined placental or maternal mosaicism). The acronym for this study is the IDENTIFY Study: Incidental DEtection of maternal Neoplasia Participants undergo an initial evaluation at the Clinical Center to diagnose possible neoplasia. All collected clinical, laboratory and imaging information is discussed in monthly multidisciplinary team meetings. If neoplasia is discovered, results are shared with participants and referring physicians and guide subsequent clinical management. Participants will be followed for up to five years post-partum to collect all available medical information. Dr. Bianchi and Amy Turriff, CGC, performed over 35 outreach activities to increase national and international awareness among obstetric care providers of the potential of NIPT to detect maternal malignancy and to establish relationships for referrals. These included multiple Ob/Gyn Grand Rounds hospital presentations, case presentations to commercial laboratories providing NIPT results, lecturing to the state of Californias Perinatal Testing Program, and participating in multiple Continuing Medical Education conferences. To educate medical oncologists we wrote a peer-reviewed commentary on the potential to detect maternal malignancy via NIPT that was published in the Journal of Clinical Oncology (IF=32) in August 2022. As a result of this outreach, participant enrollment in our IRB-approved protocol has increased significantly since enrollment began in December 2019. To date we have enrolled 98 participants. They have come from all over the US and four have come from Canada. Of these, six are Black (6.1%), four are Asian or Pacific Islander (4.1%), one is of multiple races (1.0%), 12 are White, Hispanic (12.2%), and 75 are White, non-Hispanic (76.5%). Our interim results show that 52% of participants have a clinically silent malignancy. While lymphoma is the most common diagnosis, we have also detected extremely rare tumors such as adrenocortical carcinoma (incidence=1 in 1,000,000). Other biological explanations for the unusual noninvasive prenatal testing results include confined placental mosaicism, benign uterine leiomyomas, and clonal abnormal hematopoiesis. What has been missing, to date, is the voice of the pregnant person after receiving incidental prenatal screening results. Amy Turriff and Skye Miner, PhD (Dept of Bioethics, NIHCC) designed and completed a study that examined the personal impact of receiving noninvasive prenatal screening results that suggest maternal malignancy. In this study, we sought to explore patient perspectives by interviewing 49 individuals who received non-reportable or discordant NIPT results and enrolled in the IDENTIFY study. They were interviewed before and after receiving the outcome of their clinical evaluations for cancer. Interviews were independently coded by two researchers and analyzed thematically. After analysis of the qualitative data, three themes were identified: 1) limited pre-test awareness of maternal incidental findings caused considerable confusion for the participants, whose initial concerns focused on their babies; 2) the care providers communication influenced how participants perceived their risk of cancer and their need to be evaluated; and 3) the participants perceived value in receiving maternal incidental findings from NIPT despite any stress it caused them during their pregnancies. Participants viewed the ability to detect occult malignancies as an added benefit of NIPT and felt strongly that this information should be disclosed. Admittedly, the study group may be biased because they chose to come to the NIH to be evaluated for cancer. We did not capture the experiences of people who declined to participate in the IDENTIFY study or those who were not referred to us. This study demonstrated that obstetric providers need to 1) be aware that maternal incidental findings can be found following cfDNA sequencing; 2) inform pregnant people of the potential to receive these results during pre-test counseling, and 3) provide accurate and objective information during post-test counseling. This information is crucial considering the high incidence of malignancy we are detecting in IDENTIFY study participants.

在12年以来，它成为临床可用，胎儿非整倍性的无创筛选通过测序无细胞（cf）DNA片段，在母体血液中循环已经打破了既定的全球模式产前护理。一般来说，这些测试通过映射测序的DNA片段并确定与参考基因组相比是否存在过量或减少的拷贝数来工作。美国的商业实验室都有自己的专有分析算法。大约1%的情况下，由于技术问题（如样本中DNA不足或胎儿分数低）或生物学问题（如双胞胎死亡或局限性胎盘或母体嵌合体）而产生不可报告的检测结果。 这项研究的首字母缩写是识别研究：母体肿瘤的偶然检测参与者在临床中心接受初步评估，以诊断可能的肿瘤。所有收集的临床、实验室和影像学信息在每月的多学科小组会议上进行讨论。如果发现肿瘤，结果将与参与者和转诊医生共享，并指导后续的临床管理。参与者将在产后接受长达五年的随访，以收集所有可用的医疗信息。 博士比安奇和艾米Turriff，CGC，进行了超过35个外展活动，以提高国家和国际产科护理提供者对NIPT的潜力，以检测孕产妇恶性肿瘤和建立转诊关系的认识。这些包括多个Ob/Gyn Grand Rounds医院介绍，向提供NIPT结果的商业实验室进行病例介绍，向加利福尼亚州围产期检测计划进行演讲，并参加多个继续医学教育会议。为了教育医学肿瘤学家，我们撰写了一篇关于通过NIPT检测母体恶性肿瘤的潜力的同行评审评论，于2022年8月发表在《临床肿瘤学杂志》（IF=32）上。 由于这种推广，自2019年12月开始入组以来，IRB批准的方案中的受试者入组人数显著增加。到目前为止，我们已经招募了98名参与者。他们来自美国各地，四个来自加拿大。其中，6人是黑人（6.1%），4人是亚洲人或太平洋岛民（4.1%），1人是多种族（1.0%），12人是西班牙裔白色人（12.2%），75人是非西班牙裔白色人（76.5%）。我们的中期结果显示，52%的参与者有临床沉默的恶性肿瘤。虽然淋巴瘤是最常见的诊断，但我们也发现了极其罕见的肿瘤，如肾上腺皮质癌（发病率=1/1，000，000）。对这种不寻常的非侵入性产前检查结果的其他生物学解释包括局限性胎盘镶嵌、良性子宫平滑肌瘤和克隆性异常造血。 到目前为止，缺少的是孕妇在接受偶然的产前筛查结果后的声音。Amy Turriff和Skye Miner博士（NIHCC生物伦理学系）设计并完成了一项研究，该研究检查了接受提示母体恶性肿瘤的无创产前筛查结果的个人影响。在这项研究中，我们试图通过采访49名接受非报告或不一致NIPT结果并参加IDENTIFY研究的个人来探索患者的观点。他们在接受癌症临床评估结果之前和之后接受了采访。访谈由两名研究人员独立编码，并按主题进行分析。经过对定性数据的分析，发现了三个主题：1）对母亲偶然发现的有限的测试前意识给参与者带来了相当大的困惑，他们最初的关注集中在他们的婴儿上; 2）护理提供者的沟通影响了参与者对他们的癌症风险和他们需要被评估的看法;和3）尽管在怀孕期间NIPT给参与者带来了任何压力，但参与者认为接受NIPT的母亲偶然发现是有价值的。参与者将检测隐匿性恶性肿瘤的能力视为NIPT的额外益处，并强烈认为应披露此信息。不可否认，研究小组可能存在偏见，因为他们选择来NIH接受癌症评估。我们没有捕捉到那些拒绝参加IDENTIFY研究的人或那些没有被推荐给我们的人的经历。这项研究表明，产科提供者需要1）意识到在cfDNA测序后可以发现母亲的偶然发现; 2）在测试前咨询期间告知孕妇可能会收到这些结果，以及3）在测试后咨询期间提供准确和客观的信息。考虑到我们在IDENTITY研究参与者中检测到的恶性肿瘤的高发病率，该信息至关重要。