Assessment Of Methodological Quality
Two reviewers assessed the studies quality using the Quality Assessment of Diagnostic Accuracy Studies 2 . The domains included in the risk of bias and applicability evaluation were participant recruitment, index test, reference standard, flow, and timing. We customized the signaling questions for each of the four QUADAS-2 domains . According to the signaling questions, the risk of bias and applicability were evaluated as low, high, or unclear . For each signaling question, reviewers were required to answer yes,no, or unclear. Divergent answers among reviewers were resolved through discussions. No study was excluded as a result of findings from the risk of bias assessments. However, due to the limited number of studies labeled with a low risk of bias, we could not synthesize separately the results for this subgroup.
Key Results Regarding The Diagnostic Performance Of The Molecular Panels
Afirma GEC and GSC
A total of 25 studies involving 4,538 cytologically ITNs of the 4,424 participants evaluated the Afirma GEC performance . The recruitment period ranged from May 2009 until June 2018. The reported number of non-diagnostic results of the GEC was 181 , ranging from 0 to 13.5% among individual studies. Slightly more nodules had a suspicious test result rather than negative . The nodules surgery rate with valid GEC result was 57.9%, with a significant gap between resections of those with suspicious and negative test results . Following surgery and histological evaluation, 895 of 2,365 nodules were malignant, with a malignancy rate among resected nodules of 37.8%. Ten studies performed histological evaluation to highlight the number of NIFTP lesions . Thus, 54 NIFTP cases were established, all with a suspicious Afirma GEC result. GECs SE and SP among studies ranged from 78.0 to 100% and 7.7 to 51.7%, respectively.
Thyroseq Next Generation Sequencing
Interpace Multiplatform Tests
MiRNA-Based Platforms: RosettaGX Reveal and miRInform
Valderrabano et al., tested miRInform, an initial iteration of ThyraMIR, on a total of 105 Bethesda IIIV nodules recruited from 2012 to 2014 . The surgery rate among TNs with a valid test result was 54.3%. After surgical treatment, histological appraisal revealed 26 of 63 neoplastic tumors. Valderabano et al. provided a 50.0% SE and an SP of 91.9%, respectively for miRInform.
Comparison Of Available Tests
The two molecular diagnostic tests included in Table 1 most commonly used in the United States are Afirma GSC and ThyroSeq v3, each of which reported high-quality evidence with high sensitivity and specificity in multicenter studies with ThyroSeq v3 in ten tertiary referral centers and Afirma GSC in 33% tertiary referral centers although all cytopathology diagnoses were centralized . The Afirma GSC test uses a classifier to diagnose or rule-out malignancy according to gene expression based on RNA sequencing and utilizes the same RNA sequencing data to determine mutations and gene fusions with its accompanying Xpression Atlas Panel. The ThyroSeq v3 test uses targeted DNA and RNA sequencing to determine genetic alterations including mutations, gene fusions, gene expression, and copy number alterations to diagnose or rule out malignancy. Although the high accuracy originally reported by these tests has been confirmed in some independent validation studies, other independent validation studies have demonstrated reduced accuracy and limits to the generalizability of initial validation studies . A recent randomized controlled trial found no significant difference in test performance between ThyroSeq v3 and Afirma GSC . ThyGeNEXT+ThyraMIR uses a mutation panel and a miRNA expression classifier, and ThyroidPrint uses an RT-qPCR mRNA classifier, both tests have reported similar high accuracy but lacked sufficient independent validation .
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Outcomes Of Nodules Following Afirma Gec Testing
Surveillance or surgical follow-up data were available from 189 of 215 GEC-B nodules and 134 of 148 GEC-S nodules . As expected, far fewer GEC-B nodules than GEC-S nodules were resected . Surgical and surveillance outcomes of GEC-B nodules are summarized in Table 4 and Supplementary Table S1, respectively. Of the 28 resected GEC-B nodules, 25 were histologically benign , 1 was NIFTP, and 2 were carcinomas. Although diagnostic surgery was generally recommended for GEC-S nodules, several patients opted for surveillance, the records of which were available for 19 GEC-S nodules . Of the 115 GEC-S nodules that were resected , 80 were benign , 15 were NIFTP, and 20 were carcinomas.
Afirma Gsc: Molecular Analysis In Follicular Thyroid Nodules
Afirma GSC X Atlas represents the most advanced method currently available worldwide for the genomic analysis of indeterminate thyroid nodules , Bethesda IV).
AFIRMA GSC AND AFIRMA GEC DIFFERENCES
The Afirma method is applied in the differential diagnosis of indeterminate nodules , Bethesda IV) to identify benign nodules and to avoid unnecessary diagnostic surgery. The first method of Afirma was Afirma Gene Expression Classifier , a method with high sensitivity, which allowed to reclassify as less than half of the undetermined thyroid nodules as benign. Recent technological advances have allowed us to take another step forward with the development of Afirma Genomic Sequencing Classifier that allows us to reclassify as benign well over half of the undetermined thyroid nodules . Afirma GSC represents an advanced method available for the genomic analysis of indeterminate thyroid nodules , Bethesda IV).
AFIRMA GSC PAPILLARY THYROID CARCINOMA
AFIRMA GSC MEDULLARY THYROID CARCINOMA
The Afirma GSC method also employs a classifier for medullary carcinoma , which allows a more correct therapeutic approach for patients with MTC.
AFIRMA GSC HURTLE CARCINOMA
AFIRMA GSC PARATHYROID
AFIRMA GSC vs AFIRMA GEC
AFIRMA GSC vs OTHER METHODS
AFIRMA GSC OTHER INFORMATIONS
For more information about Afirma GEC, .For more information about Afirma GSC X Atlas, .For an appointment for Afirma GSC X Atlas, you can: write an email
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Impact On Surgical Decision Making
One of the first studies to specifically investigate molecular testings impact on surgical management was a retrospective study performed by Aragon Han and colleagues in 2014 . Here, the authors compared management recommendations based on pre-operative molecular testing results to the treatment strategy recommended by a surgical management algorithm. The algorithm was based on clinical parameters developed by experts at a high-volume, tertiary academic institution and in incorporated into a calculator. They found that the strategy influenced by molecular testing differed from the recommendations of the clinical management algorithm in only 10% of the patients . Furthermore, in 6 out these 9 patients the molecular testing driven strategy was incorrect and led to overtreatment. Similar results were subsequently observed during two successive investigations by Noureldine and colleagues . In one, the authors specifically looked at the appropriateness and impact of Afirma-GEC on management of 273 patients using a similar strategy to Aragon Han et al. and found that the GEC results changed management strategy in just 23 out of 273 patients and led to overtreatment in most of these . These results were echoed by a subsequent prospective study by the same group where molecular testing only changed management plan in 7.9% patients, out of whom 91% were overtreated .
Table 1 Summary of investigations evaluating impact of molecular testing on surgical management and outcomes.
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Impact On Surgical Practice
One of the stated aims of molecular testing for indeterminate thyroid nodules is to assess the risk for malignancy, and thus determine 1) whether surgery is appropriate for that lesion and 2), if so, the extent of surgery. A corollary aim to this is reducing the number of diagnostic lobectomies performed, and ultimately spare a patient from the risks and costs of unnecessary surgery. While most studies examining the utility of these molecular tests center on their diagnostic performance , investigations on whether implementation of these tests lead to actual changes in surgical utilization and clinical practice patterns are sparse. Prospective studies assessing the impact of these tests on the rate and appropriateness of surgical intervention are lacking, and most of the information is gleaned from retrospective data only. Moreover, many of the series suggesting that implementation of molecular testing leads to reduction in number of surgeries are correlative in nature, i.e., they show that fewer surgeries were done during period of molecular testing use compared to historical time period when testing was not used, but they do not directly show a causal effect at the individual patient/nodule level .
Noninvasive Follicular Thyroid Neoplasm With Papillary
Compounding the challenge to the accuracy of molecular testing is the recent introduction of a new thyroid pathological entity: noninvasive follicular thyroid neoplasm with papillary-like nuclear features . The NIFTP category was created to distinguish an indolent class of encapsulated follicular variant of papillary thyroid carcinoma from other aggressive forms of papillary thyroid cancer. Of note, its average prevalence within indeterminate thyroid nodules is estimated to be 61% . Given that these mainstay molecular tests were developed and validated prior to this re-designation , their performance measures have been shown to deteriorate significantly when the NIFTP designation is incorporated in the classification of indeterminate nodules . For instance, the NPV of Affirma GEC declined from 96 to 81% when the NIFTP designation was retrospectively applied to the cohort studied by Samulski and colleagues . Similarly, in the cohort studied by Valderrabano and colleagues, the PPV of ThyroSeq V2 decreased from 42 to 33% when NIFTP lesions were considered benign . The performance of the ThyroSeq rule in test appears to be more significantly affected by NIFTP reclassification than the Afirma rule out test. Nevertheless, the results of both should be interpreted with a consideration that benign NIFTP lesions may be falsely classified as suspicious, and thus subjected to unnecessary surgery by these tests.
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Thyroid Ultrasound Fna And Afirma Gec Testing
Thyroid ultrasound was performed by Endocrine Certification in Neck Ultrasound certified endocrinologists and radiologists with thyroid expertise. The FNA was performed under continuous ultrasound guidance by using a 25-gauge needle. Initial FNA of a nodule typically consisted of four passes collected into CytoLyt for preparation of a ThinPrep slide. For nodules classified as Bethesda III/IV on initial FNA, repeat FNA typically consisted of two passes collected into a vial of nucleic acid preservative for Afirma GEC testing and four passes collected into CytoLyt for ThinPrep cytology. Samples for Afirma GEC were submitted to Veracyte, Inc. as per our SemiRestrictive testing policy , with the addition of seven samples classified as Bethesda V/VI on repeat FNA that were submitted for Afirma testing off-protocol.
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Icipant And Study Characteristics
We included in the review a total of 40 articles from the USA with 50 assessments of association between seven molecular panels and postsurgical histological evaluation . Table 1 summarizes the characteristics of the included studies. All 40 articles are published in English. The publication year ranged from 2012 to 2019, while the populations were enrolled between September 2009 to June 2019. All but one study were conducted in the USA, with the originates in Singapore . A minority of the studies had a prospective design , of which one research performed a parallel randomized study , and another two studies enrolled patients both retro- and prospectively .
Table 1 Characteristics of the included studies.
Among the total TNs, 4,427 had undergone surgical resection. Overall, the surgery rate was significantly higher when the test result was positive or suspicious , comparing to the surgery rate in patients with negative test results . Among the resected nodules, 1,667 were found malignant at the histopathological evaluation. The most frequent malignancy reported were classic PTC, follicular thyroid cancer , FVPTC, and Hurthle cell carcinoma diagnosed in 611, 255, 95, and 53 nodules, respectively. Conversely, we found MTC and poorly differentiated thyroid cancer in seven cases each. Sixteen studies revealed 144 NIFTP cases after histological evaluation .
Data Published In Jcem Demonstrate Strong Real
Meta-analysis of 13 independent studies suggests genomic test performs even better in real-world clinical practice as compared to original clinical validation study
SOUTH SAN FRANCISCO, Calif., December 15, 2022—-Veracyte, Inc. today announced that findings demonstrating the strong real-world performance of the Afirma Genomic Sequencing Classifier were published in TheJournal of Clinical Endocrinology & Metabolism . The data, from a meta-analysis of 13 independent studies, show that the Afirma GSC can accurately rule out thyroid cancer in patients with indeterminate thyroid nodules and that, when the test identifies a nodule as suspicious, the patients risk of malignancy is consistent with, and higher than, that reported in the tests original clinical validation study.
“The original Afirma GSC clinical validation study demonstrated that the genomic test provides reliable, accurate information to help inform important thyroid nodule diagnoses,” said Christian Nasr, M.D., division chief of Endocrinology at the University of Arizona College of Medicine and the lead author on the study. “Our analysis found that the test performs just as well and on some measures better in clinical practice. This is incredibly encouraging and reassuring for physicians who must determine the best clinical approach for patients with indeterminate thyroid nodules.”
About the Afirma GSC
Cautionary Note Regarding Forward-Looking Statements
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Comparison Of Afirma Gec Performance Between Different Testing Strategies
We stratified nodule outcomes by Bethesda classification of the repeat FNA and GEC result . For this analysis, Bethesda III/IV nodules were pooled together based on their similar recommendations for MT. Itemization of outcomes by each Bethesda category is provided in Supplementary Tables S3 and S4. Nodules classified as Bethesda III/IV on repeat FNA comprise the Restrictive testing group, those classified as Bethesda IâIV on repeat FNA comprise the SemiRestrictive group, and further inclusion of the seven nodules classified as Bethesda V/VI on repeat FNA approximate the Reflex testing group. Table 6 summarizes the benign-call rate, cancer prevalence, and cancer/NIFTP prevalence for these three testing approaches. The Restrictive approach would have missed four cancers and three NIFTPs that would have otherwise been flagged as GEC-S under the SemiRestrictive and Reflex approaches. The clinicopathologic features of these seven cancer/NIFTP cases are summarized in Table 7 all four cancers were American Joint Committee Cancer stage I and considered low risk for structural disease recurrence. Conversely, Afirma testing of nodules classified as Bethesda I or II on repeat FNA, as per the Reflex and SemiRestrictive models, led to 42 cases where GEC-S results prompted diagnostic surgeries for histologically benign tumors. Altogether, the Restrictive strategy was more specific and it was less sensitive than the Reflex and SemiRestrictive approaches for detecting NIFTP or cancer.
Thyroid Nodule Molecular Testing: Is It Ready For Prime Time
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
Cytologically indeterminate thyroid nodules remain a diagnostic and clinical challenge, and molecular testing has been advocated and advanced as a diagnostic modality to help guide treatment. While studies have expounded on the improved diagnostic certainty with these tests, data demonstrating meaningful clinical impact and supporting their routine use is still limited at best. In this review, we discuss the limitations regarding diagnostic accuracy, impact on surgical decision-making and outcomes, and cost-effectiveness of molecular testing. By highlighting the limitations of these tests, we aim to promote more thoughtful utilization of these tools in the management of thyroid nodules going forward.
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Implications Of New Surgical Guidelines For Thyroid Cancer And Niftp Diagnosis
Additionally, the utility of molecular testing in guiding the extent of surgery is undermined by changes in clinical guidelines regarding the extent of surgery. The American Thyroid Association, for instance, has suggested that differentiated thyroid cancer < 4 cm may be safely treated with lobectomy instead of traditionally performed total thyroidectomy, since limited resection has equivalent outcomes to extensive surgery in select patients . Given that fact that more limited cancer operation can lead to equivalent outcomes while sparing patients from important side effects , the impact of molecular testing in directing the extent of surgical resection becomes even more diminished.
Increased Molecular Testing Accelerates Precision Thyroid Nodule Management Cancer Care
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Thyroid nodules are common. Each year, approximately 600,000 U.S. residents with nodules undergo a fine-needle aspiration biopsy in which cells are extracted and examined to determine whether the nodule is benign or cancerous.
Fine-needle aspiration, or FNA, biopsy is mostly accurate and most nodules are benign. However, in approximately 20% to 25% of cases, the test returns an indeterminate finding, meaning there was not a conclusive identification of benign or malignant thyroid disease. Only a decade ago, most of these patients would go on to diagnostic surgery, with approximately 60% overtreated or undertreated, based on the surgery that they receive.
Ten or 15 years ago, when someone had indeterminate cytology for their nodule, there were really only two options to watch the nodule conservatively or to surgically remove it,Erik K. Alexander, MD, chief of the thyroid section at Brigham and Womens Hospital and professor of medicine at Harvard Medical School, told Endocrine Today. The problem, of course, is most patients do not want to watch things when there is a potential risk for cancer, so we were doing a lot more surgery, much of it unnecessary and much of it for benign disease.
Beyond the microscope
More data needed
The lack of clarity has been disappointing for some endocrinologists, Lee said.
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