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At physiological concentrations, reactive oxygen species (ROS), including superoxide anions and H2O2, are considered as second messengers that play key roles in cellular functions, such as proliferation, gene expression, host defence and hormone synthesis. However, when they are at supraphysiological levels, ROS are considered potent DNA-damaging agents. Their increase induces oxidative stress, which can initiate and maintain genomic instability. The thyroid gland represents a good model for studying the impact of oxidative stress on genomic instability. Indeed, one particularity of this organ is that follicular thyroid cells synthesise thyroid hormones through a complex mechanism that requires H2O2. Because of their detection in thyroid adenomas and in early cell transformation, both oxidative stress and DNA damage are believed to be neoplasia-preceding events in thyroid cells. Oxidative DNA damage is, in addition, detected in the advanced stages of thyroid cancer, suggesting that oxidative lesions of DNA also contribute to the maintenance of genomic instability during the subsequent phases of tumourigenesis. Finally, ionizing radiation and the mutation of oncogenes, such as RAS and BRAF, play a key role in thyroid carcinogenesis through separate and unique mechanisms: they upregulate the expression of two distinct ‘professional’ ROS-generating systems, the NADPH oxidases DUOX1 and NOX4, which cause DNA damage that may promote chromosomal instability, tumourigenesis and dedifferentiation.
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Low-risk papillary cancers, which represent the vast majority of thyroid cancers diagnosed today, do not require aggressive treatment or follow-up. Initial treatment consists of a total thyroidectomy without prophylactic lymph node dissection. A hemithyroidectomy is an alternative in some patients with an intrathyroidal tumor and with a normal contralateral lobe at pre-operative neck ultrasonography. The use of post-operative radioiodine should be restricted to selected patients. Follow-up at 6–18 months is based on serum thyroglobulin (Tg), Tg-antibody determination and neck ultrasonography. In the absence of any abnormality (excellent response to treatment), the risk of recurrence is extremely low and follow-up may consist of serum TSH monitoring that is maintained in the normal range, and a Tg and Tg-antibody titer determination every year. There is no need for referral to a specialized center. In patients with detectable serum Tg or detectable Tg antibodies, the trend over time of these markers on levothyroxine treatment will dictate subsequent follow-up: a decreasing trend is reassuring, but an increasing trend should lead to imaging, starting with neck ultrasonography.
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Based on experimental data, the inhibition of the MAPkinase pathway in patients with radioiodine-refractory thyroid cancer was capable of inducing a redifferentiation. Preliminary data obtained in a small series of patients were encouraging and this strategy might become an alternative treatment in those patients with a druggable mutation that induces a stimulation of the MAP kinase pathway. This is an active field of research to answer many still unresolved questions.
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Distant metastases from thyroid cancer of follicular origin are uncommon. Treatment includes levothyroxine administration, focal treatment modalities with surgery, external radiation therapy and thermal ablation, and radioiodine in patients with uptake of 131I in their metastases. Two-thirds of distant metastases become refractory to radioiodine at some point, and when there is a significant tumor burden and documented progression on imaging, a treatment with a kinase inhibitor may provide benefits.
INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
INSERM U693, UMR-S693, Assistance Publique-Hôpitaux de Paris, INSERM UMRS 1016, Service Interdépartemental de Pharmacologie et d'Analyse du Médicament, Oncologie Endocrinienne, HRA Pharma, Assistance Publique-Hôpitaux de Paris, Assistance Publique-Hôpitaux de Paris, Fac Med Paris Sud, Rue Gabriel Péri, Le Kremlin-Bicêtre F-94276, France
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Mitotane, 1,1-dichloro-2-(o-chlorophenyl)-2-(p-chlorophenyl)ethane is the most effective medical therapy for adrenocortical carcinoma, but its molecular mechanism of action remains poorly understood. Although mitotane is known to have mitochondrial (mt) effects, a direct link to mt dysfunction has never been established. We examined the functional consequences of mitotane exposure on proliferation, steroidogenesis, and mt respiratory chain, biogenesis and morphology, in two human adrenocortical cell lines, the steroid-secreting H295R line and the non-secreting SW13 line. Mitotane inhibited cell proliferation in a dose- and a time-dependent manner. At the concentration of 50 μM (14 mg/l), which corresponds to the threshold for therapeutic efficacy, mitotane drastically reduced cortisol and 17-hydroxyprogesterone secretions by 70%. This was accompanied by significant decreases in the expression of genes encoding mt proteins involved in steroidogenesis (STAR, CYP11B1, and CYP11B2). In both H295R and SW13 cells, 50 μM mitotane significantly inhibited (50%) the maximum velocity of the activity of the respiratory chain complex IV (cytochrome c oxidase (COX)). This effect was associated with a drastic reduction in steady-state levels of the whole COX complex as revealed by blue native PAGE and reduced mRNA expression of both mtDNA-encoded COX2 (MT-CO2) and nuclear DNA-encoded COX4 (COX4I1) subunits. In contrast, the activity and expression of respiratory chain complexes II and III were unaffected by mitotane treatment. Lastly, mitotane exposure enhanced mt biogenesis (increase in mtDNA content and PGC1 α (PPARGC1A) expression) and triggered fragmentation of the mt network. Altogether, our results provide first evidence that mitotane induced a mt respiratory chain defect in human adrenocortical cells.
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Recent studies suggest that the somatostatin receptor scintigraphy (SRS) grade of uptake is a predictor of response to peptide receptor radionuclide therapy (PRRT). To identify and characterize patients with well-differentiated (WD) neuroendocrine neoplasm (NEN) displaying a high-grade uptake at SRS. Patients with WD-NEN, whose SRS films were available for review, were retrospectively included. SRS was reviewed by three independent readers and classified into four subgroups based on a modified Krenning's scale (mKS): no uptake (group-0), homogeneous grade 1–2 uptake (group-1), homogeneous grade 3–4 (group-2), and heterogeneous grade 1–4 (group-3). A simplified scale (sS) of SRS was also used to look for characteristics of patients with high-grade uptake. One hundred and six WD-NEN patients were enrolled. Group-0, group-1, group-2, and group-3 were found in 17, 8, 33, and 42% of cases respectively. High-grade uptake at sS (75% of cases) was correlated with older age, functioning NEN, high chromogranin-A level, and grade 1 (G1) NEN based on mitotic count. Based on the mKS or sS scales, no difference on survival was found. Thirty-three to seventy-five percent of metastatic NEN patients can be considered candidates for PRRT based on homogeneous or heterogeneous high-grade uptake. Functioning G1 NEN patients could be the best candidates for PRRT. Randomized trials are expected to confirm this result.
Endocrinology Unit, Department of Experimental and Clinical Biomedical Sciences ‘Mario Serio’, University of Florence, Florence, Italy
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Anaplastic thyroid cancer (ATC) is a rare lethal disease. Lenvatinib is an off-label therapeutic option for ATC in most countries, except in Japan. The aim of this multicenter retrospective survey was to analyze the efficacy and the toxicity profile of off-label lenvatinib treatment in all adults advanced ATC patients, in France. Of the 23 patients analysed (14 males; mean age 64 years), 15 were pure ATC and 8 were mixed tumors (i.e. with a differentiated or poorly differentiated component). Prior treatments included neck external beam irradiation in 74%, at least one line of chemotherapy in 22 cases, two lines of chemotherapy in 11 patients, other TKI in 4 cases. A central RECIST assessment was performed. Since lenvatinib initiation, median PFS was 2.7 months (95% CI; 1.9–3.5) and median OS was 3.1 months (95% CI; 0.6–5.5). OS was significantly longer in case of mixed tumors compared with pure ATC (6.3 vs 2.7 months, P = 0.026). Best tumor response was partial response in two cases and stable disease in seven. Clinical improvement was achieved in seven patients. Lethal adverse events occurred in three patients, consisting in haemoptysis in two cases and pneumothorax in one case. Among long-surviving ATC patients (>6 months), four underwent biopsy of distant metastasis, revealing poorly differentiated histology; three of them had initial mixed ATC histology. Efficacy of lenvatinib appears limited, although pure vs mixed ATC disclose differences in disease aggressiveness and treatment response. Long-surviving ATC patients might benefit from biopsy of persistent disease, searching for histological transition or molecular target.
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Survival of metastatic gastroenteropancreatic well-differentiated endocrine carcinoma (GEP WDEC) is not well characterized. We evaluated the long-term outcome and prognostic factors for survival in 118 patients with distant metastases from GEP WDEC. Inclusion criteria were 1) pathological review by a single pathologist according to the present WHO criteria, 2) absence of previous therapy apart from surgery, 3) complete morphological evaluation within 3 months including somatostatin receptor scintigraphy, and 4) follow-up at Gustave-Roussy Institute until death or study's end. Clinical, biological marker, and pathological parameters were analyzed in univariate and multivariate statistical models. Survival after the first complete imaging work-up of the metastatic disease was determined using Kaplan–Meier method. Overall, survival for 5 years after the diagnosis of metastatic disease was 54%. In multivariate analysis, age (hazard ratio (HR): 1.05, 95% confidence interval (CI): 1.01–1.08, P=0.01), the number of liver metastases (HR: 3.4, 95% CI: 1.4–8.3, P=0.01), tumor slope (HR: 1.1, 95% CI: 1.0–1.1, P=0.001), and initial surgery (HR: 0.3, 95% CI: 0.1–0.8, P=0.01) were predictive of survival. Five-year survival was 100%, 91% (95% CI, 51–98%), 62% (95% CI, 37–83%), and 9% (95% CI, 6–32%) when patients had 0, 1, 2, 3 or more poor prognostic features respectively. This study enables the stratification of metastatic GEP WDEC patients into distinct risk groups. These risk categories can be used to tailor therapeutic approaches and also to design and interpret clinical trials.
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To progress in the stratification of the first-line therapeutic management of metastatic adrenocortical carcinoma (ACC), we searched for prognostic parameters of survival in patients treated with combined mitotane- and cisplatinum-based chemotherapy as first-line. We retrospectively studied prospectively collected parameters from 131 consecutive patients with metastatic ACC (44 with a tissue specimen available) treated at the Gustave Roussy Institute with mitotane- and platinum-based chemotherapy. Fifty-five patients with clinical, pathological, and morphological data available together with treatment characteristics including detailed follow-up were enrolled. Plasma mitotane levels and ERCC1 protein staining were analyzed. Response was analyzed according to RECIST criteria as well as overall survival (OS) from the start of cisplatinum-based chemotherapy. Parameters impacting on OS were evaluated by univariate analysis, and then analyzed by multivariate analysis. Using a landmark method, OS according to response to chemotherapy was analyzed. Objective response to combined mitotane- and cisplatinum-based chemotherapy was 27.3%. Median OS was 1 year. In the univariate analysis, resection of the primary, time since diagnosis, mitotane monotherapy as single first-line treatment, number of affected organs, plasma mitotane above 14 mg/l, and objective response were predictors of survival. In the multivariate analysis, mitotane level ≥14 mg/l and objective response to platinum-based chemotherapy were found to be independent predictors of survival (P=0.03 and <0.001). Our study suggests a prognostic role for mitotane therapy and objective response to platinum-based chemotherapy.
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Department of Endocrinology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
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The prognosis of poorly differentiated thyroid carcinomas (PDTC) defined by the Turin criteria is variable. The aim of this study on 51 PDTC patients was to determine clinical, histological and molecular prognostic factors associated with recurrence in patients with localized disease at initial treatment and with overall survival in patients with distant metastases. Of 40 patients for whom next-generation sequencing (NGS) by ThyroSeq v3 was able to be performed on historical samples, we identified high-risk molecular signature (TERT, TP53 mutations) in 24 (60%) cases, intermediate risk signature in 9 (22.5%) cases and low-risk signature in 7 (17.5%) cases. Potentially actionable mutations were identified in 10% of cases. After a median follow-up of 57.5 months, recurrence occurred in 11 (39%) of the 28 patients with localized disease. The American Thyroid Association (ATA) high risk of relapse, high mitotic count, high molecular risk signature and CD163 expression were associated with recurrence (P = 0.009, 0.01, 0.049, 0.03 respectively). After a median follow-up of 49.5 months, thyroid cancer-related death occurred in 53% of the patients with distant metastases. There was no significant prognostic factor associated with death in univariate analysis. However, none of the patients with intermediate ATA risk of recurrence and none of the patients with low-risk molecular signature died from the disease. In addition, high molecular-risk signature was associated with the presence of synchronous or metachronous distant metastasis (P = 0.007) and with poor overall survival (P = 0.01). In conclusion, ATA risk of relapse and high mitotic count was associated with higher rate of recurrence in localized PDTC. High molecular-risk signature was associated with the presence of distant metastasis and poor overall survival. Further studies are needed to determine if molecular testing adds to ATA risk stratification or response to therapy in predicting outcomes.
