- Review of:
- Schumm MA, Nikiforov YE, Nikiforova MN, et al. Association of BRAF V600E allele frequency with clinicopathologic outcomes in papillary thyroid cancer. J Clin Endocrinol Metab. Epub 2024 Nov 14:dgae774; doi: 10.1210/clinem/dgae774. PMID: 39541427.
- Key Points:
- BRAF V600E mutation:
- Is the most common mutation detected in papillary thyroid carcinoma (PTC)
- It is detected in a large variety
of cancers, from low- to high-risk tumors - This study suggests that the reason for
this variability may be related to the allele
frequency (AF) of the mutation:- The proportion of DNA molecules in the sample that carry the mutation
- Among 73 patients with an isolated BRAF V600E mutation detected via ThyroSeq v3 molecular testing:
- Those with an AF ≥ 35%:
- Had a significantly higher risk of recurrence and worse recurrence-free survival
- Those with an AF ≥ 35%:
- These findings support a more refined
approach to managing this common mutation:- Allowing for better preoperative risk assessment:
- Patients with low AF may be candidates for lobectomy or active surveillance:
- While those with high AF or other risk factors may benefit from more aggressive treatment
- Patients with low AF may be candidates for lobectomy or active surveillance:
- Allowing for better preoperative risk assessment:
- BRAF V600E mutation:
- Background:
- The BRAF V600E mutation is the most common
genetic alteration in papillary thyroid cancer (PTC) and is typically reported as either present or absent in clinical practice:- However, allele frequency (AF),
which is the proportion of mutated cells within a tumor, varies and may provide additional prognostic insights
- However, allele frequency (AF),
- This study highlights how advances in
molecular diagnostics now allow measurement of AF, offering a potential tool for refining the tumor risk stratification
- The BRAF V600E mutation is the most common
- Methods:
- This retrospective cohort study included 73 patients with Bethesda V / VI thyroid nodules confirmed to have BRAF V600E who had surgery with a diagnosis of PTC
- Quantitative AF data were obtained through
ThyroSeq v3 molecular testing and analyzed in
relation to clinicopathologic features - Markers of aggressive tumor behavior included tumor size ≥ 2 cm, gross extrathyroidal extension (ETE), and lymph node
metastases - The primary outcomes were disease
recurrence and recurrence-free survival (RFS)
- Results:
- Among the patients with an isolated BRAF V600E mutation:
- Median patient age was 45 years
- 66% were female
- 88% patients had Bethesda VI
cytology - The median BRAF AF was 25.5% (range,
0.5 to 47.3)
- Higher AF levels:
- Were associated with more aggressive tumor characteristics, including:
- Larger tumor size and the presence of gross ETE
- Were associated with more aggressive tumor characteristics, including:
- Patients with AF ≥ 35%:
- Had a significantly higher risk of recurrence and worse RFS (hazard ratio, 7.40; 95%
CI, 1.4–38.1)
- Had a significantly higher risk of recurrence and worse RFS (hazard ratio, 7.40; 95%
- Overall, after 4.1 years of follow-up:
- 9.4% of patients experienced disease recurrence, with most cases occurring in those with elevated AF
- Allele frequency was not significantly linked to
lymph node metastases or positive surgical margins
- Among the patients with an isolated BRAF V600E mutation:
- Conclusions:
- Tumors with high BRAF V600E AF were associated with more gross ETE and increased recurrence risk
- Preoperative knowledge of AF levels may help guide individualized treatment decisions
- BRAF V600E mutation is very common in PTC:
- Detected in approximately 50% of cases, and is associated with a wide spectrum of disease, from low- to high-risk tumors
- Although it is frequently associated
with extrathyroidal extension, lymph node metas-
tases, and radioiodine (RAI)-refractory disease:- This mutation is also present in small, indolent tumors and even in occult disease identified at autopsy
- This variable clinical presentation has led to ongoing controversy over whether the presence of BRAF mutation, identified either preoperatively or on the pathology report, should guide treatment decisions
- For instance, some authors argue that microscopic PTCs are less suitable for active surveillance if they harbor a BRAF mutation
- Also, the efficacy of RAI therapy in BRAF-mutated PTC has been questioned, with some studies demonstrating reduced effectiveness, while others report favorable clinical
outcomes
- The current study is intriguing, as it offers a potential explanation for the variable clinical behavior of BRAF-mutated tumors
- Schumm et al. evaluated 73 patients with Bethesda V / VI thyroid nodules positive for BRAF V600E mutation, assessing the allele frequency (AF) of the mutation
- This analysis was made possible by the ThyroSeq molecular test, which, in addition to detecting mutations, provides a quantitative assessment of mutation frequency:
- For example the proportion of DNA molecules containing the mutation among all DNA molecules obtained from a given fine-needle aspiration sample
- The authors identified a clear correlation between AF and tumor aggressiveness, with a clinically actionable threshold of ≥ 35% associated with a higher risk of recurrence
- These findings align with several recent studies that demonstrated a correlation between BRAF V600E AF (tested on surgical specimens) and aggressive histologic features
- In clinic, patients often express concern upon
learning they carry a BRAF mutation, as most online materials and social network groups emphasize its association with aggressive disease and reduced RAI responsiveness - This often leads to overtreatment, even in cases with otherwise low-risk features
- The present study introduces a potentially valuable preoperative tool to better stratify risk and guide clinical decisions:
- Such as the extent of surgery and the
appropriateness of active surveillance
- Such as the extent of surgery and the
- It improves the utility of molecular testing, as BRAF mutations alone have limited prognostic value when reported as binary (yes / no) results, when adjusted for tumor and patient characteristics
- Using this approach, a more aggressive treatment strategy can be reserved only for patients with high AF or those with dual BRAF and TERT promoter mutations (which are associated with a more aggressive clinical course)
- Conversely, patients with low AF will be suitable for lobectomy or active surveillance
- In addition to AF, there are several promising
molecular prognostic tools, such as gene expression profiles associated with vascular invasion or sodium–iodide symporter expression, which have the potential to further individualize management based on preoperative genomic analysis - The future looks promising, with increasingly tailored treatment strategies driven by advances in preoperative workup
- References:
- Schumm MA, Nikiforov YE, Nikiforova MN, et al.
Association of BRAF V600E allele frequency with
clinicopathologic outcomes in papillary thyroid
cancer. J Clin Endocrinol Metab. Epub 2024 Nov
14:dgae774; doi: 10.1210/clinem/dgae774. - Ramone T, Ghirri A, Prete A, et al. Molecular profiling of low-risk papillary thyroid carcinoma (mPTC) on active surveillance. J Clin Endocrinol Metab 2024;dgae575; doi: 10.1210/clinem/dgae575.
- Huang Y, Qu S, Zhu G, et al. BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment. J Natl Cancer Inst 2017;110(4):362-370; doi: 10.1093/jnci/djx227.
- Kim KJ, Kim SG, Tan J, et al. BRAF V600E status may facilitate decision-making on active surveillance of low-risk papillary thyroid microcarcinoma. Eur J Cancer 2020;124:161-169; doi: 10.1016/j.ejca.2019.10.017.
- Ge J, Wang J, Wang H, et al. The BRAF V600E
mutation is a predictor of the effect of radioiodine therapy in papillary thyroid cancer. J Cancer 2020;11(4):932–939; doi: 10.7150/jca.33105. - Zhu G, Deng Y, Pan L, et al. Clinical significance of the BRAF V600E mutation in PTC and its effect on radioiodine therapy. Endocr Connect 2019; doi: 10.1530/EC-19-0045.
- Huang J, Wang J, Xv J, et al. Genetic alterations and allele frequency of BRAF V600E and TERT mutation in papillary thyroid carcinoma with intermediate-to-high recurrence risk: a retrospective study. Clin Exp Med 2024;24(1):76; doi: 10.1007/s10238-024-01320-4.
- Blazekovic I, Samija I, Perisa J, et al. Association
of BRAF V600E mutant allele proportion with the dissemination stage of papillary thyroid cancer. Biomedicines 2024;12(3):477; doi: 10.3390/biomedicines12030477. - Abdulhaleem M, Bandargal S, Pusztaszeri MP,
et al. The impact of BRAF V600E mutation allele
frequency on the histopathological characteristics of thyroid cancer. Cancers (Basel) 2023;16(1):113; doi: 10.3390/cancers16010113.
- Schumm MA, Nikiforov YE, Nikiforova MN, et al.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 