Abstract
Anaplastic thyroid cancer (ATC) is an aggressive malignancy with limited therapeutic options. Although rare, the prognosis of locally advanced or metastasized diseases is poor, with a one-year survival rate in the range of 8–20% (1). Although aggressive multimodal approaches including surgery, radiation, and chemotherapy are applied, the associated adverse effects are often profound and the outcomes dismal. In view of the minimal efficacy of conventional chemotherapies and an unmet clinical need, a detailed characterization of the molecular driver mutations of an individual tumor might thus improve patient selection and provide information for a rational personalized treatment design. In this context, possible somatic mutations of driver molecules such as BRAF, ALK, PIK3CA, and others were suggested as potential druggable targets.
Here, we present the case of an 80-year-old female patient with a BRAFV600E mutation bearing ATC and an excellent and sustained response to single agent, vemurafenib. The patient first presented with a rapidly growing bilateral tumor of the thyroid gland, with the largest tumor measuring 4.5 cm. The thyroid was resected in June 2013, and the histological analysis revealed a papillary thyroid carcinoma with infiltration beyond the thyroid capsule and with a component of ATC of about 20% (Fig. 1A). There was no lymph node involvement (0/40 positive nodes, pN0). After radioiodine treatment (3420 MBq 131I) in August 2013, a rapid local relapse was observed in October 2013 that was excised surgically, and histopathological analysis revealed that it consisted of a pure ATC without differentiated papillary carcinoma. The patient then received chemoradiation (docetaxel 100 mg intravenously every 21 days for six cycles + 60 Gy in 2 Gy fractions external beam radiation). However, immediately after the end of treatment, a 18-fluoro-2-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan showed progressive disease of the cervical tumor and appearance of new pulmonary lesions (Fig. 1C). A re-biopsy revealed the presence of ATC cells without any signs of differentiated tumor parts. Mutational analysis of the tumor using ultrahigh multiplex polymerase chain reaction (IonAmpliSeq™ technology) (2), which covers genomic “hotspot” regions by potentially detecting 739 COSMIC mutations in 604 loci from 46 oncogenes and tumor suppressor genes, was performed. A point mutation located in exon 5 of the TP53 gene (c.550G>A, p.E180K) and a point mutation in exon 15 of the BRAF gene (c.1799T>A, V600E) were detected (Fig. 1B). Retrospective analysis of the primary tumor revealed that the mutations were limited to the ATC component of the tumor. Due to limited treatment options and rapid clinical deterioration of the patient with a growing cervical tumor and beginning dysphagia, we initiated therapy with vemurafenib 2 × 480 mg/day. The patient tolerated the treatment without significant adverse effects. After seven weeks, a first assessment to evaluate the effect of the treatment was performed with a PET/CT and revealed an almost complete response (Fig. 1C), which was accompanied by a massive reduction of clinical symptoms, including dysphagia, pain, and swelling, and an impressive improvement in the patient's general condition to almost normal. Subsequently, treatment was continued at the same dose of vemurafenib, with good tolerance and under dermatological surveillance for the development of skin lesions such as squamous cell carcinomas. Treatment response was further assessed at weeks 21 and 45 by 18F-FDG PET/CT scans, which revealed a sustained and excellent treatment response to vemurafenib treatment. After 61 weeks of treatment, the tumor eventually progressed.
(
Extensive efforts focused on the molecular basis of cancer development and progression led to the discovery of various molecular driver mechanisms. Based on these advances, medical oncology has (although cautiously) started to enter an era of individualized medicine, in which the treatment selection is targeting druggable or actionable molecular pathways. Molecular testing has already had a strong impact in other malignancies. One prominent example of molecular testing targeting a major driver mutation is the frequently observed BRAFV600E mutation in melanoma, which has led to a revolution in the treatment of this aggressive disease by directly inhibiting the driver mechanism. Although the BRAFV600E mutation is involved in the development and progression in various other types of cancer, targeting BRAF is not always successful. A recently published basket trial on vemurafenib in non-melanoma cancers harboring a BRAFV600E mutation suggests that the histologic context is an important determinant of the response to treatment (3). Aside from two ATC cases that were included in this trial and seemed to benefit from blocking BRAF, little is known about the therapeutic potential in BRAF-mutated ATC. In a single case report of vemurafenib in a patient with ATC (4), BRAF inhibition was only sustained for 38 days.
Our patient clearly shows that vemurafenib may be able not only to induce rapid tumor regression, but also to sustain it in select instances. In our patient, the response was sustained for 61 weeks, as assessed by 18F-FDG PET/CT, which in addition to morphological tumor shrinkage clearly demonstrated an almost complete normalization of glucose metabolism within the tumor. These findings are even more promising, as the toxicity in our patient was very mild and allowed for prolonged application of vemurafenib. Notably, vemurafenib bears potential side effects, among them skin toxicity, diarrhea, fatigue, and others. In contrast, chemo-radiation is not only characterized by low efficacy but also a high rate of toxicity, especially during radiation therapy, as almost all patients require hospitalization for parenteral nutrition or tube feeding in up to 50% of cases. While this report is limited to a single case, it suggests that mutational analysis has an impact on the choice of therapy in patients with ATC. A currently ongoing basket trial “ROAR” (NCT02034110) aims to target BRAF-mutated tumors of various origins, among them thyroid cancer, by blocking BRAF and MEK.