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Thyroid cancer: In a flourish of subtypes, genes, and drivers

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Karen Titus

January 2015—Dark matter is shrinking—at least in the thyroid cancer part of the universe.

Until recently, the percentage of papillary thyroid carcinomas with no known oncogenic drivers hovered around 25 percent. Now, with the publication of the most recent research effort by The Cancer Genome Atlas project, that number has shrunk considerably, to about 3.5 percent.

Questions about PTCs are tantalizingly close to being answered, thanks to the TCGA effort (Cell. 2014;159:676-690). “We’ve expanded the somatic mutational landscape of the most common type of thyroid cancer [PTC],” says co-lead author Thomas Giordano, MD, PhD, professor of pathology and internal medicine at the University of Michigan.

Dr. Thomas Giordano, here with research associate Michelle Vinco, co-led the three-part analysis of 496 papillary thyroid carcinomas. Perhaps the time has come, the study says, to revise the classification of thyroid cancer.

Dr. Thomas Giordano, here with research associate Michelle Vinco, co-led the three-part analysis of 496 papillary thyroid carcinomas. Perhaps the time has come, the study says, to revise the classification of thyroid cancer.

That, in turn, has direct bearing on the molecular testing of thyroid nodules, he says, and improves the performance of those assays. The eventual clinical implications could be impressive—pathologists eventually might be able to detect up to 95 percent of papillary carcinoma by FNA and reliably classify them as benign or malignant without additional surgery.

“We know that thyroid cancer is overall a relatively indolent disease,” says TCGA project member Yuri Nikiforov, MD, PhD, professor of pathology, vice chair for molecular pathology, and director, Division of Molecular and Genomic Pathology, Department of Pathology, University of Pittsburgh Medical Center. Five-year survival for well-differentiated thyroid cancer is 95 percent. “So we typically overtreat most of the patients because we cannot discriminate which cancers will be aggressive and which will not.”

Having more granularity can only help endocrinologists, says project member Robert Smallridge, MD, who is the current president of the American Thyroid Association. “The cases we wrestle with on a daily basis are the ones suspicious for follicular neoplasm, or what used to be indeterminants but now get into this classification of atypia of unknown significance-type,” says Dr. Smallridge, deputy director of the Mayo Clinic Cancer Center and the Alfred D. and Audrey M. Petersen professor of cancer research, Jacksonville, Fla. “We are stuck with telling the patient the odds remain high that the lesion is benign, but we can’t do anything further without taking you to surgery and removing all or some of your thyroid. That can be frustrating when the odds are only 15 to 20 percent it’s cancer.”

Such conundrums lay at the heart of TCGA, a study Dr. Giordano calls “exhaustive and huge.” It’s not an exaggeration. The study looked at 496 PTCs in a three-part analysis. As the paper explains, the researchers identified somatic mutations, including single nucleotide variants, small insertions and deletions, gene fusions, and copy-number alterations, which allowed them to characterize the genomic landscape of PTC. This let them identify previously unknown drivers, that so-called dark matter.

Dr.Giordano

Dr.Giordano

They then developed a gene expression signature of samples containing the mutations, characterizing the tumors based on this signature. This was followed by determining, via protein and mRNA expression data, the signaling impacts of the BRAF V600E and RAS mutations. As it turns out, the two pathways are strikingly different.

After obtaining the molecular data, the researchers developed molecular classifications of PTC and integrated them with data related to genotype, signaling, differentiation, and risk.

It could easily be said that the study was also exhausting. Recalls Dr. Giordano: “It took four years.” Initially the researchers analyzed data from 200 tumors—and decided not to publish. “We wanted to do more.” After 350 tumors, they again decided to hold off, “and pushed ourselves to do 500. I think it was a good decision, but it made us a little nervous,” he says, noting that the researchers were well past their embargo date. “So some of our results started showing up in other papers. But if enough people cherry-pick your best results, it gets a little harder to publish.”

Dr. Giordano, who led the team effort jointly with Gad Getz, PhD, of Massachusetts General Hospital and the Broad Institute of MIT and Harvard, credits the editors of Cell for allowing him and his colleagues “to tell the whole story in all its glory. Cell actually allowed us to bend their rules on both length of the paper and number of supplemental figures. They were fabulous to work with.”

For all the hard data, the study ends on an almost philosophical note: Might it be time to revise the classification of thyroid cancers?

That’s not a debate that will be settled anytime soon. But the Cell paper does settle other debates, says TCGA project member James Fagin, MD, chief of the endocrinology service and member of the Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center. The level of detail emerging from TCGA means “nobody will be able to think about papillary thyroid cancer in the same way after this study.”

Fresh thought may be in order, especially since, as the researchers note, thyroid cancer therapy is entering the realm of precision medicine.

From the perspective of endocrinologists, Dr. Fagin says, “We had a fairly simplistic perspective of this prior to the TCGA.” BRAF and RAS mutations aren’t new, and TCGA data recapitulate their importance. “But with much more profound nuances,” Dr. Fagin says. “Within each of the cohorts of tumors associated with the different drivers, there was some interesting heterogeneity that has real potential clinical interest.”

Thyroid nodules are common and, most of the time, benign. Nevertheless, a substantial portion—about a third—of cases come back indeterminate on fine-needle aspirations. “You can repeat the FNA, but if it keeps coming back indeterminate, most people eventually go to surgery,” says Dr. Giordano.

Therein lies the potential for molecular testing. If a nodule has a driver oncogenic mutation, the correlation with malignancy (depending on the mutation) is quite high. “That can give surgeons the confidence that they’re doing the right thing in proceeding to surgery,” says Dr. Giordano.

Such confidence could have widespread impact. Anywhere from 100,000 to 150,000 patients with thyroid nodules annually in the U.S. receive an indeterminate cytologic diagnosis on their nodules.

Pathologists already have good tools at hand to enhance cytology’s diagnostic yield, says Dr. Nikiforov, including the Afirma (Veracyte) gene expression assay, which uses genes with a high negative predictive value.

The other approach, direct genotyping of DNA and RNA isolated from the cells collected during FNA, is being led by Dr. Nikiforov, who is also codirector, Multidisciplinary Thyroid Center, UPMC. He launched his first panel with seven genes: BRAF, NRAS, HRAS, and KRAS, plus RET/PTC1 and RET/PTC3 and PAX8-PPARG rearrangement. These covered about 65 to 70 percent of thyroid cancers. When next-generation sequencing became available, the test panel jumped to 15 genes and included prognostic as well as diagnostic markers, such as TP53 and PIK3CA; sensitivity rose to 80 percent. The latest version, ThyroSeq v.2, has 60 genes and 90 percent sensitivity, says Dr. Nikiforov. With the new data from TCGA, “we will probably be able to package an even broader panel that will cover 95 to 97 percent of papillary carcinoma.”

Another potentially big impact from the paper, from a clinical perspective, is the demarcation of BRAF V600E and RAS tumors. Assessing the genomic data associated with each type, the researchers could see that the biologies differed significantly. That leads to the intriguing potential of tumor reclassification: Do they truly belong under the umbrella of papillary thyroid cancer?

Decades ago, the follicular variant of papillary carcinoma was essentially unrecognized—they were considered to be follicular carcinomas. The Cell paper suggests that it may be time to reunite them again. “So what’s nice about TCGA is that it will catalyze a very serious discussion on the proper classification of thyroid cancer. And that strikes at the most fundamental level of tumor pathology,” says Dr. Giordano.

Along those lines, Dr. Nikiforov is organizing an international conference just prior to the USCAP annual meeting in Boston in March to reexamine the histopathologic features and long-term follow-up for patients with encapsulated follicular variant PTC. No one’s making any grand predictions. In fact, for the pathologists on the TCGA paper, “Just getting us to agree what that classification might look like was not trivial,” Dr. Giordano says. “It’s going to be an interesting time,” he added, echoing the apocryphal Chinese curse: May you live in interesting times.

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