Innovative thyroid nodule diagnostic test avoids unnecessary surgery

By Fábio de Castro  |  FAPESP Innovative R&D – The results of a new clinical study confirm the high accuracy of an innovative diagnostic test to identify and classify thyroid nodules. The test was developed by Brazilian company Onkos Diagnósticos Moleculares. Its sensitivity surpasses that of conventional methods, and it has been shown to avoid a large number of unnecessary surgeries. The new study reinforces the promise of huge savings for medical insurance plans and the public health system if the innovation is applied on a large scale.

The molecular test is called mir-THYpe, and was developed with the support of the FAPESP Innovative Research in Small Business Program (PIPE). It has been on the market since 2018, using biomarkers to detect whether a thyroid nodule classified as indeterminate by conventional techniques is benign or malignant.

According to Marcos Tadeu dos Santos, the firm’s founder, the main technique used to diagnose thyroid cancer is fine needle aspiration, a type of biopsy procedure in which material is extracted from the patient’s neck for visual analysis.

“The vast majority of nodules are benign, but as many as 30% are classified as ‘indeterminate’, and in these cases, the standard procedure is surgical removal of all or part of the thyroid as a precaution,” Santos said. “However, only 25% of nodules are malignant, which means that 75% of the thyroidectomies performed to remove indeterminate nodules are potentially unnecessary.”

Patients submitted to thyroidectomy have to take thyroid hormone for the rest of their lives, he added. Unnecessary surgery, therefore, has a direct economic impact due to the cost to the public and private health systems, and patients also incur lifelong expenses and potential health impairments.

Onkos’s researchers recently conducted a two-year follow-up study of 440 patients submitted to the new test in all parts of Brazil. “We were able to avoid 75% of the surgical procedures that would have been performed unnecessarily,” Santos said. “Another interesting result is that the test changed the physician’s clinical conduct in 92% of cases.” The study was presented this year to the Brazilian Thyroid Meeting, and published as a preprint on medRxiv, pending peer review.

The key scientific difference in the new test, according to Santos, is that it identifies the genetic signatures of any tumor cells present in the thyroid. Artificial intelligence algorithms then interpret these markers to arrive at a positive or negative result with a high degree of accuracy. The test uses real-time PCR to analyze the expression of 11 microRNAs with 96% accuracy.

“In addition to the diagnostic markers used to determine whether modules are benign or malignant, in 2011 we included other genetic markers for use in prognosis, to determine tumor aggressiveness,” Santos said.

Proper planning of surgical procedures requires an assessment of tumor aggressiveness. “Thyroid cancer is not particularly aggressive in general. In these cases, the surgical procedure can be more conservative than those recommended for more aggressive malignant nodules,” he explained.

Health plans

Santos said the firm has applied for accreditation of the test by the National Supplementary Health Agency (ANS), which regulates Brazil’s medical insurance sector, and by the SUS, its national health service, so that the test can be offered by health plans and the public system.

Last year Onkos passed all phases of the procedure for approval by ANS, but the innovation has not yet been awarded accreditation. “We’re making corrections and submitting fresh evidence in a new application to ANS,” he added (more at: https://pesquisaparainovacao.fapesp.br/1788).

The mir-THYpe test has been included in two code sheets that are a pre-requisite for coverage by health plans: CBHPM-AMB, a table that recognizes the test as a medical procedure with the approval of the Brazilian Medical Association (AMB); and TUSS, the table used by health plans.

According to Santos, mir-THYpe is currently covered by UNIMED VTRP, a health co-op that operates in parts of Rio Grande do Sul state. “We’re running pilot tests in a major healthcare operator with nationwide coverage,” he said.

The firm has also applied to the National Commission for Inclusion of Technologies by the SUS (CONITEC). “The process requires cost-effectiveness studies. We’ve been awarded PIPE funding for healthcare technology assessment along these lines,” Santos said.

The results of the first cost-effectiveness studies were excellent. “We calculated all the costs involved in the molecular test and the surgeries it could avoid. The results showed that health plans save BRL 2,000 per patient on average by using the test,” he said.

Access to the test is private for now. When the result of a fine needle aspiration test is indeterminate, the physician asks the patient to have the molecular test performed by Onkos or a partner laboratory.

“Our logistical capacity enables us to receive samples from anywhere in Brazil,” Santos said. “Another advantage of the test compared with those available on the market is that the patient doesn’t have to undergo another fine needle aspiration, which is always unpleasant, and samples can be transported at room temperature, which makes the whole procedure straightforward.”

Importance of PIPE

Support from FAPESP via PIPE has been fundamental for development of the product, Santos stressed. The diagnostic part of the test was developed in Phase 1. Phase 2 involved development of prognostic markers to help determine the aggressiveness of malignant nodules. In Phase 3, approved recently, the scope is technical-scientific and market-related.

“In the technical-scientific part, application of the test will be extended to pediatric patients and a new nodule class,” Santos said. “Besides nodules identified as malignant, benign or indeterminate, around 10% are classified as ‘insufficient’, when not enough material is aspirated by the needle for cytological analysis. These can be analyzed for diagnostic purposes by our molecular test.”

Phase 3 of the project has also guaranteed funding for the hiring of an access leader – a professional who will be responsible for generating cost-effectiveness data and interacting with public and private actors to widen the use of the test.

Onkos was incubated at the Supera Technological Innovation Park in Ribeirão Preto, São Paulo state, and began developing the test in 2015 in partnership with Hospital de Amor in Barretos (previously known as Barretos Cancer Hospital). The product was launched in 2018, and according to Santos the platform may in future be adapted for use in diagnosing breast and prostate cancer, among others.

The article “Real-world, prospective, and multicenter validation of a microRNA-based thyroid molecular classifier” (doi: 10.1101/2020.10.27.20217356) by Marcos Tadeu dos Santos, Bruna Moretto Rodrigues, Satye Shizukuda, David Livingstone Alves Figueiredo, Giulianno Molina de Melo, Rubens Adão da Silva, Claudio Fainstein, Gerson Felisbino dos Reis, Rossana Corbo, Helton Estrela Ramos, Fernanda Vaisman and Mário Vaisman is at: www.medrxiv.org/content/10.1101/2020.10.27.20217356v1.full.