Abstract
Anaplastic thyroid cancer is one of the rarest subtypes of thyroid cancer, accounting for only 1–2% of all thyroid cancer cases. It is also one of the most aggressive: prognosis remains dismal and the disease-specific mortality rate is close to 100%. This rarity has markedly limited the availability of prospective trial results, and no standard chemotherapeutic option for unresectable or metastatic anaplastic thyroid cancer has yet been established. Nevertheless, combination therapy with a BRAF inhibitor and MEK inhibitor has shown encouraging efficacy in patients with BRAF V600E-mutated anaplastic thyroid cancer. Other novel treatments such as immune checkpoint inhibitors have also shown promising results. Owing to these therapeutic advances, the prognosis of anaplastic thyroid cancer appears to be gradually improving. However, further development of novel treatments for this rare malignancy requires the development of substantial infrastructure for international collaborative study.
Introduction
Anaplastic thyroid cancer (ATC) is one of the rarest and most aggressive subtypes of thyroid cancer (TC) (1). According to the staging guidelines of the American Joint Committee of Cancer (AJCC), all patients diagnosed with ATC are classified as having stage IV disease (AJCC 8th) (2). Although ATC accounts for only 1–2% of TC (3), historic disease-specific mortality is nearly 100% (1, 4, 5, 6), making it the most frequent cause of death among all TC patients (7). Indeed, a retrospective study using a database of the French ENDOCAN-TUTHYREF network (n = 360) demonstrated a median overall survival (OS) for ATC patients of 6.8 months. Furthermore, in patients with a high neutrophil–lymphocyte ratio – known as a poor prognostic inflammatory marker of peripheral blood, which might reflect the tumor immune microenvironment (TIME) – median OS with stage IVB/IVC disease was only 2.9 months (8, 9). If permitted by the patient’s condition, multimodal therapy including surgery, radiation therapy and chemotherapeutic agents plays a critical role in the management of ATC and may improve treatment outcomes for patients (10). Indeed, neoadjuvant approach with dabrafenib plus trametinib and pembrolizumab showed promising treatment outcomes with a median OS of 63 months and 2-year survival of 74.5% (11). However, this kind of aggressive multimodal approach may also carry the risk of adversely affecting the patient’s quality of life, and a shared decision-making approach with patients is therefore essential. Furthermore, palliative chemotherapy has an important role for patients with ATC. However, very few randomized-controlled trials (RCTs) for this extremely rare malignancy have been conducted, and no standard chemotherapeutic option for unresectable or metastatic ATC based on RCTs has accordingly been established. However, combination therapy with a BRAF inhibitor and MEK inhibitor has shown encouraging efficacy for BRAF V600E-mutated ATC (12, 13, 14), which accounts for around 40–60% of ATC (15, 16, 17), and this combination has become a standard treatment option for BRAF V600E-mutated ATC. Furthermore, other novel treatment options such as immune checkpoint inhibitors (ICIs) have also shown promising results (11, 18, 19). Thanks to recent advances in these novel therapeutic options, the prognosis of ATC patients appears to be improving year by year (1). Here, this review focuses on current evidence and future perspectives of anticancer drug therapy for ATC.
Anticancer treatment options for ATC
Cytotoxic agents
Although several prospective clinical trials for patients with ATC have been conducted, the efficacy of cytotoxic chemotherapy for ATC is limited (Table 1). Agents investigated to date include cytotoxic agents such as doxorubicin, taxanes and their combination with platinum agents (20, 21, 22, 23, 24, 25). Although most of these agents showed only a modest response of short duration, paclitaxel and doxorubicin are possible treatment options for ATC patients without driver gene alterations such as BRAF V600E, NTRK fusion and RET fusion (12, 13, 14, 26, 27).
Prospective studies of cytotoxic chemotherapy for ATC (20, 21, 22, 24, 25).
| Treatment regimen | n | Response rate | PFS |
|---|---|---|---|
| Doxorubicin | 41 | 17% | - |
| Doxorubicin + cisplatin | 43 | 26% | - |
| Docetaxel | 7 | 14% | 6 weeks |
| Weekly paclitaxel | 56 | 21% | 1.6 months |
| Paclitaxel 96h | 19 | 53% | - |
| Paclitaxel + carboplatin | 25 | 16% | 3.1 months |
| Paclitaxel + carboplatin + fosbretabulin | 55 | 20% | 3.2 months |
n, number of patients; PFS, progression-free survival; ATC, anaplastic thyroid cancer.
Molecular targeting agents
Vascular endothelial growth factor (VEGF) and its receptor (VEGF receptor; VEGF-R) play an important role in tumor growth and metastasis. VEGF-R is known to be overexpressed in ATC and VEGF-R inhibitors showed significant tumor growth inhibition in preclinical models (28). In clinical trials, several molecular targeting agents have been investigated for patients with ATC (Table 2) (29, 30, 31, 32, 33, 34). Among them, lenvatinib showed the most promising results, with a response rate of 24% in the initial report of a Japanese phase II trial. This lead to the approval of lenvatinib for ATC in Japan (32). However, subsequent phase II trials of lenvatinib for ATC from the United States and Japan showed disappointing results (33, 34). The reason why initial excitement over lenvatinib monotherapy diminished in subsequent clinical trials is uncertain. However, a French group reported that the differences in disease aggressiveness and response to lenvatinib might be related to the mixed pathology of ATC, including poorly differentiated or differentiated components (35). Another approach used VEGF-R inhibitors to enhance the efficacy of chemoradiotherapy for ATC. NRG/RTOG 0912 was a double-blinded randomized phase II trial (n = 71) to analyze the additional effects of pazopanib, a potent VEGF-R inhibitor, in chemoradiotherapy with paclitaxel. Although no significant additional effect of pazopanib was demonstrated, the treatment combination appeared to be feasible and safe (36).
Molecular targeting agents for ATC (12, 13, 14, 26, 27, 29, 30, 31, 32, 33, 34, 52).
| Treatment regimen | n | Response rate | MST | Note |
|---|---|---|---|---|
| Imatinib | 11 | 25% | 45% (6 months) | |
| Pazopanib | 15 | 0% | 3.7 months | |
| Sorafenib | 20 | 10% | 3.9 months | |
| Lenvatinib | 17 | 24% | 10.6 months | |
| Lenvatinib | 28 | 3% | 3.2 months | |
| Lenvatinib | 42 | 12% | 12% (12 months) | |
| Dabrafenib/trametinib | 36 | 56% | 14.5 months | BRAF V600E+ |
| Encorafenib/binimetinib | ||||
| ATC | 5 | 80% (4/5) | NR | BRAF V600E+ |
| Total | 22 | |||
| Vemurafenib/cobimetinib + atezolizumab | ||||
| Cohort 1 | 19 | 50% | 43.2 months | BRAF V600E+ |
| Total | 43 | |||
| Larotrectinib | ||||
| ATC | 7 | 29% (2/7) | NE | NTRK fusion+ |
| Total | 29 | |||
| Selpercatinib | ||||
| ATC | 2 | 50% (1/2) | NE | RET fusion+ |
| Total | 19 |
n, number of patients; MST, median survival time; NR, not reached; NE, not evaluable; ATC, anaplastic thyroid cancer.
With regard to the genomic landscape of ATC, previous reports have frequently described genomic alterations in TP53, TERT, BRAF, NRAS and PIK3CA among others (17, 37). Of these, BRAF V600E is a well-known driver gene alteration, which is found in 40–60% of ATC patients (15, 16, 17). In the phase II ROAR basket study, dabrafenib plus trametinib, namely combination therapy with a BRAF inhibitor and MEK inhibitor, showed very encouraging efficacy, with an overall response rate (ORR) of 56%, but with a relatively short median progression-free survival of 6.7 months and median OS of 14.5 months for patients with unresectable or metastatic BRAF V600E-mutated ATC (n = 36) (12). Furthermore, a Japanese phase II trial of encorafenib plus binimetinib, another combination therapy with a BRAF inhibitor and MEK inhibitor, showed promising efficacy, with an ORR of 55% (differentiated thyroid cancer (DTC) 47% (n = 17), ATC 80% (n = 5)) (14). These reproducible results support the further use of BRAF/MEK inhibitors for BRAF V600E-mutated ATC. The FDA (Food and Drug Administration) approved dabrafenib plus trametinib not only for BRAF V600E-mutated ATC patients but also for BRAF V600E-mutated DTC patients with no satisfactory treatment options. In addition, the Japanese PMDA (Pharmaceuticals and Medical Devices Agency) approved encorafenib plus binimetinib not only for BRAF V600E-mutated ATC patients but also for BRAF V600E-mutated DTC patients who were refractory to previous treatment options. Although the incidence of NTRK fusion and RET fusion in ATC is very low, ATC patients harboring NTRK fusion or RET fusion showed a response to a TRK inhibitor or RET inhibitor (26, 27). Since BRAF V600E mutation is the most prevalent gene alteration in ATC, immediate detection of BRAF V600E mutation is crucial for the management of ATC. Immunohistochemistry (IHC) of BRAF V600E is reliable, fast and cheap. A meta-analysis reported a pooled sensitivity of 96.8% and pooled specificity of 86.3%. A negative test largely excludes the mutation (38), and IHC test is useful for confirmation in clinical practice. Another useful non-tissue-based gene testing is liquid biopsy, which collects circulating tumor DNA to detect mutations such as BRAF-V600E. Liquid biopsy is a faster method than tissue-based mutation assay. A report from the MD Anderson Cancer Center (MDACC) showed that BRAF V600E-mutated cell-free DNA was highly concordant with the mutation detected with tissue-based assay at over 90% (39). Therefore, immediate submission to genetic testing to explore driver gene alterations is essential to identifying treatment options for this extremely aggressive malignancy. In fact, all published guidelines recommend rapid evaluation of patients with ATC at a high-volume center with expertise in treating ATC because of its extremely aggressive nature (40, 41, 42). For example, the Facilitating ATC Treatment (FAST) program established at MDACC decreased the access time and the number of successful referrals for ATC increased. The team also recommended the rapid identification of BRAF V600E-mutated ATC and the timely initiation of treatment for ATC (43, 44).
Immune checkpoint inhibitors
ICIs such as anti-programmed death-1 (PD-1) antibodies (Abs) and anti-programmed death ligand 1 (PD-L1) Abs have been approved for various malignancies. There have been a few clinical trial results of ICIs for patient with advanced TC. The phase Ib KEYNOTE-028 trial assessed the safety and efficacy of pembrolizumab for patients with PD-L1-positive advanced DTC. Pembrolizumab showed a modest response, with an ORR of 9% (45). Another phase II trial, KEYNOTE-158, reported the result in a DTC cohort (n = 103). In this trial, pembrolizumab also showed a modest response, with an ORR of 7%, and the response did not differ by PD-L1 positivity (ORR of PD-L1-positive 9%, PD-L1-negative 6%). However, the median duration of response was 18.4 months. Therefore, it is essential to find an optimal biomarker for ICIs (46). On the other hand, ATC appeared to be more responsive to ICIs than DTC. Indeed, spartalizumab, one of the anti-PD-1 Abs, was investigated for its efficacy and safety in a phase I/II trial in patients with unresectable or metastatic ATC. Spartalizumab showed encouraging results, with an ORR of 19% (PD-L1-positive; 29%, PD-L1-negative; 0%), irrespective of BRAF mutation status (19). One possible explanation for the better efficacy of anti-PD-1 Abs in ATC patients is that the TIME of ATC may be suitable for immune checkpoint inhibition. For example, CXCL13-positive T lymphocytes were enriched in ATC and might promote the development of early tertiary lymphoid structures in TIME, which is reported to play an important role in antitumor immune response (47, 48). A second possible explanation for the better efficacy of ICIs in ATC is that tumor mutational burden (TMB) is higher in ATC than in poorly differentiated thyroid cancer (PDTC), given that TMB is a biomarker for the efficacy of ICIs (37, 49). A third possible explanation for the better efficacy of ICIs in ATC is that PD-L1 expression in tumor cells, which is a well-known biomarker for ICIs, is reportedly positive in 65–81% of ATC patients (19, 50, 51). Another attractive therapeutic approach is the combination of anti-PD-1 Abs with molecular targeting agents. In a retrospective analysis from MD Anderson Cancer Center (MDACC), 12 patients who were refractory to tyrosine kinase inhibitors (TKIs: lenvatinib, dabrafenib plus trametinib and trametinib alone) received a combination of pembrolizumab plus TKIs. Among them, five patients showed an objective response to the combination of TKIs with pembrolizumab (18). Furthermore, another retrospective study from MDACC (n = 71), which compared the dabrafenib plus trametinib with pembrolizumab and dabrafenib plus trametinib for BRAF V600E-mutated ATC, reported that triple combination therapy showed the most promising efficacy, with an ORR of 73% and OS of 17 months. In total, 23 patients received surgical resection after the triple combination and 11 of 22 patients (50%) with available pathological results showed a pathological complete response (11). Another phase II trial by MDACC of vemurafenib plus cobimetinib with PD-L1 antibody of atezolizumab showed an ORR of 50% and OS of 43.2 months in a cohort of BRAF V600E-mutated ATC patients (n = 19) (52). A phase II trial of neoadjuvant pembrolizumab and dabrafenib plus trametinib for patients with BRAF V600E-mutated ATC is nearing completion (NCT04675710).
Ongoing clinical trials for novel treatment strategy for ATC
As mentioned above, anti-PD-1 Abs plus molecular targeting agents are now being investigated (Table 3). In addition to combination with BRAF/MEK inhibitors, combination therapy of anti-PD-1/PD-L1 Abs with VEGF pathway inhibitors appears promising, given previous findings of a synergistic effect and significant improvement in treatment outcomes in randomized-clinical trials for renal cell carcinoma, hepatocellular carcinoma and endometrial carcinoma (53, 54, 55). Although the peer-reviewed results have yet to be published, a phase II trial of ATLEP investigating the combination of lenvatinib and pembrolizumab for anaplastic and PDTC was reported at European Society of Medical Oncology (ESMO) 2022, and the combination showed a promising efficacy, with an ORR of 52% for ATC and 75% for PDTC (56). Other phase II trials of lenvatinib plus anti-PD-1 Abs for unresectable or metastatic ATC are now underway (Table 3).
Ongoing clinical trials for unresectable or metastatic ATC.
| NCT number | Patient | Treatment | Phase | n | Primary endpoint |
|---|---|---|---|---|---|
| NCT06374602 | ATC | Pembrolizumab + lenvatinib | II | 20 | ORR |
| NCT04171622 | ATC | Pembrolizumab + lenvatinib | II | 25 | OS |
| NCT05696548 | ATC | Nivolumab + lenvatinib | II | 51 | ORR |
| NCT05119296 | ATC | Pembrolizumab | II | 20 | ORR |
| NCT04238624 | BRAF-mutated ATC | Cemiplimab + dabrafenib/trametinib | II | 15 | ORR |
| NCT05102292 | BRAF-mutated ATC | HLX208, a BRAF inhibitor | I/II | 25 | ORR |
| NCT03085056 | ATC | Trametinib + paclitaxel | I | 13 | PFS |
| NCT04552769 | ATC | Abemaciclib | II | 17 | ORR |
| NCT06235216 | |||||
| Cohort A | DTC | Sacituzumab govitecan | II | 21 | ORR |
| Cohort B | ATC | 21 | |||
| NCT06007924 | RAIR-DTC, ATC | Avutometinib + defactinib | II | 30 | ORR |
| NCT04420754 | PDTC and ATC | AIC100 CAR-T (ICAM-1-directed) | I | 70 | AEs |
| NCT03449108 | OC, TNBC and ATC | LN-145 or LN-145-S1 (TIL) | II | 80 | ORR |
DTC, differentiated thyroid cancer; RAIR, radioactive iodine refractory; PDTC, poorly differentiated thyroid cancer; OC, ovarian cancer; TNBC, triple negative breast cancer; TIL, tumor infiltrative lymphocyte; ORR, objective response rate; PFS, progression-free survival; OS, overall survival; AEs, adverse events; ATC, anaplastic thyroid cancer.
Thanks to the BRAF/MEK inhibitors, the prognosis of BRAF V600E-mutated ATC has improved. However, unmet needs remain for ATC patients with BRAF V600E mutation refractory to BRAF/MEK inhibitors and with RAS mutation. Regarding resistance against BRAF/MEK inhibition, pan-RAF inhibitors are now under extensive investigation. Currently approved BRAF inhibitors are potent against class I BRAF V600 mutants, which function as monomers. However, a possible mechanism of acquired resistance is new genetic alterations that induce BRAF dimerization. PF-07799933 is a novel pan-BRAF inhibitor which shows antitumor activity against BRAF V600- and non-V600-mutant cancers preclinically and in treatment refractory patients, including TC patients (57). RAS mutation is a frequent gene alteration in ATC and other cancer types, including lung cancer, colorectal cancer and pancreatic cancer. Its prevalence in ATC is around 20–25% and the frequency of the isoforms of RAS mutation are 14–18% in NRAS, 3–6% in HRAS and 4–6% in KRAS (17, 58). The prognosis of RAS-mutated ATC is extremely poor, and no effective therapeutic option for this population is currently available. Although RAS-activating mutation is identified as a primary driver of oncogenesis in many cancer types, RAS mutation has long been an undruggable target. However, sotorasib and adagrasib, which are KRAS G12C inhibitors, initially showed efficacy in non-small cell lung cancer with KRAS G12C mutation (59, 60). These clinically available KRAS G12C inhibitors are inactive GDP-bound mutant KRAS (so-called KRAS-off inhibitors) since the development of GTP-competitive RAS inhibitors were unfeasible due to high GTP-binding affinity (61). Furthermore, most of the affected tumors develop resistance to these KRAS-off inhibitors by the reactivation of RAS pathway. However, RAS-on inhibitors, which can inhibit all three active GTP-bound isoforms, are now under investigation in clinical trials and are expected to overcome RAS-related resistance mechanisms (Fig. 1). Table 4 shows ongoing clinical trials RAS/RAF-mutated solid tumors, including TC.
Signal pathway in RAS/RAF-mutated TC. RTK, receptor tyrosine kinase.
Citation: European Thyroid Journal 14, 2; 10.1530/ETJ-24-0287
Ongoing trials for RAS/RAF-mutated solid tumors, including TC.
| NCT number | Treatment | Mode of action | Subject | Study phase |
|---|---|---|---|---|
| NCT05907304 | Naporafenib plus trametinib | Pan RAF inhibitor plus MEK inhibitor | RAS Q61X-mutated solid tumor | 1 |
| NCT06270082 | IK-595 | Dual MEK/RAF inhibitor | RAS- or RAF-mutated solid tumor | 1 |
| NCT05585320 | IMM-1-104 | MEK1/2 inhibitor | RAS-mutated solid tumor | 1/2 |
| NCT06299839 | PAS-004 | MEK1/2 inhibitor | RAS/NF1/RAF-mutated solid tumor | 1 |
| NCT05379985 | RMC-6236 | Pan RAS (ON) inhibitor | KRAS G12X- and RAS-mutated solid tumor | 1 |
| NCT06096974 | YL-17231 | Pan RAS inhibitor | KRAS/HRAS/NRAS-mutated solid tumor | 1/2 |
TC, thyroid cancer.
Antibody drug conjugates (ADCs) are composed of three key elements: a monoclonal antibody which binds to target antigen; a covalent linker to ensure that the payload is not prematurely released in the blood but rather within a tumor cell; and a cytotoxic payload that induces tumor cell apoptosis (62). ADCs have shown promise in other cancer types including breast cancer, gastric cancer and urothelial cancer (63, 64, 65, 66, 67, 68, 69, 70). Recently, ADCs have been under extensive development for many cancer types including TC (62). ADC is now an essential treatment strategy and combination with ICIs has shown a synergistic effect on immunogenic cell death and improved survival in urothelial carcinoma (62, 71). Regarding ATC, the TROP-2 (trophoblast cell-surface antigen 2)-directed ADC sacituzumab govitecan is now under investigation for patients with both previously treated DTC and ATC (NCT06235216). Further supporting the development of TROP-2-directed ADC in ATC, TROP-2 is expressed in 50–65% of ATC and TROP-2 overexpression is suggested to be associated with BRAF V600E mutation and aggressive behavior in papillary TC (72, 73, 74).
Adoptive cell therapies such as chimeric antigen receptor T cell therapy (CAR-T) utilizes engineered T cells to target specific antigens such as CD19 or B-cell maturation antigen (BCMA). This treatment has demonstrated high efficacy and gained approval for hematological malignancies (75, 76, 77). However, the application of adoptive cell therapy – including CAR-T therapy – to solid malignancies has not met the expectations raised in hematological malignancies and many challenges in the development of CAR-T therapy for solid malignancies remain. Nevertheless, CAR-T therapy is now under development for patients with DTC who are refractory to standard treatment and for patients with ATC. For example, ICAM-1 is a member of the immunoglobulin superfamily, which is known to play a role in the mediation of cell–cell interactions. ICAM-1 expression is highly correlated with adverse prognostic outcomes in TC patients. Furthermore, ICAM-1-directed CAR-T cells have shown significant therapeutic efficacy in animal models bearing ATC patient-specific tumors (78). Another approach to CAR-T therapy for TC is the targeting of TSH receptor. TSH receptor is highly expressed on papillary TC, and a preclinical study of TSH-R-targeted CAR-T therapy has shown therapeutic efficacy in vivo (79). AIC100 is an ICAM-1-directed CAR-T cell and a phase I trial of AIC100 for poorly differentiated TC and ATC is now underway (NCT05530754).
Conclusion and future perspectives
ATC is one of the rarest and most aggressive malignancies and its prognosis remains dismal. Nevertheless, many clinical trials for ATC are ongoing and treatment outcomes are gradually improving year by year. Most clinical trials, to date, have been small, however, with fewer than 100 patients. Further efforts to develop novel treatments for this malignancy await the development of substantial infrastructure for international collaborative investigation.
Declaration of interest
NK reports grants from Ono Pharmaceutical, Bristol-Meyers Squibb, Astra Zeneca, Chugai Pharmaceutical, Boehringer-Ingelheim, Bayer, GSK and Adlai Nortye outside the submitted work; and honoraria from Bayer, Ono Pharmaceutical, Bristol-Meyers Squibb, Novartis, Eisai, Merck Biopharma, Astra-Zeneca and Merck Sharp & Dohme. IS reports honoraria from Ono Pharmaceutical, Novartis and Eisai.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
Author contribution statement
NK made substantial contributions to the conception, drafting and reviewing of the manuscript. TK and IS made contributions to the drafting and reviewing of the manuscript.
Acknowledgements
We thank Guy Harris DO of Dmed (https://dmed.co.jp) for editing a draft of the manuscript.
References
- 1↑
Maniakas A , Dadu R , Busaidy NL , et al. Evaluation of overall survival in patients with anaplastic thyroid carcinoma, 2000–2019. JAMA Oncol 2020 6 1397–1404. (https://doi.org/10.1001/jamaoncol.2020.3362)
- 2↑
Amin MB , Greene FL , Edge SB , et al. The Eighth Edition AJCC Cancer Staging Manual: continuing to build a bridge from a population-based to a more “personalized” approach to cancer staging. CA Cancer J Clin 2017 67 93–99. (https://doi.org/10.3322/caac.21388)
- 3↑
Hundahl SA , Fleming ID , Fremgen AM , et al. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [see comments]. Cancer 1998 83 2638–2648. (https://doi.org/10.1002/(sici)1097-0142(19981215)83:12<2638::aid-cncr31>3.0.co;2-1)
- 4↑
Are C & Shaha AR . Anaplastic thyroid carcinoma: biology, pathogenesis, prognostic factors, and treatment approaches. Ann Surg Oncol 2006 13 453–464. (https://doi.org/10.1245/aso.2006.05.042)
- 5↑
Smallridge RC , Marlow LA & Copland JA . Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer 2009 16 17–44. (https://doi.org/10.1677/erc-08-0154)
- 6↑
Sugitani I , Onoda N , Ito KI , et al. Management of anaplastic thyroid carcinoma: the fruits from the ATC research consortium of Japan. J Nippon Med Sch 2018 85 18–27. (https://doi.org/10.1272/jnms.2018_85-3)
- 7↑
Smallridge RC , Ain KB , Asa SL , et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 2012 22 1104–1139. (https://doi.org/10.1089/thy.2012.0302)
- 8↑
Jannin A , Giudici F , de la Fouchardiere C , et al. Factors associated with survival in anaplastic thyroid carcinoma: a multicenter study from the ENDOCAN-TUTHYREF network. Thyroid 2023 33 1190–1200. (https://doi.org/10.1089/thy.2023.0164)
- 9↑
Xu B , Zhang L , Setoodeh R , et al. Prolonged survival of anaplastic thyroid carcinoma is associated with resectability, low tumor-infiltrating neutrophils/myeloid-derived suppressor cells, and low peripheral neutrophil-to-lymphocyte ratio. Endocrine 2022 76 612–619. (https://doi.org/10.1007/s12020-022-03008-9)
- 10↑
Jannin A , Escande A , Al Ghuzlan A , et al. Anaplastic thyroid carcinoma: an update. Cancers 2022 14 1061. (https://doi.org/10.3390/cancers14041061)
- 11↑
Hamidi S , Iyer PC , Dadu R , et al. Checkpoint inhibition in addition to dabrafenib/trametinib for BRAF(V600E)-mutated anaplastic thyroid carcinoma. Thyroid 2024 34 336–346. (https://doi.org/10.1089/thy.2023.0573)
- 12↑
Subbiah V , Kreitman RJ , Wainberg ZA , et al. Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Ann Oncol 2022 33 406–415. (https://doi.org/10.1016/j.annonc.2021.12.014)
- 13↑
Subbiah V , Kreitman RJ , Wainberg ZA , et al. Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers: the phase 2 ROAR trial. Nat Med 2023 29 1103–1112. (https://doi.org/10.1038/s41591-023-02321-8)
- 14↑
Tahara M , Kiyota N , Imai H , et al. A phase 2 study of encorafenib in combination with binimetinib in patients with metastatic BRAF-mutated thyroid cancer in Japan. Thyroid 2024 34 467–476. (https://doi.org/10.1089/thy.2023.0547)
- 15↑
Pozdeyev N , Gay LM , Sokol ES , et al. Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers. Clin Cancer Res 2018 24 3059–3068. (https://doi.org/10.1158/1078-0432.ccr-18-0373)
- 16↑
Toda S , Hiroshima Y , Iwasaki H , et al. Genomic landscape and clinical features of advanced thyroid carcinoma: a national database study in Japan. J Clin Endocrinol Metab 2024 109 2784–2792. (https://doi.org/10.1210/clinem/dgae271)
- 17↑
Saito Y , Kage H , Kobayashi K , et al. Comprehensive genomic profiling from C-CAT database unveiled over 80% presence of oncogenic drivers in anaplastic thyroid carcinoma including BRAF, RAS family, NF1, and FGFR1. Clin Endocrinol 2024 101 170–179. (https://doi.org/10.1111/cen.15098)
- 18↑
Iyer PC , Dadu R , Gule-Monroe M , et al. Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma. J Immunother Cancer 2018 6 68. (https://doi.org/10.1186/s40425-018-0378-y)
- 19↑
Capdevila J , Wirth LJ , Ernst T , et al. PD-1 blockade in anaplastic thyroid carcinoma. J Clin Oncol 2020 38 2620–2627. (https://doi.org/10.1200/jco.19.02727)
- 20↑
Shimaoka K , Schoenfeld DA , DeWys WD , et al. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 1985 56 2155–2160. (https://doi.org/10.1002/1097-0142(19851101)56:9<2155::aid-cncr2820560903>3.0.co;2-e)
- 21↑
Ain KB , Egorin MJ & DeSimone PA . Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative anaplastic thyroid cancer health intervention trials (CATCHIT) group. Thyroid 2000 10 587–594. (https://doi.org/10.1089/thy.2000.10.587)
- 22↑
Sosa JA , Elisei R , Jarzab B , et al. Randomized safety and efficacy study of fosbretabulin with paclitaxel/carboplatin against anaplastic thyroid carcinoma. Thyroid 2014 24 232–240. (https://doi.org/10.1089/thy.2013.0078)
- 23↑
Smallridge RC , Copland JA , Brose MS , et al. Efatutazone, an oral PPAR-gamma agonist, in combination with paclitaxel in anaplastic thyroid cancer: results of a multicenter phase 1 trial. J Clin Endocrinol Metab 2013 98 2392–2400. (https://doi.org/10.1210/jc.2013-1106)
- 24↑
Onoda N , Sugino K , Higashiyama T , et al. The safety and efficacy of weekly paclitaxel administration for anaplastic thyroid cancer patients: a nationwide prospective study. Thyroid 2016 26 1293–1299. (https://doi.org/10.1089/thy.2016.0072)
- 25↑
Kawada K , Kitagawa K , Kamei S , et al. The feasibility study of docetaxel in patients with anaplastic thyroid cancer. Jpn J Clin Oncol 2010 40 596–599. (https://doi.org/10.1093/jjco/hyq025)
- 26↑
Waguespack SG , Drilon A , Lin JJ , et al. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. Eur J Endocrinol 2022 186 631–643. (https://doi.org/10.1530/eje-21-1259)
- 27↑
Wirth LJ , Sherman E , Robinson B , et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med 2020 383 825–835. (https://doi.org/10.1056/nejmoa2005651)
- 28↑
Gule MK , Chen Y , Sano D , et al. Targeted therapy of VEGFR2 and EGFR significantly inhibits growth of anaplastic thyroid cancer in an orthotopic murine model. Clin Cancer Res 2011 17 2281–2291. (https://doi.org/10.1158/1078-0432.ccr-10-2762)
- 29↑
Ha HT , Lee JS , Urba S , et al. A phase II study of imatinib in patients with advanced anaplastic thyroid cancer. Thyroid 2010 20 975–980. (https://doi.org/10.1089/thy.2010.0057)
- 30↑
Bible KC , Suman VJ , Menefee ME , et al. A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer. J Clin Endocrinol Metab 2012 97 3179–3184. (https://doi.org/10.1210/jc.2012-1520)
- 31↑
Savvides P , Nagaiah G , Lavertu P , et al. Phase II trial of sorafenib in patients with advanced anaplastic carcinoma of the thyroid. Thyroid 2013 23 600–604. (https://doi.org/10.1089/thy.2012.0103)
- 32↑
Tahara M , Kiyota N , Yamazaki T , et al. Lenvatinib for anaplastic thyroid cancer. Front Oncol 2017 7 25. (https://doi.org/10.3389/fonc.2017.00025)
- 33↑
Wirth LJ , Brose MS , Sherman EJ , et al. Open-Label, single-arm, multicenter, phase II trial of lenvatinib for the treatment of patients with anaplastic thyroid cancer. J Clin Oncol 2021 39 2359–2366. (https://doi.org/10.1200/jco.20.03093)
- 34↑
Higashiyama T , Sugino K , Hara H , et al. Phase II study of the efficacy and safety of lenvatinib for anaplastic thyroid cancer (HOPE). Eur J Cancer 2022 173 210–218. (https://doi.org/10.1016/j.ejca.2022.06.044)
- 35↑
Sparano C , Godbert Y , Attard M , et al. Limited efficacy of lenvatinib in heavily pretreated anaplastic thyroid cancer: a French overview. Endocr Relat Cancer 2021 28 15–26. (https://doi.org/10.1530/erc-20-0106)
- 36↑
Sherman EJ , Harris J , Bible KC , et al. Radiotherapy and paclitaxel plus pazopanib or placebo in anaplastic thyroid cancer (NRG/RTOG 0912): a randomised, double-blind, placebo-controlled, multicentre, phase 2 trial. Lancet Oncol 2023 24 175–186. (https://doi.org/10.1016/s1470-2045(22)00763-x)
- 37↑
Landa I , Ibrahimpasic T , Boucai L , et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Investig 2016 126 1052–1066. (https://doi.org/10.1172/jci85271)
- 38↑
Singarayer R , Mete O , Perrier L , et al. A systematic review and meta-analysis of the diagnostic performance of BRAF V600E immunohistochemistry in thyroid histopathology. Endocr Pathol 2019 30 201–218. (https://doi.org/10.1007/s12022-019-09585-2)
- 39↑
Iyer PC , Cote GJ , Hai T , et al. Circulating BRAF V600E cell-free DNA as a biomarker in the management of anaplastic thyroid carcinoma. JCO Precis Oncol 2018 2 1–11. (https://doi.org/10.1200/po.18.00173)
- 40↑
Mete O , Boucher A , Schrader KA , et al. Consensus statement: recommendations on actionable biomarker testing for thyroid cancer management. Endocr Pathol 2024 35 293–308. (https://doi.org/10.1007/s12022-024-09836-x)
- 41↑
Network® NCC . NCCN clinical practice guidelines in oncology (NCCN Guidelines®), thyroid carcinoma, version 5, 2024, 2025. (https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1470)
- 42↑
Bible KC , Kebebew E , Brierley J , et al. 2021 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 2021 31 337–386. (https://doi.org/10.1089/thy.2020.0944)
- 43↑
Cabanillas ME , Williams MD , Gunn GB , et al. Facilitating anaplastic thyroid cancer specialized treatment: a model for improving access to multidisciplinary care for patients with anaplastic thyroid cancer. Head Neck 2017 39 1291–1295. (https://doi.org/10.1002/hed.24784)
- 44↑
Hamidi S , Dadu R , Zafereo ME , et al. Initial management of BRAF V600E-variant anaplastic thyroid cancer: the FAST multidisciplinary group consensus statement. JAMA Oncol 2024 10 1264–1271. (https://doi.org/10.1001/jamaoncol.2024.2133)
- 45↑
Mehnert JM , Varga A , Brose MS , et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with advanced, PD-L1-positive papillary or follicular thyroid cancer. BMC Cancer 2019 19 196. (https://doi.org/10.1186/s12885-019-5380-3)
- 46↑
Oh DY , Algazi A , Capdevila J , et al. Efficacy and safety of pembrolizumab monotherapy in patients with advanced thyroid cancer in the phase 2 KEYNOTE-158 study. Cancer 2023 129 1195–1204. (https://doi.org/10.1002/cncr.34657)
- 47↑
Han PZ , Ye WD , Yu PC , et al. A distinct tumor microenvironment makes anaplastic thyroid cancer more lethal but immunotherapy sensitive than papillary thyroid cancer. JCI Insight 2024 9 e173712. (https://doi.org/10.1172/jci.insight.173712)
- 48↑
Sautes-Fridman C , Petitprez F , Calderaro J , et al. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer 2019 19 307–325. (https://doi.org/10.1038/s41568-019-0144-6)
- 49↑
Marabelle A , Fakih M , Lopez J , et al. Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study. Lancet Oncol 2020 21 1353–1365. (https://doi.org/10.1016/s1470-2045(20)30445-9)
- 50↑
Cantara S , Bertelli E , Occhini R , et al. Blockade of the programmed death ligand 1 (PD-L1) as potential therapy for anaplastic thyroid cancer. Endocrine 2019 64 122–129. (https://doi.org/10.1007/s12020-019-01865-5)
- 51↑
Chintakuntlawar AV , Rumilla KM , Smith CY , et al. Expression of PD-1 and PD-L1 in anaplastic thyroid cancer patients treated with multimodal therapy: results from a retrospective study. J Clin Endocrinol Metab 2017 102 1943–1950. (https://doi.org/10.1210/jc.2016-3756)
- 52↑
Cabanillas ME , Dadu R , Ferrarotto R , et al. Anti-programmed death ligand 1 plus targeted therapy in anaplastic thyroid carcinoma: a nonrandomized clinical trial. JAMA Oncol 2024 10 1672–1680. (https://doi.org/10.1001/jamaoncol.2024.4729)
- 53↑
Rini BI , Plimack ER , Stus V , et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019 380 1116–1127. (https://doi.org/10.1056/nejmoa1816714)
- 54↑
Finn RS , Qin S , Ikeda M , et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med 2020 382 1894–1905. (https://doi.org/10.1056/nejmoa1915745)
- 55↑
Makker V , Colombo N , Casado Herraez A , et al. Lenvatinib plus pembrolizumab for advanced endometrial cancer. N Engl J Med 2022 386 437–448. (https://doi.org/10.1056/nejmoa2108330)
- 56↑
Dierks C , Ruf J , Seufert J , et al. 1646MO phase II ATLEP trial: final results for lenvatinib/pembrolizumab in metastasized anaplastic and poorly differentiated thyroid carcinoma. Ann Oncol 2022 33 S1295. (https://doi.org/10.1016/j.annonc.2022.07.1726)
- 57↑
Yaeger R , McKean MA , Haq R , et al. A next-generation BRAF inhibitor overcomes resistance to BRAF inhibition in patients with BRAF-mutant cancers using pharmacokinetics-informed dose escalation. Cancer Discov 2024 14 1599–1611. (https://doi.org/10.1158/2159-8290.cd-24-0024)
- 58↑
Wang JR , Montierth M , Xu L , et al. Impact of somatic mutations on survival outcomes in patients with anaplastic thyroid carcinoma. JCO Precis Oncol 2022 6 e2100504. (https://doi.org/10.1200/po.21.00504)
- 59↑
Hong DS , Fakih MG , Strickler JH , et al. KRAS(G12C) inhibition with sotorasib in advanced solid tumors. N Engl J Med 2020 383 1207–1217. (https://doi.org/10.1056/nejmoa1917239)
- 60↑
Janne PA , Riely GJ , Gadgeel SM , et al. Adagrasib in non-small-cell lung cancer harboring a KRAS(G12C) mutation. N Engl J Med 2022 387 120–131. (https://doi.org/10.1056/nejmoa2204619)
- 61↑
Punekar SR , Velcheti V , Neel BG , et al. The current state of the art and future trends in RAS-targeted cancer therapies. Nat Rev Clin Oncol 2022 19 637–655. (https://doi.org/10.1038/s41571-022-00671-9)
- 62↑
Dumontet C , Reichert JM , Senter PD , et al. Antibody-drug conjugates come of age in oncology. Nat Rev Drug Discov 2023 22 641–661. (https://doi.org/10.1038/s41573-023-00709-2)
- 63↑
Verma S , Miles D , Gianni L , et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012 367 1783–1791. (https://doi.org/10.1056/nejmoa1209124)
- 64↑
von Minckwitz G , Huang CS , Mano MS , et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med 2019 380 617–628. (https://doi.org/10.1056/nejmoa1814017)
- 65↑
Bardia A , Hurvitz SA , Tolaney SM , et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med 2021 384 1529–1541. (https://doi.org/10.1056/nejmoa2028485)
- 66↑
Powles T , Rosenberg JE , Sonpavde GP , et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med 2021 384 1125–1135. (https://doi.org/10.1056/nejmoa2035807)
- 67↑
Cortes J , Kim SB , Chung WP , et al. Trastuzumab deruxtecan versus trastuzumab emtansine for breast cancer. N Engl J Med 2022 386 1143–1154. (https://doi.org/10.1056/nejmoa2115022)
- 68↑
Modi S , Jacot W , Yamashita T , et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med 2022 387 9–20. (https://doi.org/10.1056/nejmoa2203690)
- 69↑
Andre F , Hee PY , Kim SB , et al. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet 2023 401 1773–1785. (https://doi.org/10.1016/S0140-6736(23)00725-0)
- 70↑
Shitara K , Bang YJ , Iwasa S , et al. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med 2020 382 2419–2430. (https://doi.org/10.1056/nejmoa2004413)
- 71↑
Powles T , Valderrama BP , Gupta S , et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med 2024 390 875–888. (https://doi.org/10.1056/nejmoa2312117)
- 72↑
Guan Q , Wang Y , Liao T , et al. Overexpression of trophoblast cell surface antigen 2 is associated with BRAF V600E mutation and aggressive behavior in papillary thyroid cancer. Int J Clin Exp Pathol 2018 11 4130–4139.
- 73↑
Toda S , Sato S , Saito N , et al. TROP-2, Nectin-4, GPNMB, and B7-H3 are potentially therapeutic targets for anaplastic thyroid carcinoma. Cancers 2022 14 579. (https://doi.org/10.3390/cancers14030579)
- 74↑
Seok JY , Astvatsaturyan K , Peralta-Venturina M , et al. TROP-2, 5hmC, and IDH1 expression in anaplastic thyroid carcinoma. Int J Surg Pathol 2021 29 368–377. (https://doi.org/10.1177/1066896920978597)
- 75↑
Bishop MR , Dickinson M , Purtill D , et al. Second-line tisagenlecleucel or standard care in aggressive B-cell lymphoma. N Engl J Med 2022 386 629–639. (https://doi.org/10.1056/nejmoa2116596)
- 76↑
Westin JR , Oluwole OO , Kersten MJ , et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N Engl J Med 2023 389 148–157. (https://doi.org/10.1056/nejmoa2301665)
- 77↑
San-Miguel J , Dhakal B , Yong K , et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med 2023 389 335–347. (https://doi.org/10.1056/nejmoa2303379)
- 78↑
Min IM , Shevlin E , Vedvyas Y , et al. CAR T therapy targeting ICAM-1 eliminates advanced human thyroid tumors. Clin Cancer Res 2017 23 7569–7583. (https://doi.org/10.1158/1078-0432.ccr-17-2008)
- 79↑
Li H , Zhou X , Wang G , et al. CAR-T cells targeting TSHR demonstrate safety and potent preclinical activity against differentiated thyroid cancer. J Clin Endocrinol Metab 2022 107 1110–1126. (https://doi.org/10.1210/clinem/dgab819)
