Mabel Ryder

Evolving molecularly targeted therapies for advanced-stage thyroid cancers

Increased understanding of disease-specific molecular targets of therapy has led to the regulatory approval of two drugs (vandetanib and cabozantinib) for the treatment of medullary thyroid cancer (MTC), and two agents (sorafenib and lenvatinib) for the treatment of radioactive- iodine refractory differentiated thyroid cancer (DTC) in both the USA and in the EU. The effects of these and other therapies on overall survival and quality of life among patients with thyroid cancer, however, remain to be more-clearly defined. When applied early in the disease course, intensive multimodality therapy seems to improve the survival outcomes of patients with anaplastic thyroid cancer (ATC), but salvage therapies for ATC are of uncertain benefit. Additional innovative, rationally designed therapeutic strategies are under active development both for patients with DTC and for patients with ATC, with multiple phase II and phase III randomized clinical trials currently ongoing. Continued effort is being made to identify further signalling pathways with potential therapeutic relevance in thyroid cancers, as well as to elaborate on the complex interactions between signalling pathways, with the intention of translating these discoveries into effective and personalized therapies. Herein, we summarize the progress made in molecular medicine for advanced-stage thyroid cancers of different histotypes, analyse how these developments have altered — and might further refine — patient care, and identify open questions for future research.

Leveraging the immune system to treat advanced thyroid cancers

Inflammation has long been associated with the thyroid and with thyroid cancers, raising seminal questions about the role of the immune system in the pathogenesis of advanced thyroid cancers. With a growing understanding of dynamic tumour-immune cell interactions and the mechanisms by which tumour cells evade antitumour immunity, the field of cancer immunotherapy has been revolutionised. In this Review, we provide evidence to support the presence of an antitumour immune response in advanced thyroid cancers linked to cytotoxic T cells and NK cells. This antitumour response, however, is likely blunted by the presence of immunosuppressive pathways within the microenvironment, facilitated by tumour-associated macrophages or increased expression of negative regulators of cytotoxic T-cell function. Current and future efforts to incorporate immune-based therapies into existing tumour cell or endothelial-derived therapies-eg, with kinase inhibitors targeting tumour-associated macrophages or antibodies blocking negative regulators on T cells-could provide improved and durable responses for patients with disease that is otherwise refractory to treatment.

Pembrolizumab-Induced Thyroiditis: Comprehensive Clinical Review and Insights Into Underlying Involved Mechanisms

Context Thyroid immune-related adverse events (irAEs) in patients treated with programmed death receptor-1 (PD-1) blockade are increasingly recognized as one of the most common adverse effects. Our aim was to determine the incidence and examine the potential mechanisms of anti-PD-1-induced thyroid irAEs. Design Single-center, retrospective cohort study. Patients and Measurements We studied 93 patients with advanced cancer (ages 24 to 82 years; 60% males) who received at least one infusion of pembrolizumab. Thyroid test results and thyroid imaging modalities were reviewed. Comprehensive 10-color flow cytometry of peripheral blood was performed. Results Thirteen (14%) thyroid irAEs were observed. Thyroiditis occurred in seven patients (54%), from which four recovered. New onset of hypothyroidism overt/subclinical developed in three patients. Levothyroxine dosing required doubling in three patients with a known history of hypothyroidism. Thyroperoxidase antibodies were positive in the minority of the patients [4/13 (31%)] and diffuse increased 18fludeoxyglucose uptake of the thyroid gland was observed in the majority [7/11 (64%)] of patients. We observed more circulating CD56+CD16+ natural killer (NK) cells and an elevated HLA-DR surface expression in the inflammatory intermediate CD14+CD16+ monocytes in anti-PD-1-treated patients. Conclusions Thyroid dysfunction is common in cancer patients treated with pembrolizumab. Reversible destructive thyroiditis and overt hypothyroidism are the most common clinical presentations. The mechanism of thyroid destruction appears independent of thyroid autoantibodies and may include T cell, NK cell, and/or monocyte-mediated pathways. Because the thyroid is a frequent target of anti-PD-1 therapies, patients with therapeutically refractory thyroid cancer may be ideal candidates for this treatment.

A multidisciplinary approach to toxicity management of modern immune checkpoint inhibitors in cancer therapy

Immune-related Adverse Events (irAEs) are the most significant toxicities associated with the use of checkpoint inhibitors, and result from disinhibition of the host’s immune homeostasis. The adverse effects experienced from immunotherapy are significantly different from those of chemotherapy and, to a lesser extent, targeted therapy. Early recognition and diagnosis of these toxicities is often challenging, but is critically important because of the potentially life-threatening nature and associated morbidity. Gastrointestinal, dermatologic, endocrine, and liver toxicities are the most commonly observed. Less commonly, the eyes, pancreas, kidneys, lungs, bone marrow, or nervous system may be affected. Although most irAEs may resolve with supportive care or discontinuation of drug, in severe cases, they may require hospitalization and immune suppressants, such as steroids, and/or may even cause death. The management of immune-related side effects requires a multidisciplinary approach.

Expression of PD-1 and PD-L1 in anaplastic thyroid cancer patients treated with multimodal therapy: Results from a retrospective study

Context Anaplastic thyroid cancer (ATC) is rare and a highly fatal malignancy. The role of programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) as prognostic and/or predictive markers in ATC is unknown. Objective Multimodal therapy offers the best chance at tumor control. The objective of this study was to detect potential associations of PD-1/PD-L1 axis variables with outcome data in ATC. Design Retrospective study of a uniformly treated cohort. Setting Single institution retrospective cohort study. Patients or Other Participants Sixteen patients who received intensity-modulated radiation therapy (15 had preceding surgery) were studied. Main Outcome Measure Patients treated with multimodal therapy were followed and assessed for overall survival (OS) and progression-free survival (PFS). Results All samples demonstrated PD-1 expression in inflammatory cells whereas tumor cells were primarily negative. PD-L1 was expressed on ATC tumor cells in most samples and showed mainly membranous staining. High PD-1 expression (>40% staining) in inflammatory cells was associated with worse overall survival (OS; hazard ratio, 3.36; 95% confidence interval, 1.00 to 12.96; P < 0.05) and trended toward worse PFS, whereas high PD-L1 expression in tumor cells (>33% staining) trended toward worse PFS and OS. Conclusion PD-1/PD-L1 pathway proteins are highly expressed in ATC tumor samples and appear to represent predictive markers of PFS and OS in multimodality-treated ATC patients.

Strategies for improving the reporting of human immunophenotypes by flow cytometry

BackgroundFlow cytometry is the gold standard for phenotyping and quantifying immune cells. New technologies have greatly increased our capacity to measure both routine and complex immunophenotypes. The reporting of immunophenotype data is not consistent in human studies yet it is quite critical for understanding disease specific changes, responses to immunotherapies, and normal immune homeostasis. Here we examine the barriers that hinder cross comparisons of flow cytometry data collected from human studies and clinical trials.FindingsWe demonstrate that phenotypes reported as percentages within a cell compartment (i.e. myeloid derived suppressor cells as a percent of mononuclear cells) without providing data on the parent population may contribute to misleading conclusions. The enumeration of phenotypes as cell counts (cells/μl) provides a basis to more accurately compare the relationships among phenotypes. Finally, we provide evidence that density gradient centrifugation, which eliminates the ability to measure phenotypes as cell counts, can affect the expression of surface markers and consequently alter the distribution of particular immunophenotypes.ConclusionsWe propose that by measuring immunophenotypes as cell counts from minimally manipulated samples (whole blood) will improve the reporting of flow data and facilitate more direct comparisons of data across human studies.

Survival in Response to Multimodal Therapy in Anaplastic Thyroid Cancer

Context Historical outcomes in anaplastic thyroid cancer (ATC) have been dismal. Objective To determine whether an initial intensive multimodal therapy (MMT) is associated with improved ATC survival. Design MMT was offered to all patients with newly diagnosed ATC treated at the Mayo Clinic from 2003 through 2015; MMT vs care with palliative intent (PI) was individualized considering clinical status and patient preferences. Outcomes were retrospectively analyzed by American Joint Committee on Cancer stage and treatments compared with patient cohort data from 1949 through 1999. Patients Forty-eight patients (60% male; median age, 62 years); 18 treated with PI, 30 with MMT. Main Outcome Measure Overall survival (OS) and progression-free survival determined by Kaplan-Meier method. Results Median OS and 1-year survival for the later cohort were 9 months [95% confidence interval (CI), 4 to 22 months] and 42% (95% CI, 28% to 56%) vs 3 months and 10% for the earlier cohort. Median OS was 21 months compared with 3.9 months in the pooled MMT vs PI groups for the later cohort [hazard ratio (HR), 0.32; P = 0.0006]. Among only patients in the later cohort who had stage IVB disease, median OS was 22.4 vs 4 months (HR, 0.12; 95% CI, 0.03 to 0.44; P = 0.0001), with 68% vs 0% alive at 1 year (MMT vs PI). Among patients with stage IVC cancer, OS did not differ by therapy. Conclusion MMT appears to convey longer survival in ATC among patients with stage IVA/B disease.

Differentiation of Benign and Malignant Thyroid Nodules by Using Comb-push Ultrasound Shear Elastography: A Preliminary Two-plane View Study

RATIONALE AND OBJECTIVES Low specificity of traditional ultrasound in differentiating benign from malignant thyroid nodules leads to a great number of unnecessary (ie, benign) fine-needle aspiration biopsies that causes a significant financial and physical burden to the patients. Ultrasound shear wave elastography is a technology capable of providing additional information related to the stiffness of tissues. In this study, quantitative stiffness values acquired by ultrasound shear wave elastography in two different imaging planes were evaluated for the prediction of malignancy in thyroid nodules. In addition, the association of elasticity measurements with sonographic characteristics of thyroid gland and nodules is presented. MATERIALS AND METHODS A total number of 155 patients (106 female and 49 male) (average age 57.48 ± 14.44 years) with 173 thyroid nodules (average size 24.89 ± 15.41 mm, range 5-68 mm) scheduled for fine-needle aspiration biopsy were recruited from March 2015 to May 2017. Comb-push shear elastography imaging was performed at longitudinal and transverse anatomic planes. Mean (Emean) and maximum (Emax) elasticity values were obtained. RESULTS Measurements at longitudinal view were statistically significantly higher than measurements at transverse view. Nodules with calcifications were associated with increased elasticity, and nodules with a vascular component or within an enlarged thyroid gland (goiter) were associated with a lower elasticity value. Receiver operating characteristic curve analysis was performed for Emean and Emax at each imaging plane and for the average of both planes. Sensitivity of 95.45%, specificity of 86.61%, 0.58 positive predictive value, and 0.99 negative predictive value were achieved by the average of the two planes for each Emean and Emax parameters, with area under the curve of 92% and 93%, and a cutoff value of 49.09 kPa and 105.61 kPa, respectively. CONCLUSIONS The elastic properties of thyroid nodules showed promise to be a good discriminator between malignant and benign nodules (P < .0001). However, probe orientation and internal features such as calcifications, vascular component, and goiter may influence the final elastography measurements. A larger number of malignant nodules need to be studied to further validate our results.

Methodology, criteria and characterization of patient-matched thyroid cell lines and patient-derived tumor xenografts.

Objective To investigate the molecular underpinnings of thyroid cancer, preclinical cell line models are crucial; however, ∼40% of these have been proven to be either duplicates of existing thyroid lines or even nonthyroid-derived lines or are not derived from humans at all. Therefore, we set out to establish procedures and guidelines that should proactively avoid these problems, which facilitated the creation of criteria to make valid preclinical models for thyroid cancer research. Design Based on our recommendations, we systematically characterized all new cell lines that we generated by a standardized approach that included (1) determination of human origin, (2) exclusion of lymphoma, (3) DNA fingerprinting and histological comparisons to establish linkage to presumed tissue of origin, (4) examining thyroid differentiation by screening two to three thyroid markers, (5) examination of biological behavior (growth rate, tumorigenicity), and (6) presence of common thyroid cancer genetic changes (TP53, BRAF, PTEN, PIK3CA, RAS, TERT promoter, RET/PTC, PAX8/PPARγ, NF1, and EIF1AX). Results We established seven new thyroid cell lines (LAM136, EAM306, SDAR1, SDAR2, JEM493, THJ529, and THJ560) out of 294 primary culture attempts, and 10 patient-derived tumor xenografts (PDTXs; MC-Th-95, MC-Th-374, MC-Th-467, MC-Th-491, MC-Th-493, MC-Th-504, MC-Th-524, MC-Th-529, MC-Th-560, and MC-Th-562) out of 67 attempts. All were successfully validated by our protocols. Conclusions This standardized approach for cell line and PDTX characterization should prevent (or detect) future cross-contamination and ensure that only valid preclinical models are used for thyroid cancer research.

Treatment of lateral neck papillary thyroid carcinoma recurrence after selective lateral neck dissection

Background: There is a paucity of data regarding optimal treatment options and outcomes for recurrent disease after lateral neck dissection in patients with papillary thyroid carcinoma. Methods: Retrospective review of patients who underwent either percutaneous ethanol injection or surgery for first‐time ipsilateral recurrences after ipsilateral lateral neck dissection for papillary thyroid carcinoma was performed. Results: Follow‐up data were available for 54 patients with recurrences in 57 lateral necks treated by either percutaneous ethanol injection (n = 32) or surgery (n = 25). Tumor burden at the time of lateral neck recurrence differed between the groups including the largest lymph node diameter (mean: 13 mm vs 18 mm, P < .01) and the mean number of metastatic lymph nodes identified on ultrasound (1.3 vs 1.9, P = .04). Each modality alone achieved similar estimated rates of disease control at 36 months (75% for percutaneous ethanol injection and 74% for surgery, P = .8) with similar number of reinterventions (1.8 for percutaneous ethanol injection, 1.6 for surgery, P = .6). Conclusions: Both ethanol ablation and surgery can achieve disease control in the majority of patients with recurrences after ipsilateral lateral neck dissection for papillary thyroid carcinoma. Ethanol ablation, when used for treatment of a single small lymph node, can result in outcomes that are similar to reoperative surgery for larger and multiple lymph nodes.