Secondary RAS Mutations Linked to Thyroid Cancer Severity, Mortality

Nancy A. Melville

October 28, 2022

Dr Athanasios Bikas

MONTREAL — Key genetic mutations secondary to RAS mutations that are common in differentiated thyroid cancer (DTC) strongly correlate with higher risk and more advanced cancers, as well as substantially increased mortality rates, new research shows.

"Identification of key additional mutations in patients with RAS-mutant thyroid cancers confers a more aggressive phenotype, increases mortality risk in DTC, and can explain the diversity of RAS-mutated thyroid neoplasia," said first author Athanasios Bikas, MD, of Brigham and Women's Hospital in Boston, Massachusetts, when presenting the findings at the American Thyroid Association (ATA) 2022 Annual Meeting.

"These data support genomic profiling of DTC tumors to inform prognosis and to identify clinically actionable mutations," he said.

RAS, along with BRAF, mutations are among the most common genetic mutations associated with thyroid cancer, with RAS mutations observed in thyroid lesions ranging from benign to highly aggressive tumors.

With next-generation genetic sequencing shedding new light on the genetic distinctions behind cancers and their implications, Bikas and colleagues sought to investigate the relevance of alterations that are secondary to RAS mutations in thyroid cancer.

For the study, they evaluated data from 78 patients with thyroid cancer who were treated at their center from January 2014 and December 2021. All patients had been assessed with a custom-targeted next generation sequencing assay (OncoPanel) used at Brigham and Women's Hospital.

Among the patients, 69 had DTC, three had poorly differentiated thyroid cancer (PDTC), and six had anaplastic thyroid cancer (ATC).

Overall, most patients (77%) had only a RAS mutation, with the driver mutation being NRAS in 57%, HRAS in 32%, and KRAS in 11%.

The remaining 23% of patients had secondary oncogenic RAS mutations, and while only 14% of those with DTCs had secondary mutations, the rate was 100% (all six patients) of those with ATC.

There were no differences in terms of gender or age between RAS-only patients and those with secondary mutations.

However, among the DTC patients, compared with those who had a RAS-only mutation, those with secondary mutations had a significantly higher likelihood of being classified as ATA high risk of recurrence (77% vs 12%; P < .001); they had larger primary tumors (4.7 vs 2.5 cm; P = .002) and were much more likely to be at a more advanced stage (stage 3 or 4) at presentation (67% vs 3%; P < .001).

With a follow-up of 65 months, the mortality rate among DTC patients was more than 10-fold higher among carriers of the secondary mutations compared with RAS mutation alone (20% vs 2%; P = .011).

The 5-year survival rate was 98.1% among RAS-only patients versus 70% among secondary mutation patients (P = .009).

"Our study presents novel findings as we show that additional oncogenic alterations in RAS-positive differentiated thyroid cancers are associated not only with worse clinicopathologic characteristics, but also increased mortality," Bikas told Medscape Medical News.

Noting that the patient numbers are small, the study "included a well-balanced cohort of thyroid cancers," Bikas said. "Therefore, we do expect the same trends to be observed across larger cohorts."

Similar Findings Observed With BRAF

In another recent study, Bikas and his team reported similar findings among patients with papillary thyroid cancer with a BRAF V600E mutation.

Compared to those with the mutation alone, those with secondary mutations also had a higher risk of recurrence, larger baseline tumors, and more advanced stage at presentation.

And disease-specific mortality at 65 months among those with secondary mutations was also about 10-times higher than those with BRAF-only mutations (13.8% vs 1.4%; P = .005).

They further identified a subcluster of patients with mutations in the PI3K/AKT/mTOR pathway, which were independently and strongly associated with disease-specific mortality (odds ratio, 47.9; P < 0.001).

Prognostic Value or "Confirming What's Already Known"?

Commenting on the latest research during the session, co-moderator Benjamin Gigliotti, MD, of the University of Rochester, New York, brought up a key question emerging about molecular testing: What is the true prognostic significance?

"One of the major questions in the clinical application of molecular diagnostics is whether it adds independent predictive or prognostic value to traditional histopathologic or radiographic assessment or staging," he said. "Or are we just confirming tumors that we already knew were bad through other metrics or does this really add information?"

Bikas responded that the findings do indeed add important value to the goal of precision medicine.

"I think that slowly but steadily we are moving to a more personalized approach, and this could determine whether we can catch those tumors early or late and give clues as to how aggressive they are, so I do think this is very useful information," he said.

Elaborating to Medscape Medical News, Bikas added that with genomics, "we can identify additional alterations that we can then potentially target with specific inhibitors in cases of more aggressive cancers."

"Moreover, [mutations identified] can be used to tailor the provider's follow-up approach, as a more aggressive genomic profile might require closer follow-up, while a more conservative approach can be adopted in a tumor without additional oncogenic mutations."

Commenting for Medscape Medical News, Gigliotti said this study adds important insights to existing research.

"There have been many [efforts] in characterizing the molecular landscape of thyroid cancers over the last decade, but this [research] is unique in focusing on RAS-mutant tumors across the differentiation spectrum and specifically cataloging second hits/alterations and how that correlated with stage at presentation, risk of recurrence, and a hard outcome of DTC-specific mortality," he said. 

In addition to relatively small patient numbers, follow-up time is another study limitation, Gigliotti noted.

"While 65-month follow-up is laudable and difficult to accomplish in practice, it's still a relatively short follow-up given DTC's relative indolence and high survival rates, even at 10 years," he said.

"That being said, the dramatic difference in mortality is significant," Gigliotti noted.

"I would be interested to see more thorough clinical characterization of the patients with two mutations, [for instance], were they more likely to be refractory to radioactive iodine treatment?"

The findings of the secondary mutations in all of the ATC patients meanwhile underscore the question of the prognostic value of the information, Gigliotti noted.

"It was not surprising that all six of the ATCs harbored 'double' mutations since they typically have a much higher tumor burden," he explained.

"These tumors are well recognized to be bad actors at the time of diagnosis, and the molecular diagnostics are more helpful in identifying treatment targets (such as BRAF V600E) rather than aiding in prognosis."

Bikas and Gigliotti have reported no relevant financial relationships.

ATA 2022 Annual Meeting. Oral Abstract 42. Presented October 22, 2022.

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