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Congress Report: ENDO 2015

Congress Report: ENDO 2015

Thyroid disorders and their management received major coverage in this conference. Some of the most interesting presentations are summarized here, by Professor Ali S Alzahrani

Interim analysis of an RCT suggests early initiation of levothyroxine prevents overt hypothyroidism following RAI for Graves' disease

Summary of presentation by Spyridoula Maraka, Mayo Clinic, Rochester, MN, USA

Definite conclusions cannot be drawn, but interim findings of this ongoing study indicate no safety issues with low-dose L-thyroxine therapy early after RAI therapy for Graves’ disease

Radioactive iodine (RAI) is the most commonly used treatment for Graves’ disease. Its efficacy has been demonstrated and it has a good safety profile. Although highly effective for treatment of hyperthyroidism, most patients treated with RAI develop permanent hypothyroidism and need long-term L-thyroxine replacement therapy.

Hypothyroidism can occur any time from a few weeks to several months following RAI therapy, but usually develops within 6–12 weeks. The time taken depends on factors such as: severity of hyperthyroidism; size of goiter; underlying disease; and activity of administered RAI.

Patients usually receive follow-up appointments 6–8 weeks after RAI therapy. However, researchers from the Mayo Clinic (Rochester, MN, USA) noticed that most patients develop clinically significant post-RAI hypothyroidism before they are diagnosed and treated with L-thyroxine. To try to lessen the risk of developing such significant hypothyroidism, a double-blind, placebo-controlled trial was designed to evaluate the safety and efficacy of early initiation of L-thyroxine replacement therapy.

Patients with history of arrhythmias or significant heart or psychiatric disease were excluded. At the time of ENDO 2015, 17 patients had been enrolled and an interim analysis was presented.

Patients treated with RAI for Graves’ disease were randomly assigned to early L-thyroxine replacement therapy (11 patients) or placebo (six patients) at 4 weeks following RAI therapy. The initial dose was 25 μg daily, increasing to 50 μg daily after 2 weeks. Patients were evaluated at 8 weeks for hyper- and hypothyroidism, and completed a health-related quality of life (HRQoL) questionnaire.

Patient characteristics were similar (median age, 52.7 and 55.3 years in the L-thyroxine and placebo arms, respectively). About two-thirds of participants in each arm were females. Goiter size was ~30 g in both groups.

At 8 weeks following RAI therapy, the rate of hyperthyroidism was similar (18% for L-thyroxine; 23% for placebo). Hypothyroidism occurred in 54.5% of the L-thyroxine and 66.7% of the placebo arms. Thyroid symptom scores were similar but the HRQoL questionnaire showed more symptoms in the L-thyroxine-treated patients versus those on placebo.

 

SELECT trial exploratory analysis indicates lenvatinib-associated hypothyroidism did not affect treatment response in progressive differentiated thyroid cancer

Summary of presentation by Steven Sherman, MD, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Increased TSH levels during tyrosine kinase inhibitor therapy for thyroid cancer do not affect treatment outcome

Two tyrosine kinase inhibitors, sorafenib and lenvatinib, have been approved for refractory metastatic differentiated thyroid cancer. Thyroid hormone requirements frequently increase during therapy with these agents, and patients may develop clinically significant hypothyroidism if not carefully monitored and treated.

The SELECT trial1 is a phase 3, double-blind, placebo-controlled study that randomized patients with progressive differentiated thyroid cancer to lenvatinib or placebo. It showed significant improvement in progression-free survival (PFS) and overall response rates in the lenvatinib arm versus placebo.

In a follow-up exploratory study, researchers from MD Anderson Cancer Center, Texas, USA, questioned whether development of hypothyroidism during lenvatinib therapy may have affected response rate and therapeutic outcome.

Using worst post-baseline TSH level as the primary indicator of hypothyroidism, lenvatinib-associated hypothyroidism did not result in less response to lenvatinib or worse PFS. Thus, lenvatinib-associated hypothyroidism did not seem to affect response to therapy, but longer longitudinal follow-up is needed to confirm these findings.

Reference

1. Schlumberger M, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621–30.

 

New knowledge of mechanisms of resistance to tyrosine kinase inhibitors in BRAF-positive papillary thyroid cancer

Resistance to tyrosine kinase inhibitors in BRAF-positive thyroid cancer is partially mediated through upregulation of HER3; dual inhibition of MAPK pathway is more effective than a single inhibitor

An up-to-date presentation by James Fagin (MD, Memorial Sloan Kettering Cancer Center, New York, NY, USA) on mechanisms of resistance to tyrosine kinase inhibitors in thyroid cancer was presented. These are some of the salient points:

  • Based on recent data from the Cancer Gene Atlas Consortium, thyroid cancer in general has low mutation rates.
  • Analysis of ~500 cases of thyroid cancer using different next-generation sequencing platforms showed the usual mutations known in thyroid cancer, the most common being BRAFV600E, NRAS, HRAS, KRAS and known fusion oncoproteins such as RET/PTC and PAX8/PPARy rearrangements, but new genes were also identified. Based on these data, thyroid cancer can be classified as BRAF-like or RAS-like with relatively distinct gene expression, mRNA profile, and methylation and proteomic patterns.
  • BRAF-like tumours are characteristically associated with down regulation of many genes involved in iodine uptake and processing such as NIS and thyroid peroxidase.
  • The MAPK pathway is a principle pathway in the pathogenesis of thyroid cancer but the impact of genetic mutations on activation of MAPK kinase pathway varies: RTK and RAS mutations have moderate but BRAF mutations have very potent effects.
  • In a doxycycline-stimulatable BRAF-positive mouse model: with increasing stimulation of BRAF, the histological structure changes and gene expression studies change within a week. When the stimulation is aborted or antagonized, the histological and gene expression changes reverse towards normal. This was corroborated by studying the RAI uptake in the same mouse model.

 

Taking the above findings to a clinical trial, use of selumetinib, an ERK inhibitor, was successful in restoring the RAI uptake to the extent that some patients who were RAI-negative gained enough RAI uptake to be eligible for treatment with RAI. This was best achieved in patients with RAS mutations rather than BRAF mutations, again indicating the strong effect of BRAF on RAI uptake mechanisms.

  • BRAF-positive thyroid cancer is refractory to MAPK inhibition. For example, resistance to vemurafenib is lineage-specific. This means that BRAF-positive melanoma cells are much more responsive than BRAF-positive thyroid or colon cell lines.
  • Gene-expression studies of BRAF-positive thyroid cell lines showed an increased expression of HER3 and inhibition of HER3 significantly improved sensitivity. MAPK kinase inhibitors de-repress HER3 gene leading to increased expression of HER3, which is activated by the high level of neuregulin 1 (NRG1).
  • In addition to HER3-activation by MAPK inhibitors, when the pathway is inhibited with one agent, it becomes more sensitive to any ligand that activates the MAPK pathway. 

 

Because of these mechanisms, dual inhibition of the MAPK pathway is much more effective than single inhibition.

 

Thyroid dysfunction and the heart

Key points of a presentation by Paul Ladenson, MD, Johns Hopkins University School of Medicine, Baltimore, MD, USA

  • Recognition of the classic effects of hypothyroidism on the heart function dates back to the 1930s, when X-radiography showed that a dilated heart reverted to normal with thyroid hormone therapy.
  • Chester Ridgeway showed the reversibility of dilated cardiomyopathy with thyroid hormone therapy (on echocardiogram).
  • Paul Ladenson and colleagues showed that the alpha myosin subunit was downregulated in a myxoedematous young patient (reversed by thyroid hormone therapy).
  • In the Colorado Thyroid Function Study, Ridgeway et al. showed a proportional direct relationship between serum cholesterol and serum TSH, even in slightly elevated TSH group (5.1–10.0 mIU/L).
  • Use of thyroid hormone analogues has been shown to decrease cholesterol. 

 

Increasing incidence of thyroid cancer

Data suggest an increasing incidence of small and large tumours, no reduction (or an increase) in mortality, more aggressive tumours and an expected major increase in costs of treating the disease in future

Steven Sherman (The University of Texas MD Anderson Cancer Center, Houston, TX, USA) gave a presentation that highlighted the progressive increase in incidence of thyroid cancer over the last 40 years. This increase is associated with a number of negative consequences for patients and raises the burden on healthcare resources.

  • Most of this increase has been in cases of papillary thyroid cancer, although rates of the follicular variant of papillary thyroid cancer have also been increasing.
  • Although most increase has occurred in microcarcinomas, data from USA and France showed an increase in larger tumours as well.
  • In 2015, an estimated 62,450 new cases of thyroid cancer will be diagnosed in the USA – accounting for 4% of all cancers and the 4th most common cancer in women

 

             a) There are some racial differences: Caucasian men and women have the highest incidence and African-American men and women have the lowest incidence 

             b) Female:male ratio is ~3:1 and the median ages are 49 and 54 years, respectively.

  • Mortality remains low, with only 1950 people predicted to die from thyroid cancer in the USA in 2015

 

           a) However, mortality correlates with age, even in localized disease

           b) As a patient’s age increases, the risk of mortality increases, regardless of cancer stage

           c) Patients with localized disease have a lower risk than those with regional disease, and both groups have lower risk than those with metastatic disease.

  • It is a long-held belief that men with thyroid cancer have poorer survival rates than women, but this does not seem to be true

 

           a) In general, men do not live as long as women, and thyroid cancer is diagnosed later in men

           b) After adjusting for age and disease stage, mortality risk for thyroid cancer is the same for both genders.

  • The increased incidence of thyroid cancer is even evident in children and adolescents. This suggests the increase is biological in nature.
  • Most countries show an increasing incidence of thyroid cancer.
  • Mortality is not significantly increasing, but neither is it decreasing despite improvements in diagnostic and therapeutic methods.
  • Some studies suggest an increasing rate of BRAF-positive papillary thyroid cancer but a recent study suggested some decrease in BRAF-positive and a sharp increase in RAS-positive tumours, probably secondary to improvements in recognition and diagnosis of the follicular variant of papillary thyroid cancer.

 

ENDO 2015 – the 97th Annual Meeting and Expo of the Endocrine Society – was held in San Diego, CA, USA, 5–8 March 2015. Over 8000 clinicians, mostly endocrinologists, attended the 4-day conference, which included nearly 140 sessions of clinical updates, symposia, meet-the-professor sessions, debates and plenary sessions

Ali Saeed Alzahrani

Scientist and Head Molecular Endocrinology Section
Department of Molecular Oncology
King Faisal Specialist Hospital & Research Centre
Riyadh, Saudi Arabia
Consultant Endocrinologist
Department of Medicine
AlFaisal University
Riyadh, Saudi Arabia
Professor of Medicine and Endocrinology
AlFaisal University
Riyadh, Saudi Arabia
ENDO 2015
Endocrine Society
Management of thyroid disorders
levothyroxine
Graves’ disease
hypothyroidism
hyperthyroidism
radioactive iodine
SELECT trial
Lenvatinib-associated hypothyroidism
thyroid cancer
Mechanisms of resistance to tyrosine kinase inhibitors in thyroid cancer
BRAF-positive
RAS-positive
Thyroid dysfunction and the heart
Increasing incidence of thyroid cancer