The Role of BRAF V600E As Prognostic Indicator for Patients With Papillary Thyroid Carcinoma

Mahsa Javid, DPhil, FRCS, FRCSC, University of Louisville, Kentucky, shares insights on the changing role of BRAF V600E when managing patients with papillary thyroid carcinoma. Previously, BRAF V600E positivity has been used as a prognostic indicator for this patient population. Dr Javid, referring to recent research, questions this use.

In conclusion, Dr Javid said, “Because of a change in classification, particularly of NIFTP [non-invasive follicular thyroid neoplasm with papillary-like nuclear features] since 2017, we need to modify our understanding of the role of the BRAF V600E mutation in papillary thyroid cancer.”

Transcript:

Hello, I'm Mahsa Javid. I'm the Endowed Chair of Endocrine Surgery at the University of Louisville in Louisville, Kentucky.

What is the role of BRAF V600E in papillary through carcinoma as we currently understand it?

The BRAF V600E mutation is the most frequent oncogenic genetic alteration found in papillary thyroid carcinoma, or PTC for short. The question of its role though in PTC is actually not a straightforward one. Even its prevalence has been widely reported across the globe in various studies ranging from 27% to 87%. The Cancer Genome List cohort had a rate of 59.7%. Currently in the West, it's reported to occur in about 45% of cases, though the true occurrence is likely to be much higher than that, closer to 70% to 80%. And the issue with understanding the role of this mutation and even its prevalence really focuses around a change in pathological classification that occurred in 2017, when certain thyroid lesions were classified differently. There were lesions that were referred to as encapsulated follicular variant of PTC, and these were included in the BRAF wild type group of papillary thyroid carcinomas in studies. But they're now classified as benign lesions called non-invasive follicular thyroid neoplasm with papillary-like nuclear features or NIFTP, for short.

Prior to 2017, studies that included these benign lesions in their PTC groups may have caused some differences in the actual prevalence of the V600E mutation. Actual cancers, which were predominantly the BRAF V600E mutated ones were thought to be more aggressive. And for a couple of decades now, at least in the West, the thinking has been that this mutation portends a poorer prognosis, and the cancers with this V600E mutation were thought to have more high risk features in the clinical pathological sense, such as extra thyroidal extension, higher rates of lymph node metastasis and recurrence, and really portend a worse prognosis with increased disease specific mortality. However, in the East, particularly in Southeast Asia, this was less of an issue. I think probably because they saw the NIFTP lesions less frequently. And so data from Eastern population seemed to be more consistent, and the prevalence in those populations for the V600E mutation has always been higher up to 70% to 80%, which I think appears to be closer to the true prevalence.

How is BRAF V600E accounted for in guidance, such as the risk stratification system from the American Thyroid Association?

The guidelines are always evolving, and there are new American Thyroid Association guidelines for differentiated thyroid cancer that are due to be published soon. And I look forward to those as I think they will be powerful, because the prior guidelines were created in 2015, before NIFTP. But in any case, the various guidelines, including those from the ATA, as I alluded to in my editorial, really hedged their opinion on the role of the BRAF V600E mutation in clinical management. They acknowledged the role of molecular testing, including identification of the V600E mutation and that it has been useful in facilitating appropriate management in some patients with PTC. However, they don't fully endorse its use, especially for prognostication. And in particular, they do not recommend routinely using results from molecular testing for initial risks stratification. And specifically that the BRAF status has a limited role in guiding initial patient management. Yet on the other hand, they also state that results from molecular testing may modify the initial surgical approach.

The NCCN guidelines specifically states that if pre-operative molecular testing suggests PTC, especially in the case of a BRAF V600E mutation or a PTC that was diagnosed on initial cytology. So, it seems that the guidelines suggest that the identification of the V600E mutation preoperatively really doesn't change any recommendations for treatment in PTC at least initially. But it could. And there are a few specific scenarios that the ATA quote where preoperative identification of the mutation in nodules that were either suspicious or indeterminate on initial cytology could then be treated as cancers if they were found to have a mutation. And that’s because the presence of this mutation has a limited positive predictive value for recurrence. It should not be used to impact the decision of whether or not to do a prophylactic central neck dissection in PTC. But they do go on to state that although they don't recommend its routine use for initial postoperative risks stratification, it can potentially refine risk estimates during postoperative surveillance.

Please summarize the study published by Lai et al, “BRAF V600E mutation lacks association with poorer clinical prognosis in papillary thyroid carcinoma” in Annals of Surgical Oncology.

Lai et al performed a retrospective chart review of 672 patients who underwent thyroid surgery for PTC at their single institution, and they studied the prevalence of the V600E mutation in particular. And its correlation is in fact associated with aggressive tumor features such as macroscopic, extra thyroidal extension, lymph node metastasis, and distant metastasis. And their median follow-up time was 70 months and recurrence rate was 8.2%. And what they found was that the BRAF V600E mutation was present in almost 77% of their patients, so on that higher end.

They found that there was no association between BRAF status and all those high-risk features such as extra thyroidal extension, lymph node metastases, multifocal disease, or even age and sex. But interestingly, and this is fascinating, is that they found that patients without the BAF V600E mutation were more likely to have larger primary tumors and also distant metastases and advanced stage.

What is the significance of the results from this study, and do they change our understanding of BRAF V600E in PTC?

I think the first significance of this study is that it solidifies the idea that the BAF V600E mutation does not in and of itself predict prognosis in PTC. The study confirmed a high prevalence of the mutation almost 80%, and yet we know that only a few patients will have recurrence. Most do very well, and recurrence, especially the development of distant metastases, is low. And the study confirms that the BRAF status should not be used as a single prognostic indicator or determine initial patient management.

And the other significance, and this is the part where I think is it's definitely augmenting our current knowledge, is that the study showed that patients without the BRAF V600E mutation were more likely to have more aggressive disease, including the development of distant metastases. And this is very significant because although there's some controversy about whether or not the BRAF V600E mutation portends some worse aggressive features, particularly in Western studies, things like extra thyroid extension, lymph node metastases, the mutation increases the risk of developing distant metastases. This shows the opposite in fact, that those patients without the V600E mutation are more likely to develop distant metastases.

This all augments our understanding of the role of the V600E mutation as well, and basically points to the need for further studies. In particular, the molecular risk factors for distant metastasis and poorer outcomes needs further investigation in both groups, the BRAF V600E positive, and in particular those with negative mutations.

In your own practice, how do you approach the issue of BRAF V600E when managing patients with PTC?

Generally, there are 2 or 3 situations where this mutation may be of interest during the management of patients with PTC: preoperatively and then following surgical resection. In the preoperative setting, I often perform my own fine needle aspiration biopsies on nodules that I find suspicious. And if the results of those biopsies come back as indeterminate, which are generally the grades 3 and 4 on the Bethesda scale on cytology, then I will have that sample sent for molecular testing. However, the results of molecular testing are not highly predictive of malignancy in and of themselves unless there is a BRAF V 600 D mutation. And in that case, when there is such a mutation, there's about a 99% risk of malignancy. And in that situation, I recommend surgical resection rather than observation. However, I don't think there is sufficient evidence that a cancer with the V600E mutation should be treated any differently than one that is BRAF-wild type.

For example, the current recommendation for small thyroid cancers that are under 4 cm is to perform a lobectomy rather than a total thyroidectomy. If I've sent a biopsy of a small nodule under 4 cm for molecular testing and the V600E mutation is identified preoperatively, I would still recommend the lobectomy. If however, there is the coexistence of the BRAF V600E mutation and another gene mutation that is indicative of aggressive disease, and those could be things such as the TERT promoter promoter, which has been reported to be a strong oncogenic driver in thyroid cancer or other mutations in the PIK3CA, TP53, or AK1, then I think it's reasonable to recommend total thyroidectomy even for a small cancer.

And then in the postoperative settings, there are 2 scenarios. Straight after resecting the tumor, we'll have the pathological review, and there is a role for molecular testing to determine whether or not further treatment such as radioactive iodine or closer follow-up even is warranted. But again, I think if there's a single mutation of just the BRAF V600E, I don't think that would be sufficient to recommend additional treatment initially. Whereas if there is another co-mutation with a second more aggressive gene, then I would discuss it at our endocrine multidisciplinary team meeting, and depending on other risk factors, potentially recommend further treatment. And then there's the final scenario in those patients who have in fact had a recurrence and have a BRAF V600E mutation. And in these cases, patients can often be treated with targeted therapy, which may include BRAF inhibitors, and particularly this may be useful in patients with iodine refractory disease in whom the metastasis will no longer be responsive to radioactive iodine treatment.

Is there anything you would like to add about this topic?

I think in conclusion we can say that because of a change in classification, particularly of NIFTP since 2017, we need to modify our understanding of the role of the BRAF V600E mutation in papillary thyroid cancer. I think we need to be looking at the prevalence. We may find that in fact it occurs at a higher rate than previously thought, and probably I think we'll find that it cannot be used as a single prognostic indicator or guide. Initial management strategy to bear in mind is that a lot of coexisting mutations are probably present. A lot of studies only looked at this V600E mutation and not others. I think it's very likely that we'll need to do more panels on pathological specimens to see if there are coexisting co-mutations that may portend poor or prognosis, and those may change our initial risk strategy in these patients.

Sources:

Javid M. Questioning the role of BRAF V600E as a prognostic indicator in papillary thyroid carcinoma. Ann Surg Oncol. Published online: February 5, 2025. doi:10.1245/s10434-025-16963-0

Lai H-F, Hang J-F, Kuo P-C, et al. BRAF V600E mutation lacks association with poorer clinical prognosis in papillary thyroid carcinoma. Ann Surg Oncol. 2024; 31: 3495-3501. doi:10.1245/s10434-024-14935-4