Evolving therapeutic strategies for patients with differentiated thyroid cancer

Dilemma: How to manage incidental, low-risk differentiated thyroid cancers

Over the last 30 years, there has been a sharp rise in the incidence of thyroid cancer, with a large proportion of newly diagnosed cases representing incidental, small, papillary thyroid cancers (PTCs).

Mabel Ryder, M.D., of the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic's campus in Rochester, Minnesota, says: "The vast majority of these PTCs are indolent with excellent 20-year survival rates of over 95 percent. It is now becoming clear that treating such patients with total thyroidectomy, radioactive iodine (RAI) therapy and thyroid-stimulating hormone (TSH) suppression may induce greater harm than benefit in patients.

"The newly revised American Thyroid Association Guidelines for the Management of Thyroid Nodules and Differentiated Thyroid Cancer (expected to be published in late 2014) reflect the evolving needs in this area by supporting lobectomy for low-risk PTCs and a risk-adapted approach for postoperative management that encourages limited use of RAI, shortened and less profound TSH suppression therapy, and optimized surveillance testing for patients with excellent prognoses."

Moreover, the guidelines propose less aggressive approaches to biopsy and therapy of solitary thyroid nodules less than 1 centimeter and PTCs.

Advanced-stage differentiated thyroid cancers

In contrast, 10 to 20 percent of patients present with or develop advanced, metastatic RAI-refractory (RAIR) thyroid cancer. Keith C. Bible, M.D., Ph.D., of the Division of Medical Oncology, notes that: "Data from the Surveillance, Epidemiology, and End Results (SEER) database estimates that 1,800 people die of thyroid cancer annually, with the majority of deaths from patients with RAIR disease. Moreover, death rates from thyroid cancer, while overall low, have appeared to increase over the past 30 years, indicating a strong need for more effective therapies for high-risk patients."

FDA-approved sorafenib for advanced differentiated thyroid cancers

Current approaches in the treatment of advanced RAIR thyroid cancers involve drugs that target not only the cancer cell but also the tumor microenvironment. Dr. Bible notes: "Sorafenib, an orally bioavailable multikinase inhibitor that primarily targets vascular endothelial growth factor receptor (VEGFR), is the first FDA-approved tyrosine kinase inhibitor (TKI) for advanced RAIR thyroid cancer. In the phase III DECISION trial that led to Food and Drug Administration (FDA) approval, progression-free survival was 10.8 months vs. 5.8 for sorafenib- vs. placebo-treated patients, respectively.

"However, overall survival was no different between the groups, and sorafenib-treated patients had increased therapy-related toxicities and lower quality of life. A major challenge faced by endocrinologists and medical oncologists is thus now in determining when the optimal time is to initiate kinase inhibitor therapy in patients who are often asymptomatic from their disease."

Alternative therapeutic strategies for RAIR differentiated thyroid

Tyrosine kinase inhibitors in RAIR differentiated thyroid cancers

TKIs that target oncogenes or their downstream signaling pathways or both to reverse tumor progression or restore radioiodine sensitivity in RAIR disease have yielded promising, albeit mixed, results. Dr. Ryder explains: "Dabrafenib or vemurafenib, for example, inhibit mutant BRAF-V600E, a common oncogenic event in advanced PTCs, and have estimated partial response rates of approximately 30 percent, significantly lower than observed for BRAF-mutant metastatic melanoma, and also lower than response rates reported for several VEGFR-inhibitory kinase inhibitors.

"Published preclinical data suggests that thyroid cancer cells, unlike melanomas, have intrinsic resistance to the anti-tumor effects of BRAF-V600E inhibition that may be mediated by compensatory activation of additional, but potentially targetable kinases, such as HER2 or HER3."

A recent promising alternative strategy is to use a short-term inhibition of phospho-MEK to attempt to restore RAI uptake in RAIR disease. Dr. Bible notes: "In a small study published in The New England Journal of Medicine in 2013, some patients with advanced RAIR thyroid cancer treated with selumetinib for five weeks experienced restored RAI uptake and restored sensitivity to RAI therapy in RAS-, but not BRAF-, mutant thyroid cancers.

"This small but potentially paradigm-shifting study suggests that RAI therapy, in the context of mitogen-activated protein kinase (MAPK) pathway inhibition, may have therapeutic benefits in selected patients with advanced-stage disease. Moreover, short-term kinase inhibition therapy has the advantage of minimizing morbidity as well as the potential development of acquired resistance associated with chronic kinase inhibitor use. Efforts remain underway to enhance RAI sensitivity in BRAF-mutant PTCs, which account for disproportionately higher deaths from thyroid cancer."

Targeting stromal-derived TAMs

Allan B. Dietz, Ph.D., of the Division of Transfusion Medicine, says: "Targeting stromal cells, in particular tumor-associated macrophages (TAMs), in advanced thyroid cancers has been little-studied but yet represents a potentially promising emerging therapeutic strategy.

"Dr. Ryder demonstrated for the first time in a large number of human thyroid cancers that TAMs heavily infiltrate poorly differentiated thyroid cancers (PDTCs) and anaplastic thyroid cancers. Moreover, in PDTCs, increased TAMs correlated with increased invasion and decreased overall survival. Using preclinical models of BRAF-induced thyroid cancers, Dr. Ryder demonstrated that recruitment of TAMs in early- and advanced-stage thyroid cancers could be genetically as well as pharmacologically inhibited, and that this impairs PTC initiation as well as facilitates PTC regression."

Dr. Ryder comments: "My focus now is on characterizing the immune phenotype of patients with advanced thyroid cancers in order to better understand immune response in advanced-stage thyroid cancers. In addition, I am examining how TAMs may influence resistance to existing therapeutics, and whether combination strategies to target TAMs, as well as the tumor cells, may improve disease response rates."

Conclusion

The landscape of thyroid cancer management is rapidly evolving with a more minimalistic, individualized approach for low-risk patients, and more targeted and evidence-based therapeutic approaches for advanced-stage disease. Dr. Ryder concludes: "A multidisciplinary team approach involving endocrinologists, surgeons, radiologists and oncologists remains the key for the optimal care of patients across the spectrum of low-risk to advanced-stage disease."

For more information

Ho AL, et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. The New England Journal of Medicine. 2013;368:623.