DURABLE RESPONSE IN A CASE OF METASTATIC ANAPLASTIC THYROID CANCER USING A COMBINATION OF TYROSINE KINASE INHIBITORS AND A CHECK POINT INHIBITOR

Abstract

Anaplastic thyroid cancer (ATC) is a highly uncommon (less than 2% of thyroid malignancies) and aggressive type of cancer, with aggressive behavior and, therefore, exhibiting poor prognosis. ATC tumors are automatically labeled as stage IV disease regardless of standard criteria such as tumor burden or metastasis. ATC tumors require a diversified treatment approach that includes surgical resection, followed by a complete an aggressive combination of radiation and chemotherapy and/or palliative care. Despite best efforts, 1-year overall survival of patients is 20% to 40% with nearly universal mortality rate. Consequently, novel approaches (targeted therapy, immunotherapy) have been studied, alone or in combination, to improve the dire prognosis of these patients. BRAF V600E mutation is the most common genetic mutation found in ATC. We report the case of a 57-year-old man diagnosed with stage IVc (undifferentiated) ATC with hepatic and osseous metastases. The molecular analysis of the tumor revealed a V600E BRAF-mutation. The patient was treated with Dabrafenib and Trametinib, and achieved remission 5 weeks after starting the treatment. Subsequently, he had a thyroidectomy, and pembrolizumab was added to the two tyrosine kinase inhibitors. 9 months later he is still in remission. This case illustrates the importance of obtaining molecular information in anaplastic thyroid cancer and the urgent need of studies investigating the combination of tyrosine kinase inhibitors and check-point inhibitors in patients with V600E BRAF- mutations.

INTRODUCTION

Anaplastic thyroid cancer (ATC) is a highly uncommon and aggressive type of cancer, representing less than 2% of thyroid malignancies. Despite their low incidence, such tumors frequently present at an advanced stage, affect people over the age of 60 years, display aggressive behavior and are, therefore, associated with poor prognosis. ATC tumors are automatically labeled as stage IV disease regardless of standard criteria such as tumor burden or metastasis and are further sub-classified as IVa, IVb, and IVc according to the extent of invasion of the surrounding tissue layers (UICC 8^th) (1,2). ATC tumors require a diversified treatment approach that includes surgical resection, followed by a complete an aggressive combination of radiation and chemotherapy and/or palliative care (3,4). Population-based studies noted the median survival of ATC patients to be anywhere from 5 to 12 months and the 1-year overall survival to range from 20% to 40% with nearly universal mortality rate (5, 6). Consequently, novel approaches (targeted therapy, immunotherapy) have been studied, alone or in combination, to improve the dire prognosis of these patients. Considering all of the genetic abnormalities examined in ATC tumors, BRAF V600E mutation is the most common (25–48%) (7,8). Following the positive results of a Phase 2 study reported by Subbiah et al. (6) in 2018 that showed a response rate of 69% in 16 evaluable patients treated with the combination of BRAF inhibitor dabrafenib plus MEK inhibitor trametinib, the combination of these two drugs received FDA approval in May 2018 for the treatment of locally advanced or metastatic V600E-positive ATC. The doses of tyrosine kinase inhibitors used in the study were 150 mg twice a day for dabrafenib and 2 mg once a day for trametinib. All 16 patients enrolled in the study had previously received radiation therapy, chemotherapy, or underwent surgery. After 8 weeks of continuous treatment, 10 patients registered partial responses, and one patient achieved complete response (resolution of multiple pulmonary metastases) which persisted for the duration of the follow-up (120 weeks).

CASE REPORT

A 57-year-old man with no previous medical history, no family history of cancer, on no medications, and with a healthy lifestyle (non-smoker, exercises daily, healthy diet) noticed a mass in his neck with subsequent hoarseness 6 weeks and 2 weeks, respectively, prior to admission. Laryngoscopy found a left vocal cord paralysis and no other lesions. A computed tomography (CT) scan with intravenous contrast revealed a heterogeneous cystic/solid mass within the left thyroid visceral space that invaded into the inferior left lobe of the thyroid and effaced the left tracheoesophageal groove. Left vocal cord paresis, with loss of the fat along the left margin of the trachea without discrete luminal invasion was also noted. The lesion was also intimately associated with the cervical esophagus. A rounded sclerotic lesion in the right transverse process of the T2 vertebra raised the suspicion of an osseous metastatic lesion. A PET-CT scan performed in June 2019 revealed no evidence for a thyroid mass. However, it showed a 4.2 cm left visceral space necrotic lymph node, hypermetabolic metastatic subcarinal and right hilar lymphadenopaties, a 1.8 cm hypermetabolic periportal lymph node, enlargement and hypermetabolism of the left sternocleidomastoid muscle with FDG uptake - possibly representing muscular metastasis, a right hepatic lobe 1.6 cm metastasis, and a right C2 transverse process hypermetabolic osseous metastasis (Fig.1). Pathologic studies of the left neck biopsy showed a high-grade malignant neoplasm, predominantly necrotic tissue with scant malignant pleomorphic cells (Fig. 2a, Fig. 2b), with subsequent immunohistochemical (IHC) results as follows: positive tumor cells for CK AE1/AE3 (Fig. 3a) and PAX-8 (Fig. 3b). The staining for p40, TTF-1, CMV, and HSV was negative. The IHC for PDL1 CPS score was >80%. Given the morphologic and immunohistochemical findings, and the location of the tumor, the diagnostic was stage IVc (undifferentiated) ATC. The thyroglobulin was slightly elevated (32.5 ng/mL, normal up to 29 ng/mL), the other laboratory studies were grossly normal. The molecular analysis of the tumor revealed a V600E BRAF-mutation. The patient was started on Dabrafenib and Trametinib. Strikingly, 5 weeks after starting the treatment, a repeated PET-CT scan showed complete remission (Fig. 4). The only abnormality noted on a CT scan of the neck done at the same time was the persistence of the sclerotic lesion of the transverse process of the T2 vertebra. One month later, the patient underwent thyroidectomy. Subsequently, starting 6 weeks after the thyroidectomy, pembrolizumab was added to the two tyrosine kinase inhibitors. After 9 months of treatment, currently, the patient continues to be in complete remission.

Figure 1.

June 2019 PET-CT scan revealing no evidence for a thyroid mass, hypermetabolic metastatic subcarinal and right hilar lymphadenopathies, muscular, osseous and hepatic metastasis.

Figure 2.

A) Pathologic examination revealing high grade malignant neoplasm, predominantly necrotic tissue with scant malignant pleomorphic cells (HE, 20x); B) Pathologic examination revealing high grade malignant neoplasm, predominantly necrotic tissue with scant malignant pleomorphic cells (HE, 40x).

Figure 3.

A) Immunohistochemical (IHC) result: positive tumor cells for CK AE1/AE3 (20x); B) Immunohistochemical (IHC) result: positive tumor cells for PAX-8 (20x).

Figure 4.

August 2019 PET-CT scan showing complete remission.

DISCUSSION

Thyroid cancer (TC) accounts for more than 90% of endocrine-related malignancies. Histologically, there are 5 types of TC: papillary thyroid cancer (PTC – the most common, comprising approximatively 80% of cases), follicular thyroid cancer (FTC – accounting for 10% of TC), medullary thyroid cancer (MTC – originating from thyroid C cells), poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer. With the exception of MTC, the rest of thyroid tumors arise from thyroid follicular cells. PTC and FTC (the majority of tumors) are considered differentiated cancers and display favorable prognosis with > 98% five-year survival (9), contrary to ATC which is generally fatal even if discovered early and radically resected (10). As a result, the American Joint Committee on Cancer (AJCC) (1) classifies all cases of ATC as stage IV as follows: stage IVa consists of tumors confined to the gland, stage IVb describes ATC with extrathyroidal extension (with or without lymph node metastases), while stage IVc represents tumors that have spread to distant sites.

ATC patients typically present with a neck mass that may be accompanied by dysphagia, hoarseness, stridor and dyspnea due to compression of local structures, such as trachea, esophagus, or adjacent recurrent laryngeal nerve (11, 12). The rapid enlargement of the neck mass can associate erythema and edema of the overlying skin. Furthermore, patients could display signs and symptoms from metastases (13). According to literature, ATC develops in the fifth to seventh decades of life, and men are less frequently affected (7). As in the case presented here, ATC is not correlated with prior history of thyroid disease.

Following diagnosis of ATC, the American Thyroid Association generally advise complete surgical resection when the tumor is confined to the thyroid parenchyma, unless the patient has prior conditions that would preclude surgery. Current guidelines recommend total thyroidectomy and central node dissection with negative margins (14). Intriguingly, there is evidence that incomplete resection is comparable to negative margins in terms of overall patient survival (15). However, complete resection remains challenging due to the local invasion of the tumor.

Anaplastic thyroid tumors do not respond to radioactive iodine (I131) ablation therapy which is commonly used in the differentiated types of thyroid cancer (papillary and follicular) due to the lack of sodium-iodine symporters and undifferentiated phenotype. As a result, external beam radiation therapy is used instead of I131 treatment. While studies suggest that patients with stage IVa and IVb showed improved survival after post-operative radiotherapy (16), these results are contingent upon the ability to resect the tumor, which is only feasible in a limited number of cases. Multimodal loco-regional treatment that incorporates higher (60–75 Gy) versus lower (45–59.9 Gy) radiation doses represents an alternative for unresectable tumors (17). Currently, there is ongoing research to re-sensitize ATC cells to radioiodine therapy (18).

Cytotoxic chemotherapy has been for decades the main treatment for metastatic disease and has also been used for stage IVb unresectable tumors. Historically, first-line treatment included single-agent therapy with paclitaxel or doxorubicin or combined therapies (e.g. carboplatin/paclitaxel, docetaxel/doxorubicin), but chemotherapy was associated with considerable adverse effects with minimal clinical benefit (14, 19).

The most frequently mutated genes in ATC include the oncogenic genes BRAF, NRAS, KRAS, and HRAS and the tumor suppressor genes TP53, NF1, and PTEN (5). BRAF V600E is the most common mutation for which, currently, therapies are available and is found in approximately 20-50% of anaplastic thyroid cancers (8). At the time of writing this report, there are two other genetic fusions for which there are available therapies: the NTRK fusion and the RET fusion (20-22). Also, another thyrosine kinase inhibitor, Lenvatinib, has been used with clinical benefit in some circumstances and is recommended by the NCCN guidelines (8).

In our case, following the diagnosis of stage IVc anaplastic thyroid carcinoma with a BRAF V600E mutation, the patient was started directly on a combination of dabrafenib and trametinib, with no other previous treatment. After 5 weeks of treatment, a PET-CT scan showed complete remission and, subsequently, a complete thyroidectomy was performed. Given the presence of a high PD-L1 expression in the tumor cells, the patient continued treatment with a combination of dabrafenib, trametinib, and added pembrolizumab to the two tyrosine kinase inhibitors. Nine months later, to the day of this report, the patient maintained a complete response (the only persistent abnormality is the sclerotic lesion of the transverse process of the T2 vertebra).

Several studies determined that the surface of ATC tumors expresses PD-L1 (23, 24) and that such tumors are diffusely infiltrated with T-lymphocytes bearing PD-1 receptor (25). Accordingly, there are positive results from a phase 1 study using pembrolizumab (a monoclonal antibody against the PD-1 receptor) in advanced differentiated thyroid cancers after progression (26), and, also from a retrospective study in which ATC patients were treated with pembrolizumab in combination to kinase inhibitors as salvage therapy at the time of progression (27).

In conclusion, this case illustrates the importance of obtaining molecular studies in anaplastic thyroid cancer, a cancer associated historically with a very poor prognostic. As many as 50% of anaplastic thyroid cancers may harbor a BRAF V600E mutation and, for patients having tumors harboring this mutation, the combination of Dabrafenib and Trametinib, possibly combined with check-point inhibitors, can significantly prolong their life as in the case reported here. The combination of tyrosine kinase inhibitors and check point inhibitors may be worth investigating in future clinical trials, specifically in patients with tumors exhibiting both BRAF V600E mutations and high PD-L1 expressions.

Conflict of interest

The authors declare that they have no conflict of interest.