Secondary RAS mutations associated with thyroid cancer severity and mortality

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

“Identification of important additional mutations in patients with RAS-mutant thyroid cancer confers a more aggressive phenotype, increases the risk of mortality in DTC and may explain the diversity of RAS-mutant thyroid neoplasms,” said first author Athanasios Bikas, MD, of Brigham and Women’s Hospital in Boston, Massachusetts, when presenting the findings at the 2022 American Thyroid Association (ATA) Annual Meeting.

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

RASalong with BRAFMutations are among the most common genetic mutations associated with thyroid cancer RAS Mutations observed in thyroid lesions ranging from benign to highly aggressive tumors.

Using next-generation genetic sequencing that sheds new light on the genetic differences behind cancer and their implications, Bikas and colleagues attempted to examine the relevance of changes that result 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 to December 2021. All patients had been evaluated with a custom 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, where is the driver mutation NRAS at 57%, HRAS in 32% and KRAS at 11%.

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

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

However, among the DTC patients compared to those who a RAS-only mutation, those with secondary mutations had a significantly higher likelihood of being classified as ATA at high risk of recurrence (77% vs. 12%; P < 0.001); they had larger primary tumors (4.7 vs. 2.5 cm; P = 0.002) and were much more likely to be at a more advanced stage (stage 3 or 4) at presentation (67% vs. 3%; P < 0.001).

At a follow-up of 65 months, the mortality rate in DTC patients was more than 10-fold higher in carriers of the secondary mutations compared to RAS mutation alone (20% vs. 2%; P = 0.011).

The 5-year survival rate was 98.1% RAS– only patients versus 70% of patients with secondary mutation (P = 0.009).

“Our study presents new insights as we show that additional oncogenic changes in RAS-Positive differentiated thyroid cancer is associated not only with poorer clinicopathological features but also with increased mortality,” said Bikas Medscape Medical News.

Considering the small patient numbers, the study included “a balanced cohort of thyroid cancers,” Bikas said. “Hence, we expect the same trends to be observed across larger cohorts.”

Similar findings were observed with BRAF

In another recent study, Bikas and his team reported similar results in papillary thyroid cancer patients 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 was also about 10-fold higher in those with secondary mutations than those with BRAF-only mutations (13.8% vs. 1.4%; P = 0.005).

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

forecast value or “Confirm what‘s already known“?

Co-moderator Benjamin Gigliotti, MD, from the University of Rochester, New York, commented on the latest research during the session and posed a key question that arises when it comes to molecular testing: What is the true prognostic significance?

“One of the key questions in the clinical application of molecular diagnostics is whether it adds independent predictive or prognostic value to traditional histopathological or radiological assessment or staging,” he said. “Or are we just confirming tumors that we already knew were bad by other metrics, or does that really add information?”

Bikas replied that the results do indeed add important value to the goal of precision medicine.

“I think that we are slowly but steadily moving towards a more personalized approach and this could dictate whether we can detect these tumors early or late and provide clues as to how aggressive they are, so I think this is very useful information.” .” he said.

elaboration to Medscape Medical NewsBikas added that with genomics, we can “identify additional changes that we can then potentially target with specific inhibitors in cases of more aggressive cancers.”

“Furthermore, [mutations identified] can be used to customize the provider’s follow-up approach, as a more aggressive genomic profile may require closer follow-up, while a tumor with no additional oncogenic mutations may require a more conservative approach.”

Comment for Medscape Medical NewsGigliotti said this study adds important insights to existing research.

“There were many [efforts] in characterizing the molecular landscape of thyroid cancer over the past decade, but this [research] is unique in focusing on RAS-mutant tumors across the spectrum of differentiation and specific cataloging of second hits/changes and how this correlates with stage at presentation, risk of recurrence and a hard outcome in DTC-specific mortality,” he said.

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

“While a 65-month follow-up is commendable and difficult to accomplish in practice, given the relative inertia and high survival rates of DTC, it’s still a relatively short follow-up even at 10 years,” he said.

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

“I would be interested in a more thorough clinical characterization of patients with two mutations, [for instance]were they rather refractory to treatment with radioactive iodine?”

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

“It was not surprising that all six ATCs contained ‘double’ mutations as they typically have a much higher tumor burden,” he explained.

“These tumors are known bad actors at the time of diagnosis, and molecular diagnostics are more helpful in identifying treatment targets (such as BRAF V600E) instead of supporting the forecast.”

Bikas and Gigliotti have no relevant financial relationships reported.

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

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