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Originally published as JCO Early Release 10.1200/JCO.2008.17.3682 on June 9 2008 © 2008 American Society of Clinical Oncology.
Refractory Thyroid Cancer: A Paradigm Shift in Treatment Is Not Far Off
Memorial Sloan-Kettering Cancer Center, New York, NY Historically, thyroid cancers have received relatively little attention from the medical oncology community. As recently as the 2005 Annual Meeting of the American Society of Clinical Oncology, when the word "thyroid" is searched, only five abstracts can be identified in the meeting's abstract database. None reported the use of novel therapeutics. As such, the inclusion of not one but two clinical trial reports focusing on thyroid cancer in this issue of the Journal of Clinical Oncology1,2 is noteworthy, even without further elaboration. Why has there been limited interest in developmental therapeutics for thyroid malignancies in the past? Much has to do with the natural history of thyroid carcinomas, traditional management paradigms, and the limitations of available chemotherapies. More than 90% of thyroid malignancies are derived from the thyroid follicular cell. The vast majority are differentiated tumors, with the papillary subtype predominating (approximately 80%); most of the remainder are follicular carcinomas and related variants. For these differentiated tumors, standard treatment with primary surgery and thyroid-stimulating hormone (TSH) suppression with supraphysiologic thyroid hormone administration often suffices. Depending on disease stage, patient age, and a variety of histopathologic factors, ablation of the thyroid remnant with radioactive iodine 131 (RAI) is added.3 This collective strategy is associated with an overall survival rate of approximately 90% at 20 years.4 The prognosis remains relatively favorable even among patients who experience relapse, as the annual mortality rate is far less than the annual rate of recurrence.5 Indeed, many patients with recurrent disease, even when incurable, will have an indolent course over months to years, with few or no symptoms without active anticancer therapy beyond TSH suppression. At relapse, further surgery, repeat RAI, external-beam radiation, or even observation with continued TSH suppression have all been commonly prioritized before chemotherapy. Drugs such as doxorubicin (the only United States Food and Drug Administration–approved agent), cisplatin, or bleomycin—administered as single agents or as part of some combination regimen—benefit a minority of patients, and related toxicities may be significant.6-8 With few clinical trials and disappointing efficacy from available chemotherapy drugs, patients have frequently not been referred to a medical oncologist until quite late in their disease course, if at all. Consequently, most medical oncologists have limited experience in the management of thyroid malignancies. Referring a patient with thyroid cancer to a medical oncologist early might risk the premature initiation of ineffective and potentially toxic chemotherapy when observation might have arguably been the better course. Instead, it has been our experience that when established therapeutic approaches fail, alternative systemic strategies have been used, even though their benefit is unclear or controversial, in part because they are better tolerated than traditional chemotherapies. These interventions have been typically orchestrated by specialists in endocrinology or nuclear medicine. Examples include empiric therapeutic dosing with RAI in the absence of significant uptake on dosimetry and attempts to enhance the efficacy of RAI in refractory tumors by inhibiting the release of iodine through the use of lithium3,9 or a putative redifferentiating strategy by pretreatment with isotretinoin.10 Therapy with somatostatin analogs has also been used in patients with tumors that demonstrate significant uptake on octreotide scanning.11,12 Although the prognosis for thyroid cancer is in general quite favorable when standard management paradigms are applied, some patients do much less well. RAI-refractory, recurrent, or metastatic disease is prognostically more worrisome, and death from thyroid cancer within 3 years under these circumstances is common.13,14 Anaplastic thyroid cancer, although rare, is typically unresectable at presentation, highly resistant to therapy, uniformly RAI resistant, and associated with a median survival of less than 1 year.15 Medullary thyroid cancer, both hereditary and sporadic varieties, are derived from the parafollicular C cells. RAI plays no role in the management of medullary cancers, which have a worse prognosis than the much more common papillary tumors.16 Therefore, the favorable prognosis for most patients with thyroid cancer should not make us complacent. Better drugs are clearly needed to treat refractory thyroid cancers, and their development and evaluation certainly deserve more attention. In editorials, conclusions are frequently safe and noncontroversial. But so-called better drugs can be years away in development, and the time until standards of care are affected will be even longer. Nonetheless, many thyroid oncologists, including us, are optimistic about the outlook for identifying new agents that will potentially benefit patients with refractory thyroid cancers in the immediate future. A central reason is that our understanding of the molecular biology of thyroid cancer has reached sufficient maturity at a time when new drugs are available to inhibit kinases and pathways of interest that are disrupted in this disease. Furthermore, there is growing appreciation among clinical investigators, the Cancer Therapy Evaluation Program of the National Cancer Institute, and the pharmaceutical industry, among others, that thyroid cancers not only deserve more attention in drug development, but also represent an opportunity for proof-of-principle studies evaluating new targeted therapies. For example, papillary thyroid cancers are associated with mutually exclusive mutations of genes encoding effectors in the mitogen-activated protein (MAP) kinase pathway: the tyrosine kinase receptors RET and NTRK, all three RAS genes, and BRAF.17,18 As such, constitutive MAP kinase activation is considered by many investigators to be a key event in papillary thyroid cancer development and progression, making blockade of this pathway a rational therapeutic approach. This concept is further buttressed by observations that RAI-refractory papillary thyroid cancers may be more likely to harbor BRAF mutations,19 and the growth of thyroid cancer cell lines with BRAF mutations is inhibited by Raf kinase inhibitors in vitro.20,21 Similarly, effective inhibitors of vascular endothelial growth factor receptor signaling are available, with well-established efficacy in other solid tumors. Angiogenesis inhibition also has a strong rationale in thyroid cancers, because they are highly vascularized and overexpress the ligand for vascular endothelial growth factor receptor.22-24 Given this background, the results of two phase II studies reported in this issue of the Journal of Clinical Oncology evaluating different targeted therapies in patients with advanced thyroid cancer have special significance. The multicenter trial from Cohen et al1 used axitinib (AG-013736), an orally administered angiogenesis inhibitor. The study from Gupta-Abramson et al2 at the University of Pennsylvania used the oral agent sorafenib (Nexavar; Bayer Healthcare, West Haven, CT; Onyx Pharmaceuticals, Richmond, CA), which inhibits not only angiogenesis, but also RAF and RET kinases, which are important targets in thyroid cancers. Although these are different agents, the two studies had many similarities. Eligible patients in both studies included a full spectrum of thyroid cancer histologic subtypes—from differentiated to anaplastic, with both medullary and nonmedullary cancers allowed—but papillary and follicular histologies predominated. All patients were judged by the involved investigators to be resistant or refractory to RAI. Although no complete responses were reported, a significant minority of patients had a major response to therapy by Response Evaluation Criteria in Solid Tumors (RECIST): 30% and 23%, respectively, for axitinib and sorafenib. Stable disease for no less than 3 months was also common, reported in 38% and 53%, respectively. The response waterfall plots indicated that most of these patients with stable disease had some objective disease regression, albeit of insufficient magnitude to fulfill RECIST criterion for a partial response, further suggesting that the reports of stable disease reflected at least in part therapeutic effect rather than simply slow growth of disease. Median progression-free survival rates were similar in both studies at approximately 18 months. The oral route of administration and noncytotoxic, targeted mechanism of action did not mean a lack of side effects. Grade 3 or 4 toxicities with both agents were not rare: 32% of patients treated with axitinib had at least one treatment-related adverse that was grade 3 or worse, and 47% of patients treated with sorafenib required dose reductions to control toxicities. Discontinuation of treatment occurred in 13% and 20% of patients treated with axitinib or sorafenib, respectively, because of toxicity. These reports are welcome news, but there is a need for confirmation of the reported activity of these agents, as well as more information regarding their tolerability and optimal dosing, particularly among patients receiving therapy for more prolonged periods. Given the observed efficacy of these agents, the median duration of therapy in these studies was approximately 5 to 6 months, so many patients continued on therapy well beyond this duration of time. These two articles represent the first wave of such reports. Abstracts presented over the last year suggest that the publication of clinical trials evaluating other oral targeted therapies of interest in refractory thyroid cancers will be forthcoming.25-28 Easily administered, active, and tolerable agents are clinically relevant when they offer disease regression or prolonged disease stabilization in a setting where existing options require parenteral administration and are relatively ineffective. Apart from their use in patients with aggressive, rapidly progressive disease, one can envision a scenario in which active agents with favorable side effect profiles also would be attractive options for selected patients with more indolent, RAI-refractory tumors, who are now simply observed. In this latter population of patients, however, it should be emphasized that along with efficacy, drug tolerability becomes a particularly important consideration, because many of these patients will be relatively asymptomatic, and rapid disease progression is not imminent. Additional insights are gained when the two reported studies are reviewed from a methodologic perspective. These insights not only allow one to better interpret their results, but also to highlight issues that deserve careful consideration as new studies are planned. Selected points deserve emphasis. Because many patients will have indolent disease even when not receiving therapy, the criteria for patient selection need to be clearly defined, particularly when stable disease and freedom from progression are end points of interest. Eligibility criteria such as "disease progression in the year prior to initiation of treatment," "iodine-refractory metastatic thyroid cancer," "disease not controlled by RAI," or "disease for which RAI is not an appropriate therapy" are certainly all reasonable. Optimally, however, the criteria used for these judgments need to be more precisely stated to facilitate reproducibility among different observers and to allow interpretation and comparison of results. For example, how was disease progression before treatment documented: by RECIST criteria? Increasing thyroglobulin levels? Progression of disease over 3, 6, or 12 months? Obviously, if progression is only based, for example, on an upward trend in thyroglobulin levels that required 12 months for documentation, a report of stable disease by RECIST criteria for 6 months becomes less meaningful. The importance of care in documentation of disease progression before treatment is well illustrated in a study of motesanib in patients with medullary thyroid cancer. The durable stable disease rate among all study participants was 47%, but this rate decreased to 21% among those patients with documented pretreatment disease progression.28 Another example involves the role of positron emission tomography (PET) in eligibility assessment. Because uptake by thyroid cancer metastatic lesions of fluorodeoxyglucose on PET (FDG-PET positive) is inversely associated with RAI uptake and directly associated with more rapid progression and increased mortality,29 the requirement for FDG-PET positivity is a potentially useful eligibility criterion in terms of identifying a population that has RAI-refractory disease. However, the standardized uptake values and number of metastatic lesions that are FDG-positive are important to consider and specify, because prognosis may vary markedly with each of these variables.29 Similarly, the histologic variants of thyroid cancer differ significantly in their biologic behavior (eg, papillary v anaplastic) and in the specific types and frequencies of the oncogenic mutations they harbor (eg, RET/PTC1 is associated with classical papillary thyroid cancer—progression to anaplastic thyroid cancer is rare; BRAF mutation is associated with the tall cell variant of papillary thyroid cancer and may progress to poorly differentiated and even anaplastic thyroid cancer). There is growing appreciation of a phenotypic/genotypic correlation in thyroid cancers. Hence clinical trials with kinase inhibitors that include all subtypes without distinctions can easily overlook important findings. For example, Hürthle cell carcinomas do not have mutations of genes encoding MAP kinase effectors, so that Raf inhibition makes less sense as a therapeutic strategy. TSH suppression is an important adjunct in the management of patients with differentiated but RAI-refractory tumors. Hypothyroidism has been associated with the use of tyrosine kinase inhibitors30,31; in the sorafenib study, one third of patients were referred for adjustments in their thyroid hormone replacement therapy because of an increase in their TSH levels. Most of these patients had been on a stable dose of thyroid hormone replacement before the start of sorafenib. Therefore, monitoring of TSH levels and adjusting thyroid hormone replacement therapy as indicated are an important cointervention when administering similar kinase inhibitors. When a drug with the capability of multitarget inhibition is evaluated, one of the challenges is determining which part of the drug's spectrum of activity is most responsible for the observed anticancer effect. For example, in the sorafenib study, it is not clear whether the beneficial effects of sorafenib seen in this trial are due to its antiangiogenic properties, to which these tumors seem to be particularly vulnerable, its ability to block Raf kinase activity, or its impact on some other target. Although sorafenib inhibits growth of cancer cell lines harboring oncogenic BRAF mutations in vitro, it does so with a wide range of concentrations that inhibit by 50%32 and has proven ineffective as a single agent in clinical trials for melanomas, a tumor where this target is also of great interest.33 Notably, response to the combination of carboplatin, paclitaxel, and sorafenib was not correlated with BRAF mutational status in patients with melanoma.34 Accordingly, the drug's properties as a Raf antagonist in human cancers have been questioned.35 Highly selective MEK antagonists preferentially inhibit growth of cancer cells of different lineages with BRAF mutations,36 including thyroid cancers,37-39 and may ultimately be a better way to address this question. One way to illuminate this issue is to include genotype data on the cancers treated and relevant pharmacodynamic studies, as well as sequential biopsies in selected patients with accessible tumors to assess in vivo alterations of biologic pathways. In both of these studies, decrease in thyroglobulin levels occurred in the majority of patients for whom data on this marker were available, but the correlation with the extent of objective tumor regression seemed imperfect. A recent evaluation of gefitinib in thyroid cancer noted dramatic regressions in thyroglobulin levels, yet the best objective response observed was stable disease.27 Accordingly, care should be taken when interpreting changes in tumor marker levels as a measure of response, clinical benefit, or antitumor effect. Less than 10% of patients entered onto these two single-arm studies had the worst prognostic, poorly differentiated/anaplastic subtypes. Given the previously noted potential for indolent growth of RAI-refractory, differentiated thyroid cancers, the reported encouraging rates of stable disease, so-called clinical benefit (partial response plus stable disease), and progression-free/overall survivals must be evaluated cautiously. Although careful attention to the above-discussed design features will increase the value of phase II assessments, a randomized comparison of each agent to a standard approach would be the preferred mechanism to provide greater clarity regarding their potential efficacy benefits. An obvious question is what to use for the control arm of such a study. As the only United States Food and Drug Administration–approved agent, doxorubicin would seem to be a logical and defensible choice. However, legacy drugs like doxorubicin had activity documented in a different era of clinical trial methodology and reporting and would likely not pass the scrutiny of United States Food and Drug Administration review for a thyroid-specific indication by current standards. Practice guidelines from the National Comprehensive Cancer Network indicate that "cytotoxic therapy has shown to have minimal efficacy" in RAI-refractory thyroid cancer, which is certainly consistent with our experience, and endorse clinical trial participation for patients with non-RAI avid tumors.40 Another question is what to select as the primary end point for such comparative assessments of efficacy. Overall survival is the gold standard answer. For an otherwise unselected population of patients with RAI-refractory thyroid cancer, however, a large sample size and long follow-up will likely be necessary—both are challenges to trial feasibility. Considering these circumstances, a placebo control (with early stopping rules) remains an appropriate option at the current time for phase III assessments of new therapeutics in patients with RAI-refractory, differentiated thyroid carcinomas. In addition, freedom from progression or progression-free survival, rather than overall survival, may be better choices as primary efficacy end points for phase III trials in this population, given the potential for indolent disease behavior. These end points also facilitate the inclusion of a crossover option at the time of progression for patients randomly assigned to the placebo arm, a strategy that should enhance patient acceptance of the planned random assignment. Overall survival would be a more attractive and feasible primary end point if trial participation was limited by the use of clinical, pathologic, or molecular factors to those individuals with rapidly progressive disease. As we move forward with the evaluation of new drugs for thyroid cancer, a strong case can be made for designing trials in which participants are selected based on the presence of specific genetic alterations in their cancers that drug monotherapy or combinations would potentially target. Although this strategy risks slowing accrual rates, fewer patients may be necessary to answer the specific efficacy question being asked, aiding overall trial efficiency. The evaluation of subsequent salvage drug therapies will also be facilitated by the availability of information regarding tumor genotype, and the type of, and response to, prior therapy. In conclusion, it is particularly gratifying that years of research in tumor biology and drug development have coalesced. Translation of these research advances into therapeutic benefits for patients with refractory thyroid cancer, and a related paradigm shift in the treatment of these tumors, appear not far off. Support of well-designed clinical trials will be critical to realizing these benefits in a timely way. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: David G. Pfister, AstraZeneca, Exelixis Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: David G. Pfister, James A. Fagin Financial support: David G. Pfister Administrative support: David G. Pfister Provision of study materials or patients: David G. Pfister, James A. Fagin Collection and assembly of data: David G. Pfister, James A. Fagin Data analysis and interpretation: David G. Pfister, James A. Fagin Manuscript writing: David G. Pfister, James A. Fagin Final approval of manuscript: David G. Pfister, James A. Fagin NOTES published online ahead of print at www.jco.org on June 9, 2008 REFERENCES
1. Cohen EEW, Rosen LS, Vokes EE, et al: Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: Results from a phase II study. J Clin Oncol doi:10.1200/JCO.2007.15.9566 [epub ahead of print on June 9, 2008] 2. Gupta-Abramson V, Troxel AB, Nellore A, et al: Phase II trial of sorafenib in advanced thyroid cancer. J Clin Oncol doi:10.1200/JCO.2008.16.3279 [epub ahead of print on June 9, 2008] 3. Cooper DS, Doherty GM, Haugen BR, et al: Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 16:109-142, 2006[Medline] 4. Brenner H: Long-term survival rates of cancer patients achieved by the end of the 20th century: A period analysis. Lancet 360:1131-1135, 2002[CrossRef][Medline] 5. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97:418-428, 1994[CrossRef][Medline] 6. Haugen BR: Management of the patient with progressive radioiodine non-responsive disease. Semin Surg Oncol 16:34-41, 1999[Medline] 7. Shimaoka K, Schoenfeld D, DeWys WD, et al: A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 56:2155-2160, 1985[CrossRef][Medline] 8. De Besi P, Busnardo B, Toso S, et al: Combined chemotherapy with bleomycin, adriamycin, and platinum in advanced thyroid cancer. J Endocrinol Invest 14:475-480, 1991[Medline] 9. Koong SS, Reynolds JC, Movius EG, et al: Lithium as a potential adjuvant to 131I therapy of metastatic, well differentiated thyroid carcinoma. J Clin Endocrinol Metab 84:912-916, 1999 10. Short SC, Suovuori A, Cook G, et al: A phase II study using retinoids as redifferentiation agents to increase iodine uptake in metastatic thyroid cancer. Clin Oncol (R Coll Radiol) 16:569-574, 2004[Medline] 11. Robbins RJ, Hill RH, Wang W, et al: Inhibition of metabolic activity in papillary thyroid carcinoma by a somatostatin analogue. Thyroid 10:177-183, 2000[Medline] 12. Kohlfuerst S, Igerc I, Gallowitsch HJ, et al: Is there a role for sandostatin treatment in patients with progressive thyroid cancer and iodine-negative but somatostatin-receptor-positive metastases? Thyroid 16:1113-1119, 2006[CrossRef][Medline] 13. Pittas AG, Adler M, Fazzari M, et al: Bone metastases from thyroid carcinoma: Clinical characteristics and prognostic variables in one hundred forty-six patients. Thyroid 10:261-268, 2000[Medline] 14. Wang W, Larson SM, Fazzari M, et al: Prognostic value of [18F]fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer.J Clin Endocrinol Metab 85:1107-1113, 2000 15. Lim S, Lee NY, Fury MG, et al: Doxorubicin and concurrent radiotherapy for anaplastic thyroid cancer: We need to do better. J Clin Oncol 25:669s, 2007 (abstr 16506)[CrossRef] 16. Cupisti K, Wolf A, Raffel A, et al: Long-term biochemical and clinical follow-up in medullary thyroid carcinoma: A single institution's experience over 20 years. Ann Surg 246:815-821, 2007[Medline] 17. Kimura ET, Nikiforova MN, Zhu Z, et al: High prevalence of BRAF mutations in thyroid cancer: Genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 63:1454-1457, 2003 18. Soares P, Trovisco V, Rocha AS, et al: BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC. Oncogene 22:4578-4580, 2003[CrossRef][Medline] 19. Xing M, Westra WH, Tufano RP, et al: BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 90:6373-6379, 2005 20. Ouyang B, Knauf JA, Smith EP, et al: Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo. Clin Cancer Res 12:1785-1793, 2006 21. Salvatore G, De FV, Salerno P, et al: BRAF is a therapeutic target in aggressive thyroid carcinoma. Clin Cancer Res 12:1623-1629, 2006 22. Fenton C, Patel A, Dinauer C, et al: The expression of vascular endothelial growth factor and the type I vascular endothelial growth factor receptor correlates with the size of papillary thyroid cancer in children and young adults. Thyroid 10:349-357, 2000[Medline] 23. Lennard CM, Patel A, Wilson J, et al: Intensity of vacular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer. Surgery 129:552-558, 2001[CrossRef][Medline] 24. Bauer AJ, Patel A, Terrell R, et al: Systemic administration of vascular endothelial growth factor monoclonal antibody reduces the growth of papillary thyroid carcinoma in a nude mouse model. Ann Clin Lab Sci 33:192-199, 2003 25. Sherman SI, Schlumberger MJ, Droz J, et al: Initial results from a phase II trial of motesanib diphosphate (Amgen 706) in patients with differentiated thyroid cancer (DTC). J Clin Oncol 25:303s, 2007 (abstr 6017) 26. Wells SA, Gosnell JE, Gagel RF, et al: Vandetanib in metastatic hereditary medullary thyroid cancer: Follow-up results of an open-label phase II trial. J Clin Oncol 25:303s, 2007 (abstr 6018) 27. Pennell NA, Daniels GH, Haddad RI, et al: A phase II study of gefitinib in patients with advanced thyroid cancer. J Clin Oncol 25:304s, 2007 (abstr 6020) 28. Schlumberger M, Elisei R, Sherman SI, et al: Phase 2 trial of motesanib diphosphate (AMG 706) in patients with medullary thyroid cancer (MTC). Presented at 89th Annual Meeting of the Endocrine Society, Toronto, Ontario, Canada; June 2-5, 2007 29. Robbins RJ, Wan Q, Grewal RK, et al: Real-time prognosis for metastatic thyroid carcinoma based on 2-[18F]fluoro-2-deoxy-D-glucose-positron emission tomography scanning. J Clin Endocrinol Metab 91:498-505, 2006 30. Rini BI, Tamaskar I, Shaheen P, et al: Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 99:81-83, 2007 31. de Groot JW, Zonnenberg BA, Plukker JT, et al: Imatinib induces hypothyroidism in patients receiving levothyroxine. Clin Pharmacol Ther 78:433-438, 2005[CrossRef][Medline] 32. Sharma A, Trivedi NR, Zimmerman MA, et al: Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors. Cancer Res 65:2412-2421, 2005 33. Eisen T, Ahmad T, Flaherty KT, et al: Sorafenib in advanced melanoma: A phase II randomized discontinuation trial analysis. Br J Cancer 95:581-586, 2006[CrossRef][Medline] 34. Flaherty KT: Chemotherapy and targeted therapy combinations in advanced melanoma. Clin Cancer Res 12:2366s-2370s, 2006 35. Chiloeches A, Marais R: Is BRAF the Achilles’ Heel of thyroid cancer? Clin Cancer Res 12:1661-1664, 2006 36. Solit DB, Garraway LA, Pratilas CA, et al: BRAF mutation predicts sensitivity to MEK inhibition. Nature 439:358-362, 2006[CrossRef][Medline] 37. Leboeuf R, Baumgartner JE, Benezra M, et al: BRAFV600E mutation is associated with preferential sensitivity to MEK inhibition in thyroid cancer cell lines. J Clin Endocrinol Metab [epub ahead of print on April 1, 2008] 38. Ball DW, Jin N, Rosen DM, et al: Selective growth inhibition in BRAF mutant thyroid cancer by the mitogen-activated protein kinase kinase 39. Liu D, Liu Z, Jiang D, et al: Inhibitory effects of the mitogen-activated protein kinase kinase inhibitor CI-1040 on the proliferation and tumor growth of thyroid cancer cells with BRAF or RAS mutations. J Clin Endocrinol Metab 92:4686-4695, 2007 40. National Comprehensive Cancer Network: NCCN Practice Guidelines in Oncology, version 2.2007: Thyroid Cancer. www.nccn.org Related Articles
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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inhibitor AZD6244. J Clin Endocrinol Metab 92:4712-4718, 2007
