The Risk Of Recurrence In Papillary Thyroid Cancer
PTC represents the majority of thyroid carcinomas . It is characterized by excellent prognosis, almost 100% probability of 5-year overall survival . Therefore, in PTC the risk of disease recurrence is most frequently analyzed in relation to the prognosis, i.e., the disease-free survival but not the overall survival unlike in other types of cancers with higher mortality rates .
The risk of relapse or persistent disease is related to about 30% of PTC patients and depends, among other things, on the adopted definition of recurrence .
The incidence of recurrence depends on whether clinical detection is considered alone or whether it is analyzed together with biochemical recurrence.
From the perspective of a surgeon, structural recurrence seems to be the most significant due to the fact that these patients are most frequently scheduled for surgery. In the context of the therapeutic strategy, the significance of biochemical recurrence cannot be omitted since such patients require a change in routine diagnostic and therapeutic management, e.g., additional treatment with radioactive iodine or increased follow-ups.
Features Of Infiltrating Immune Cells In Braf
As risk score, HTR3A and NIPAL4 were associated with the poor prognosis of PTC patients with BRAF mutation, and we further evaluated the correlation between immune cells and the above three factors. We observed that the Tr1, nTreg, iTreg and Tfh cell numbers were increased in the high-NIPAL4 group and that the Tr1, nTreg, iTreg, Th1, Tfh, gamma delta T, and CD4+ T cell numbers were increased in the high-HTR3A group and high-risk group conversely, the Th17 cell number was decreased. In addition, macrophages were increased only in the high-risk group, while CD8+ naive cells decreased only in the high-HTR3A group. The infiltration scores between the low-NIPAL4 and high-NIPAL4 groups, the low-HTR3A group and the high-HTR3A group, and the low- and high-risk groups were all statistically significant . These findings suggested that HTR3A expression and NIPAL4 expression were likely to be involved in BRAF-mutated PTC by interfering with immune cells.
Figure 10 Violin plot showing the compression of each immune cell type in the low/high NIPAL4 groups , low/high HTR3A groups and low/high risk groups . The high-risk/HTR3A/NIPAL4 groups had a higher degree of immune cell infiltration , suggesting that the risk score, HTR3A and NIPAL4 are involved in the prognosis of BRAF-mutated PTC by interfering with immune cells.
Sample Selection And Dna Isolation
In all, 16 patients with anaplastic thyroid carcinoma were identified from a search of the archival surgical pathology files of The Johns Hopkins Hospital between 1985 and 2003. After initial patient identification, all original histologic slides were reviewed by one of us to confirm the diagnosis, and an appropriate block was retrieved for DNA extraction. The paraffin blocks were sectioned, and tissues sections were microdissected to obtain greater than 80% neoplastic cells. When the slides showed an anaplastic thyroid carcinoma arising in association with a well-differentiated thyroid carcinoma, the anaplastic and well-differentiated components were separately collected and analyzed. DNA was extracted using standard protocols as previously published.
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Therapeutic Potential Of Inhibiting The Map Kinase Pathway Using Novel Inhibitors In Thyroid Cancer
Although thyroid cancer is usually indolent and curable with the current standard treatments of surgery, often followed by adjuvant radioiodine therapy, there remain many patients whose conditions are incurable, disabling, and even fatal. The most difficult cases, for which there is no effective current treatment, are those that are inoperable and have lost radioiodine avidity. This includes ATC, which is often positive for BRAF mutation . A novel effective treatment is needed desperately for these patients . As activation of the MAP kinase pathway by various genetic alterations, including BRAF mutation, plays a pivotal role in thyroid tumor genesis and progression, efforts targeted at inhibiting this pathway may lead to development of novel effective therapy for thyroid cancer.
Critical Remarks Concerning A Multicentre Retrospective Analysis Of The Relationship Between The Mutation And Disease Recurrence
These observations, however, did not dispel the controversy concerning prognostic and predictive significance of BRAF mutation in PTC. After publishing the results of the analysis, the discussion in Journal of Clinical Oncology on the real relationship between the mutation and the cancer relapse was initiated. Bal et al. argued that inaccurate definition of recurrence was used and the definition was applied also for persistent disease. The accusations were also related to a short median follow-up and a relatively high incidence of recurrence. These accusations are not fully legitimate . In PTC persistent disease is commonly linked with the real recurrence due to the fact that routine follow-ups occur every 6 or 12 months and it is not possible to fully differentiate recurrence from persistent disease as defined in the classic oncological definition. Recurrence is the symptom occurrence after complete remission lasting up to 6 months after the end of treatment.
The majority of relapses occur in the first years of the follow-up, therefore a 3-year follow-up may be considered sufficient, and the reported percentage of recurrence is within the range given by other authors .
Furthermore, Yarchoan et al. appreciated the value of the studies of Xing et al. as the largest multicenter retrospective study on prognostic significance of BRAF mutation .
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What You Need To Know
- The BRAF gene provides instructions to a protein responsible for managing important cell functions related to growth.
- If there is a mutation in the gene, it stops working correctly and signals cells to divide uncontrollably, which leads to a tumor.
- Doctors can collect and analyze a sample of the tumor or use blood tests to detect the BRAF mutation.
- If you have a BRAF-mutated tumor, oncologists may be able to use targeted treatments to temporarily turn off the mechanisms fueling tumor growth.
Precision Medicine: Braf Mutations In Thyroid Cancer
Amanda Podolski, Enrico Castellucci, Balazs Halmos
Department of Medical Oncology, Montefiore Medical Center, Bronx , , USA
Contributions: Conception and design: A Podolski, B Halmos Administrative support: B Halmos Provision of study materials or patients: A Podolski, B Halmos Collection and assembly of data: A Podolski Data analysis and interpretation: None Manuscript writing: All authors Final approval of manuscript: All authors.
Correspondence to:
Abstract: Mutations in BRAF are commonly seen in thyroid carcinoma and can have therapeutic and prognostic implications. The BRAF V600E mutation is seen in approximately 40% of cases of papillary thyroid carcinoma , and is associated with aggressive clinicopathological features, higher recurrence rate, and disease related mortality. Significant advances have occurred in the development of new therapeutic targets of the MAP kinase pathway, which is activated in the setting of BRAF mutations, including BRAF and mitogen extracellular kinase inhibitors. BRAF alterations other than V600E are less common in PTC, and their clinical significance remains to be established. Here we present a case of a male with poorly differentiated thyroid carcinoma, with papillary and follicular features, who was noted to have a BRAF K601E mutation. The patient was subsequently treated with a BRAF inhibitor, dabrafenib, and MEK inhibitor, trametinib.
Keywords: Thyroid cancer BRAF mutation RET mutation V600 K601E
doi: 10.21037/pcm.2019.09.04
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Thyroid Cancer Patients Demographics
AUBMC thyroid carcinoma database from 2001 to 2011 revealed 385 thyroid cancers with PTC as the predominant type constituting 91.7% of the cases. The overall female-to-male ratio of the PTC cases was 2.5:1. Approximately 26% of the patients were < 30 years old, 56% were between 3149 years old, and 18% were > 50 years old. The frequency of each PTC histopathologic subtype was as follows: 123 cases of cPTC , 76 cases of PTMC , 15 cases of PTMC-FV , and 39 cases of PTC-FV .
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Braf Mutationone Of The Most Frequent Events In The Pathogenesis Of Ptc
The beginning of 2000 marked the interest in BRAF gene mutation in thyroid cancer. At that time studies on the role of the mutation in other cancers had been already known . BRAF gene is localized on chromosome 7.
It codes cytoplasmic serine/threonine kinase which influences the activation of mitogen-activated pathway kinases . BRAF gene mutations activate the MAPK pathway resulting in the intensity of cellular proliferation, inhibition of differentiation and apoptosis. In other words, they lead to a loss of control over the cellular cycle, initiating the development of malignancy as a result. BRAF mutation is one of the most prevalent molecular events in the pathogenesis of PTC in adults . Point mutation T1799A is the most common and the most examined mutation of all BRAF gene mutations. It results in the exchanging valine to glutamate at residue 600 near the catalytic center of the protein . Finding this mutation is possible not only in postoperative material but also, which is more significant, in fine needle aspiration biopsy material and may be known at diagnosis of PTC .
Detection Of Brafv600e Mutation As A Molecular Marker In Thyroid Cancer
Fine-needle aspiration biopsy as the gold standard for preoperative evaluation of thyroid lesions has recently been used in conjunction with molecular testing to improve the accuracy of diagnosis from cytology. These molecular markers including BRAF, RAS, RET/PTC and PAX8/PPAR were proved to be feasible and helpful to increase the diagnostic accuracy for patients with indeterminate thyroid nodules . The indeterminate thyroid nodules accounted for 10-15% of overall outcomes on FNABs and were grouped to three subcategories that are follicular lesions of undetermined significance, follicular and oncocytic neoplasms, and suspicious nodules for malignancy .
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Cancers That May Involve Braf Mutations
At the current time, several different types of cancer have been found to harbor BRAF mutations. However, the frequency, as well as the response to BRAF inhibitors, varies.
BRAF mutations are an example of how cancer treatment is changing. In the past, cancers were usually treated according to type . BRAF inhibitors, in contrast, are what are now considered “tumor agnostic” medications.
This means that the drugs may work for different types of cancer . However, the cancer cells must have the same type of mutation responsible for driving the growth of the tumor.
Reading studies about BRAF mutations can be confusing. When the term “BRAF wild-type” or BRAF WT is used to describe a tumor, it refers to a cancer that does not have a BRAF mutation.
Role Of Braf Mutations In Melanoma Lung Cancer And More
Oliver Eng, MD, is a double board-certified surgeon and surgical oncologist and an Assistant Professor of Surgery at the University of Chicago.
BRAF mutations are DNA changes in some cancer cells that can be treated with newer targeted therapies.
BRAF mutations are found in roughly half of melanomas. Medications that target these mutations have significantly improved the survival rates of metastatic melanoma. BRAF mutations are also present in some non-small cell lung cancers, colon cancers, and other tumor types.
Verywell / Jessica Olah
Genomic testing of tumors can look for DNA alterations and determine if the cancer will respond to drugs targeting mutations.
This article looks at what a BRAF mutation is and its frequency in different types of cancer. It also looks at testing, treatment options, and recent advances.
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Braf Kras And Nras Analysis Using Reverse Hybridization
The BRAF, KRAS, and NRAS StripAssays were utilized to detect different point mutations and deletions in the genes coding for BRAF and NRAS. The detection sensitivity for mutant alleles is 1%, performed according to the manufacturers instructions. Mutational analysis was performed by polymerase chain reaction and reverse hybridization as follows: first, a multiplex PCR amplification using biotinylated oligonucleotide primers was performed for BRAF, KRAS, and NRAS gene sequence amplification second, reverse hybridization of the amplification products was ensued via a test strip, which contains allele-specific oligonucleotide probes for mutations and controls immobilized on a parallel array and finally, bound biotinylated sequences were visualized using streptavidin-alkaline phosphatase conjugate and enzymatic color development. Positive control samples included defined mutated cell line DNA or clones.
Data Extraction And Quality Assessment
Two reviewers carefully reviewed the full text of the eligible studies and independently extracted relevant information. Data including the names of authors, publication year, country, geographical region or ethnicity, study period, number of patients, BRAF mutation status, recurrence rates, and hazard ratio of recurrences were obtained with a structured data collection form. The NewcastleOttawa scale was used for the assessment of study quality studies with scores of 8 or higher were eligible for inclusion in this meta-analysis.
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A Critical Approach To The Practical Application Of The Analysis Of Braf Mutation As An Independent Molecular Prognostic And Predictive Factor
The strongest argument against using BRAF mutation analysis as an independent prognostic and predictive risk factor in patients with PTC is its high prevalence whereas the risk of persistent disease or recurrence is related to about 30% of population .
At present, it seems that BRAF mutation is one of the factors influencing the prognosis and it should be analyzed in correlation with other prognostic factors .
The most recent revision of ATA recommendations is also related to it.
Despite the fact that previously Prescott et al. demonstrated that adding BRAF status to different commonly applied risk scales improves the possibility of the proper patient classification . It allows for a better prediction related to the risk of relapse. The 5-year cumulative recurrence incidence observed by these authors was 20% in BRAF vs. 8% in BRAF patients. BRAF was associated with the time to recurrence when it was added to the following risk-scales: AMESHR 2.43, MACISHR 2.46, TNMHR 2.51, ATA recurrence risk categoryHR 2.44.
Due to a lack of evident confirmation of a direct influence of mutation on the increase in relapse risk, ATA most recent recommendations do not indicate a routine application of BRAF status for initial risk stratification in differentiated thyroid cancer. However, due to the fact that a clinician may possess such knowledge, ATA demonstrates the continuous risk scale for the assessment of the risk of relapse, considering BRAF and/or TERT status .
C Mapk Pathway And Its Activating Genetic Alterations
As illustrated in , the RET/PTC Ras Raf mitogen extracellular kinase MAPK/ERK pathway is a classical conserved intracellular signaling pathway that plays a fundamental role in cell functions such as proliferation, differentiation, apoptosis, and survival , and, when aberrantly activated, tumorigenesis . Physiological activation of this pathway is triggered by a large array of growth factors, hormones, and cytokines through their receptors on the cell membrane. In normal cells, the activation of the Raf kinase occurs through direct interaction with GTP-bound Ras, a membrane-bound small G protein. Activated Raf, a serine/threonine protein kinase, phosphorylates and activates the immediate down-stream MEK, which, also a serine/threonine protein kinase, in turn phosphorylates and activates ERK. The activated ERK phosphorylates regulatory protein molecules in the nucleus and ultimately alters gene expression with consequent changes in the biological activities of the cell.
Fig. 1.
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Time Scores Were Associated With Pathological Stage In Braf
To determine the relationship between TIME scores and clinical features, the neoplasm disease stage , tumor stage , metastasis stage , lymph node stage and progression-free survival of the BRAF mutated cohort were analyzed. Although the TIME scores had no significant correlations with PFS , the StromalScore was correlated with T classification , and the ESTIMATEScore was significantly associated with stage and T classification . These results implied that TIME scores were correlated with pathological stages in patients with BRAF-mutated PTC.
Figure 2 Correlation of TIME scores with clinicopathological staging characteristics. The StromalScore was correlated with the T classification of the TNM staging system , and the ESTIMATEScore was significantly associated with the stage and T classification . ImmuneScore had no correlation with the tumor stage or the T classification, M classification, or N classification of the TMN staging system .
Summary And Future Directions
Further work is needed in the following several areas: the elucidation of the specific molecular and cellular alterations and events that are caused by BRAF mutation and MAP kinase pathway activation in thyroid cancer the possible restoration of the ability of thyroid cancer cells to metabolize iodide by interfering with BRAF mutation-initiated aberrant signaling the improvement of the diagnostic utility of BRAF mutation, possibly through combination with other specific molecular markers for thyroid cancer in conjunction with FNAB, and through the establishment of a BRAF mutation-based blood test the clinical application of the prognostic value of BRAF mutation in guiding the optimal short- and long-term managements of thyroid cancer patients and further preclinical and clinical studies on the therapeutic potential of novel inhibitors of MAP kinase pathway. It is anticipated that rapid advancements in these areas will occur in the next few years.
Table 1
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Disease Recurrence And Ln Metastases
LN metastases are the most common cause of disease recurrence in PTC. The possibility of a preoperative assessment of the risk of LN metastases would be significant for a surgeon. As a result, patients might be properly qualified for central lymphadenectomy to avoid this prophylactic procedure and an unnecessary increase in incidence risk of postoperative complications .
The attempt was made to use BRAF mutation in predicting the risk of metastases to cervical LNs . Based on uni- and multivariable analyses Joo et al. confirmed the relationship between the mutation and a higher risk of metastases to the central LNs, suggesting that prophylactic central neck dissection should be based on the assessment of BRAF mutation diagnosed in the fine needle aspiration . Howell et al. presented similar conclusions and their study confirmed the relationship between BRAF mutation and a risk of metastases to the central LNs . These authors expressed the opinion according to which preoperative assessment of BRAF mutation may be used to plan the extent of surgical treatment.
Xing et al. in the multicenter study also confirmed a correlation between the mutation and the risk of LN metastases and a higher risk of recurrence . However, some studies did not confirm the presence of such a relationship .
The observed divergence is obviously related to a retrospective nature of the analyses, different group selection and different time of follow-up.