Mechanisms of Disease: cancer targeting and the impact of oncogenic RET for medullary thyroid carcinoma therapy

AbstractThe aim of this study is to analyze the impact of combined treatment (thyroidectomy and radiotherapy and radioactive iodine treatment) on patients’ long-term survival with medullary thyroid carcinoma. This is a retrospective study of 59 patients treated from 1977 to 2006 for medullary carcinoma at the Institute of Oncology in Vilnius, Lithuania. Survival was estimated by the Kaplan-Meier method. Univariate and multivariate Cox proportional hazard models were used to explore the association of prognostic factors with long-term survival. The survival of MTC patients was 88.0% (95% CI 68.0–88.9), 67.9% (95% CI 52.3–79.4) and 60.5% (95% CI 43.2–74.0), respectively, 5, 10 and 15 years after diagnosis. In survival analysis, only the type of surgery and lymph node involvement were found to be significant prognostic factors. The results of this study suggest that treatment with radioiodine and external beam radiotherapy do not improve significantly the long-term survival of surgically treated MTC patients.

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Chemoembolization for Liver Metastases from Medullary Thyroid Carcinoma

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-2401 ◽

2006 ◽

Vol 91 (7) ◽

pp. 2496-2499 ◽

Cited By ~ 75

Author(s):

J. Fromigué ◽

T. De Baere ◽

E. Baudin ◽

C. Dromain ◽

S. Leboulleux ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Liver Metastases ◽

Medullary Thyroid Carcinoma ◽

Median Duration ◽

Early Stage ◽

Somatostatin Analogs ◽

Evaluation Criteria ◽

Distant Metastases ◽

Medullary Thyroid ◽

The Impact

Abstract Background: Medullary thyroid carcinoma (MTC) is a well-differentiated neuroendocrine tumor. Distant metastases are the main cause of cancer-related death. Systemic chemotherapy produces only rare tumor responses. Somatostatin analogs and other available modalities are poorly effective to control symptoms. Aims: The aim of our study was to evaluate the impact of liver transarterial chemoembolization (TACE) in MTC patients with predominant and progressive liver metastases. Patients and Methods: Twelve MTC patients underwent 18 TACE courses (mean, 1.5; range, 1–2). Response evaluation criteria in solid tumors were used to evaluate tumor responses. Symptomatic responses were defined by more than a 25% decrease of symptoms intensity. Results: Partial radiological tumor response was obtained in five patients (42%) with a median duration of 17 months (mean, 19; range, 15–28 months), stabilization in five (42%) with a median duration of 24 months (mean, 24; range, 4–39 months), and progression in the remaining two (16%). The five partial tumor responses were observed in the nine patients with less than 30% liver involvement. Clinical response was observed in two of the five patients with diarrhea. Carcinoembryonic antigen did not appear to be a useful marker in this setting. Significant grade 3–4 toxicity was observed in one patient who had a major tumor necrosis after TACE. Conclusion: TACE should be considered for treating MTC patients with progressive and predominant liver metastasis, and preferably at an early stage during the course of metastatic disease.

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Estimation of Risk of Inherited Medullary Thyroid Carcinoma in Apparent Sporadic Patients

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.5.1374 ◽

2001 ◽

Vol 19 (5) ◽

pp. 1374-1380 ◽

Cited By ~ 68

Author(s):

M. Wiench ◽

Z. Wygoda ◽

E. Gubala ◽

J. Wloch ◽

K. Lisowska ◽

...

Keyword(s):

Genetic Analysis ◽

Thyroid Carcinoma ◽

Medullary Thyroid Carcinoma ◽

Older Patients ◽

Inherited Disease ◽

Medullary Thyroid ◽

Extended Analysis ◽

Sporadic Disease ◽

Exon 11 ◽

The Impact

PURPOSE: The study was undertaken to evaluate the frequency of inherited medullary thyroid carcinoma (MTC) among patients with apparent sporadic disease. A stepwise algorithm was used depending on clinical indices and the age of patient at MTC diagnosis. PATIENTS AND METHODS: One hundred sixteen patients with MTC verified by postoperative pathologic examination were subjected to genetic analysis of RET exons 10, 11, 13, 14, and 16 by means of polymerase chain reaction, restriction endonuclease digestion, and DNA sequencing. RESULTS: Among 116 apparent sporadic MTC patients, we identified eleven (9.5%) RET germline mutation carriers. Seven of these (6.0%) were found by routine analysis (exons 10 and 11). The frequency of inherited disease among patients younger than 45 years at diagnosis was 10.2% by analysis of typical mutations in exons 10 and 11. Extended genetic analysis (sequencing of exons 11, 13, 14, and 16) yielded 6.1% additional diagnoses, giving a risk of 16.3% in this age group. One previously unreported mutation in exon 11 affected codon 649 (TCG>TTG, Ser>Leu). In the true sporadic MTC patients younger than 30 years at diagnosis, frequencies of 36% and 4.5% in polymorphic variants L769L and S836S, respectively, were observed. The frequency for L769L was higher than in older patients (P < .05). CONCLUSION: The frequency of inherited disease among apparent sporadic medullary thyroid carcinoma patients is close to 10% in the Polish population of MTC patients. The extended analysis of all known RET proto-oncogene mutation sites is obligatory in patients younger than 45 years at diagnosis, but we also see the need to analyze the impact of rarer mutations in older patients.

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Impact of Advanced Age on the Clinical Presentation and Outcome of Sporadic Medullary Thyroid Carcinoma

Cancers ◽

10.3390/cancers13010094 ◽

2020 ◽

Vol 13 (1) ◽

pp. 94

Author(s):

Antonio Matrone ◽

Carla Gambale ◽

Alessandro Prete ◽

Paolo Piaggi ◽

Virginia Cappagli ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Survival Time ◽

Medullary Thyroid Carcinoma ◽

Age Groups ◽

Age At Diagnosis ◽

Younger Patients ◽

Sporadic Medullary Thyroid Carcinoma ◽

Medullary Thyroid ◽

Group B ◽

The Impact

Sporadic medullary thyroid carcinoma (MTC) is a rare malignancy with a heterogeneous clinical course. Several potential prognostic factors have been investigated, but the impact of some of these is controversial, such as age at diagnosis. We evaluated the data of 432 sporadic MTC patients followed-up for a median of 7.4 years. Patients were divided and compared according to their age at diagnosis in group A (<65 years—n = 338, 78.2%) and group B (≥65 years—n = 94, 21.8%). No differences were detected between the two groups. Median follow-up time was significantly longer in patients <65 than ≥65 years. We observed 41 (9.5%) cancer-related death events. The death rate was similar between the two age groups. However, the Kaplan Meier curve showed a longer survival time for younger patients compared to older patients [HR 2.5 (CI 95%: 1.27–4.94), p < 0.01]. Nevertheless, no differences in the aggressiveness of the disease at presentation and in the number and type of treatments performed were found in the two subgroups of dead patients. In patients with sporadic MTC, age at diagnosis did not correlate with any clinical and pathological features. Cancer-related death events are similar in older and younger patients, but survival time is longer in the younger.

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The Extent of Surgery for Thyroid Medullary Cancer

Tumori Journal ◽

10.1177/030089169408000604 ◽

1994 ◽

Vol 80 (6) ◽

pp. 427-432 ◽

Cited By ~ 11

Author(s):

Maria Rosa Pelizzo ◽

Paolo Bernante ◽

Andrea Piotto ◽

Antonio Toniato ◽

Maria Elisa Girelli ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Total Thyroidectomy ◽

Neck Dissection ◽

Medullary Thyroid Carcinoma ◽

Radical Neck Dissection ◽

Stage I ◽

Stage Iii ◽

Medullary Thyroid ◽

The Impact

Aims Evaluation of the impact of the extent of primary surgery and reintervention on the outcome of patients with medullary thyroid carcinoma. Methods Seventy-two patients with medullary thyroid carcinoma (MTC) were surgically treated between 1967 and 1992. Results Fifty-five cases were sporadic, 5 patients had MEN 2A, 4 MEN 2B syndrome and 8 familial non-MEN MTC; 1 patient had stage I disease, 30 patients stage II, 36 stage III and 5 stage IV. Sixty-four had their initial treatment at our center, and 8 came for subsequent treatment. At first treatment, 8 patients were subjected to partial thyroidectomy, 10 to total thyroidectomy, 53 to total thyroidectomy with neck dissection, and 1 to only radical neck dissection; postoperative serum calcitonin (Ct) levels returned to normal in 3, 6 and 27 patients, respectively. In the patient with only radical neck dissection, Ct levels remained elevated. No patient with Ct normalization after surgery became responsive to pentagastrin in the follow-up. Thirteen patients had a reoperation due to nodal relapse. At a mean follow-up of 5.7 years (6-252 months), the 10-year survival rate was 84.5% with a significant difference between patients under and over 40 years of age (96.4 vs 57%), between stage I-II (100%) and stage III, IV (83.8%, 0% respectively). At the last follow-up, 36 (50%) patients were alive and disease free and 26 were alive with disease (15 with distant metastases). Of the 10 deaths, 7 were due to tumor recurrence, 3 to 120 months after surgery. Conclusions Data suggest that an earlier diagnosis rather than more extensive surgery could improve survival and reduce recurrences. However, the least treatment required is total thyroidectomy plus central neck and upper mediastinum clearance and in addition, according to the extent of nodal involvement, mono- or bilateral neck dissection. To avoid ineffective reoperation due to distant (mainly liver) micro-metastases, persistent residual microscopic disease requires a more aggressive restaging.

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