Oncology/Hematology

Biomarkers Tied to Recurrent Thyroid Cancer

Published: Oct 28, 2013 | Updated: Oct 28, 2013

By Elizabeth DeVita Raeburn, Contributing Writer, MedPage Today

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A pair of microRNA (miRNA) biomarkers were strong predictors of papillary thyroid cancer (PTC) recurrence, according to researchers.

MicroRNA-222 and microRNA-146b were overexpressed 10.8-fold and 8.9-fold in the tissue samples of patients with recurrent PTC compared with samples from patients who did not recur (P=0.014 and P=0.038, respectively), reported James C. Lee, FRACS, of the Kolling Institute for Medical Research in St. Leonards, Australia, and colleagues.

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After the PTC group underwent total thyroidectomy, the biomarkers decreased 2.7-fold and 5.1-fold, respectively (P=0.03 for both), in patient plasma draws, they added.

Both miRNAs were also elevated in plasma of another subset of patients with multinodular goiter, and decreased after total thyroidectomy.

This study is the largest comparing pre- and postoperative plasma miRNA levels in patients with PTC, and the first to include patients with multinodular goiter, the authors pointed out.

However, the results suggest the presence of these biomarkers in plasma might not be useful in diagnosing new cases of PTC, because they don't appear to distinguish between malignant and benign follicular growth, they cautioned.

PTC is the most common endocrine malignancy, and its incidence has been on the rise over the past few decades. For most patients, the prognosis is good, with more than 90% surviving to at least 10 years. However, up to 30% of patients recur at that point, and predicting that recurrence has been a challenge.

Specific biomarkers indicating disease aggressiveness, or likelihood of recurrence, would allow aggressive adjuvant therapy or more rigorous surveillance for these cohorts, while sparing other patients unnecessary treatment and surveillance.

Previous researchers have reported that they have been able to measure miRNA levels in fine-needle aspiration samples.

"If differential levels of recurrence-associated miRNAs can be demonstrated in fine-needle aspiration samples, then even surgical decisions, such as the extent of lymph node dissection, may be guided by miRNA levels," Lee's group wrote.

A number of molecular markers for severity of disease and recurrence have been investigated, including the BRAF mutation, p27, p21, cyclin D1, CEACAM-1, osteopnton and E-cadheren. "However, to date, none have reached the stage of clinical application," the authors said.

The researchers used archival tissue samples from patients who had recurred with PTC and patients who had not recurred for the first part of the study. For the second, they recruited healthy volunteers, as well as patients newly diagnosed with PTC or multinodular goiter who were scheduled to undergo total thyroidectomy.

Blood samples were drawn both pre-and postoperatively for the patients who underwent surgery.

According to the results, miRNA-222 and miRNA-146b were associated with the presence of the BRAF mutation, suggesting that these biomarkers may be part of an oncogenic signature associated with more aggressive disease.

A previous study reported miRNA-146b and miRNA-222 over-expressed in aggressive PTC, and an in vitro study found that miRNA-146b overexpression increased cell migration and invasion, as well as resistance to chemotherapy-induced apoptosis.

Although these results are promising, the authors said larger, longitudinal studies are need to confirm the potential of these two miRNAs as surveillance tools and as indicators of the severity of disease.

Further in vitro studies are also required "to clarify the mechanism of action of these miRNAs within PTC tissue in the context of recurrence as well as their mechanism of secretion into, and functions within, the circulation," they concluded.

This research was partly funded by an institutional cancer grant to the University of Sydney. Lee was the recipient of the Neville Brown Scholarship and Australian Postgraduate Award in 2012.

The authors reported no conflicts of interest.

TKI Switch Shows Promise in Thyroid Cancer

TKI Switch Shows Promise in Thyroid Cancer:

'via Blog this'

Kinase inhibitors target advanced thyroid cancer - ONA

Kinase inhibitors target advanced thyroid cancer - ONA:

'via Blog this'

Researchers Identify A Protein That May Predict Who Will Have Thyroid Cancer Recurrence - Health News - redOrbit

October 9, 2013

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Findings from the first study to show a specific function of the immune system in the proliferation of thyroid cancer may ultimately change the course of treatment

Researchers at the National Institutes of Health (NIH), Bethesda, MD, have taken the first steps to determine if a protein, called Programmed Death Ligand 1 (PD-L1), can help to predict which thyroid cancer patients will most likely have a recurrence of the disease. Study findings were presented today at the 2013 Clinical Congress of the American College of Surgeons.

More than 80 percent of patients diagnosed with thyroid cancer have a type called papillary thyroid cancer, which usually grows on only one side of the thyroid gland, according to the American Cancer Society.1 Most of these patients are women and some have been exposed to ionizing radiation, reports the Centers for Disease Control and Prevention.2

Although the five-year survival rate is 93 percent at stage three,3 the number of people diagnosed with papillary thyroid cancer each year has more than doubled in the last 25 years to 60,220, the American Cancer Society reports.4 Although thyroid cancer is not usually aggressive, the National Cancer Institute estimates that 10 to 30 percent of these patients still end up having a recurrence.5

Previous research has already shown a connection between papillary thyroid cancer and the immune system through inflammatory thyroid disease, reports study coauthor Ryan J. Ellis, a researcher in the endocrine oncology branch of the NIH and a fourth-year medical student at the University of Pennsylvania’s Perelman School of Medicine.

This NIH study specifically focused on the role of a specific protein, PD-L1, which is normally present in the body’s immune system to assist with communication between immune cells and help regulate immune response. PD-L1 is also present in some papillary thyroid cancer cells, and may actually help to protect the tumor from the immune system.

“If the immune system tries to approach the tumor and its immediate surrounding area, PD-L1 will make the immune system take a step back and turn off,” Mr. Ellis explained.

This protection may then allow the cancer to grow and eventually spread, often to the lymph nodes.

Focusing on prognosis

For other types of cancer, previous clinical trials have used certain treatments to block PD-L1 on the cancerous tumor, allowing the immune system to infiltrate and attack the cancer, explained Myriem Boufraqech, PhD, study coauthor and researcher in the endocrine oncology branch of the NIH. However,

Dr. Boufraqech, Mr. Ellis, and their colleagues wanted to deter-mine the role that PD-L1 plays in predicting whether patients have a more aggressive form of papillary thyroid cancer.

For this study, the researchers looked at resected tumor samples from more than 200 patients. The tumor samples had been stored at extreme freezing temperatures, about negative 80 degrees Celsius. They then used gene expression microarrays to collect data on more than 30,000 genes in each sample—including the PD-L1 gene.

Next, the investigators were able to confirm these findings by focusing on PD-L1 expression in each sample. The final step was to compare PD-L1 levels with medical records of how the patients fared.

“In this cohort of patients, we found that those with high levels of PD-L1 were about twice as likely to have a recurrence as patients with normal PD-L1 levels,” Mr. Ellis reported. Results also showed that higher levels of PD-L1 were associated with a higher tendency of having the cancer spread to the lymph nodes.

Next steps and ultimate goals

Mr. Ellis explained that this study is still too early and the cohort group is too small to say whether PD-L1 is associated with a higher likelihood of dying from papillary thyroid cancer, mainly because the number of people who die from the disease is very low.

“This is the first study to show a specific function of the immune system in the proliferation of thyroid cancer,” said Lisa Zhang, PhD, study coauthor and a researcher in the endocrine oncology branch of the NIH.

As the study moves from data analysis into a mouse model and ultimately to clinical trials, Mr. Ellis said the findings could potentially change how surgeons provide care to papillary thyroid cancer patients before and after their cancer operations. “The real potential is being able to differentiate, by the time of surgical treatment, who may have a more aggressive type of thyroid cancer,” Mr. Ellis said. “Surgeons could potentially look at the patient’s PD-L1 expression following biopsy or immediately after resection to see if the patient is more likely to have a recurrence.”

“That approach could change the course of treatment,” he added, “and allow surgeons, medical endocrinologists, and oncologists to more intelligently make postoperative decisions for their patients that would help to reduce the risk of a recurrence.” Electron Kebebew, MD, FACS, also participated in this study.

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On the Net:

• American College of Surgeons

Source: American College of Surgeons

Thyroid Cancer Raises Heart Risk

http://www.medpagetoday.com/Endocrinology/GeneralEndocrinology/42139

By Todd Neale, Senior Staff Writer, MedPage Today

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Having had differentiated thyroid cancermay increase the risk of dying from cardiovascular disease, even after accounting for traditional cardiovascular risk factors, a Dutch study showed.

Over about 9 years of follow-up, the risk of cardiovascular death in these cancer patients was more than three times as high (hazard ratio 3.35, 95% CI 1.66-6.74) and the risk of all-cause mortality was more than four times as high (HR 4.40, 95% CI 3.15-6.14) as patients in the general population, according to Joop Lefrandt, MD, PhD, of the University Medical Center Groningen in the Netherlands, and colleagues.

"To the best of our knowledge, this is the first study reporting an increased risk of cardiovascular mortality in patients with differentiated thyroid carcinoma," they reported online in the Journal of Clinical Oncology, adding that the results "stress the importance of a close follow-up and could encourage assessment and treatment of cardiovascular risk factors during follow-up for [the cancer]."

The researchers also found that each 10-fold drop in the level of thyroid stimulating hormone (TSH) was associated with a greater risk of cardiovascular mortality (HR 3.08, 95% CI 1.32-7.21), "supporting the current European Thyroid Association and the American Thyroid Association guidelines of tempering TSH suppression in patients with low risk of cancer recurrence."

Differentiated thyroid carcinoma is associated with a relatively good prognosis, with reported 10-year survival rates of 80% to 95%.

"Since the survival rate ... is high, there is increasing interest in possible harmful long-term effects of treatment," the authors noted. "Particularly, the use and the extent of thyroid hormone suppression therapy have become controversial in recent years, since thyroid hormone suppression therapy may increase cardiovascular morbidity."

To explore the issue, Lefrandt and colleagues examined data from 524 patients treated for differentiated thyroid carcinoma at their center. All were diagnosed from January 1980 to June 2010 and were treated with total thyroidectomy and radioiodine ablation. The patients were then matched by age and sex to 1,572 cancer-free participants in a population-based study performed in the same geographic region.

Additional therapies administered in the carcinoma group included adjuvant neck radiotherapy for local uncontrolled disease in 35 patients and systemic sorafenib (Nexavar) for progressive distant metastatic disease in five patients. No other systemic cancer therapies were used.

In both groups, the average age was 49 and about a quarter of the patients were men. Median follow-up was 8.5 years in the carcinoma group and 10.5 years in the control group.

During follow-up, 19.1% of the patients in the carcinoma group died, including 4.2% from cardiovascular disease (myocardial infarction, stroke, abdominal aortic aneurysm, or pulmonary embolism), 7.4% from progression of the cancer, and 7.4% from other or unknown causes.

In the control group, 5.4% died from any cause, including 1.5% from cardiovascular disease and 3.9% from other or unknown causes.

Risks of both all-cause and cardiovascular mortality were higher in the carcinoma group after adjustment for age, sex, and established cardiovascular risk factors, including body mass index, diabetes, smoking, hypertension, hypercholesterolemia, and history of cardiovascular disease at baseline.

And lower levels of TSH were associated with an increase in cardiovascular -- but not all-cause -- mortality after adjustment for those same factors plus differentiated thyroid carcinoma risk classification, histology, cumulative radioiodine dose, and neck radiotherapy.

Although the mechanism behind the elevated risk of cardiovascular death is unknown, "an increased risk for atrial fibrillation, impaired diastolic function, and an increased left ventricular mass have been found in patients with differentiated thyroid carcinoma receiving thyroid hormone suppression therapy," according to the authors. "Induction of these adverse cardiovascular effects ... may lead to an increased risk for stroke, heart failure, and myocardial infarction, respectively, and possibly contribute to the increased cardiovascular mortality."

The study was limited, they acknowledged, by the observational design, which precludes a definitive conclusion about causality, by differences in how causes of death were determined in the cases and the controls, by changes in the TSH assays used over time, and by possible bias stemming from trends in the treatment of cardiovascular disease.

The authors reported no conflicts of interest.

Research Round Up: Large Study Finds Association between Marriage Status and Improved Cancer Outcomes

Posted online September 23, 2013 on www.jco.org.

An analysis of data collected in a large retrospective study showed that married patients tend to live longer after a cancer diagnosis than unmarried patients. Married patients are also more likely to have earlier-stage cancer at diagnosis and more likely to receive appropriate treatments, such as surgery and radiation therapy.  The findings also suggest that more effort should be invested in improving social support services for unmarried patients with cancer.

For patients who are married, spouses are the primary source of social support ─ they share the emotional burden of the illness, encourage the patient to seek evaluation of abnormal symptoms and pursue screening, accompany patients to doctor’s visits, ensure they follow through with recommended treatments and receive appropriate pain management and help them cope with the various mental and emotional stresses of a cancer diagnosis and care. Married people also tend to have less anxiety and depression, two factors that have been linked to decreased cancer survival.

In this study, researchers assessed national cancer registry data of more than 700,000 patients diagnosed between 2004 and 2008. They found that being married decreased the odds of having metastatic disease when first diagnosed with cancer by 17% and increased the odds of receiving appropriate therapy by 53%. At any given time, a patient who was married was 20% more likely to be alive, on average, than a patient who was not married, regardless of tumor stage at diagnosis.

These benefits of marriage were consistent among each of the ten leading causes of cancer-related death in the United States ─ lung, colorectal, breast, pancreatic, prostate, liver/bile duct, non-Hodgkin lymphoma, head and neck, ovarian, and esophageal cancer, and persisted when researchers accounted for differences in characteristics of married vs. unmarried patients (for example, household income, education, race, gender).

What This Means for Patients

These findings add to the growing body of literature that suggests that marriage and, more broadly, social support helps patients cope with and survive cancer. Patients who are married tend to have better social support networks in place. Patients who are not married, however,  are encouraged to reach out to family and friends, cancer and faith-based support groups, social workers, or their doctors, nurses and other healthcare professionals to obtain the social support that they need, including assistance with decision-making, coping strategies, supportive and palliative care, and management of depression and anxiety.   

Thyroid Cancer May Hike Risk of CVD Mortality

By Todd Neale, Senior Staff Writer, MedPage Today

Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

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Action Points

• This observational cohort study demonstrated an increased risk of cardiovascular death among individuals who received thyroidectomy radioiodine ablation for differentiated thyroid carcinoma.
• Be aware that greater suppression of TSH, achieved through levothyroxine supplementation, was associated with greater cardiovascular risk.

Patients with differentiated thyroid cancerhad a greater risk of dying from cardiovascular disease compared with their peers who did not have cancer, even after accounting for traditional cardiovascular risk factors, a Dutch study showed.

The risk of cardiovascular mortality during follow-up was more than three times as high (hazard ratio 3.35, 95% CI 1.66-6.74) and the risk of all-cause mortality was more than four times as high (HR 4.40, 95% CI 3.15-6.14), according to Joop Lefrandt, MD, PhD, of the University Medical Center Groningen in the Netherlands, and colleagues.

"To the best of our knowledge, this is the first study reporting an increased risk of cardiovascular mortality in patients with differentiated thyroid carcinoma," they reported online in the Journal of Clinical Oncology, adding that the results "stress the importance of a close follow-up and could encourage assessment and treatment of cardiovascular risk factors during follow-up for [the cancer]."

The researchers also found that each 10-fold drop in the level thyroid stimulating hormone (TSH) was associated with a greater risk of cardiovascular mortality (HR 3.08, 95% CI 1.32-7.21), "supporting the current European Thyroid Association and the American Thyroid Association guidelines of tempering TSH suppression in patients with low risk of cancer recurrence."

Differentiated thyroid carcinoma is associated with a relatively good prognosis, with reported 10-year survival rates of 80% to 95%.

"Since the survival rate ... is high, there is increasing interest in possible harmful long-term effects of treatment," the authors noted. "Particularly, the use and the extent of thyroid hormone suppression therapy have become controversial in recent years, since thyroid hormone suppression therapy may increase cardiovascular morbidity."

To explore the issue, Lefrandt and colleagues examined data from 524 patients treated for differentiated thyroid carcinoma at their center. All were diagnosed from January 1980 to June 2010 and were treated with total thyroidectomy and radioiodine ablation. The patients were then matched by age and sex to 1,572 cancer-free participants in a population-based study performed in the same geographic region.

Additional therapies administered in the carcinoma group included adjuvant neck radiotherapy for local uncontrolled disease in 35 patients and systemic sorafenib (Nexavar) for progressive distant metastatic disease in five patients. No other systemic cancer therapies were used.

In both groups, the average age was 49 and about a quarter of the patients were men. Median follow-up was 8.5 years in the carcinoma group and 10.5 years in the control group.

During follow-up, 19.1% of the patients in the carcinoma group died, including 4.2% from cardiovascular disease (myocardial infarction, stroke, abdominal aortic aneurysm, or pulmonary embolism), 7.4% from progression of the cancer, and 7.4% from other or unknown causes.

In the control group, 5.4% died from any cause, including 1.5% from cardiovascular disease and 3.9% from other or unknown causes.

Risks of both all-cause and cardiovascular mortality were higher in the carcinoma group after adjustment for age, sex, and established cardiovascular risk factors, including body mass index, diabetes, smoking, hypertension, hypercholesterolemia, and history of cardiovascular disease at baseline.

And lower levels of TSH were associated with an increase in cardiovascular -- but not all-cause -- mortality after adjustment for those same factors plus differentiated thyroid carcinoma risk classification, histology, cumulative radioiodine dose, and neck radiotherapy.

Although the mechanism behind the elevated risk of cardiovascular death is unknown, "an increased risk for atrial fibrillation, impaired diastolic function, and an increased left ventricular mass have been found in patients with differentiated thyroid carcinoma receiving thyroid hormone suppression therapy," according to the authors. "Induction of these adverse cardiovascular effects ... may lead to an increased risk for stroke, heart failure, and myocardial infarction, respectively, and possibly contribute to the increased cardiovascular mortality."

The study was limited, they acknowledged, by the observational design, which precludes a definitive conclusion about causality, by differences in how causes of death were determined in the cases and the controls, by changes in the TSH assays used over time, and by possible bias stemming from trends in the treatment of cardiovascular disease.

The authors reported no conflicts of interest.