Medullary thyroid carcinoma (MTC) accounts for 2–4% of thyroid cancers. It has the particularity of being a neuroendocrine tumor associated with a proto-oncogene germline RET mutation: germline in 20–25% of cases, somatic in 70–80% of metastatic sporadic cases. Locally advanced and metastatic MTCs are called “refractory”. Individual prognosis is difficult, since the clinical behavior of the disease varies greatly from one patient to another. However, histological factors, such as high-grade forms, associated with greater risk of tumor progression and death, have been recently identified, and biological factors, such as the doubling time of plasma calcitonin, may help assess prognosis. Treatment of refractory medullary thyroid carcinoma has progressed considerably over recent years, with the advent of targeted therapies such as multi-kinase inhibitors and selective RET inhibitors. Management requires multidisciplinary expertise, and is tailored to the individual clinical situation patient, the molecular characteristics of the tumor, and the progression of the disease. These advances have led the ENDOCAN-TUTHYREF rare-cancer network of the French National Institute for Cancer (INCa), dedicated to refractory thyroid cancer, to draw up a set of consensus recommendations. This article focuses on refractory medullary thyroid cancer.

# Introduction

Medullary thyroid cancer (MTC) is a neuroendocrine tumor that develops from calcitonin-secreting C cells of the thyroid gland. It accounts for 2–3% of thyroid cancers in women and 4–5% in men, with incidence of 1–2 per million [1,2]. MTC is sporadic in 75–80% of cases, and familial in 20–25%, linked to germline mutations of the RET gene [1,3,4]. Incidence is relatively stable, although an upward trend was reported in the USA between 1983 and 2020 [5]. The proportion of locally advanced or metastatic MTCs is between 10% and 30% [1]. By analogy with differentiated thyroid cancer of follicular origin, in which prognosis deteriorates when refractory, all metastatic MTCs and non-resectable locally advanced are considered refractory. The number of new cases per year in France is around 50 to 60. Treatment options used to be very limited. Since chemotherapy is not very effective, it was not until the advent of targeted therapies that validated systemic treatments became available [1,6].

# Prognosis

The prognosis of MTC is highly dependent on tumor stage at diagnosis [6–9]. In patients with localized disease, overall 10-year survival is excellent, at 95%. However, lymph node extension is found at diagnosis in 45% of patients and distant metastases in 10% [9]. In metastatic disease, prognosis is rather poor, with 10-year survival around 20% [1]. More favorable results have been reported in recent series, possibly due to better management. Based on the French ENDOCAN-TUTHYREF network national database, in a cohort of 355 metastatic patients, median overall survival was 9.5 years, with survival rates of 69% at 5 years, 48.5% at 10 years and 40% at 15 years (unpublished raw data).

Individual prognosis remains difficult to establish, as the clinical behavior of the disease varies greatly from patient to patient, with some metastatic patients showing very slow growth and others rapid growth. However, the doubling time of the plasma biomarker of MTC, calcitonin, is a reliable prognostic marker, associated with poorer survival if<6 months and better prognosis if>24 months [10]. The strongest prognostic factor reported so far is histological. The International Medullary Thyroid Carcinoma Grading System (IMTCGS) recently implemented a 2-tier score that classifies MTC based on proliferative activity and tumor necrosis on histology. The presence of≥1 parameter out of mitotic index≥5 per 2 mm2, Ki67 proliferative index≥5% and tumor necrosis identifies high-grade cases, and lack of all 3 identifies low-grade cases. High IMTCGS grade was independently associated with lower overall, disease-specific and distant metastasis- and locoregional-free survival compared to low grade in one pivotal study [11]. This grading system is included in the latest WHO thyroid tumor classification [12].

# What molecular abnormalities should be explored in MTC?

The major role of the RET proto-oncogene in MTC tumorigenesis was identified early on [13]. Located on chromosome 10 (10q11.2) and comprising 21 exons, it encodes a transmembrane tyrosine kinase receptor, activation of which leads to overexpression of several signaling pathways, including the MAPK and PI3K pathways, conferring cell survival, proliferation, migration and angiogenesis capacities.

The presence of pathogenic point mutations leading to excessive receptor activation, the intensity of which varies according to the variant, is found at germline level in around 25% of MTCs, bringing them under the concept of type-2 multiple endocrine neoplasia. These mutations particularly concern the cysteine- or tyrosine-rich domains of exons 8, 10, 11, 13, 14, 15 and 16, and should be systematically investigated when MTC is diagnosed. Somatic RET mutations can be identified in around 50–60% of sporadic MTCs and up to 80% in refractory/metastatic disease [14–16]. The M918T mutation (exon 16) is the most frequent, associated with increased aggressiveness and affecting around 70–80% of sporadic metastatic MTCs and a minority of microcarcinomas [14,17]. In the absence of germline RET mutation, screening for somatic mutation should be the first step.

Around 20% of sporadic MTCs and 60% of wild-type RET MTCs have mutations in the RAS genes (particularly HRAS and KRAS) [14,18,19]. These mutations are almost always mutually exclusive of RET mutations. Other recurrent mutations, involving the MET, FGFR and PDGFR genes, are reported at much lower frequencies. Exceptional cases of ALK fusion have been reported [20]. In a recent publication analyzing 181 sporadic MTCs using next-generation sequencing (NGS), over 80% of tumors showed molecular alteration – mainly point mutations in the RET or RAS genes [21].

The main aims of somatic molecular abnormality testing in routine clinical practice are to guide therapeutic management by predicting response to selective inhibitors, and to understand the causes of therapeutic failure or escape. Screening for targetable mutations is indicated in case of non-operable locally advanced carcinoma, progressive metastatic carcinoma for which systemic treatment is considered, or failure of systemic therapy targeting RET 
                     [21].

NGS techniques are recommended for broader analysis of the gene and the various possible mutations. Since the aim is to screen for point mutations rather than fusion genes, DNA sequencing may be proposed as a first step, initially targeting the most frequently affected exons (https://www.has-sante.fr/upload/docs/application/pdf/2022-07/synthese_acte_ associe_ retsevmo_et_alterations_gene_ret_vd.pdf). If this is not accessible, more targeted techniques such as real-time PCR can be considered [13,22]. All these molecular analyses can be performed on frozen or formalin-fixed paraffin-embedded (FFPE) material. No in situ techniques such as immunohistochemistry have been validated for detection of these mutations. It is preferable to carry out molecular genotyping as soon as refractory MTC has been diagnosed, even if the indication for systemic therapy is not immediate, as preserved tissues deteriorate over time, limiting the quality of subsequent nucleic acid extraction.

In the absence of RET mutation, RAS mutation testing may be discussed, given the ongoing development of therapies targeting these mutations which are currently being evaluated but have no validated indication in MTC. RAS mutations are usually identified on multigene NGS panels used in routine clinical practice.

Currently in France, for MTCs with an indication for systemic treatment in the absence of somatic RET or RAS mutation or of germline RET mutation, or with RET mutation and progression under anti-RET treatment, extensive sequencing is available under the France Médecine Génomique plan. This analysis requires prior validation of the indication by a dedicated tumor board of the ENDOCAN-TUTHYREF network, with frozen tumor material in sufficient quantity (https://pfmg2025.aviesan.fr/professionals/preindications-and-implementation/refractory-thyroid-tumors/). Since October 2023, analyses have been possible on the latest FFPE blocks. In particular, these techniques enable identification of rare targetable mutations and evaluation of tumor mutational burden (TMB), which can predict response to immunotherapy in therapeutic trials.

# When to start systemic treatment and how to prepare the patient?

Before introducing systemic treatment, the challenge is to fix the timing, so as to achieve disease control with only acceptable side-effects compared to expected benefit. In low-volume non-progressive metastatic cancer, locoregional treatment or active surveillance is systematically discussed. Treatment decision and frequency of monitoring may be dictated by tumor burden and the tumor growth pattern. Locoregional treatment is preferable for oligometastatic disease or oligometastatic progression. Metastatic locations may require local control before initiation of systemic treatment, in case of symptomatic disease and/or risk of complications such as bone metastases or uncontrolled brain metastases. Local treatments (surgery, radiotherapy and interventional radiology techniques such as thermoablation, etc.) thus play a prominent role in the therapeutic strategy. The decision to introduce systemic treatment must always be individualized and made in a multidisciplinary tumor board by physicians with expertise in endocrine oncology, after discussion with the patient and taking account of the criteria presented in Fig. 1
                     .

It is essential to prepare patients for treatment with targeted therapy, so as to limit the incidence and severity of the adverse effects expected with this therapeutic class [23]. The objective of this preparation is to prevent cardiovascular (hypertension, heart failure, QTc prolongation), renal (proteinuria) and/or digestive (nausea/vomiting, diarrhea) toxicity, as well as weight loss, sarcopenia and dermatological toxicity (palmoplantar keratosis, skin rash, stomatitis). Management is multidisciplinary, involving many professionals, including oncologists, endocrinologists, cardiologists, nephrologists, clinical pharmacists, dieticians, coordination nurses and advanced practice nurses, even before treatment is initiated. Quality of life, psychological state and social situation must be assessed. Good general health and absence of symptoms are associated with better prognosis and lower incidence of toxic effects. Comorbidities and associated treatments must be carefully analyzed. Therapeutic patient education in the prevention and management of the main toxicities is strongly encouraged.

# Which treatments (targeted therapies or chemotherapy) are validated for MTC?

For patients with progressive metastatic MTC, therapeutic options used to be very limited. As chemotherapy was not very effective, it was not until the advent of targeted therapies that validated systemic treatments became available [6,7,24]. Targeted therapies with multikinase inhibitors or selective RET inhibitor are now the gold standard if local therapeutic options are not to be considered.

## Multikinase inhibitors

Vandetanib and cabozantinib are first-generation multikinase inhibitors targeting both RET and angiogenesis pathways.

Vandetanib led the way with the ZETA randomized placebo-controlled phase-III study, published in 2012 [25]. It included 331 patients with non-operable (5%) or metastatic (95%) locally advanced MTC. Tumor progression according to RECIST was not one of the inclusion criteria. Median progression-free survival (PFS), not achieved in the vandetanib arm, was 30.5 months versus 19.3 months in the placebo arm. The objective response rate was 45% (Table 1
                        ). Median overall survival did not differ between the two groups. In 2017, a post-hoc analysis [26] confirmed the efficacy of treatment for PFS of patients showing progression at inclusion (21.4 months vs. 8.4 months for placebo).

Cabozantinib was tested in the EXAM phase-III trial, published in 2013 [27,28], which included 330 patients with inoperable, locally advanced or metastatic MTC progressing over 14 months according to RECIST. The trial showed better PFS in the treated arm (11.2 months vs. 4 months in the placebo arm) (Table 1). The objective response rate was 27% and response duration was 14 months. There was no effect on overall survival.

The very different characteristics of the patients included in the trials makes it impossible to compare the two molecules in terms of efficacy. The side-effects are those frequently reported during anti-angiogenic treatments. With vandetanib, grade 3 or 4 adverse events were reported in half the patients. The most frequent were diarrhea, high blood pressure and QT interval prolongation. Dose reduction was required for a third of patients, and discontinuation for toxicity in 12% [25]. On cabozantinib, grade 3 and 4 adverse events were reported in three-quarters of patients, the most frequent being diarrhea, hand-foot syndrome, hypertension, constipation, vomiting and mucositis. Dose reduction was required for 80% of patients, and 20% discontinued due to intolerance [27]. A recent meta-analysis, based on phase I, II and III studies and retrospective real-life series, reported treatment discontinuation due to intolerance in 39% and 66% of patients treated with vandetanib and cabozantinib respectively [29].

In France, only vandetanib is covered by the national health insurance system in first line for advanced or metastatic and progressive MTC. Recently, however, European approval of vandetanib was restricted to patients harboring RET mutations, as it was considered that the ZETA study failed to prove efficacy in RET-negative patients in terms of overall response rate, which is a questionable evaluation criterion.

## Selective RET inhibitors

Recent studies focused on the search for highly selective RET inhibitors. This led to the development of selpercatinib, active against the various RET mutations, including the V 804 resistance mutation [30]. Other selective inhibitors [31] have been developed, but have not had approval in Europe in the MTC indication. Selpercatinib was first tested in the LIBRETTO-001 phase I-II trial, the results of which in 143 RET mutation-positive patients were published in 2020 [30]. The response rate was 73% in 1st-line patients, maintained at 1 year in 93% of cases. In patients previously treated with cabozantinib or vandetanib, the response rate was 69%. Adverse events (hypertension, increased transaminases, or more rarely diarrhea and hyponatremia) led to dose reduction in 30% of patients; discontinuation was necessary in only 2%. These promising results have enabled early access to 2nd-line therapy, after treatment with vandetanib or cabozantinib.

What remained to be done was to compare efficacy between selpercatinib and reference treatments. This was achieved in the LIBRETTO-531 multicenter randomized phase-III trial [17]. This study included 291 patients with metastatic or locally advanced, RET mutated medullary cancer, progressive over 14 months after inclusion and naive to any treatment. Patients were compared with a control group treated with cabozantinib or vandetanib, at the investigator's discretion, on a 2:1 ratio. Selpercatinib reduced tumor size in 69% of cases, versus 40% with reference treatments, and reduced the risk of disease progression by 72% compared with the control group. The toxicity profile was also favorable, with 39% vs. 77% dose reductions and 4.8% vs. 27% treatment discontinuations with selpercatinib and the control arm, respectively.

The results of this trial, demonstrating the superiority of selpercatinib over reference treatments in terms of progression-free survival, response rate and tolerability, led to EMA approval and French national health insurance cover for the first-line treatment of RET-mutated patients with advanced MTC.

Secondary progression may occur during RET therapy [32], due to acquisition of resistance mutations in the RET gene (on-target mutation) (L730I, G810S, etc.) or, more often, to other genes (MET, NTRK, RAS amplification, etc.), leading to bypass mechanisms of treatment resistance [32,33]. In the event of progression under RET-selective inhibitors, biopsy from progressive lesions can identify any resistance mutations and guide subsequent management. Mutational profile may differ according to the site, and a few cases of aggressive histology have been reported after anti-RET treatment, raising fears of tumor dedifferentiation in some patients [34,35]. In the absence of an accessible lesion, sequencing of circulating tumor DNA may be considered. Data concerning the performance of liquid biopsies in MTC are as yet limited [35–37], but encouraging, as reported in a recent series in which 12 patients were analyzed by liquid biopsy after progression under RET inhibitors [35].

## Other treatments

A few small retrospective series suggested efficacy for alkylating agents such as dacarbazine, in certain forms of medullary cancer that are rapidly progressive and resistant to conventional treatment [38,39]. A few pilot studies suggested efficacy for certain anti-angiogenic treatments, such as lenvatinib, evaluated in a single-arm phase-2 trial [40]. These treatments may be proposed in 2nd or 3rd line in case of progression, in the absence of a validated therapeutic alternative. Finally, a preliminary study suggested that immunotherapy could be an option for patients who have failed conventional treatments, and notably non- RET-mutated patients, if they have a high level of intra-tumoral mutation (TMB-H>10 mut/Mb) [41].

## Decision-making algorithm for refractory MTC

In addition to systemic treatments, local treatments (surgery, radiotherapy and interventional radiology) also have their place in the therapeutic strategy. These have not been covered in the present article, but are detailed in a cross-sectional chapter in this issue dedicated to locoregional treatments. Taken together, these elements make it possible to propose a personalized, multimodal management algorithm that takes account of tumor extent, progression and molecular characteristics (Fig. 2
                        ).

# Conclusion

Management of refractory MTC has progressed considerably in recent years, thanks to developments in genetics and the advent of promising targeted systemic therapies. Multidisciplinary treatment is essential, and must be individually adapted to the patient's clinical situation, the molecular characteristics of the tumor and the progression of the disease. In France, the ENDOCAN-TUTHYREF network has significantly improved access to expert center care and shared treatment decision-making via regional rare-cancer boards and national tumor boards. The guidelines drawn up by the network, available online at https://www.tuthyref.com/fr/, are an additional tool to aid therapeutic decision-making. Targeted therapy requires rigorous monitoring to ensure that the various adverse effects are treated proactively, to preserve quality of life and treatment adherence. Therapeutic resources are still limited in medullary cancers without RET mutation and in cases of therapeutic escape, but the inclusion of these patients in the France Genomic Medicine 2025 plan may enable new targets to be identified, and we can look forward to new therapeutic advances in the coming years.