Friday, November 20, 2015

ATA Guidelines Update Thyroid Nodule and Cancer Management

http://www.medscape.com/viewarticle/854765#vp_1

Nancy A Melville
|November 20, 2015 New guidelines from the American Thyroid Association (ATA) offer wide-ranging recommendations on the extensive clinical challenges involved in the management of thyroid nodules and differentiated thyroid cancer (DTC), as rates of nodule detection soar and options for risk assessment for thyroid cancer become at once more advanced yet more complicated. For the first time, a medical oncologist was included among the authors of the guidelines.
"A major goal of these guidelines is to minimize potential harm from overtreatment in a majority of patients at low risk for disease-specific mortality and morbidity, while appropriately treating and monitoring those patients at higher risk," writes the ATA guidelines task force.
In compiling the new "ATA management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer," published online November 18 in Thyroid, the task force of experts conducted an exhaustive review of evidence to update recommendations to reflect the rapid advances in technology and science that have significantly transformed the field since the publication of the previous guidelines in 2009.
"The most notable aspect of the guidelines from my perspective is the extreme depth of coverage and level of detail and nuance included in discussions in support of each recommendation," Keith C Bible, MD, a task-force member and chair of the endocrine malignancies disease–oriented group at the Mayo Clinic Cancer Center, in Rochester, Minnesota, told Medscape Medical News.
"This guideline document is much more detailed and comprehensive than other available guidelines and provides practical clinical guidance for providers so as to encourage thoughtful and individualized patient care," he added.
In total, the guidelines include 101 recommendations, including some important changes from the 2009 guidelines as well as new sections altogether on issues including: the follow-up of patients with thyroid nodules who do not have a biopsy; molecular testing for patients with indeterminate cytology; assessing the risk for recurrence; management of voice and parathyroid issues around surgery; and the definition and management of radioiodine-refractory DTC.
First Time a Medical Oncologist Included in Task Force
The task force for the new guidelines is also the first to include a medical oncologist, helping with guidance on issues such as the use of kinase inhibitors for DTC, Dr Bible noted.
"[A lot of] new data have emerged related to the use of kinase inhibitors as therapeutics in progressive, metastatic, and symptomatic DTC patients," he explained. "The 2015/16 guidelines are considerably expanded and revised in this respect, with two kinase inhibitors, sorafenib [Nexavar, Bayer] and lenvatinib [Lenvima, Eisai], now subject to regulatory approval in the US and the European Union for use in DTC."
The guidelines specifically make a weak recommendation, based on moderate-quality evidence, that kinase-inhibitor therapy be considered in DTC patients who fail to respond to radioactive-iodine therapy or who have metastatic, rapidly progressive, symptomatic, or imminently threatening disease.
Another notable change in the guidelines is a shift in recommendations on the use of radioactive iodine in patients with thyroid cancer, which may spark some debate, Dr Bible said.
"The new guidelines present I think a more nuanced approach to the use of radioactive iodine," he explained.
"[There is a] move further away from recommending uniform use of radioactive iodine in all thyroid-cancer patients, leaving some proponents of radioactive-iodine therapy unhappy with the guidelines."
According to the new recommendations, radioactive-iodine remnant ablation after thyroidectomy is not routinely recommended for low-risk DTC patients or after lobectomy or total thyroidectomy for patients with unifocal or multifocal papillary microcarcinoma in the absence of other adverse features. The recommendation is classified as "weak," based on low-quality evidence.
Radioactive-iodine adjuvant therapy, meanwhile, "should be considered" after total thyroidectomy in DTC patients with intermediate risk and is routinely recommended after total thyroidectomy in patients at high risk, according to the guidelines. The recommendation is also classified as weak, based on low-quality evidence.
Guidance on Surgery for DTC, Management of Thyroid Nodules
Another key change is the recommendation that lobectomy or thyroidectomy are both reasonable surgical approaches for DTC 1 to 4 cm, a shift from 2009 guidelines, which recommended thyroidectomy for all nodules larger than 1 cm, explained Bryan R Haugen, MD, of the University of Colorado, Aurora, who led the task force.
Another recommendation, that thyroid nodules smaller than 1 cm do not need to be biopsied and that not all larger than 1 cm need to be biopsied, is the subject of debate, challenged in a study presented last month at the 2015 International Thyroid Congress and Annual Meeting of the American Thyroid Association (ITC/ATA).
In that study, which looked at nearly 1000 thyroid nodules, researchers found no significant difference in prognosis and disease recurrence between nodules that were smaller than 1 cm compared with those larger than 1 cm.
Factors that did show statistically significant association with the highest risk included extrathyroid extension, aggressive histology, positive surgical margins, and capsular or lymphovascular invasion.
Senior author Emad Kandil, MD, chief of the endocrine surgery section at Tulane University School of Medicine, in New Orleans, Louisiana, told Medscape Medical News that choosing not to cytologically evaluate smaller nodules, as is the new ATA recommendation, "may not be justified in the light of identical outcomes and disease recurrence risk as for larger nodules."
This is because "larger people will have larger thyroids and smaller people will have smaller thyroids, so we can't just focus on size of nodules," Dr Kandil explained. "The focus should be on molecular markers and not just the size."
Dr Haugen responded that the researchers' conclusion "is a reasonable caution" but noted that ATA advocates only omitting cytological evaluation with fine-needle aspiration"in those patients who have ultrasound features that do not indicate a concern, such as no abnormal lymph nodes and no ultrasound evidence of extrathyroid extension or tumor at the capsule of the thyroid gland." He also noted that Dr Kandil and colleagues "did not analyze for these features preoperatively."
Discovering the presence of a positive BRAF mutation is not turning out to be as predictive of risk as once thought, Dr Haugen said. "We are still cautioning that forgoing fine-needle aspiration in patients with sonographically suspicious nodules smaller than 1 cm should be done only in carefully selected patients."
Epidemic of Thyroid Cancer
Recommendations are likely to continue to evolve as detection rates of thyroid cancers rise, adding to the pressing need for more evidence to help guide clinical decision making, Dr Bible stressed.
"There is an 'epidemic' of papillary thyroid cancer noted worldwide, particularly in developed countries, apparently arising primarily due to increased detection of minute papillary cancers, either from intentional thyroid-cancer screening (for instance, in South Korea) or by incidental detection from the increasing use of medical imaging (for instance, in the United States)," he explained.
"Available data suggest that the vast majority of these micropapillary cancers would not have previously been recognized and furthermore suggest that most appear to be indolent and not requiring of aggressive therapy — but more evidence is required to define how to respond most appropriately."
Dr Haugen has received grant/research support from Veracyte and Genzyme, as well as a one-time speaker honorarium from Genzyme. Dr Bible has no relevant financial relationships. Disclosures for the coauthors are listed in the paper. Dr Kandil has no relevant financial relationships.
Thyroid. Published online November 18, 2015. Article
 

Friday, November 6, 2015

Advanced Thyroid Cancer Responds Well to Targeted Therapies


http://www.targetedonc.com/conference/cfs-2015/advanced-thyroid-cancer-responds-well-to-targeted-therapies

The treatment paradigm for advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) in all ages has been greatly changed due to kinase inhibitors sorafenib (Nexavar) and lenvatinib (Lenvima), with combination strategies hoping to further build upon this success, Marcia Brose, MD, told physicians at the 33rd Annual Chemotherapy Foundation Symposium. - See more at: http://www.targetedonc.com/conference/cfs-2015/advanced-thyroid-cancer-responds-well-to-targeted-therapies#sthash.MRSCiHGI.dpuf
To further build upon these results, the phase II UPCC 19309 trial gave patients with metastatic DTC who were progressing despite prior therapy with sorafenib a combination of sorafenib and everolimus (Afinitor). PFS was the primary endpoint of the study.

The median PFS with the combination was 13.9 months (95% CI, 7.15-24.75). There was 1 partial response among the 33 evaluable patients enrolled in the study (3%). Additionally, 18 patients had stable disease for ≥6 months, for a clinical benefit rate of 58%.

These findings were surprising, since an earlier study exploring the combination had caused toxicity, for a reason that is not yet understood, said Brose. Further analysis of data from this study showed patients with PFS over 40 months, she added. Given the level of efficacy seen, further clinical trials are planned to confirm the results. - See more at: http://www.onclive.com/conference-coverage/CFS-2015/targeted-therapies-improve-outcomes-in-advanced-thyroid-cancer#sthash.TL6KN1bK.dpuf
- See more at: http://www.targetedonc.com/conference/cfs-2015/advanced-thyroid-cancer-responds-well-to-targeted-therapies#sthash.MRSCiHGI.dpuf
The treatment paradigm for advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) in all ages has been greatly changed due to kinase inhibitors sorafenib (Nexavar) and lenvatinib (Lenvima), with combination strategies hoping to further build upon this success, Marcia Brose, MD, told physicians at the 33rd Annual Chemotherapy Foundation Symposium.

Over 65,000 new cases of DTC and 2000 deaths are expected this year, said Brose, director of the Thyroid Cancer Therapeutics Program at the University of Pennsylvania. In 5% to 15% of patients, the disease becomes RAI-refractory, with median survival estimated at 2.5 to 3.5 years.

Prior to sorafenib becoming the first kinase inhibitor approved for RAI-refractory DTC in 2013, the ineffecitve chemotherapy doxorubicin was the standard, Brose said, with the pivotal phase III DECISION trial being the first successful analysis of a kinase inhibitor in this setting.

“Here we had patients with definite evidence of progression, as well as evidence of RAI-refractory [DTC] either because the disease did not take up radioactive iodine or because the disease took up radioactive iodine and grew anyway,” Brose said.

In the study, 417 patients were randomized in a 1:1 ratio to sorafenib or placebo, and crossover was allowed at the time of progression, with the primary endpoint of progression-free survival (PFS). The sorafenib cohort had a PFS of 10.8 months; whereas, PFS for the placebo group was 5.8 months (HR, 0.587; 95% CI, 0.454–0.758; P <.0001).

In 2015, the multikinase inhibitor lenvatinib joined sorafenib as an approved therapy for patients with RAI-refractory DTC. This agent demonstrated value for patients with progression on prior sorafenib, Brose said.

In the phase III SELECT study, patients were randomized in a 2:1 ratio to lenvatinib or placebo. A portion of these patients had received prior VEGF/VEGFR-targeted therapy, providing hints at an optimal sequence for these therapies.

In the full population, lenvatinib achieved an 18.3-month PFS versus 3.6 months for placebo. “This is clearly a different population than the DECISION trial, with patients more rapidly progressing,” Brose said.

“In the second-line, we also had a very good PFS, at 15.1 months. Now, it’s been argued by some that because it’s active in the second-line that lenvatinib can be used in the first- or second-line after sorafenib, whereas others argue lenvatinib is suitable for first-line treatment only,” Brose said. “I think both are true, and I think it’s just very good for our patients that we now have two lines of therapy.”

Further data from the SELECT trial indicated that patients over 65 years did well, achieving 16.7-month PFS versus 20.2 months for the younger group. The risk of death in this group was reduced by 47% with lenvatinib (HR, 0.53; CI, 95%, 0.31-0.91), marking this as the first survival benefit for older patients with DTC.

“What really caught our eye is that treatment with lenvatinib improved their overall survival to that actually comparable or at least within range of the patients who are under 65,” Brose said.

To further build upon these results, the phase II UPCC 19309 trial gave patients with metastatic DTC who were progressing despite prior therapy with sorafenib a combination of sorafenib and everolimus (Afinitor). PFS was the primary endpoint of the study.

The median PFS with the combination was 13.9 months (95% CI, 7.15-24.75). There was 1 partial response among the 33 evaluable patients enrolled in the study (3%). Additionally, 18 patients had stable disease for ≥6 months, for a clinical benefit rate of 58%.

These findings were surprising, since an earlier study exploring the combination had caused toxicity, for a reason that is not yet understood, said Brose. Further analysis of data from this study showed patients with PFS over 40 months, she added. Given the level of efficacy seen, further clinical trials are planned to confirm the results. - See more at: http://www.onclive.com/conference-coverage/CFS-2015/targeted-therapies-improve-outcomes-in-advanced-thyroid-cancer#sthash.TL6KN1bK.dpuf
- See more at: http://www.targetedonc.com/conference/cfs-2015/advanced-thyroid-cancer-responds-well-to-targeted-therapies#sthash.MRSCiHGI.dpuf
The treatment paradigm for advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC) in all ages has been greatly changed due to kinase inhibitors sorafenib (Nexavar) and lenvatinib (Lenvima), with combination strategies hoping to further build upon this success, Marcia Brose, MD, told physicians at the 33rd Annual Chemotherapy Foundation Symposium.

Over 65,000 new cases of DTC and 2000 deaths are expected this year, said Brose, director of the Thyroid Cancer Therapeutics Program at the University of Pennsylvania. In 5% to 15% of patients, the disease becomes RAI-refractory, with median survival estimated at 2.5 to 3.5 years.

Prior to sorafenib becoming the first kinase inhibitor approved for RAI-refractory DTC in 2013, the ineffecitve chemotherapy doxorubicin was the standard, Brose said, with the pivotal phase III DECISION trial being the first successful analysis of a kinase inhibitor in this setting.

“Here we had patients with definite evidence of progression, as well as evidence of RAI-refractory [DTC] either because the disease did not take up radioactive iodine or because the disease took up radioactive iodine and grew anyway,” Brose said.

In the study, 417 patients were randomized in a 1:1 ratio to sorafenib or placebo, and crossover was allowed at the time of progression, with the primary endpoint of progression-free survival (PFS). The sorafenib cohort had a PFS of 10.8 months; whereas, PFS for the placebo group was 5.8 months (HR, 0.587; 95% CI, 0.454–0.758; P <.0001).

In 2015, the multikinase inhibitor lenvatinib joined sorafenib as an approved therapy for patients with RAI-refractory DTC. This agent demonstrated value for patients with progression on prior sorafenib, Brose said.

In the phase III SELECT study, patients were randomized in a 2:1 ratio to lenvatinib or placebo. A portion of these patients had received prior VEGF/VEGFR-targeted therapy, providing hints at an optimal sequence for these therapies.

In the full population, lenvatinib achieved an 18.3-month PFS versus 3.6 months for placebo. “This is clearly a different population than the DECISION trial, with patients more rapidly progressing,” Brose said.

“In the second-line, we also had a very good PFS, at 15.1 months. Now, it’s been argued by some that because it’s active in the second-line that lenvatinib can be used in the first- or second-line after sorafenib, whereas others argue lenvatinib is suitable for first-line treatment only,” Brose said. “I think both are true, and I think it’s just very good for our patients that we now have two lines of therapy.”

Further data from the SELECT trial indicated that patients over 65 years did well, achieving 16.7-month PFS versus 20.2 months for the younger group. The risk of death in this group was reduced by 47% with lenvatinib (HR, 0.53; CI, 95%, 0.31-0.91), marking this as the first survival benefit for older patients with DTC.

“What really caught our eye is that treatment with lenvatinib improved their overall survival to that actually comparable or at least within range of the patients who are under 65,” Brose said.

To further build upon these results, the phase II UPCC 19309 trial gave patients with metastatic DTC who were progressing despite prior therapy with sorafenib a combination of sorafenib and everolimus (Afinitor). PFS was the primary endpoint of the study.

The median PFS with the combination was 13.9 months (95% CI, 7.15-24.75). There was 1 partial response among the 33 evaluable patients enrolled in the study (3%). Additionally, 18 patients had stable disease for ≥6 months, for a clinical benefit rate of 58%.

These findings were surprising, since an earlier study exploring the combination had caused toxicity, for a reason that is not yet understood, said Brose. Further analysis of data from this study showed patients with PFS over 40 months, she added. Given the level of efficacy seen, further clinical trials are planned to confirm the results. - See more at: http://www.onclive.com/conference-coverage/CFS-2015/targeted-therapies-improve-outcomes-in-advanced-thyroid-cancer#sthash.TL6KN1bK.dpuf
- See more at: http://www.targetedonc.com/conference/cfs-2015/advanced-thyroid-cancer-responds-well-to-targeted-therapies#sthash.MRSCiHGI.dpuf

Wednesday, November 4, 2015

New Thyroid Cancer Guidelines Reflect Altered Treatment Landscape

https://www.mskcc.org/blog/new-thyroid-guidelines-reflect-altered-treatment-landscape


By Miriam Falco
on Monday, November 2, 2015


Newly released thyroid cancer treatment recommendations from the American Thyroid Association (ATA) suggest that monitoring an early-stage papillary thyroid tumor — instead of removing it — can be a very reasonable option.

For nodules or tumors smaller than one centimeter that appear to be confined to the thyroid gland, the new guidelines say, patients may be able to avoid immediate surgery and instead have the tumor observed to see if it grows.

This suggestion is one notable aspect of the ATA guidelines, published in October, which consist of treatment recommendations that address screening, staging, risk assessment, and surgical approaches for thyroid cancer.

“The new guidelines are all about risk stratification and are completely removing one-size-fits-all treatment recommendations,” says Memorial Sloan Kettering endocrinologist Michael Tuttle, who has been actively involved in shaping these guidelines. “Now treatment will be individualized for high- and low-risk patients.”

In many cases, the new recommendations reflect a prevailing sentiment among thyroid cancer experts that less extensive treatment often produces the best outcomes for patients because most very small thyroid cancers grow quite slowly and never pose a threat.

In fact, the ATA guidelines advise that growths smaller than one centimeter that do not need treatment should not even be biopsied. And in cases in which surgery is required, the guidelines say that partial removal of the thyroid (lobectomy) should be considered instead of always performing a total thyroidectomy.

Richard Wong, Chief of MSK’s Head and Neck Service, says the guidelines will help prevent unnecessary ultrasounds and needle biopsies and will help reduce the “overdiagnosis of a condition in which the treatment could be more problematic than the underlying disease.”

Overdiagnosis and Overtreatment

Thyroid cancer has been on the rise in the United States over the last several decades, more than doubling between 1973 and 2002. The detection of small thyroid cancers especially increased with the introduction of ultrasounds into routine practice in the 1990’s. Since that time, it has become clear that most of these very small thyroid cancers grow slowly and never pose a threat.

As a result, physicians at MSK and elsewhere have come to recognize that a large number of patients were being biopsied or treated unnecessarily. The new ATA guidelines will help patients and physicians figure out when to intervene and when to take a more conservative approach.

The guidelines recommend practices that in most cases are already followed at MSK. For example, the watchful waiting technique — also known as “active surveillance”— used with early-stage papillary thyroid tumors is already part of MSK’s approach. The new ATA guidelines are significant because they “formally endorse observation” as a possible treatment option, Dr. Tuttle says.
 “If at some point we decide that a tumor we have been watching should be removed, the surgical treatment will almost certainly be just as effective in the future as it would have been if we took it out when it was diagnosed,” he says “While some small tumors are not appropriate for this method — depending on location and other factors — these make up a tiny group.”

Dr. Wong points out that most physicians and hospitals do not currently have an active-surveillance program. He adds that the new ATA guidelines will make practitioners more comfortable with the concept of observing a tiny cancer that is statistically highly unlikely to ever cause harm.
MSK has also been on the forefront with the approach of selecting the more conservative surgery, lobectomy, for low-risk thyroid cancers, Dr. Wong explains. The ATA guidelines are now more supportive of this concept for selected cancers.  Research published more than two decades ago by former MSK Head and Neck Service Chief Jatin Shah and surgical oncologist Ashok Shaha supported such an approach, which was somewhat controversial at the time. “It is gratifying to see how the academic thyroid community has finally followed their lead,” Dr. Wong says.

Thursday, October 29, 2015

Genetically Modified Super Tomato May Help Fight Cancer, Diabetes And Alzheimer’s Disease

http://www.techtimes.com/articles/100488/20151028/genetically-modified-super-tomato-may-help-fight-cancer-diabetes-and-alzheimer-s-disease.htm


By Katherine Derla, Tech Times | October 28, 3:29 AM

 A study led by John Innes Centre researchers in the United Kingdom (UK) resulted in the mass production of natural compounds in a single, genetically modified fruit - a tomato. These compounds include life-extending Resveratrol found in wine and Genistein found in tofu which has cancer-preventing benefits.

By introducing a protein called AtMYB12, which is normally found in a garden weed called thale cress (Arabidopsis thaliana), scientists found that the protein activates a wide set of genes responsible for natural compound production in the tomato plant. The AtMYB12 acts like a plug or tap that scientists can control to reduce or increase the amount of natural compounds that can benefit the plant and in turn, humans.
The researchers noted that the introduction of the AtMYB12 protein did not only increase the plant's ability to create the Resveratrol and Genistein, it also influenced the plant's ability to devote more carbon and energy in the compound creation.

"Medicinal plants with high value are often difficult to grow and manage, and need very long cultivation times to produce the desired compounds. Our research provides a fantastic platform to quickly produce these valuable medicinal compounds in tomatoes. Target compounds could be purified directly from tomato juice," said co-author Dr. Yang Zhang
The research team is optimistic that the same genetic switching technique can be used to mass manufacture other natural compounds involved in the production of several medicines. Tomatoes are relatively cheap to produce and can be turned into juice form where the compounds can be extracted. Eventually, the fruit itself could soon become a medicinal plant with increased levels of illness-fighting compounds.

The study provides a basis for a more cost-efficient industrial production of valuable natural compounds from plants compared to extracting small amounts from tons of soybeans and grapes. The researchers believe their design can be applied to other compounds such as alkaloids and terpenoids.

Co-author Cathie Martin stressed that their study delivers a design to mass produce not just phenylpropanoid compounds but potentially more natural compounds that can extracted from aromatic amino acids.

The researchers published their study in the Nature Communications journal on Oct. 26.

Camomile tea could improve blood glucose control in type 2 diabetes

 http://www.diabetes.co.uk/news/2015/oct/camomile-tea-could-improve-blood-glucose-control-in-type-2-diabetes-91406398.html

Jack Woodfield
Tue, 27 Oct 2015

An Iranian study finds that drinking three cups of camomile tea a day could improve control of blood glucose levels in people with type 2 diabetes.

Researchers from Tabriz University of Medical Sciences aimed to investigate how the effects of camomile tea would affect glycemic control and antioxidant levels in type 2 subjects. Antioxidants are chemicals that protect or delay against cell damage.

64 participants with type 2 diabetes were recruited, all of whom were aged between 30 and 60. They consumed camomile tea three times per day immediately after meals for eight weeks. A control group also followed this routine, but they drank water instead.

The camomile tea group had significantly reduced HbA1c and serum insulin levels, as well as significantly increased total antioxidant capacity compared to those in the control group.

The researchers concluded that camomile tea could be useful in reducing diabetes risk factors. They added: "Short-term intake of chamomile tea has beneficial effects on glycemic control and antioxidant status in patients with type 2 diabetes."

However, the researchers noted that a larger sample population and a longer intervention period would be necessary in order to demonstrate significant clinical improvements.

This study was published in the journal Nutrition.

Wednesday, October 28, 2015

Vemurafenib/Sorafenib Combo Shows Promise in Papillary Thyroid Carcinoma

http://www.onclive.com/conference-coverage/thyroid-2015/vemurafenib-sorafenib-combo-shows-promise-in-papillary-thyroid-carcinoma

W. Todd Penberthy, PhD
Published Online: Thursday, October 22, 2015
- See more at: http://www.onclive.com/conference-coverage/thyroid-2015/vemurafenib-sorafenib-combo-shows-promise-in-papillary-thyroid-carcinoma#sthash.JZnsUABZ.dpuf
W. Todd Penberthy, PhD
Published Online: Thursday, October 22, 2015
 Published Online:  Thursday, October 22, 2015

Interesting article but for some reason it won't let me copy and paste.  Check it out at the website above.

Dual targeting of BRAF V600E–positive papillary thyroid carcinoma (PTC) with the anti-BRAF V600E agent vemurafenib (Zelboraf) and the angiogenesis inhibitor sorafenib (Nexavar) showed promising clinical activity, according to research presented at the 2015 International Thyroid Congress.

Sorafenib was approved in 2013 for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma refractory to radioactive iodine treatment. Antitumor activity with vemurafenib in BRAF V600E–positive PTC was previously demonstrated in a phase II study presented at the 2013 European Cancer Congress. In the study, the median progression-free survival in treatment-naïve patients who received vemurafenib was 15.6 months.

Carmelo Nucera, MD, PhD, assistant professor at Harvard Medical School, and colleagues used cell cultures of human metastatic/recurrent BRAF V600E -PTCs and tested the effects of vemurafenib versus sorafenib used as single agents or in combination. To date, they have used predominately three types of assays. These include biochemical assays of enzyme activity along with two dynamic cellular assays—measures of cell-cycle proliferation and in vitro microenvironmental analysis: migration and motility.

Nucera pointed out that BRAF V600E PTCs responded to vemurafenib than sorafenib. In contrast, with wild-type BRAF cells, the BRAF inhibitor does not work and sorafenib works very well. Ultimately the combination overlaps in activity, Nucera said.

The key, according to Nucera, is tumor heterogeneity, and therefore, the tumor microenvironment needs to be considered. Macrophages, for example, are an important component in the anaplastic pericyte microenvironment. Macrophages and endothelial cells exist in this microenvironment.

Nucera’s group observed that the pericytes act like stem cells, interacting with endothelial cells to regulate angiogenesis. Pericytes spread after exposure to various signaling molecules like PDGFR-β, according to Nucera. Pericytes have a strong capability to produce an extracellular matrix, which may ultimately confer advantage to PTC cells to promote their migration and invasion.

Higher PDGFR-β was observed by Nucera et al in BRAF V600E cells than in the wild-type equivalent, but addition of a BRAF inhibitor caused down-regulation of PDGFR-β activation. No response was seen after sorafenib treatment, while the combination belies the treatment of the single sorafenib agent.

Nucera’s study preliminarily suggests that the combination of an antiangiogenic compound and a BRAF inhibitor may be more effective than either agent alone, not only in blocking the proliferation of PTC cells, but also in preventing cell types like pericytes in the microenvironment from promoting otherwise reproductive advantages to PTC cells.

Nucera highlighted that these results indicate for the first time that PTC cells express VEGFR2, and this dual combination treatment with anti–BRAF V600E and antiangiogenesis therapy is likely to improve therapeutic response in metastatic BRAF V600E–positive PTC cells by directly reducing cell survival and migratory capacities via pERK1/2 and pPDGFR-β down-regulation.

Richard Kloos, MD, cochair for the session and professor of Medicine at Ohio State University, stated that the value of adding sorafenib must be that the BRAF activity is not strong enough. Kloos then asked whether or not the sorafenib effect is really a dose effect working through BRAF.

Nucera elaborated that the BRAF inhibitor is working on the BRAF system. Therefore, if you use a pan¬–tyrosine kinase inhibitor (TKI) like sorafenib, you can improve the activity to kill any tumor cell, said Nucera. The rationale for using an antiangiogenic agent is that you have a human system with many different cells with many different TK targets. In Nucera’s observations, combining the BRAF inhibition with a pan-TKI will fundamentally work on any tumor cell.


Sisms J, Antonello Z, Nucera C, et al. Combinatorial targeting with anti-BRAFV600E and anti-angiogenesis therapy enhances cell death and suppresses cell migration in metastatic papillary thyroid carcinoma. Presented at: 2015 International Thyroid Congress; October 18-23, 2015; Orlando, FL. Abstract 106.
- See more at: http://www.onclive.com/conference-coverage/thyroid-2015/vemurafenib-sorafenib-combo-shows-promise-in-papillary-thyroid-carcinoma#sthash.JZnsUABZ.dpuf
Published Online: Thursday, October 22, 2015
W. Todd Penberthy, PhD

Dual targeting of BRAF V600E–positive papillary thyroid carcinoma (PTC) with the anti-BRAF V600E agent vemurafenib (Zelboraf) and the angiogenesis inhibitor sorafenib (Nexavar) showed promising clinical activity, according to research presented at the 2015 International Thyroid Congress. - See more at: http://www.onclive.com/conference-coverage/thyroid-2015/vemurafenib-sorafenib-combo-shows-promise-in-papillary-thyroid-carcinoma#sthash.JZnsUABZ.dpuf
Dual targeting of BRAF V600E–positive papillary thyroid carcinoma (PTC) with the anti-BRAF V600E agent vemurafenib (Zelboraf) and the angiogenesis inhibitor sorafenib (Nexavar) showed promising clinical activity, according to research presented at the 2015 International Thyroid Congress. - See more at: http://www.onclive.com/conference-coverage/thyroid-2015/vemurafenib-sorafenib-combo-shows-promise-in-papillary-thyroid-carcinoma#sthash.JZnsUABZ.dpuf
Dual targeting of BRAF V600E–positive papillary thyroid carcinoma (PTC) with the anti-BRAF V600E agent vemurafenib (Zelboraf) and the angiogenesis inhibitor sorafenib (Nexavar) showed promising clinical activity, according to research presented at the 2015 International Thyroid Congress.

Sorafenib was approved in 2013 for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma refractory to radioactive iodine treatment. Antitumor activity with vemurafenib in BRAF V600E–positive PTC was previously demonstrated in a phase II study presented at the 2013 European Cancer Congress. In the study, the median progression-free survival in treatment-naïve patients who received vemurafenib was 15.6 months.

Carmelo Nucera, MD, PhD, assistant professor at Harvard Medical School, and colleagues used cell cultures of human metastatic/recurrent BRAF V600E -PTCs and tested the effects of vemurafenib versus sorafenib used as single agents or in combination. To date, they have used predominately three types of assays. These include biochemical assays of enzyme activity along with two dynamic cellular assays—measures of cell-cycle proliferation and in vitro microenvironmental analysis: migration and motility.

Nucera pointed out that BRAF V600E PTCs responded to vemurafenib than sorafenib. In contrast, with wild-type BRAF cells, the BRAF inhibitor does not work and sorafenib works very well. Ultimately the combination overlaps in activity, Nucera said.

The key, according to Nucera, is tumor heterogeneity, and therefore, the tumor microenvironment needs to be considered. Macrophages, for example, are an important component in the anaplastic pericyte microenvironment. Macrophages and endothelial cells exist in this microenvironment.

Nucera’s group observed that the pericytes act like stem cells, interacting with endothelial cells to regulate angiogenesis. Pericytes spread after exposure to various signaling molecules like PDGFR-β, according to Nucera. Pericytes have a strong capability to produce an extracellular matrix, which may ultimately confer advantage to PTC cells to promote their migration and invasion.

Higher PDGFR-β was observed by Nucera et al in BRAF V600E cells than in the wild-type equivalent, but addition of a BRAF inhibitor caused down-regulation of PDGFR-β activation. No response was seen after sorafenib treatment, while the combination belies the treatment of the single sorafenib agent.

Nucera’s study preliminarily suggests that the combination of an antiangiogenic compound and a BRAF inhibitor may be more effective than either agent alone, not only in blocking the proliferation of PTC cells, but also in preventing cell types like pericytes in the microenvironment from promoting otherwise reproductive advantages to PTC cells.

Nucera highlighted that these results indicate for the first time that PTC cells express VEGFR2, and this dual combination treatment with anti–BRAF V600E and antiangiogenesis therapy is likely to improve therapeutic response in metastatic BRAF V600E–positive PTC cells by directly reducing cell survival and migratory capacities via pERK1/2 and pPDGFR-β down-regulation.

Richard Kloos, MD, cochair for the session and professor of Medicine at Ohio State University, stated that the value of adding sorafenib must be that the BRAF activity is not strong enough. Kloos then asked whether or not the sorafenib effect is really a dose effect working through BRAF.

Nucera elaborated that the BRAF inhibitor is working on the BRAF system. Therefore, if you use a pan¬–tyrosine kinase inhibitor (TKI) like sorafenib, you can improve the activity to kill any tumor cell, said Nucera. The rationale for using an antiangiogenic agent is that you have a human system with many different cells with many different TK targets. In Nucera’s observations, combining the BRAF inhibition with a pan-TKI will fundamentally work on any tumor cell.


Sisms J, Antonello Z, Nucera C, et al. Combinatorial targeting with anti-BRAFV600E and anti-angiogenesis therapy enhances cell death and suppresses cell migration in metastatic papillary thyroid carcinoma. Presented at: 2015 International Thyroid Congress; October 18-23, 2015; Orlando, FL. Abstract 106.
- See more at: http://www.onclive.com/conference-coverage/thyroid-2015/vemurafenib-sorafenib-combo-shows-promise-in-papillary-thyroid-carcinoma#sthash.JZnsUABZ.dpuf
W. Todd Penberthy, PhD
W. Todd Penberthy, PhD
Published Online: Thursday, October 22, 2015
- See more at: http://www.onclive.com/conference-coverage/thyroid-2015/vemurafenib-sorafenib-combo-shows-promise-in-papillary-thyroid-carcinoma#sthash.JZnsUABZ.dpuf