Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors—A Retrospective Multi-Center Registry Analysis
Abstract
:Simple Summary
Abstract
1. Introduction
2. Materials and Methods
2.1. Setting
2.2. Data Acquisition
2.3. Sample Selection, DNA/RNA Extraction and Mutation Analysis
2.4. Statistical Analysis
3. Results
3.1. Clinical Characteristics
3.2. Analysis of Genetic Alterations Occurring in MTC Cases
3.3. Multi-Tyrosine Kinase Inhibitor Therapy
3.4. Outcome after First- and Second-Line Treatments
3.5. Outcome with Vandetanib and Cabozantinib Treatments
3.6. Biochemical Response of First-Line Treatment
3.7. Predictive Factors Affecting OS in First- and Second-Line Treatments
3.8. Safety and Tolerability
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Appendix A
Patient No. | RET Mutation; Codon | Exon | Biological Significance | Gene; Codon of Further Mutations | Biological Significance |
---|---|---|---|---|---|
Hereditary MTC | |||||
1 | yes; M918T | 16 | pathogenic | ||
2 | yes; M918T | 16 | pathogenic | unknown | |
3 | yes; C634R | 11 | pathogenic | EGFR-V843I; CDKN2B-T95M; MAP2K1-D67N | likely pathogenic; VUS; pathogenic |
4 | yes; C634R | 11 | pathogenic | ||
5 | yes; C620G | 10 | pathogenic | unknown | |
6 | yes; C620S | 10 | pathogenic | ||
7 | yes; unknown | unknown | |||
Sporadic MTC | |||||
8 | yes; M918T | 16 | pathogenic | ERBB2-D1115V | VUS |
9 | yes; M918T | 16 | pathogenic | KRAS-G12V; PIK3CA-E542V; TP53-A39fs | pathogenic; pathogenic; pathogenic |
10 | yes; M918T | 16 | pathogenic | ||
11 | yes; M918T | 16 | pathogenic | ||
12 | yes; M918T | 16 | pathogenic | ||
13 | yes; M918T | 16 | pathogenic | ||
14 | yes; M918T | 16 | pathogenic | ||
15 | yes; M918T | 16 | pathogenic | ||
16 | yes; M918T | 16 | pathogenic | ||
17 | yes; M918T | 16 | pathogenic | ||
18 | yes; M918T | 16 | pathogenic | ||
19 | yes; M918T | 16 | pathogenic | ||
20 | yes; M918T | 16 | pathogenic | ||
21 | yes; M918T | 16 | pathogenic | ||
22 | yes; M918T | 16 | pathogenic | ||
23 | yes; M918T | 16 | pathogenic | ||
24 | yes; M918T | 16 | pathogenic | ||
25 | yes; M918T | 16 | pathogenic | ||
26 | yes; M918T | 16 | pathogenic | ||
27 | yes; M918T | 16 | pathogenic | ||
28 | yes; M918T | 16 | pathogenic | ||
29 | yes; M918T | 16 | pathogenic | ||
30 | yes; A883F | 15 | pathogenic | ||
31 | yes; A883F | 15 | pathogenic | ||
32 | yes; C618R | 10 | pathogenic | ||
33 | yes; C634R | 11 | pathogenic | ||
34 | yes; p.Glu632_Cys634delinsGly | 11 | pathogenic | ||
35 | yes; A886G | 11 | pathogenic | ||
36 | yes; 30 bp insertion; c.1936_1937ins30—p.Ser645_ Phe646insCysAlaArgAlaAlaAlaValLeuPheSer | 11 | VUS | ||
37 | yes; p.D898_E901del | pathogenic | |||
38 | yes; 5′/3′-imbalance | VUS | |||
39 | yes; unknown | ||||
40 | no | HRASQ61L | pathogenic | ||
41 | no | ||||
42 | no | ||||
Unknown Germline Status | |||||
43 | yes; M918T | 16 | |||
44 | yes; M918T | 16 | |||
45 | yes; M918T | 16 | |||
46 | yes; M918T | 16 | |||
47 | yes; M918T | 16 | |||
48 | no |
Characteristics Prior to MKI | With RET Variant | Without RET Variant |
---|---|---|
Number of patients | 36 | 4 |
Germline RET variant | 7 (19%) | 0 |
Somatic RET variant (no germline variant) | 26 (72%) | 0 |
Somatic RET variant (unknown germline variant) | 3 (8%) | 0 |
Male sex | 29 (81%) | 3 (75%) |
Median age at the first diagnosis (years) (range) | 46 (15–74) | 62 (56–78) |
UICC stage at the first diagnosis | ||
III | 6 (18%; n = 33) | 0 |
IV | 27 (82%; n = 33) | 3 (100%; n = 3) |
Lymphatic metastases at the first diagnosis | 34 (100%; n = 34) | 3 (75%) |
Distant metastases at the first diagnosis | 23 (77%; n = 30) | 3 (100%; n = 3) |
Brain | 0 | 0 |
Lung | 14 (61%) | 1 (33%) |
Liver | 9 (39%) | 2 (67%) |
Mediastinum | 9 (41%; n = 22) | 0 |
Bone | 11 (48%) | 2 (67%) |
Initial thyroidectomy | 33 (92%) | 3 (75%) |
Surgery for metastases | 7 (20%; n = 35) | 0 |
Calcitonin doubling time prior to MKI start (months) median (range) | 8 (4–31; n = 15) | NA |
Peptide receptor radionuclide therapy prior to MKI | 3 (9%; n = 35) | 0 |
Chemotherapy prior to MKI | 1 (3%) | 0 |
Local radiation therapy prior to MKI | 5 (14%) | 0 |
Radiation therapy of metastatic sites prior to MKI | 8 (22%) | 0 |
Ablative procedures prior to MKI | 3 (8%) | 0 |
Characteristics at MKI Initiation | ||
Indication for MKI therapy | ||
Extensive metastases at the first diagnosis | 13 (37; n = 35) | 4 (100%) |
Morphological progression | 22 (63%; n = 35) | 0 |
Median age at MKI initiation (range) | 56 (22–79) | 62 (56–78) |
Months between the first diagnosis and MKI initiation median (range) | 36 (0–242) | 2 (2–7) |
Lymphatic metastases at MKI initiation | 33 (92%) | 3 (100%; n = 3) |
Distant metastases at MKI initiation | 34 (97%; n = 35) | 4 (100%) |
Brain | 1 (3%) | 0 |
Lung | 17 (50%) | 1 (25%) |
Liver | 21 (62%) | 3 (75%) |
Mediastinum | 16 (47%) | 0 |
Bone | 19 (56%) | 3 (75%) |
Median calcitonin level (pg/mL) at MKI initiation (range) | 1863 (4–89,300; n = 31) | 600 (396–22,224; n = 3) |
Median CEA level (ng/mL) at MKI initiation (range) | 137 (3–3360; n = 28) | 31.4 (n = 1) |
First-line therapy | ||
Cabozantinib | 3 (8%) | 2 (50%) |
Vandetanib | 33 (92%) | 2 (50%) |
First-Line Treatment | With RET Variant (n = 36) | Without RET Variant (n = 4) |
---|---|---|
Median duration of first-line treatment (months) (range) | 21 (1–149; n = 36) | 7 (3–14) |
Best response | ||
PD | 5 (15%; n = 34) | 3 (75%) |
SD 8–24 weeks | 3 (9%; n = 34) | 0 |
SD ≥ 24 weeks | 15 (44%; n = 34) | 1 (25%) |
PR | 11 (32%; n = 34) | 0 |
CR | 0 | 0 |
Time interval from start of first-line therapy to the start of second-line therapy (months) (range) | 16 (0–84; n = 14) | 9 (4–15; n = 3) |
Discontinuation of therapy | 27 (75%) | 4 (100%) |
PD | 18 (67%) | 2 (50%) |
Drug intolerance | 9 (33%) | 2 (50%) |
Second-line treatment | With RET variant (n = 22) | Without RET variant (n = 3) |
Median duration of second-line treatment (months) (range) | 10 (1–100; n = 21) | 8 (3–13; n = 2) |
Best response | ||
PD | 3 (19%) | 1 (33%) |
SD 8–24 weeks | 8 (36%) | 1 (33%) |
SD ≥ 24 weeks | 4 (18%) | 1 (33%) |
PR | 6 (27%) | 0 |
CR | 0 | 0 |
Discontinuation of therapy | 20 (91%) | 2 (67%) |
PD | 11 (55%) | 2 (100%) |
Drug intolerance | 9 (45%) | 0 |
Vandetanib-treated patients | With RET Variant (n = 43) | Without RET Variant (n = 4) |
Median duration of vandetanib treatment (months) (range) | 20 (1–149; n = 42) | 3 (3–4; n = 3) |
Best response | ||
PD | 4 (10%; n = 41) | 3 (75%) |
SD 8–24 weeks | 6 (15%; n = 41) | 1 (25%) |
SD ≥ 24 weeks | 18 (44%; n = 41) | 0 |
PR | 13 (32%; n = 41) | 0 |
CR | 0 | 0 |
Discontinuation of therapy | 33 (77%) | 4 (100%) |
Progression | 24 (73%) | 3 (75%) |
Drug intolerance | 9 (27%) | 1 (25%) |
Cabozantinib-treated patients | With RET Variant (n = 15) | Without RET Variant (n = 3) |
Median duration of cabozantinib treatment (months) (range) | 7 (1–39) | 13 (9–14) |
Best response | ||
PD | 4 (27%) | 1 (33%) |
SD 8–24 weeks | 5 (33%) | 0 |
SD ≥ 24 weeks | 1 (7%) | 2 (67%) |
PR | 4 (27%) | 0 |
CR | 0 | 0 |
Discontinuation of therapy | 14 (93%) | 2 (67%) |
Progression | 5 (36%) | 1 (50%) |
Drug intolerance | 9 (64%) | 1 (50%) |
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Characteristics Prior to MKI | With RET Variant | Without RET Variant |
---|---|---|
Number of patients | 44 | 4 |
Germline RET variant | 7 (16%) | 0 |
Somatic RET variant (no germline variant) | 32 (73%) | 0 |
Somatic RET variant (unknown germline variant) | 5 (11%) | 0 |
Male sex | 33 (75%) | 3 (75%) |
Median age at the first diagnosis (years) (range) | 45 (15–74) | 62 (56–78) |
UICC stage at the first diagnosis | ||
III | 6 (15%; n = 41) | 0 |
IV | 35 (85%; n = 41) | 3 (100%; n = 3) |
Lymph node metastases at the first diagnosis | 42 (100%; n = 42) | 3 (75%) |
Distant metastases at the first diagnosis | 26 (72%; n = 36) | 3 (100%; n = 3) |
Brain | 0 | 0 |
Lung | 16 (62%) | 1 (33%) |
Liver | 10 (38%) | 2 (67%) |
Mediastinum | 11 (44%; n = 25) | 0 |
Bone | 12 (46%) | 2 (67%) |
Initial thyroidectomy | 41 (93%) | 3 (75%) |
Surgery for metastases | 11 (26%; n = 43) | 0 |
Calcitonin doubling time prior to MKI start (months) median (range) | 8 (4–31; n = 18) | NA |
Peptide receptor radionuclide therapy prior to MKI | 5 (12%; n = 43) | 0 |
Chemotherapy prior to MKI | 1 (2%) | 0 |
Local radiation therapy prior to MKI | 6 (14%) | 0 |
Radiation therapy of metastatic sites prior to MKI | 8 (18%) | 0 |
Ablative procedures prior to MKI | 3 (7%) | 0 |
Characteristics at MKI Initiation | ||
Indication for MKI therapy | ||
Extensively metastatic disease at diagnosis | 15 (35%; n = 43) | 4 (100%) |
Morphological progression | 28 (65%; n = 43) | 0 |
Median age at MKI initiation (range) | 53 (22–79) | 62 (56–78) |
Median months between the first diagnosis and MKI initiation (range) | 48 (0–242) | 2 (2–7) |
Lymph node metastases at MKI initiation | 41 (93%) | 3 (100%; n = 3) |
Distant metastases at MKI initiation | 42 (98%; n = 43) | 4 (100%) |
Brain | 2 (5%) | 0 |
Lung | 23 (55%) | 1 (25%) |
Liver | 23 (55%) | 3 (75%) |
Mediastinum | 20 (48%) | 0 |
Bone | 23 (55%) | 3 (75%) |
Median calcitonin level (pg/mL) at MKI initiation (range) | 2220 (4–254,000; n = 38) | 600 (396–22,224; n = 3) |
Median CEA level (ng/mL) at MKI initiation (range) | 137 (3–3360; n = 35) | 31.4 (n = 1) |
First-line therapy | ||
Cabozantinib | 3 (7%) | 2 (50%) |
Vandetanib | 33 (75%) | 2 (50%) |
Sorafenib | 7 (16%) | 0 |
Imatinib | 1 (2%) | 0 |
Multiple Cox Regression | |
---|---|
Predictive Factors (Coefficients) (Candidate Predictive Factors: Months between the First Diagnosis and MKI Start (Numeric), UICC Stage at the First Diagnosis (Factor—III, IV), Type of First-Line Therapy (Factor—Cabozantinib, Vandetanib), Number of Metastases at Diagnosis (Numeric)) | |
p-value-based backward model selection (threshold of 0.10) | Number of metastases at diagnosis (−0.558) |
p-value-based stepwise model selection (threshold of 0.10) | Number of metastases at diagnosis (−0.558) |
AIC-based backward model selection | Months between the first diagnosis and MKI start (−0.008) Number of metastases at diagnosis (−0.652) |
AIC-based stepwise model selection | Months between the first diagnosis and MKI start (−0.008) Number of metastases at diagnosis (−0.652) |
Penalized regression (Lasso)-based model selection (λ = 0.08) | Months between the first diagnosis and MKI start (−0.003) Number of metastases at diagnosis (−0.401) |
Multiple Cox Regression | |
Predictive Factors (Coefficients) (Candidate Predictive Factors: Months Between the First Diagnosis and Second-Line MKI Start, UICC Stage at the First Diagnosis, Type of Second-Line Therapy, Number of Metastases at Diagnosis) | |
p-value-based backward model selection (threshold of 0.10) | Months between the first diagnosis and second-line MKI start (−0.008) Type of second-line therapy (vandetanib vs. cabozantinib, −1.607) |
p-value-based stepwise model selection (threshold of 0.10) | Type of second-line therapy (vandetanib vs. cabozantinib, −1.505) |
AIC-based backward model selection | Months between the first diagnosis and second-line MKI start (−0.008) Type of second-line therapy (vandetanib vs. cabozantinib, −1.607) |
AIC-based stepwise model selection | Months between the first diagnosis and second-line MKI start (−0.008) Type of second-line therapy (vandetanib vs. cabozantinib, −1.607) |
Penalized regression (Lasso)-based model selection (λ = 0.22) | Months between the first diagnosis and second-line MKI start (−0.003) Type of second-line therapy (vandetanib vs. cabozantinib, −0.731) Number of metastases at diagnosis (0.065) |
Cabozantinib (n = 15) | Vandetanib (n = 43) | |
---|---|---|
Discontinuation of/change in therapy due to drug intolerance | 9 (60%) | 9 (21%) |
Bleeding | 0 | 3 (7%) |
Change in blood count | 2 (13%) | 3 (7%) |
Electrolyte change | 1 (7%) | 4 (9%) |
Mucositis | 5 (33%) | 3 (7%) |
Diarrhea | 6 (40%) | 23 (53%) |
Dysgeusia/Ageusia | 1 (7%) | 0 |
Fatigue | 6 (40%) | 12 (28%) |
Fistula formation | 0 | 1 (2%) |
Hand–foot syndrome | 5 (33%) | 1 (2%; n = 42) |
Hypertension | 0 | 3 (7%) |
Infection | 3 (20%) | 1 (2%) |
Decreased appetite/weight loss | 8 (53%) | 9 (21%) |
Nausea | 2 (13%) | 3 (7%; n = 42) |
QTc interval prolongation | 0 | 10 (23%) |
Proteinuria | 1 (7%) | 0 |
Skin rash | 2 (13%) | 19 (44%) |
TSH elevation | 2 (14%; n = 14) | 0 |
Thrombosis/thromboembolism | 0 | 1 (2%; n = 42) |
Vomiting | 1 (7%) | 2 (5%) |
Loss of kidney function | 1 (7%) | 3 (7%) |
Need for dose reduction | 10 (67%) | 14 (33%) |
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Koehler, V.F.; Adam, P.; Fuss, C.T.; Jiang, L.; Berg, E.; Frank-Raue, K.; Raue, F.; Hoster, E.; Knösel, T.; Schildhaus, H.-U.; Negele, T.; Siebolts, U.; Lorenz, K.; Allelein, S.; Schott, M.; Spitzweg, C.; Kroiss, M., on behalf of the German Study Group for Rare Malignant Tumors of the Thyroid and Parathyroid Glands. Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors—A Retrospective Multi-Center Registry Analysis. Cancers 2022, 14, 3405. https://doi.org/10.3390/cancers14143405
Koehler VF, Adam P, Fuss CT, Jiang L, Berg E, Frank-Raue K, Raue F, Hoster E, Knösel T, Schildhaus H-U, Negele T, Siebolts U, Lorenz K, Allelein S, Schott M, Spitzweg C, Kroiss M on behalf of the German Study Group for Rare Malignant Tumors of the Thyroid and Parathyroid Glands. Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors—A Retrospective Multi-Center Registry Analysis. Cancers. 2022; 14(14):3405. https://doi.org/10.3390/cancers14143405
Chicago/Turabian StyleKoehler, Viktoria Florentine, Pia Adam, Carmina Teresa Fuss, Linmiao Jiang, Elke Berg, Karin Frank-Raue, Friedhelm Raue, Eva Hoster, Thomas Knösel, Hans-Ulrich Schildhaus, Thomas Negele, Udo Siebolts, Kerstin Lorenz, Stephanie Allelein, Matthias Schott, Christine Spitzweg, and Matthias Kroiss on behalf of the German Study Group for Rare Malignant Tumors of the Thyroid and Parathyroid Glands. 2022. "Treatment of RET-Positive Advanced Medullary Thyroid Cancer with Multi-Tyrosine Kinase Inhibitors—A Retrospective Multi-Center Registry Analysis" Cancers 14, no. 14: 3405. https://doi.org/10.3390/cancers14143405