Barbara Jarzab

Vandetanib in Patients With Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-Blind Phase III Trial

PURPOSE There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib, a once-daily oral inhibitor of RET kinase, vascular endothelial growth factor receptor, and epidermal growth factor receptor signaling, has previously shown antitumor activity in a phase II study of patients with advanced hereditary MTC. PATIENTS AND METHODS Patients with advanced MTC were randomly assigned in a 2:1 ratio to receive vandetanib 300 mg/d or placebo. On objective disease progression, patients could elect to receive open-label vandetanib. The primary end point was progression-free survival (PFS), determined by independent central Response Evaluation Criteria in Solid Tumors (RECIST) assessments. RESULTS Between December 2006 and November 2007, 331 patients (mean age, 52 years; 90% sporadic; 95% metastatic) were randomly assigned to receive vandetanib (231) or placebo (100). At data cutoff (July 2009; median follow-up, 24 months), 37% of patients had progressed and 15% had died. The study met its primary objective of PFS prolongation with vandetanib versus placebo (hazard ratio [HR], 0.46; 95% CI, 0.31 to 0.69; P < .001). Statistically significant advantages for vandetanib were also seen for objective response rate (P < .001), disease control rate (P = .001), and biochemical response (P < .001). Overall survival data were immature at data cutoff (HR, 0.89; 95% CI, 0.48 to 1.65). A final survival analysis will take place when 50% of the patients have died. Common adverse events (any grade) occurred more frequently with vandetanib compared with placebo, including diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%), hypertension (32% v 5%), and headache (26% v 9%). CONCLUSION Vandetanib demonstrated therapeutic efficacy in a phase III trial of patients with advanced MTC (ClinicalTrials.gov NCT00410761).

Cabozantinib in Progressive Medullary Thyroid Cancer

PURPOSE Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I. PATIENTS AND METHODS We conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety. RESULTS The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients. CONCLUSION Cabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial

BACKGROUND Patients with radioactive iodine ((131)I)-refractory locally advanced or metastatic differentiated thyroid cancer have a poor prognosis because of the absence of effective treatment options. In this study, we assessed the efficacy and safety of orally administered sorafenib in the treatment of patients with this type of cancer. METHODS In this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial (DECISION), we investigated sorafenib (400 mg orally twice daily) in patients with radioactive iodine-refractory locally advanced or metastatic differentiated thyroid cancer that had progressed within the past 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centres in 18 countries. To be eligible for inclusion, participants had to have at least one measurable lesion by CT or MRI according to Response Evaluation Criteria In Solid Tumors (RECIST); Eastern Cooperative Oncology Group performance status 0-2; adequate bone marrow, liver, and renal function; and serum thyroid-stimulating hormone concentration lower than 0·5 mIU/L. An interactive voice response system was used to randomly allocate participants in a 1:1 ratio to either sorafenib or matching placebo. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival, assessed every 8 weeks by central independent review. Analysis was by intention to treat. Patients in the placebo group could cross over to open-label sorafenib upon disease progression. Archival tumour tissue was examined for BRAF and RAS mutations, and serum thyroglobulin was measured at baseline and at each visit. This study is registered with ClinicalTrials.gov, number NCT00984282, and with the EU Clinical Trials Register, number EudraCT 2009-012007-25. FINDINGS Patients were randomly allocated on a 1:1 basis to sorafenib or placebo. The intention-to-treat population comprised 417 patients (207 in the sorafenib group and 210 in the placebo group) and the safety population was 416 patients (207 in the sorafenib group and 209 in the placebo group). Median progression-free survival was significantly longer in the sorafenib group (10·8 months) than in the placebo group (5·8 months; hazard ratio [HR] 0·59, 95% CI 0·45-0·76; p<0·0001). Progression-free survival improved in all prespecified clinical and genetic biomarker subgroups, irrespective of mutation status. Adverse events occurred in 204 of 207 (98·6%) patients receiving sorafenib during the double-blind period and in 183 of 209 (87·6%) patients receiving placebo. Most adverse events were grade 1 or 2. The most frequent treatment-emergent adverse events in the sorafenib group were hand-foot skin reaction (76·3%), diarrhoea (68·6%), alopecia (67·1%), and rash or desquamation (50·2%). INTERPRETATION Sorafenib significantly improved progression-free survival compared with placebo in patients with progressive radioactive iodine-refractory differentiated thyroid cancer. Adverse events were consistent with the known safety profile of sorafenib. These results suggest that sorafenib is a new treatment option for patients with progressive radioactive iodine-refractory differentiated thyroid cancer. FUNDING Bayer HealthCare Pharmaceuticals and Onyx Pharmaceuticals (an Amgen subsidiary).

Association Between BRAF V600E Mutation and Mortality in Patients With Papillary Thyroid Cancer

IMPORTANCE BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. OBJECTIVE To investigate the relationship between BRAF V600E mutation and PTC-related mortality. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of 1849 patients (1411 women and 438 men) with a median age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. MAIN OUTCOMES AND MEASURES Patient deaths specifically caused by PTC. RESULTS Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) (P < .001) in BRAF V600E-positive vs mutation-negative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]). CONCLUSIONS AND RELEVANCE In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.

Combination chemotherapy in advanced adrenocortical carcinoma

BACKGROUND Adrenocortical carcinoma is a rare cancer that has a poor response to cytotoxic treatment. METHODS We randomly assigned 304 patients with advanced adrenocortical carcinoma to receive mitotane plus either a combination of etoposide (100 mg per square meter of body-surface area on days 2 to 4), doxorubicin (40 mg per square meter on day 1), and cisplatin (40 mg per square meter on days 3 and 4) (EDP) every 4 weeks or streptozocin (streptozotocin) (1 g on days 1 to 5 in cycle 1; 2 g on day 1 in subsequent cycles) every 3 weeks. Patients with disease progression received the alternative regimen as second-line therapy. The primary end point was overall survival. RESULTS For first-line therapy, patients in the EDP-mitotane group had a significantly higher response rate than those in the streptozocin-mitotane group (23.2% vs. 9.2%, P<0.001) and longer median progression-free survival (5.0 months vs. 2.1 months; hazard ratio, 0.55; 95% confidence interval [CI], 0.43 to 0.69; P<0.001); there was no significant between-group difference in overall survival (14.8 months and 12.0 months, respectively; hazard ratio, 0.79; 95% CI, 0.61 to 1.02; P=0.07). Among the 185 patients who received the alternative regimen as second-line therapy, the median duration of progression-free survival was 5.6 months in the EDP-mitotane group and 2.2 months in the streptozocin-mitotane group. Patients who did not receive the alternative second-line therapy had better overall survival with first-line EDP plus mitotane (17.1 month) than with streptozocin plus mitotane (4.7 months). Rates of serious adverse events did not differ significantly between treatments. CONCLUSIONS Rates of response and progression-free survival were significantly better with EDP plus mitotane than with streptozocin plus mitotane as first-line therapy, with similar rates of toxic events, although there was no significant difference in overall survival. (Funded by the Swedish Research Council and others; FIRM-ACT ClinicalTrials.gov number, NCT00094497.).

Phase II Study of Safety and Efficacy of Motesanib in Patients With Progressive or Symptomatic, Advanced or Metastatic Medullary Thyroid Cancer

PURPOSE This phase II study investigated the efficacy and tolerability of motesanib, an investigational, highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit in advanced medullary thyroid cancer (MTC). PATIENTS AND METHODS Patients with locally advanced or metastatic, progressive or symptomatic MTC received motesanib 125 mg/d orally for up to 48 weeks or until unacceptable toxicity or disease progression. The primary end point was objective response by independent review. Other end points included duration of response, progression-free survival, safety, pharmacokinetics, and changes in tumor markers. RESULTS Of 91 enrolled patients who received motesanib, two (2%) achieved objective response (95% CI, 0.3% to 7.7%); their duration of response was 32 weeks (censored) and 21 weeks (disease progressed). Eighty-one percent of patients had stable disease (48% had durable stable disease > or = 24 weeks), 8% had disease progression as best response, and 9% were not evaluated; 76% experienced a decrease from baseline in target lesion measurement. Median progression-free survival was 48 weeks (95% CI, 43 to 56 weeks). Among patients with tumor marker analysis, 69 (83%) of 83 and 63 (75%) of 84 had decreased serum calcitonin and carcinoembryonic antigen during treatment, respectively, compared with baseline. The most common treatment-related adverse events were diarrhea (41%), fatigue (41%), hypothyroidism (29%), hypertension (27%), and anorexia (27%). In pharmacokinetic analyses, motesanib trough concentrations were lower compared with differentiated thyroid cancer patients from the same study. CONCLUSION Although the objective response rate was low, a significant proportion of MTC patients (81%) achieved stable disease while receiving motesanib.

Polymorphic mature microRNAs from passenger strand of pre-miR-146a contribute to thyroid cancer

Prior work has shown that heterozygosity G/C of single nucleotide polymorphism (SNP rs2910164) within the precursor of microRNA-146a predisposes to PTC (odds ratio = 1.62, P = 0.000007) although the mechanism was unclear. Here, we show that GC heterozygotes differ from both GG and CC homozygotes by producing 3 mature microRNAs: 1 from the leading strand (miR-146a), and 2 from the passenger strand (miR-146a*G and miR-146a*C), each with its distinct set of target genes. TaqMan analysis of paired tumor/normal samples revealed 1.5- to 2.6-fold overexpression of polymorphic miR-146a* in 7 of 8 tumors compared with the unaffected part of the same gland. The microarray data showed that widely different transcriptomes occurred in the tumors and in unaffected parts of the thyroid from GC and GG patients. The modulated genes are mainly involved in regulation of apoptosis leading to exaggerated DNA-damage response in heterozygotes potentially explaining the predisposition to cancer. We propose that contrary to previously held views transcripts from the passenger strand of miRs can profoundly affect the downstream effects. Heterozygosity for polymorphisms within the premiR sequence can cause epistasis through the production of additional mature miRs. We propose that mature miRs from the passenger strand may regulate many genetic processes.

Gene Expression Profile of Papillary Thyroid Cancer: Sources of Variability and Diagnostic Implications

The study looked for an optimal set of genes differentiating between papillary thyroid cancer (PTC) and normal thyroid tissue and assessed the sources of variability in gene expression profiles. The analysis was done by oligonucleotide microarrays (GeneChip HG-U133A) in 50 tissue samples taken intraoperatively from 33 patients (23 PTC patients and 10 patients with other thyroid disease). In the initial group of 16 PTC and 16 normal samples, we assessed the sources of variability in the gene expression profile by singular value decomposition which specified three major patterns of variability. The first and the most distinct mode grouped transcripts differentiating between tumor and normal tissues. Two consecutive modes contained a large proportion of immunity-related genes. To generate a multigene classifier for tumor-normal difference, we used support vector machines-based technique (recursive feature replacement). It included the following 19 genes: DPP4, GJB3, ST14, SERPINA1, LRP4, MET, EVA1, SPUVE, LGALS3, HBB, MKRN2, MRC2, IGSF1, KIAA0830, RXRG, P4HA2, CDH3, IL13RA1, and MTMR4, and correctly discriminated 17 of 18 additional PTC/normal thyroid samples and all 16 samples published in a previous microarray study. Selected novel genes (LRP4, EVA1, TMPRSS4, QPCT, and SLC34A2) were confirmed by Q-PCR. Our results prove that the gene expression signal of PTC is easily detectable even when cancer cells do not prevail over tumor stroma. We indicate and separate the confounding variability related to the immune response. Finally, we propose a potent molecular classifier able to discriminate between PTC and nonmalignant thyroid in more than 90% of investigated samples.

Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer

PURPOSE To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). PATIENTS AND METHODS This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). RESULTS The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation-positive and 11.6% (125 of 1,082) of BRAF V600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus -negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus -negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. CONCLUSION This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

B-Raf(V600E) and thrombospondin-1 promote thyroid cancer progression.

Although B-RafV600E is the most common somatic mutation in papillary thyroid carcinoma (PTC), how it induces tumor aggressiveness is not fully understood. Using gene set enrichment analysis and in vitro and in vivo functional studies, we identified and validated a B-RafV600E gene set signature associated with tumor progression in PTCs. An independent cohort of B-RafV600E-positive PTCs showed significantly higher expression levels of many extracellular matrix genes compared with controls. We performed extensive in vitro and in vivo validations on thrombospondin-1 (TSP-1), because it has been previously shown to be important in the regulation of tumor angiogenesis and metastasis and is present in abundance in tumor stroma. Knockdown of B-RafV600E resulted in TSP-1 down-regulation and a reduction of adhesion and migration/invasion of human thyroid cancer cells. Knockdown of TSP-1 resulted in a similar phenotype. B-RafV600E cells in which either B-RafV600E or TSP-1 were knocked down were implanted orthotopically into the thyroids of immunocompromised mice, resulting in significant reduction in tumor size and fewer pulmonary metastases from the primary carcinoma as compared with the control cells. Treatment of orthotopic thyroid tumors, initiated 1 week after tumor cell implantation with PLX4720, an orally available selective inhibitor of B-RafV600E, caused a significant tumor growth delay and decreased distant metastases, without evidence of toxicity. In conclusion, B-RafV600E plays an important role in PTC progression through genes (i.e., TSP-1) important in tumor invasion and metastasis. Testing of a patients thyroid cancer for B-RafV600E will yield important information about potential tumor aggressiveness and also allow for future use of targeted therapies with selective B-RafV600E inhibitors, such as PLX4720.