Thursday, October 30, 2014

Gene Study May Improve Thyroid Ca Management

Genetic analysis of nearly 500 papillary thyroid carcinomas revealed new markers for aggressive tumors which could lead to more targeted treatments for patients with the cancer.
Researchers with The Cancer Genome Atlas (TCGA) identified several new cancer genes and several new variations of existing genes in their multiplatform analysis of 496 papillary thyroid carcinomas (PTCs), which account for about 80% of all thyroid cancers.
The findings suggest that thyroid cancers should be reclassified into molecular subtypes that better reflect their underlying signaling and differentiation properties, researcherThomas J. Giordano, MD, PhD, of the University of Michigan in Ann Arbor, and colleagues, wrote in the Oct. 23 issue of Cell.
They also provide new insight into how mutated cancer genes and other genomic alterations drive disease development, said Carolyn Hutter, PhD, who is program director in the division of genomic medicine for the National Human Genome Research Institute and a project team leader for TCGA.
TCGA researchers are conducing genetic analysis on 10,000 tumors from patients with 30 different malignancies to better understand the biological causes of cancer. The goal, Hutter said, is to give investigators the knowledge they need to develop therapies specific to a cancer's genomic profile.
Hutter told MedPage Today that a significant amount of knowledge can be gained by exploring the genomic and cellular alteration similarities and differences of diverse tumor types -- known as pan-cancer analysis.
"We are finding shared driver mutations across cancers, and this has therapeutic implications," she said. "I believe this research will inform the treatment of many cancers in the future."
Thyroid Cancer Incidence Increasing
Thyroid cancer incidence has increased threefold over the last 3 decades, and the prevalence of different genetic profiles has also changed during this period, the researchers wrote.
More than 20,000 new cases of PTC are diagnosed in the U.S. each year, and overtreatment of the highly curable cancer is an increasing concern, Giordano toldMedPage Today. The cancer is treated with surgery, thyroid hormone, and radiation, with a 5-year survival rate of over 95%.
Previous genetic studies suggest a high frequency (70%) of activating somatic alterations of genes encoding effectors in the mitogen-activated protein kinase (MAPK) signaling pathway, including point mutations of BRAF and the RAS genes, as well as fusions of theRET and NTRK1 tyrosine kinases, the researchers noted.
MAPK pathway alterations have been shown to be strongly associated with distinct clinicopathologic characteristics, and gene expression and DNA methylation profiles. Mutations in members of the P13K pathway, such as PTENPIK3CA and AKT1 have also been reported at low frequencies.
As in the other TCGA studies, the analysis of the 496 PTC tumors examined mutations, copy number alterations, mRNA expression, miR expression, protein expression and DNA methylation.
Genetic Cause of Most PTCs Now Known
The analysis confirmed that PTCs are driven mainly by mutations in BRAF, primarily the V600E mutation, or in RAS. The analysis also showed that BRAF-driven tumors have a broader range of genetic complexity than has previously been appreciated.
"We basically defined all the mutations that occur in papillary thyroid cancer, which has a lot of implications for molecular diagnostics and other areas," Giordano said.
Because the BRAF and RAS are mutually exclusive in PTC but share the same signal pathway, the researchers were able to look for gene expression signatures that reflected whether a tumor was more BRAF- or RAS-like.
They observed a low frequency of somatic alterations (relative to other carcinomas) and extended the set of known PTC driver alterations to include EIF1AXPPM1D, and CHEK2.
"The relative low overall density of somatic mutations may be the biological basis for the indolent clinical behavior of PTC," the researchers wrote, adding that the discovery of new driver alterations for the cancer reduces the percentage of PTC cases with an unknown oncogenic driver from 25% to less than 4%, which could have a major impact on preoperative decision-making.
"This paper has implications for who need surgery and for how much surgery they need," Giordano said. "A lot of people in molecular diagnostics are working on this, and now that we have a fuller genomic landscape those molecular tests should become much more informative."
Finding Should Lead to Less Overtreatment
The researchers wrote that molecular testing of mutation hotspots, rearrangements, and gene expression through fine-needle aspiration of specimens is now used in clinical practice in an effort to reduce thyroidectomies performed for benign nodules and tumors and determining the extent of initial surgery (lobectomy versus total thyroidectomy).
Beyond the driver mutations, the researchers identified individual genes (CHEK2, ATM, and TERT) and sets of functionally related genes (chromatin remodeling) with alterations or expression patterns (miR-21 and miR-146b) that define clinically relevant subclasses of papillary thyroid carcinoma and may contribute to loss of differentiation and tumor progression.
"Specifically, increased expression of miR-21 was associated with a known aggressive form of PTC (tall cell variant) and may be a critical event in its pathogenesis," they wrote. "Similarly, TERT promoter mutations identified a subset of aggressive, less-differentiated PTCs, consistent with recent reports. Our study also indicates that BRAFV600E PTC represents a diverse group of tumors, consisting of at least four molecular subtypes, with variable degrees of thyroid differentiation."
The researchers concluded that BRAFV600E PTC should not be considered a homogeneous group in clinical studies and that future studies should include molecular components designed to capture the genetic diversity among PTCs.
"Our paper really cements the notion that, moving forward, clinical trials of thyroid cancer must capture the underlying genetic complexity of individual tumors," Giordano said. "Without this knowledge it will be difficult to fully interpret the results."
PTC Good Model for Studying BRAF and RAS
The demonstration of significant signaling differences in RAS-driven and BRAFv600E-driven PTCs and the relative simplicity of the PTC genome, with dominant mutually exclusive driving events, makes PTC an ideal model for studying the sequencing consequences of BRAF and RAS mutations, he added.
A main conclusion from the analysis is that RAS-driven and BRAFv600E-driven PTCs are dramatically different in their genomic, epigenomic, and proteomic profiles, the researchers noted.
"RAS-driven tumors are so fundamentally different from tumors that have BRAF600E or other BRAF-like mutations that we concluded that they really don't belong together under the big diagnosis of PTC," Giordano said.
This finding is consistent with the known histologic differences and the published literature, but the researchers noted that the breadth and depth of their findings have wider implications for basic pathobiology, tumor classification schemes, and traditional and targeted therapies.
PTC Isn't a 'Uniform, Homogenous Cancer'
Based on the strength of the findings, Giordano and colleagues wrote that pathologic reclassification of follicular-patterned thyroid lesions is justified.
"A refined classification scheme that more accurately reflects the genotypic and phenotypic differences between and within (RAS- and BRAFv600E-driven) PTC would lead to more precise surgical and medical therapy, especially as thyroid cancer therapy enters the realm of precision medicine," they wrote.
Giordano said some of the findings from the analysis are already being incorporated into new PTC assays.
"Our paper clearly shows at least four molecular subtypes, so it is probably no longer appropriate to consider PTC a uniform, homogeneous type of cancer," he told MedPage Today.
TCGA research is funded by the National Institutes of Health.
The researchers declared no relevant relationships with industry.

Primary source: Cell
Source reference: Giordano TJ, et al "Integrated genomic characterization of papillary thyroid carcinoma" Cell 2014; DOI: 10.1016/j.cell.2014.09.050.'

Study on papillary thyroid carcinoma to be presented at 84th Annual Meeting of the ATA

Published on October 30, 2014 at 8:50 AM · No Comments

The prevalence of papillary thyroid carcinoma (PTC), the most common type of thyroid cancer, is increasing rapidly. New research to determine the impact of radioactive iodine (RAI) therapy on survival in PTC, describing a novel blood test able to detect circulating BRAFV600E-positive tumor DNA, and identifying a long non-coding RNA specifically associated with the thyroid that is down-regulated in PTC compared to normal thyroid tissue in patient-derived clinical specimens and cell cultures will be featured in oral presentations delivered at the 84th Annual Meeting of the American Thyroid Association, October 29-November 2, 2014, in Coronado, California.

In the presentation "Impact of Radioactive Iodine on Survival in Papillary Thyroid Carcinoma," Paritosh Suman, M.D. and colleagues from North Shore University Health System (Evanston, IL), explore the benefit of (RAI) treatment following surgery to remove the thyroid in patients with PTC, and whether survival benefit relates to tumor size. In a retrospective study of nearly 285,000 patients treated over 13 years, with a mean follow-up of 7 years, the authors found that 47% of patients had RAI therapy and it showed a small but statistically significant survival benefit regardless of the tumor size.

Carrie Lubitz, M.D., M.P.H., Massachusetts General Hospital (Boston), and coauthors previously described a novel blood-based assay for detecting the V600E mutation in the BRAF gene in patients with melanoma. The BRAFV600E mutation is the most common genetic alteration in patients with PTC and is associated with a poorer prognosis, higher risk of metastasis and mortality, and resistance to RAI therapy. In the presentation "Detection of Circulating BRAFV600E in Patients with Papillary Thyroid Carcinoma," Lubitz et al. used the assay to measure circulating BRAFV600E levels in blood samples from patients with PTC and compared the results to conventional BRAFV600E assays. Circulating BRAFV600E levels were detectable in the blood of PTC patients, suggesting the feasibility of using the assay for diagnosis, post-operative surveillance, and to monitor treatment response to BRAF inhibitors.

Carmelo Nucera, M.D., Ph.D., Harvard Medical School and Beth Israel Deaconess Medical Center (Boston, MA) and colleagues discovered a large non-coding RNA (LincRNA) neighboring the thyroid peroxidase (TPO) gene that is present in significantly lower numbers in BRAFV600E-positive PTC tissue samples than in normal thyroid tissue. The LincRNA is specifically associated with thyroid tissue compared to other human tissues or cell types. The authors propose that the LincRNA might have an important role in regulating iodine metabolism associated gene expression and could serve as a biomarker for monitoring patients undergoing targeted therapies and for early diagnosis of BRAFV600E-PTC. They describe their findings in the presentation "Identification of Iodine Metabolism-Associated Large Non-coding RNA (LincRNA) Differentially Expressed in BRAFV600E-postivie Papillary Thyroid Cancer Versus Normal Thyroid Tissue."

"The identification of new circulating markers, if validated, should improve both the diagnosis and longitudinal follow-up of patients with papillary thyroid cancer," says Robert C. Smallridge, M.D. President Elect of the ATA.

American Thyroid Association (ATA)

Novel therapeutic approaches to improve thyroid cancer outcomes

Published on October 30, 2014 at 8:08 AM · No Comments

Novel therapeutic approaches to improve outcomes in thyroid cancer, for example using targeted delivery of cytotoxic drugs to tumor cells, will be among the topics featured in oral and poster presentations delivered at the 84th Annual Meeting of the American Thyroid Association, October 29-November 2, 2014, in Coronado, California. Researchers will also present the results of an updated analysis from a national study of thyroid hormone suppression therapy, and the potential survival benefit from combining lithium with radioiodine therapy in metastatic thyroid cancer.

Renata Jaskula-Sztul, Ph.D., University of Wisconsin Medical School (Madison), and colleagues will deliver an oral presentation entitled "Targeted Delivery of a Novel Histone Deacetylase Inhibitor, AB3, Using Unimolecular Micelles to Improve Antitumor Effect in Medullary Thyroid Cancer." MTC is a neuroendocrine tumor that accounts for 3-5% of thyroid cancers. Treatment includes surgical removal of the tumor and adjuvant therapies designed to target any remaining tumor cells locally or that may have metastasized to distant locations. The researchers describe the use of tumor-targeting micelles (unimolecular micelles conjugated with the somatostatin analog KE108) to deliver a novel antitumor agent, the histone deacetylase inhibitor AB3. They report that targeted delivery of the nanocarrier was associated with increased uptake of the micelles by MTC cells in culture and an improved cytotoxic effect, suggesting the possibility for better therapeutic outcomes and less systemic toxicity with this type of drug delivery approach in patients.

In the presentation "Long-Term Moderate Thyroid Hormone Suppression Therapy Is Associated with Improved Outcomes in Differentiated Thyroid Carcinoma: National Thyroid Cancer Treatment Cooperative Study Group Registry Analysis 1987-2012," a team of researchers provides an updated analysis of nearly 5,000 patients with differentiated thyroid carcinoma (DTC), evaluating their overall survival and disease-free survival based on their initial treatment (thyroidectomy, post-operative radioiodine [RAI]) and long-term TSH-suppressive thyroid hormone therapy (THST). Aubrey Carhill, M.D., The University of Texas MD Anderson Cancer Center (Houston), and coauthors confirm that thyroidectomy followed by RAI correlates with survival benefit in high risk but not low risk disease patients. Only moderate (not aggressive) THST was associated with improved survival, in all disease stages, and was predictive of improved disease-free survival for at least 3 years in patients identified as disease-free after initial therapy.

The poster presentation "Usefulness of Combined Therapy with 131I and Lithium in Patients with Metastatic Radioiodine-refractory Thyroid Cancer" describes a study by Ilhan Lim, M.D., Ph.D. and colleagues, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences (Seoul), of the therapeutic potential of lithium in combination with RAI in patients with metastatic DTC that has not responded to RAI treatment. Patients received oral lithium for 7 days, from 5 days before RAI therapy to 1 day after RAI. The researchers report a 45% response rate to the combined therapy after 6 months: 13/29 patients had stable disease and 16/29 patients had progressive disease. While the patients with stable disease at 6 months had better progression-free survival over time, they did not have better overall survival than the patients with progressive disease at 6 months. Compared to patients who received only conventional RAI, the patients who received combined treatment showed slightly higher 10-year survival rates than patients with conventional RAI (67.9% vs. 66.8%, p>0.05). Although it is not possible to compare the two groups equally, patients who received Li combined treatment survived longer (126.2 vs. 105.4 months) after propensity score matching.

American Thyroid Association (ATA)