Although thyroid cancer usually has an excellent prognosis, few therapeutic options are available in the refractory setting. Based on the recent results of phase II studies with tyrosine kinase inhibitors, we designed a retrospective analysis of patients with metastatic thyroid cancer treated with sorafenib in seven Spanish referral centers. Consecutive patients with progressive metastatic thyroid cancer (papillary, follicular, medullary, and anaplastic) not suitable for curative surgery, radioactive-iodine therapy, or radiotherapy were treated with sorafenib 400 mg twice a day. The primary end point was objective response rate (RR). Secondary end points included toxicity, median progression-free survival (mPFS), median overall survival (mOS), and correlation between tumor marker levels (thyroglobulin, calcitonin, and carcinoembryonic antigen) and efficacy. Between June 2006 and January 2010, 34 patients were included in the study. Sixteen patients presented differentiated thyroid carcinomas (DTC) of which seven (21%) were papillary, nine (26%) follicular, 15 (44%) medullary (MTC), and three (9%) were anaplastic (ATC). Eleven (32%) patients achieved partial response and 14 (41%) had stable disease beyond 6 months. Regarding histological subtype, RRs were 47% (seven of 15) for MTC, 19% (three of 16) for DTC, and 33% (one of three) for ATC. With a median follow-up of 11.5 months, mPFS were 13.5, 10.5, and 4.4 months for DTC, MTC, and ATC respectively. Tumor markers were evaluated in 22 patients, and a statistically significant association was observed between RR and decrease in tumor marker levels >50% (P=0.033). In this retrospective trial, sorafenib showed antitumor efficacy in all histological subtypes of thyroid cancer, warranting further development in this setting.
Jaume Capdevila, Lara Iglesias, Irene Halperin, Ángel Segura, Javier Martínez-Trufero, Maria Ángeles Vaz, Jesús Corral, Gabriel Obiols, Enrique Grande, Juan Jose Grau, and Josep Tabernero
Natassia E Bufalo, Janaina L Leite, Ana C T Guilhen, Elaine C Morari, Fabiana Granja, Ligia V M Assumpcao, and Laura S Ward
In contrast to most human malignancies, epidemiologic studies have frequently reported a reduced risk of differentiated thyroid cancer in tobacco consumers. Cytochrome P4501A1 (CYP1A1) gene variants may be related to an increased capacity to activate polycyclic aromatic hydrocarbons, producing highly reactive electrophilic intermediates that might damage DNA. Hence, the germline inheritance of a wild-type CYP1A1 gene may decrease the susceptibility for thyroid cancer. The present study was designed to investigate CYP1A1 (m1 and m2) role in thyroid tumorigenesis and its connection with GSTM1, GSTT1, GSTP1, GSTO1, and codon 72 of p53 genotypes. A total of 248 patients with thyroid nodules, including 67 benign goiters, 13 follicular adenomas, 136 papillary carcinomas, and 32 follicular carcinomas, and 277 controls with similar ethnic backgrounds were interviewed on their lifetime dietary and occupational histories, smoking habit, previous diseases, and other anamnestic data. DNA was extracted from a blood sample and submitted to PCR-restriction fragment length polymorphism assays. The wild-type CYP1A1m1 genotype was more frequent among papillary carcinoma patients (74.26%) than in the control population (62.45%; P = 0.0147), reducing the risk for this type of cancer (odds ratio = 0.564; 95% confidence interval = 0.357–0.894). A multiple logistic regression analysis showed an inverse correlation between cigarette smoking (P = 0.0385) and CYP1A1 germline inheritance (P = 0.0237) with the susceptibility to papillary carcinomas. We were not able to find any correlation between smoking, clinical features, parameters of aggressiveness at diagnosis or during follow-up, and any of the GST or CYP genotypes considered separately or in different combinations. We suggest that CYP1A1 genotype might be associated with the reported reduced risk to papillary carcinomas among smokers.
Federica Panebianco, Alyaksandr V Nikitski, Marina N Nikiforova, Cihan Kaya, Linwah Yip, Vincenzo Condello, Abigail I Wald, Yuri E Nikiforov, and Simion I Chiosea
ALK fusions are found in various tumors, including thyroid cancer, and serve as a diagnostic marker and therapeutic target. Spectrum and outcomes of ALK fusions found in thyroid nodules and cancer are not fully characterized. We report a series of 44 ALK-translocated thyroid neoplasms, including 31 identified preoperatively in thyroid fine-needle aspirates (FNA). The average patients’ age was 43 years (range, 8–76 years); only one with radiation history. All 19 resected thyroid nodules with ALK fusion identified preoperatively were malignant. Among nodules with known surgical pathology (n = 32), 84% were papillary thyroid carcinomas (PTCs) and 16% poorly differentiated thyroid carcinomas (PDTCs). PTCs showed infiltrative growth with follicular architecture seen exclusively (30%) or in combination with papillary and/or solid growth (37%). Tumor multifocality was seen in 10 (31%) PTC cases. Most PDTC had a well-differentiated PTC component. Lymph node metastases were identified in 10/18 (56%) patients with neck dissection. The most common ALK fusion partners were STRN (n = 22) and EML4 (n = 17). In five cases, novel ALK fusion partners were discovered. All five PDTCs carried STRN-ALK fusion. On follow-up, ten patients were free of disease at 2–108 months, whereas two patients with PDTC died of disease. In summary, ALK fusion-positive thyroid carcinomas are typically infiltrative PTC with common follicular growth, which may show tumor dedifferentiation associated with increased mortality. Compared to EML4-ALK, STRN-ALK may be more common in PDTC, and ~10% of ALK fusions occur to rare gene partners. When ALK fusion is detected preoperatively in FNA samples, malignancy should be expected.
J M Gómez, N Gómez, M Sahún, A Rafecas, C Villabona, and J Soler
Despite the usual excellent prognosis of differentiated thyroid carcinoma, some patients die because of disease. It has been speculated that lethal disease may have a better prognosis if patients are treated with extensive surgery plus 131I ablative treatment. We have analyzed a group of 223 patients with differentiated thyroid carcinoma treated under a uniform therapeutic protocol of surgery and followed for 3 to 17.7 years, in order to differentiate patients with a high and a low risk of mortality and the influence of therapy on survival rate.
The therapeutic protocol was as follows. If the diagnosis was papillary carcinoma, subtotal thyroidectomy was performed and cervical nodes were removed if they were suspicious for cancer. If the diagnosis was follicular carcinoma, a total thyroidectomy was performed. 131I was given in cases of patients who were more than 60 years old or who had extrathyroid disease or metastases in papillary carcinomas and in macroangioinvasive follicular carcinomas. In survival analysis, the event used as the end-point was death due to thyroid carcinoma and summarized by the Kaplan-Meier curve and the Mantel-Cox method.
We found three independent prognostic factors which determined mortality: over 60 years of age, tumor size larger than 6 cm and metastases. On the basis of these factors we identified two risk groups: a low-risk group (A), who had no risk factors, composed of 153 patients whose survival rate at 205 months was 100% and a high-risk group (B), who had one or more risk factors, composed of 55 patients whose survival rate at 213 months was 39.6%. Seventeen patients in this second group died from thyroid carcinoma. We therefore analyzed the effect of treatment in group B. Patients who had more extensive surgery had a similar survival rate to those who had less extensive surgery and 131I administration did not modify the survival rate.
These data support the idea that the identification of low-risk groups may facilitate a more rational approach to treatment of differentiated thyroid carcinoma, avoiding aggressive therapy in cases with a good prognosis.
Endocrine-Related Cancer (1997) 4 459-464
Xiaoli Liu, Justin Bishop, Yuan Shan, Sara Pai, Dingxie Liu, Avaniyapuram Kannan Murugan, Hui Sun, Adel K El-Naggar, and Mingzhao Xing
Mutations 1 295 228 C>T and 1 295 250 C>T (termed C228T and C250T respectively), corresponding to −124 C>T and −146 C>T from the translation start site in the promoter of the telomerase reverse transcriptase (TERT) gene, have recently been reported in human cancers, but not in thyroid cancers yet. We explored these mutations in thyroid cancers by genomic sequencing of a large number of primary tumor samples. We found the C228T mutation in 0 of 85 (0.0%) benign thyroid tumors, 30 of 257 (11.7%) papillary thyroid cancers (PTC), 9 of 79 (11.4%) follicular thyroid cancers (FTC), 3 of 8 (37.5%) poorly differentiated thyroid cancers (PDTC), 23 of 54 (42.6%) anaplastic thyroid cancers (ATC), and 8 of 12 (66.7%) thyroid cancer cell lines. The C250T mutation was uncommon, but mutually exclusive with the C228T mutation, and the two mutations were collectively found in 11 of 79 (13.9%) FTC, 25 of 54 (46.3%) ATC, and 11 of 12 (91.7%) thyroid cancer cell lines. Among PTC variants, the C228T mutation was found in 4 of 13 (30.8%) tall-cell PTC (TCPTC), 23 of 187 (12.3%) conventional PTC, and 2 of 56 (3.6%) follicular variant PTC samples. No TERT mutation was found in 16 medullary thyroid cancer samples. The C228T mutation was associated with the BRAF V600E mutation in PTC, being present in 19 of 104 (18.3%) BRAF mutation-positive PTC vs 11 of 153 (7.2%) the BRAF mutation-negative PTC samples (P=0.0094). Conversely, BRAF mutation was found in 19 of 30 (63.3%) C228T mutation-positive PTC vs 85 of 227 (37.4%) C228T mutation-negative PTC samples (P=0.0094). We thus for the first time, to our knowledge, demonstrate TERT promoter mutations in thyroid cancers, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.
Aruna V Krishnan and David Feldman
Calcitriol, the hormonally active form of vitamin D, exerts multiple anti-proliferative and pro-differentiating actions including cell cycle arrest and induction of apoptosis in many malignant cells, and the hormone is currently being evaluated in clinical trials as an anti-cancer agent. Recent research reveals that calcitriol also exhibits multiple anti-inflammatory effects. First, calcitriol inhibits the synthesis and biological actions of pro-inflammatory prostaglandins (PGs) by three mechanisms: i) suppression of the expression of cyclooxygenase-2, the enzyme that synthesizes PGs; ii) up-regulation of the expression of 15-hydroxyprostaglandin dehydrogenase, the enzyme that inactivates PGs; and iii) down-regulation of the expression of PG receptors that are essential for PG signaling. The combination of calcitriol and nonsteroidal anti-inflammatory drugs results in a synergistic inhibition of the growth of prostate cancer (PCa) cells and offers a potential therapeutic strategy for PCa. Second, calcitriol increases the expression of mitogen-activated protein kinase phosphatase 5 in prostate cells resulting in the subsequent inhibition of p38 stress kinase signaling and the attenuation of the production of pro-inflammatory cytokines. Third, calcitriol also exerts anti-inflammatory activity in PCa through the inhibition of nuclear factor-κB signaling that results in potent anti-inflammatory and anti-angiogenic effects. Other important direct effects of calcitriol as well as the consequences of its anti-inflammatory effects include the inhibition of tumor angiogenesis, invasion, and metastasis. We hypothesize that these anti-inflammatory actions, in addition to the other known anti-cancer effects of calcitriol, play an important role in its potential use as a therapeutic agent for PCa. Calcitriol or its analogs may have utility as chemopreventive agents and should be evaluated in clinical trials in PCa patients with early or precancerous disease.
Catherine Ory, Nicolas Ugolin, Céline Levalois, Ludovic Lacroix, Bernard Caillou, Jean-Michel Bidart, Martin Schlumberger, Ibrahima Diallo, Florent de Vathaire, Paul Hofman, José Santini, Bernard Malfoy, and Sylvie Chevillard
Both external and internal exposure to ionizing radiation are strong risk factors for the development of thyroid tumors. Until now, the diagnosis of radiation-induced thyroid tumors has been deduced from a network of arguments taken together with the individual history of radiation exposure. Neither the histological features nor the genetic alterations observed in these tumors have been shown to be specific fingerprints of an exposure to radiation. The aim of our work is to define ionizing radiation-related molecular specificities in a series of secondary thyroid tumors developed in the radiation field of patients treated by radiotherapy. To identify molecular markers that could represent a radiation-induction signature, we compared 25K microarray transcriptome profiles of a learning set of 28 thyroid tumors, which comprised 14 follicular thyroid adenomas (FTA) and 14 papillary thyroid carcinomas (PTC), either sporadic or consecutive to external radiotherapy in childhood. We identified a signature composed of 322 genes which discriminates radiation-induced tumors (FTA and PTC) from their sporadic counterparts. The robustness of this signature was further confirmed by blind case-by-case classification of an independent set of 29 tumors (16 FTA and 13 PTC). After the histology code break by the clinicians, 26/29 tumors were well classified regarding tumor etiology, 1 was undetermined, and 2 were misclassified. Our results help shed light on radiation-induced thyroid carcinogenesis, since specific molecular pathways are deregulated in radiation-induced tumors.
Brian Hung-Hin Lang, Chung-Yau Lo, Wai-Fan Chan, King-Yin Lam, and Koon-Yat Wan
A number of risk-group stratification or staging systems have been found useful at stratifying patients with differentiated thyroid carcinoma into risk groups. Those identified as high risk could be subjected to more aggressive treatment, while those at low risk could be spared of such treatment. However, the best stratification system in patients with follicular thyroid carcinoma (FTC) remains unclear. Through a comprehensive MEDLINE search from 1965 to 2005, a total of 18 different staging systems were identified in the literature and 14 of them were applicable to 171 patients, with FTC managed at our institution from 1961 to 2001. Cancer-specific survivals (CSS) were calculated by Kaplan–Meier method and were compared by log-rank test. Using Cox proportional hazards analysis, the relative importance of each staging system in determining CSS was calculated by the proportion of variation in survival time explained (PVE). CSS were predicted by 13 out of the 14 staging systems significantly (P < 0.001). The three highest ranked staging systems by PVE were the new American Joint Commitee on Cancer/Union Internationale Centre le Cancer 6th edition, tumour, node, metastases (TNM; 22.4), followed by the Clinical Class (21.2) and the metastases, age, completeness of resection, invasion, size (MACIS; 20.4). In conclusion, 13 out of the 14 presently available staging systems predicted CSS significantly in FTC. When predictability was measured by PVE, the TNM system was found to have the best predictability and thus, should be the stratification system of choice for FTC in the future.
Urbain Weyemi, Bernard Caillou, Monique Talbot, Rabii Ameziane-El-Hassani, Ludovic Lacroix, Odile Lagent-Chevallier, Abir Al Ghuzlan, Dirk Roos, Jean-Michel Bidart, Alain Virion, Martin Schlumberger, and Corinne Dupuy
NADPH oxidase 4 (NOX4) belongs to the NOX family that generates reactive oxygen species (ROS). Function and tissue distribution of NOX4 have not yet been entirely clarified. To date, in the thyroid gland, only DUOX1/2 NOX systems have been described. NOX4 mRNA expression, as shown by real-time PCR, was present in normal thyroid tissue, regulated by TSH and significantly increased in differentiated cancer tissues. TSH increased the protein level of NOX4 in human thyroid primary culture and NOX4-dependent ROS generation. NOX4 immunostaining was detected in normal and pathologic thyroid tissues. In normal thyroid tissue, staining was heterogeneous and mostly found in activated columnar thyrocytes but absent in quiescent flat cells. Papillary and follicular thyroid carcinomas displayed more homogeneous staining. The p22phox protein that forms a heterodimeric enzyme complex with NOX4 displayed an identical cellular expression pattern and was also positively regulated by TSH. ROS may have various biological effects, depending on the site of production. Intracellular NOX4–p22phox localization suggests a role in cytoplasmic redox signaling, in contrast to the DUOX localization at the apical membrane that corresponds to an extracellular H2O2 production. Increased NOX4–p22phox in cancer might be related to a higher proliferation rate and tumor progression but a role in the development of tumors has to be further studied and established in the future.
Devora Champa, Marika A Russo, Xiao-Hui Liao, Samuel Refetoff, Ronald A Ghossein, and Antonio Di Cristofano
Poorly differentiated tumors of the thyroid gland (PDTC) are generally characterized by a poor prognosis due to their resistance to available therapeutic approaches. The relative rarity of these tumors is a major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance, and consequently to the development of novel therapies. By simultaneously activating Kras and deleting p53 (Trp53) in thyroid follicular cells, we have generated a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. In several cases, tumors further progress to anaplastic carcinomas. The poorly differentiated tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Using primary carcinomas as well as carcinoma-derived cell lines, we also demonstrate that these tumors are intrinsically resistant to apoptosis due to high levels of expression of the Bcl2 family members, Bcl2a1 (Bcl2a1a) and Mcl1, and can be effectively targeted by Obatoclax, a small-molecule pan-inhibitor of the Bcl2 family. Furthermore, we show that Bcl2 family inhibition synergizes with MEK inhibition as well as with doxorubicin in inducing cell death. Thus, our studies in a novel, relevant mouse model have uncovered a promising druggable feature of aggressive thyroid cancers.