The relationship between genetic characteristics and clinical characteristics and the efficacy of 131I therapy in children and adolescents with locally advanced or metastatic differentiated thyroid cancer

doi:10.19401/j.cnki.1007-3639.2022.05.002

Abstract

Abstract:

Background and purpose: The molecular characteristics of differentiated thyroid cancer (DTC) in children and adolescents and its role in clinical practice remain unclear. This study intended to explore the genetic characteristics and its relationship with clinical characteristics and efficacy of ¹³¹I therapy in locally advanced or metastatic pediatric and adolescent DTC patients. Methods: A thyroid cancer-related gene panel (ThyroLead®) was used to test the primary tumors from children and adolescents with DTC treated in Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from December 2020 to July 2021. The samples were sequenced, the clinicopathological characteristics and ¹³¹I treatment history were retrospectively collected, and the relationship between their genetic characteristics and clinicopathological characteristics and the efficacy of ¹³¹I therapy was analyzed. Results: All the 39 children present locally advanced or metastatic disease. All the children with accessible data had lymph node metastasis, 91.4% (32/35) of whom had lateral lymph node metastasis, and 61.5% (24/39) patients had distant metastasis. Thyroid cancer-related gene variants were detected in 61.5% (24/39) of the patients, among which RET fusion (38.5%, 15/39) and BRAF V600E point mutation (12.8%, 5/39) were the most common. No statistically significant differences were found in clinical characteristics between the mutation group and the non-mutation group (P>0.05). Most of the children (91.7%, 22/24) with distant metastases remained structural incomplete response (SIR) status after ¹³¹I treatment. Nine patients were considered radioactive iodine-refractory (RAIR) status, and 8 of them had thyroid cancer driver mutations, among which NCOA4/RET accounted for 62.5% (5/8). Among cases with RET genetic variations, NCOA4/RET fusion-positive patients tended to present more distant metastasis than those with other forms of RET fusion (33.3% vs 88.9%, P=0.089). Conclusion: Compared with point mutations, fusion gene mutations, especially RET fusions, are more common in locally advanced or metastatic pediatric and adolescent DTC patients. NCOA4/RET fusion-positive tumor has more aggressive behaviors and are more likely to become RAIR.

Key words: Pediatric and adolescent thyroid cancer, Locally advanced, Metastases, Genetic alterations, RET fusions, Radioactive iodine-refractory

CLC Number:

R736.1

SUN Di, SUN Yuqing, ZHANG Xin, HUANG Lisha, LIN Yansong. The relationship between genetic characteristics and clinical characteristics and the efficacy of ¹³¹I therapy in children and adolescents with locally advanced or metastatic differentiated thyroid cancer[J]. China Oncology, 2022, 32(5): 380-387.

Figures/Tables 4

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Tab. 2

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References 28

[1]	WARD E, DESANTIS C, ROBBINS A, et al. Childhood and adolescent cancer statistics, 2014[J]. CA Cancer J Clin, 2014, 64(2): 83-103. doi: 10.3322/caac.21219
[2]	MILLER K D, FIDLER-BENAOUDIA M, KEEGAN T H, et al. Cancer statistics for adolescents and young adults, 2020[J]. CA Cancer J Clin, 2020, 70(6): 443-459. doi: 10.3322/caac.21637
[3]	BERNIER M O, WITHROW D R, BERRINGTON DE GONZALEZ A, et al. Trends in pediatric thyroid cancer incidence in the United States, 1998-2013[J]. Cancer, 2019, 125(14): 2497-2505. doi: 10.1002/cncr.32125
[4]	HAY I D, GONZALEZ-LOSADA T, REINALDA M S, et al. Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008[J]. World J Surg, 2010, 34(6): 1192-1202. doi: 10.1007/s00268-009-0364-0
[5]	ALZAHRANI A S, MURUGAN A K, QASEM E, et al. Single point mutations in pediatric differentiated thyroid cancer[J]. Thyroid, 2017, 27(2): 189-196. doi: 10.1089/thy.2016.0339
[6]	HAY I D, JOHNSON T R, KAGGAL S, et al. Papillary thyroid carcinoma (PTC) in children and adults: comparison of initial presentation and long-term postoperative outcome in 4 432 patients consecutively treated at the mayo clinic during eight decades (1936-2015)[J]. World J Surg, 2018, 42(2): 329-342. doi: 10.1007/s00268-017-4279-x
[7]	PAWELCZAK M, DAVID R, FRANKLIN B, et al. Outcomes of children and adolescents with well-differentiated thyroid carcinoma and pulmonary metastases following ¹³¹I treatment: a systematic review[J]. Thyroid, 2010, 20(10): 1095-1101. doi: 10.1089/thy.2009.0446
[8]	ALZAHRANI A S, ALSWAILEM M, MORIA Y, et al. Lung metastasis in pediatric thyroid cancer: radiological pattern, molecular genetics, response to therapy, and outcome[J]. J Clin Endocrinol Metab, 2019, 104(1): 103-110. doi: 10.1210/jc.2018-01690
[9]	BIKO J, REINERS C, KREISSL M C, et al. Favourable course of disease after incomplete remission on (131)I therapy in children with pulmonary metastases of papillary thyroid carcinoma: 10 years follow-up[J]. Eur J Nucl Med Mol Imaging, 2011, 38(4): 651-655. doi: 10.1007/s00259-010-1669-9
[10]	CORDIOLI M I, MORAES L, CURY A N, et al. Are we really at the dawn of understanding sporadic pediatric thyroid carcinoma?[J]. Endocr Relat Cancer, 2015, 22(6): R311-R324. doi: 10.1530/ERC-15-0381
[11]	ALZAHRANI A S, QASEM E, MURUGAN A K, et al. Uncommon TERT promoter mutations in pediatric thyroid cancer[J]. Thyroid, 2016, 26(2): 235-241. doi: 10.1089/thy.2015.0510
[12]	ALZAHRANI A S, ALSWAILEM M, ALSWAILEM A A, et al. Genetic alterations in pediatric thyroid cancer using a comprehensive childhood cancer gene panel[J]. J Clin Endocrinol Metab, 2020, 105(10): 3324-3334. doi: 10.1210/clinem/dgaa389
[13]	GUO K, QIAN K, SHI Y, et al. Clinical and molecular characterizations of papillary thyroid cancer in children and young adults: a multicenter retrospective study[J]. Thyroid, 2021, 31(11): 1693-1706. doi: 10.1089/thy.2021.0003
[14]	AMIN M B, EDGE S B, GREENE F L, et al. AJCC cancer staging manual[M]. 8th ed. New York: Springer, 2017.
[15]	HAUGEN B R, ALEXANDER E K, BIBLE K C, et al. 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer[J]. Thyroid, 2016, 26(1): 1-133. doi: 10.1089/thy.2015.0020
[16]	GALUPPINI F, VIANELLO F, CENSI S, et al. Differentiated thyroid carcinoma in pediatric age: genetic and clinical scenario[J]. Front Endocrinol (Lausanne), 2019, 10: 552. doi: 10.3389/fendo.2019.00552
[17]	FRANCIS G L, WAGUESPACK S G, BAUER A J, et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer[J]. Thyroid, 2015, 25(7): 716-759. doi: 10.1089/thy.2014.0460
[18]	SATAPATHY S, BAL C. Genomic landscape of sporadic pediatric differentiated thyroid cancers: a systematic review and meta-analysis[J]. J Pediatr Endocrinol Metab, 2022. Online ahead of print.
[19]	RANGEL-POZZO A, SISDELLI L, CORDIOLI M I V, et al. Genetic landscape of papillary thyroid carcinoma and nuclear architecture: an overview comparing pediatric and adult populations[J]. Cancers, 2020, 12(11): 3146. doi: 10.3390/cancers12113146
[20]	NIKIFOROV Y E, ROWLAND J M, BOVE K E, et al. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children[J]. Cancer Res, 1997, 57(9): 1690-1694.
[21]	GERTZ R J, NIKIFOROV Y, REHRAUER W, et al. Mutation in BRAF and other members of the MAPK pathway in papillary thyroid carcinoma in the pediatric population[J]. Arch Pathol Lab Med, 2016, 140(2): 134-139. doi: 10.5858/arpa.2014-0612-OA
[22]	FRANCO A T, RICARTE-FILHO J C, LAETSCH T W, et al. Oncogene-specific inhibition in the treatment of advanced pediatric thyroid cancer[J]. J Clin Invest, 2021, 131(18): e152696. doi: 10.1172/JCI152696
[23]	PEKOVA B, SYKOROVA V, DVORAKOVA S, et al. RET, NTRK, ALK, BRAF and MET fusions in a large cohort of pediatric papillary thyroid carcinomas[J]. Thyroid, 2020, 30(12): 1771-1780. doi: 10.1089/thy.2019.0802
[24]	OISHI N, KONDO T, NAKAZAWA T, et al. Frequent BRAF V600E and absence of TERT promoter mutations characterize sporadic pediatric papillary thyroid carcinomas in Japan[J]. Endocr Pathol, 2017, 28(2): 103-111. doi: 10.1007/s12022-017-9470-y
[25]	NIKIFOROV Y E, NIKIFOROVA M N, GNEPP D R, et al. Prevalence of mutations of ras and p53 in benign and malignant thyroid tumors from children exposed to radiation after the Chernobyl nuclear accident[J]. Oncogene, 1996, 13(4): 687-693.
[26]	SMIDA J, ZITZELSBERGER H, KELLERER A M, et al. p53 mutations in childhood thyroid tumours from Belarus and in thyroid tumours without radiation history[J]. Int J Cancer, 1997, 73(6): 802-807. doi: 10.1002/(SICI)1097-0215(19971210)73:6<802::AID-IJC5>3.0.CO;2-6
[27]	MALAGUARNERA R, VELLA V, VIGNERI R, et al. p53 family proteins in thyroid cancer[J]. Endocr Relat Cancer, 2007, 14(1): 43-60. doi: 10.1677/erc.1.01223
[28]	MARTI J L, JAIN K S, MORRIS L G T. Increased risk of second primary malignancy in pediatric and young adult patients treated with radioactive iodine for differentiated thyroid cancer[J]. Thyroid, 2015, 25(6): 681-687. doi: 10.1089/thy.2015.0067

Clinical characteristic	All patients	Mutation negative	Mutation positive	P value	U value
Age at diagnosis/year median (IQR)	12.1 (9.1-16.2)	11.9 (7.3-14.1)	13.1 (10.0-16.8)	0.172	228.000
Adolescence or not				0.323^*
Children	21	10	11
Adolescent	18	5	13
Gender				0.742^*
Male	18	6	12
Female	21	9	12
Number of surgery median (IQR)	2 (1-2)	1 (1-2)	2 (1-2)	0.618	198.000
Tumor size D/cm median (IQR)	2.7 (1.5-3.9)	3.0 (1.4-3.5)	2.5 (1.5-4.0)	0.558	130.500
Histology				1.000^*
PTC	38	15	23
FTC	1	0	1
T stage				0.471	145.500
T₁+T₂	16	7	9
T₃+T₄	17	5	12
NA	6	3	3
N stage				0.601	158.500
N_1a	3	2	1
N_1b	32	11	21
NA	4	2	2
M stage				1.000^*
M₀	15	6	9
M₁	24	9	15
Number of RAI therapy median (IQR)	2 (1-2)	1 (1-3)	2 (1-2)	0.943	177.500
Cumulative RAI dose D/mCi median (IQR)	180 (125-300)	160 (70-225)	260 (150-300)	0.202	207.000
RAIR or not				0.228^*
No	30	11	19
Yes	9	1	8
Follow-up period t/month median (IQR)	40.0 (21.0-57.0)	36.0 (21.0-72.0)	41.5 (23.0-56.8)	0.700	193.500
ATA response classification at last follow-up				0.853	186.500
ER	5	2	3
IDR	8	3	5
BIR	4	2	2
SIR	22	8	14

No.	Age at diagnosis/year	Gender	Number of surgery	Tumor size D/cm	Histology (subtype)	T stage	N stage	M stage (site)	Number of RAI therapy	Cumulative RAI dose D/mCi	Follow-up period t/month	Classification of RAIR	Genetic variation
1	16.0	Male	2	4	PTC (classic)	3b	1b	1 (lung)	2	270	51	4^*	NCOA4/RET fusion
2	7.0	Male	1	2.8	PTC (follicular)	3b	1b	1 (lung)	2	250	57	4^*	TP53 R213E mutation, NCOA4/RET fusion
3	13.2	Female	1	4.0	PTC (NA)	2	1b	1 (lung)	3	425	43	4^*	NCOA4/RET fusion
4	14.8	Male	2	3.5	PTC (classic)	2	1b	1 (lung)	2	300	52	4^*	NCOA4/RET fusion
5	11.9	Female	3	2.5	PTC (NA)	4a	1b	1 (lung）	2	270	45	2^#	NCOA4/RET fusion
6	8.9	Male	2	2.5	PTC (DSV)	2	1b	1 (lung)	5	280	78	4^*	CCDC6/RET fusion
7	9.1	Female	1	1.5	PTC (classic)	3b	1b	1 (lung)	2	165	40	1^△	TFG/NTRK1 fusion
8	16.8	Male	3	4.5	PTC (classic)	4b	1b	1 (lung & bone)	2	180	134	1^△	BRAF V600E mutation
9	11.2	Female	2	1.4	PTC (NA)	1b	1b	1 (lung)	3	315	106	1^△	negative

The relationship between genetic characteristics and clinical characteristics and the efficacy of ¹³¹I therapy in children and adolescents with locally advanced or metastatic differentiated thyroid cancer

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