Advances in the management of MEN2: from improved surgical and medical treatment to novel kinase inhibitors

Abstract

Medullary thyroid carcinoma (MTC), a tumor derived from the neural crest, occurs either sporadically or as the dominant component of the type 2 multiple endocrine neoplasia (MEN) syndromes, MEN2A and MEN2B. The discovery that mutations in the RET protooncogene cause hereditary MTC was of great importance, since it led to the development of novel methods of diagnosis and treatment. For example, the detection of a mutated RET allele in family members at risk for inheriting MEN2A or MEN2B signaled that they would develop MTC, and possibly other components of the syndromes. Furthermore, the detection of a mutated allele created the opportunity, especially in young children, to remove the thyroid before MTC developed, or while it was confined to the gland. The discovery also led to the development of molecular targeted therapeutics (MTTs), mainly tyrosine kinase inhibitors, which were effective in the treatment of patients with locally advanced or metastatic MTC. While responses to MTTs are often dramatic, they are highly variable, and almost always transient, because the tumor cells become resistant to the drugs. Clinical investigators and the pharmaceutical industry are focusing on the development of the next generation of MTTs, which have minimal toxicity and greater specificity for mutated RET.

The evolving clinical, genetic and therapeutic landscape of multiple endocrine neoplasia type 2

“…In 'Advances in the management of MEN2', Samuel Wells provides an historical overview of the clinical description of MEN2 with its associated phenotypes and the development of genetic testing for RET point mutations that has further defined the disease subtypes, MEN2A and MEN2B (Wells 2018). The review also provides an update on current standard-of-care management and treatment options in the context of these mutations, including recommendations on biochemical screening, early surgical intervention, chemotherapy and the future hope of cure or long-term stability of disease offered by new molecular targeted therapeutics (Wells 2018).…”

“…The review also provides an update on current standard-of-care management and treatment options in the context of these mutations, including recommendations on biochemical screening, early surgical intervention, chemotherapy and the future hope of cure or long-term stability of disease offered by new molecular targeted therapeutics (Wells 2018). While Wells' review focuses on MTC in MEN2, Carole Guerin and coworkers elaborate on differences in phenotype of MEN2-associated PHEO and hyperparathyroidism compared to non-MEN2 familial forms with a discussion on changes to the clinical management of these conditions to improve patient quality of life (Guerin et al 2018).…”

“…In addition to surgical management, MEN2 has provided an ideal opportunity for precision medicine interventions using tyrosine kinase inhibitors to block RET activity. The current clinical use of previously developed and re-directed smallmolecule multi-kinase inhibitors, such as vandetanib and cabozantinib, in patients with advanced or metastatic MTC, has prolonged progression-free survival and stable disease, most notably for patients with the more aggressive MEN2B phenotype (Redaelli et al 2018, Wells 2018). Yet, the poor efficacy and safety risks associated with off-target effects of these therapeutics leave much to be improved.…”

Current surgical management in RET mutation carriers [Aktualne postępowanie chirurgiczne u nosicieli mutacji proto-onkogenu RET]

“…Unlike papillary carcinoma, the incidence of MTC remains stable, whereas over the last decades the prognosis in this cancer has clearly improved. One of the reasons is earlier detection of the disease and adopting the right therapeutic management at the optimal time [1][2][3][4].…”

“…Currently, it is mostly believed to be a component of the MEN2A syndrome characterised by a reduced activity of the RET protein, a milder course of MTC, which is revealed at a later age. In addition, these mutations do not activate neoplastic transformation in the adrenal or parathyroid gland cells [2,18]. treatment of patients with HMTC is impossible without this knowledge [2].…”