Results G

[G] Directions for future research

Directions for future research include: 1) The refinement of the cancer phenotype (especially age-related penetrance of component features) associated with specific mutations of RET to allow for more individualized surveillance and management recommendations, including the timing of prophylactic surgery. These questions will likely be best answered in the setting of an international consortium able to accrue large numbers of patients. Further studies are needed to answer whether there are truly mutations that predispose to only FMTC, or, rather do these mutations confer lower (but not nonexistent) penetrance for PHEO and PHPT. 2) The identification of potential modifier genes and ‘‘polymorphisms’’ within RET on the clinical phenotype (350–356). 3) Improving murine models of MEN2. 4) Advancing knowledge of the role of RET signaling pathways in MTC biology; including tumorigenesis and progression, to devise novel therapies (357– 359). 5) Elucidating the reasons for tissue selectivity of tumors given the ‘‘germline’’ mutation status present in every cell. 6) Identifying the potential role of targeting RET or its signaling cascade at the level of the gene, mRNA, and/or protein in the prevention and treatment of MEN 2 (359).

In the absence of nonsurgical methods to prevent MTC, the optimal timing of prophylactic thyroidectomy in MEN 2 and FMTC remains an issue that may benefit from further study, particularly in identifying parameters that can identify subsets of patients in whom surgery can be safely delayed, thereby minimizing risks. Refinement of criteria that may allow the safe avoidance of central neck dissections may reduce the incidence of hypoparathyroidism and recurrent laryngeal nerve injuries. This includes a need for establishment and reporting of the normal Ct range on each Ct assay in children, especially in the first 12 months of life for the rare MEN 2B patients. Educational opportunities should be explored on how to optimally perform and interpret neck US in young children to differentiate suspicious from benign lymph nodes. The development and recognition of centralized referral centers for such rare cases would likely be of benefit, but are only practical if the medical and medical insurance communities endorsed such referral patterns. The fact that a high percentage of MEN 2B children are not cured of MTC due to both early metastases and late diagnosis suggests the need for effective therapy beyond that of extirpative surgery.

In the setting of established MTC, the optimal extent of preoperative metastatic screening is unclear. Should all patients have a significant metastatic survey preoperatively, or should this evaluation be minimized with the potential for further evaluation based on the postoperative Ct level? If a more complete preoperative evaluation is considered, should it be based on the extent of neck disease, the serum Ct level, or both?

New strategies to treat metastatic MTC are being evaluated and include radioimmunotherapy and vaccine-based therapies. There has been recent focus on the use of compounds that inhibit the function of receptors or intracellular kinases. Compounds have been developed that block kinases with greater or lesser degrees of specificity that are involved in the pathogenesis or progression of cancer. In MTC, the most obvious kinase target is RET due to its critical role in familial cases, as well as in 40–50% of sporadic cases. Molecules that block RET kinase activity directly, or that block subsequent downstream signaling molecules, have been shown to inhibit MTC cell proliferation and reduce the production of active peptides (360–362). Other targets for therapeutic intervention are proteins that facilitate cancer cell growth and/or blood vessel formation, such as vascular endothelial growth factor and its receptors. Currently, several kinase inhibitors are under evaluation in clinical trials and preliminary evidence indicates that they may have important clinical benefits (363). However, the final results of these trials and adequate followup observation times are needed. Further, most of these targeted therapies are more likely to be cytostatic rather than cytoreductive. While clinical stability is important in patients with progressive disease, most clinical trials are based on RECIST criteria that are designed to detect complete and partial tumor remissions, the latter defined as the reduction of the summed greatest tumor lengths of >30%. Additionally, these therapies have significant short and/or long-term toxicities. Thus, new approaches to clinical trial design and analysis are likely to be needed to evaluate the relevance of these new compounds regarding clinically important measures: progression-free survival, disease-specific survival, overall survival, and quality of life.

Major future challenges including the likelihood that single agent–targeted therapies will not be a panacea, and that tumors will evade these blocks in signaling pathways and eventually manifest progressive disease. Thus, combination or sequential therapies may be required. Another concern is that targeted therapies may actually exert pressure on the tumor to find these alternative mechanisms for continued survival and growth, and thus may encourage more aggressive tumor behavior or dedifferentiation. Further, while reductions in tumor volume may be seen, many of these compounds are more likely to induce tumor stabilization, and therefore the optimal duration of therapy is unknown. Realistically, patients with metastatic MTC may be faced with taking a systemic therapy for the remainder of their lives, and the long-term effects of blocking these pathways for prolonged periods of time are currently unknown. The emergence of an effective systemic therapy, or combination of therapies, that is well-tolerated may lead to its potential use as an adjuvant treatment to surgery, or as an option for primary treatment for selected patients.