Longitudinal Natural History Study of Children and Adults with Rare Solid Tumors: Initial Results for First 200 Participants

Abstract

Understanding of tumor biology and identification of effective therapies is lacking for many rare tumors. My Pediatric and Adult Rare Tumor (MyPART) network was established to engage patients, advocates, and researchers and conduct a comprehensive longitudinal Natural History Study of Rare Solid Tumors. Through remote or in-person enrollment at the NIH Clinical Center, participants with rare solid tumors ≥4 weeks old complete standardized medical and family history forms, patient reported outcomes, and provide tumor, blood and/or saliva samples. Medical records are extracted for clinical status and treatment history, and tumors undergo genomic analysis. A total of 200 participants (65% female, 35% male, median age at diagnosis 43 years, range = 2-77) enrolled from 46 U.S. states and nine other countries (46% remote, 55% in-person). Frequent diagnoses were neuroendocrine neoplasms (NEN), adrenocortical carcinomas (ACC), medullary thyroid carcinomas (MTC), succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (sdGIST), and chordomas. At enrollment, median years since diagnosis was 3.5 (range = 0-36.6), 63% participants had metastatic disease and 20% had no evidence of disease. Pathogenic germline and tumor mutations included SDHA/B/C (sdGIST), RET (MTC), TP53 and CTNNB1 (ACC), MEN1 (NEN), and SMARCB1 (poorly-differentiated chordoma). Clinically significant anxiety was observed in 20%-35% of adults. Enrollment of participants and comprehensive data collection were feasible. Remote enrollment was critical during the COVID-19 pandemic. Over 30 patients were enrolled with ACC, NEN, and sdGIST, allowing for clinical/genomic analyses across tumors. Longitudinal follow-up and expansion of cohorts are ongoing to advance understanding of disease course and establish external controls for interventional trials.

Significance: This study demonstrates that comprehensive, tumor-agnostic data and biospecimen collection is feasible to characterize different rare tumors, and speed progress in research. The findings will be foundational to developing external controls groups for single-arm interventional trials, where randomized control trials cannot be conducted because of small patient populations.

FIGURE 1

A, Number of participants by rare tumor diagnoses (N = 197). B, Diagnoses with only one participant enrolled (N = 1). C, Month of enrollment of 197 participants in 2019 and 2020, relative to the start of COVID pandemic restrictions at NIHCC in March 2020. Clinic cohort patients are shown in red and field cohort patients are in blue.

FIGURE 2

Variant genes found in 3 or more patients for ACC, N = 27 (A), GIST, N = 22 (B), and NEN, N = 24 (C). Variant genes found in 2 or more patients for MTC, N = 8 (D) and chordoma, N = 5 (E). TSO500 gene panel sequencing identified pathogenic or likely pathogenic mutations for most tumors (F), with NEN and chordoma showing the lowest percentage of pathogenic mutations identified. ACC and MTC tumor analysis identified the highest percentage of pathogenic mutations. G, sdGIST and MTC had the most actionable mutations in Tier 1A. Germline sequencing on participants was performed using directed variant, single gene, or small gene panels (<100 genes; hatched bars) or using comprehensive large gene panels or WES (solid bars; H). The proportion of Path/LP mutations identified (red) varied by tumor type. I, The most common Path/LP germline mutations found were SDHA/B/C, in participants with sdGIST and their family members, and RET, in an ACC, three MTCs, and a pheochromocytoma.

FIGURE 3

Imaging and histology for 3 highlighted patients. A, Axial CT image of the abdomen showing a mass in the descending colon (arrow) in a 15-year-old male diagnosed with poorly differentiated adenocarcinoma. B, Histology shows high dysplasia and stromal microinvasion. C, MRI of the lumbar spine in a 36-year-old female diagnosed with malignant melanotic schwannoma shows oval-shaped mass in left neural foramen of L3-L4 with avid enhancement on sagittal T1-weighted fat-suppressed image (arrow). Histology (D) shows pigmented spindle and epithelioid cells. E, MRI displays two left supraclavicular masses on T1-weighted image in a 75-year-old male with metastatic poorly differentiated carcinoma of unknown primary in the neck. F, Histology shows epithelioid tumor cells. Scale bar = 100 µm and is the same for B, D, and F.

FIGURE 4

Molecular analysis for 3 highlighted patients. A, Path (red), LP (gold), and VUS (Blue) variants identified by TSO500 in colon adenocarcinoma from 15-year-old male. Pathogenic germline mutations were identified in MLH1 (c.156del p.Glu53Argfs*4) and APC (c.3329C>A, p.Ser1110*) and VUS in SMAD4 (c.947A>G, p.Asn316Ser; hatched bars). B, Variants identified by TSO500 in a malignant melanotic schwannoma from a 36-year-old female, with Path mutations in NF1 (c.276dupA, p.C93fs*14) and PRKAR1A (c.207_208delGA, p.K70fs*11) and LP variant in SETD2 (c.4405dupA, p.M1469fs*6).C, Variants identified in two lymph node metastases collected 1 year apart from a carcinoma of unknown primary in a 75-year-old male (purple collected first, green collected second). VUS with higher percentage VAF (>45%) were identified in both samples (NCOR1, MST1R, ABL2, ROS1, ESR1, FAT1, POLE, NTRK3, and GEN1), as well as low VAF (∼6%) VUS in ZNF703. Pathogenicity of variants is indicated in y-axis label.