Thursday, December 4, 2014
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.
The genomic landscape of papillary thyroid cancer (PTC), the most common form of thyroid cancer, has just been redefined with respect to its somatic molecular alterations.
In a new study published October 23 in Cell, the analysis identifies new mutations, expands on information of alterations already known, and provides insights into what the future may hold for the diagnosis and clinical management of patient with thyroid nodules and PTCs.
"This understanding of the genomic landscape of thyroid cancer will refine how it's classified and improve molecular diagnosis. This will help us separate those patients who need aggressive treatment from those whose tumor is never likely to grow or spread," Thomas J. Giordano, MD, PhD, professor of pathology at the University of Michigan Medical School, Ann Arbor, said in a university press release.
TCGA Research Network
The Cancer Genome Analysis (TCGA), a project funded by the National Institutes of Health, has led the way in redefining molecular landscapes for several cancers, including breast, lung, ovary, and colon cancers.
In this report, an analysis was undertaken in the largest collection of PTCs from patients primarily without radiation exposure, which is a known PTC risk factor. Tumor samples and matched germline DNA were available from 496 patients and included various histologic types: classical type, follicular variant, tall-cell variant, and some uncommon types of PTC.
The first level of analysis provided mutational information by using different "platforms" (see figure below). At this level, several new mutated genes were identified, including EIF1AX, PPM1D, andCHEK2. Mutations were also identified in MAPK-related genes, BRAF, NRAS, HRAS, and KRAS. Mutations in tumor suppressor genes (eg, TP53, RB1, PTEN), numerous gene fusions (eg, RET andBRAF fusions) and TERT were in the newly expanded mutational landscape of PTC.
Unlike many other cancers, the thyroid genome is considered relatively quiet because it harbors fewer mutations and copy number alterations. This meant that the researchers could perform some integrated bioinformatic analyses not possible with more complex cancers.
Using data from multiple genomic platforms, TCGA researchers could define in greater detail mutational "drivers." In this analysis, researchers identified drivers in all but 3.5% of cases — down from 25% of tumors without apparent driving alterations.
The drivers were divided into two main groups: "BRAFV600E-like" mutations and "RAS-like" mutations. Using a 71-gene signature, a BRAFV600E-RAS score (BRS: –1 to +1) was developed, which showed a distinct separation of BRAFV600E-like from RAS-like tumors (see figure in the article's Graphical Abstract).
A thyroid differentiation score (TDS), developed on the basis of expression of thyroid metabolism and function genes, indicated a correlation across all the tumors analyzed. RAS-like tumors were uniformly highly differentiated, while BRAFV600E tumors displayed significant variation in differentiation. Currently, allBRAF-mutant PTCs are considered to be a homogeneous clinicopathologic group. However, the TDS indicates otherwise.
Ramifications for PTC Classification
"We will no longer be able to talk of BRAFV600E as a single tumor type. Indeed, the granular level at which we have teased out some of these mutations tells us that tumors with the most commonly understood and studied mutation in thyroid cancer — BRAFV600E — are not as homogeneous as is commonly believed," Dr Giordano said.
"PTC is too nonspecific a diagnosis," said Ronald J. Koenig, MD, PhD, also from the University of Michigan Medical School but not associated with the study. "It is not easy to predict how a panel of mutations will make a cancer more aggressive. That's where TCGA researchers have helped," he toldMedscape Medical News.
This comprehensive analysis informed TCGA researchers that thyroid cancer, especially the follicular variant of PTC, begs to be reclassified according to molecular characteristics.
This would allow endocrinologists and oncologists to identify slow-growing, highly differentiated tumors from aggressive, less-differentiated tumors, Dr Giordano told Medscape Medical News.
Indeed, classical-type PTCs are rich in RET rearrangements, follicular-variant PTCs have RAS-like molecular features, and the aggressive tall-cell variants are enriched in BRAFV600E.
Designing clinical trials to evaluate targeted agents can benefit from these observations and the underlying genetics can help inform trial results, Dr Giordano said.
But although TCGA network has re-examined the molecular landscape across several tumor types, the role of the pathologist is not going to be passé, Dr Koenig told Medscape Medical News. The two are going to complement each other, he added.
Implications for Clinical Practice
In the clinical management of PTC, genetic testing is not routine, Dr Koenig told Medscape Medical News: "Genetic testing is done in less than 5% of patients."
In patients with thyroid nodules whose biopsy specimens are indeterminate, a gene signature can help assess the risk for malignancy and therefore can aid in clinical decision making, he said. There is no standard of care for integrating genetics into the clinical management of patients with PTC, Dr Koenig said.
According to Dr Koenig, "Most patients are cured by surgery or radioactive iodine [RAI] treatment." Differentiation is important if RAI therapy is to work, Dr Giordano explained to Medscape Medical News. Undifferentiated carcinomas and some less differentiated PTCs have lost their avidity for RAI. Indeed, RAI-resistant PTCs are enriched in BRAFV600E mutations, he added.
Although Dr Koenig agrees that TCGA has expanded understanding of the molecular defects across PTC, he indicated that most patients with BRAFV600E> actually do well with the current standard of care. TCGA has helped us understand how thyroid cancers with one bad gene can become aggressive when they accumulate additional mutations, he added.
In this regard, a separate but recent study published online October 20 in the Journal of Clinical Oncology found that the prevalence of BRAFV600E in 2000 patients with PTC was 48.5%. More significantly, PTC recurred in 20.9% of these patients. The investigators concluded that patients withBRAFV600E PTC were at an 82% higher risk for PTC recurrence compared with patients who did not have this mutation.
Those researchers indicated that PTC recurred even in patients with low-risk disease and suggested that "management of these patients is highly controversial."
Indeed, TCGA researchers would suggest that molecular testing of these patients may help in the risk stratification and clinical management of these patients.
"Our study will take molecular testing to the next level," Dr Giordano told Medscape Medical News. The expanded mutational landscape of thyroid cancer will improve the preoperative evaluation of thyroid nodules and better inform surgical decisions by helping to distinguish patients with benign nodules from those with thyroid cancer, he added.
This study was funded by several grants from the National Institutes of Health. Multiple authors identified relationships with industry.
Cell. 2014;159:676-690. Abstract
Veracyte Announces Positive Coverage Policy for Afirma® Gene Expression Classifier... -- SOUTH SAN FRANCISCO, Calif., Dec. 2, 2014 /PRNewswire/ --
Veracyte Announces Positive Coverage Policy for Afirma® Gene Expression Classifier... -- SOUTH SAN FRANCISCO, Calif., Dec. 2, 2014 /PRNewswire/ --:
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Tuesday, November 25, 2014
Hi, Everyone - It's been pointed out to me that I haven't sent a clinical trial update for awhile. It's been about 6 months, so maybe it is time to let you know how things are going.
As with my old study, my study location is Mercy Hospital in St. Louis. I fly or drive down every 4 weeks to pick up the next cycle's drug supply. There's the possibility that I'll be allowed to pick up a 2-cycle supply after a year on the study, which would be nice. I have a C/T scan every 8 weeks to see how things are going. This drug is not a cure, but it's hoped is that it will prevent the existing tumors from growing and prevent the emergence of new tumors. I had a scan last week and got a good report: No new tumors and no growth in the existing tumors. My old study kept me going for 7 years and I'm hoping this study will beat that!
The side effects for this drug are similar to my old study but so far have not been as severe. The main ones for me have been high blood pressure, foggy-headedness, digestive unhappiness, hoarseness, and fatigue. A couple weeks ago I was diagnosed with a new one: Type 2 Diabetes. This is very common on the drug. I've started pricking my finger for a blood glucose test every morning and am taking an oral drug (Glipizide) to help control it. The best thing about having diabetes is that now I can lose some weight without the oncologists having a fit! (It's actually kind of fun watching them try to process it. Cognitive Dissonance is an amusing thing in an MD. That's why they're not lawyers, I guess.)
So far, I've been able to fly out of Lincoln to get to St. Louis instead of driving to Omaha and flying out of there. It's unusual for Lincoln fares to be anywhere close to Omaha's, so I hope it lasts. The only bad thing about flying out of Lincoln is that the time is St. Louis is so short I don't get to see Sara's family and I really miss that.
Everyone in St. Louis is tense waiting for the Ferguson grand jury to issue it's findings. When I was down there last week there was a lot of increased security on the train platforms and in the bus transport centers. One of the med techs I work with lives in Ferguson. She's scared to go to work in the morning for fear she won't be able to get home in the evening. Her grandkids are scared to go to school. From the bus, one can see businesses with boarded up windows and big signs announcing that they're still open. The hospital has a disaster plan in place and there's extra security there, too. It feels like a war is about to break out. I can't imagine what it's like to live with that every day.
The other big mystery in St. Louis is trying to figure out why gas is 60 cents cheaper than in Lincoln. I suspect that's one mystery that's not going to be solved.
Hope you're all well and a Happy Thanksgiving. Thanks for your continuing prayers and support!
UAlberta research team finds that inhibiting a key enzyme decreases the early development of tumours, their spread to other organs and improves the effectiveness of chemotherapies
A team of researchers from the University of Alberta has discovered a new approach to fighting breast and thyroid cancers by targeting an enzyme they say is the culprit for the "vicious cycle" of tumour growth, spread and resistance to treatment.
A team led by University of Alberta biochemistry professor David Brindley found that inhibiting the activity of an enzyme called autotaxin decreases early tumour growth in the breast by up to 70 per cent. It also cuts the spread of the tumour to other parts of the body (metastasis) by a similar margin. Autotaxin is responsible for producing lysophosphatidic acid, a signaling molecule that promotes cancer cell survival, growth and metastasis. It is also linked to resistance to the beneficial effects of chemotherapy and radiotherapy.
"Autotaxin causes a lot of serious problems in the treatment of breast and other cancers. Essentially, the body hijacks this enzyme to help a tumour grow, survive treatment and spread to other areas of the body," said Brindley, senior author of a series of related studies. "By inhibiting it, we found we could block the growth of breast and thyroid tumours and break the cycle of treatment resistance."
Autotaxin is normally involved in wound repair and tissue regeneration. It also drives inflammatory conditions such as colitis, arthritis and cancer. Brindley believes it is this inflammation-associated event that is especially problematic and could fuel breast and thyroid tumour growth.
According to Brindley, a tumour is like a wound that does not heal. The body hijacks autotaxin to help a tumour grow, resist being killed by chemotherapy and radiotherapy, and to spread to other areas of the body. As the tumour grows or is damaged by treatment, it produces more inflammatory mediators, which in turn produce more autotaxin. That then increases the production of more inflammatory mediators. The research team found that it could block the growth of breast and thyroid tumours by breaking the vicious cycle with the autotaxin inhibitor.
Brindley's team--which included co-authors Matthew Benesch, a Vanier Scholar, Killam Laureate, and MD/ PhD candidate in the Faculty of Medicine & Dentistry; Ganesh Venkatraman, an Alberta Innovates-Health Solutions sponsored PhD candidate; Xiaoyun Tang, a Canadian Breast Cancer Foundation-funded postdoctoral fellow; and endocrine surgeon Todd McMullen--used a drug developed by Ono Pharmaceuticals in Japan to inhibit autotaxin activity.
Daily doses of the drug reduced the initial phase of breast tumour growth by 60 to 70 per cent in experimental models. The inhibitor compound also cut tumour metastasis to the lungs by a similar margin. Later tests with a different technique for blocking the effects of lysophosphatidic acid enabled the team to block breast and thyroid tumour growth and spread by up to 80 per cent.
Brindley said his team was surprised when Benesch discovered that autotaxin is not produced by breast cancer cells themselves, but largely by the surrounding breast fat tissue. As the tumour develops and causes inflammation in the breast, the fat tissue produces more autotaxin, aggravating the problem by making the tumour grow more, metastasize and resist further treatment.
"With this drug we are cutting this vicious cycle," he said, explaining that by blocking autotaxin the researchers saw a five-fold reduction in inflammation markers in the blood, and a ten-fold reduction in the breast fat tissue adjacent to the tumour.
The research team is now trying to promote the testing of the compound in human clinical trials in Edmonton--the first autotaxin inhibitor to make it to the clinic after more than 10 years of research. Brindley says that it shows it's not a "pie in the sky" theory but a potential new therapy that could be used in combination with chemotherapy to improve the treatment of cancer patients.
"We've shown that the autotaxin inhibitor has strong therapeutic potential, even though we are at the early stages" he said. "A third of women with breast cancer die from metastasis and many thyroid cancer patients do not respond well to treatment. If we can improve the treatment of these patients, it will be a very big deal."
"This is a very exciting discovery on many levels," said Liz Viccars, CEO, Canadian Breast Cancer Foundation - Prairies/NWT Region. "We are very proud to have supported this work in Dr. Brindley's lab with a CBCF-funded research grant, as well as supporting Dr. Tang's contributions through one of our inaugural Fellowship Grants.
"This discovery is an exceptional demonstration of fundamental basic research potentially leading to the development and implementation of personalized cancer therapies and treatments. The impact of such findings will improve the quality of life and patient care for those dealing with breast and other cancers."
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