S P E C I A L

F E A T U R E

E d i t o r i a l

The Value of Molecular Diagnostics for Indeterminate Thyroid Nodules Lawrence Lee, Elliot J. Mitmaker, and Jacques How Steinberg-Bernstein Centre for Minimally Invasive Surgery and Innovation (L.L.), Department of Surgery (L.L., E.J.M.), and Division of Endocrinology (J.H.), McGill University Health Centre, Montreal, QC, Canada H3G 1A4

I

n current clinical practice, fine-needle aspiration biopsy (FNAB) of thyroid nodules will result in indeterminate cytology (atypia of undetermined significance [AUS] or follicular lesion of undetermined significance [FLUS], follicular neoplasm [FN] or suspicious for FN, and suspicious for malignancy) in 15–30% of patients (1). Despite a low risk of malignancy, diagnostic surgery is often necessary in determining a final pathology. However, recent advances in molecular diagnostics may potentially aid clinicians by identifying certain patients in whom surgery can be safely avoided. Two novel molecular tests have become commercially available in the past several years. The gene-expression classifier (GEC) (Afirma; Veracyte, Inc) is based on an expression profile of 142 gene mRNA, which gained prominence after the large industry-sponsored multicenter validation study by Alexander et al (2) on a total study sample of 265 samples of indeterminate nodules from 49 participating centers. This study demonstrated high sensitivity (92%) and high negative predictive value (93%), but low specificity (52%) and positive predictive value (PPV; 47%) for the GEC. Subset analyses of nodules with AUS/FLUS and FN cytology demonstrate a similar diagnostic performance. Given these findings, the GEC has been proposed as a “rule-out” test; that is, nodules with indeterminate cytology and a benign GEC result could be managed by close observation, rather than proceeding to diagnostic surgery. However, diagnostic performance was less favorable for nodules with “suspicious for malignancy” cytology, and therefore these nodules should not undergo GEC testing and should rather proceed directly to surgery. Another molecular diagnostic test

has been developed based on the presence of point mutations of BRAF and RAS, and rearrangements of RET/PTC and PAX8/PPAR␥. Contrary to the GEC, the gene mutation panel (miRInform; Asuragen Inc) was shown to have high specificity (96 –99%) and PPV (87–95%), but low sensitivity (57– 63%) and negative predictive value (72– 94%) for indeterminate nodules in a study of FNAB samples from 513 nodules at a single academic center (3). This mutation panel can be used as a “rule-in” approach; that is, indeterminate nodules with positive markers can proceed directly to a total thyroidectomy due to the high probability of malignancy, rather than a two-stage operation. The utility of these new tests is recognized because they have been included in the 2013–14 revisions of the National Comprehensive Cancer Network guidelines on thyroid carcinoma (4). In this issue of the JCEM, McIver et al (5) have reported their results on the use of a GEC in the management of patients with indeterminate thyroid nodules based on cytopathology at a large tertiary academic institution. Importantly, FNAB cytopathology was determined by their specialized thyroid cytopathologists, rather than undergoing an initial “screening” process by Thyroid Cytology Partners, as is otherwise required by Veracyte (the manufacturer of the GEC) in clinical practice. In their study, the GEC was offered to all patients with AUS/FLUS or FN cytology. Patients with a benign GEC classification were managed observantly (n ⫽ 16), whereas those with a “suspicious” result were offered surgery (n ⫽ 44). Among these 60 patients, only 36 (60%) underwent surgery (four with benign GEC, and 32 with suspicious GEC). The overall prevalence of malignancy in these patients was 16% (6 of

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received September 25, 2014. Accepted October 9, 2014.

Abbreviations: AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance; FN, follicular neoplasm; FNAB, fine-needle aspiration biopsy; GEC, gene-expression classifier; PPV, positive predictive value; PRO, patient-reported outcome.

For article see page 4069

4062

jcem.endojournals.org

J Clin Endocrinol Metab, November 2014, 99(11):4062– 4065

doi: 10.1210/jc.2014-3650

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 December 2014. at 09:31 For personal use only. No other uses without permission. . All rights reserved.

doi: 10.1210/jc.2014-3650

36). Diagnostic performance characteristics (for resected patients) were lower than reported by Alexander et al (2), especially sensitivity (83 vs 93%) and specificity (10 vs 52%). These characteristics were only marginally improved if patients with a benign GEC under observant management were included. Importantly, the proportion of “benign” GEC results in their study was lower than previously reported (2) (28 vs 38%). Certainly these new molecular diagnostics have the potential to significantly alter the management of indeterminate thyroid nodules, yet there remain several important issues that must be resolved before their widespread adoption. This study calls into question the generalizability of the diagnostic performance of the GEC. The landmark report by Alexander et al (2) largely recruited from community centers and only included samples that were read by local pathologists as definitively nonbenign or malignant. In their study (2), three expert cytopathologists further classified these specimens according to the Bethesda classification system. In clinical practice, however, cytology samples are routinely sent to and screened by Thyroid Cytology Partners, an independent partner to Veracyte, and only cytologically indeterminate nodules undergo GEC testing. Unfortunately, the diagnostic accuracy of these cytological examinations is unknown, given that consensus among thyroid cytopathologists is moderate at best, especially within the indeterminate categories (6). Furthermore, the proportion of indeterminate nodules has increased with the implementation of the Bethesda system, and the rate of malignancy within this category varies widely (7). McIver et al (5) reported a lower than expected rate of benign GEC results, which the authors suggest was a result of more accurate Bethesda classification by their large academic center’s dedicated thyroid cytopathologists. This issue has already been eloquently raised in a separate editorial (8). In short, more accurate classification of thyroid cytopathology according to the Bethesda system may reduce the number of nodules requiring further diagnostic evaluation. The application of these results can be interpreted as follows: using data from Alexander et al (2), 48% (87 of 180) of benign nodules still resulted in a “suspicious” GEC and required surgery (ie, false positives). This is a reflection of the poor specificity and PPV of the GEC. Data of McIver et al (5) reported even poorer specificity and PPV, which meant that 90% (27 of 30) of nodules with a suspicious GEC resulted in benign pathology after surgery. Other studies have reported similar results with a higher proportion of false positives (43–54%), especially in the subgroup of patients with oncocytic indeterminate cytology (9, 10). There is an urgent need for further studies to clarify this issue. However, these studies, much like that of

jcem.endojournals.org

4063

McIver et al (5), all suffer from verification bias, that is, the true incidence of malignancy is unknown because few patients underwent surgical resection when a benign GEC result was reported. Therefore, true sensitivity and specificity are not known, thereby limiting any interpretation of diagnostic performance. Despite these caveats, one argument in support of the GEC is that without it, all patients with indeterminate nodules would require surgery. Duick et al (11) reported that only 8% of patients with cytologically indeterminate nodules and benign GEC result underwent surgery, compared to the 74% rate reported in the literature. However, the GEC is only useful if nodules test as “benign.” Although 38% of nodules in the study of tested benign, this proportion was only 28%, according to McIver et al (5). Again, one potential reason for this discrepancy was the more accurate cytopathology input in the latter study. Given the rate of high false positives, can the GEC be considered a valuable diagnostic modality? To answer this question, one must first understand the definition of value. Michael Porter, an influential Harvard economist, has defined value in health care as attainment of the best outcomes that matter to the patient at lowest cost (12). Furthermore, both costs and outcomes must be measured over the full cycle of care. To measure one without the other may be potentially misleading and may result in ineffective care (12). In order for the GEC to be considered a “valuable” test, it has to improve outcomes at the same cost, maintain outcomes at lower cost, or in the bestcase scenario, improve outcomes while lowering costs. Porter’s definition has two important implications: patient-centric outcomes and cost efficiency. Important outcomes for a given diagnostic modality certainly extend beyond its performance characteristics. Although patients consider the accurate diagnosis of a thyroid malignancy as important, it is unclear whether that is the most relevant outcome for them. Clinical outcomes that are important to the physician often do not have any tangible meaning for patients. To demonstrate this, a study comparing clinician and patient expectations on the relevant outcomes in benign thyroid disease demonstrated that clinicians focused on thyroid-characteristic problems, whereas patients considered nonphysical aspects such as psychosocial problems and impact on daily life as more relevant (13). Of all of the relevant outcomes cited by either group, only half were rated as important by both patients and healthcare professionals. Similar discrepancies between treatment effectiveness and patient-reported outcomes (PROs) have been shown in cancer patients (14). There is an emphasis on the importance of the patient’s perspective, and increasingly PROs are being included as outcome measures of clinical trials. A thyroid-specific PRO has even been

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 December 2014. at 09:31 For personal use only. No other uses without permission. . All rights reserved.

4064

Lee et al

The Value of Molecular Diagnostics

developed and validated (15). However, a wide range of outcomes may exist for any given disease, making comparison among trials difficult. The development of core outcome sets, defined as standardized sets of outcomes prioritized by the relevant stakeholders that can include both PROs and clinical outcomes, may reduce this problem and improve outcome reporting in clinical trials (16). To date, a thyroid-specific core outcome set has not been established, but one may potentially include clinical outcomes such as thyroid-specific symptoms and survival and PROs such as psychosocial and functional outcomes. Currently, only clinical and cost outcomes have been reported for the GEC studies, but the patient’s perspectives in this regard are unknown. Also, there are no long-term outcomes of the GEC. The risk of missing a malignant nodule is not unsubstantial; its reported sensitivity of 92% means that one in every 12 malignancies will result in a “benign” GEC, and a delay in diagnosis has been associated with worse prognosis (17). In keeping with the value paradigm, outcomes are maintained or improved only if the benefits of avoiding surgery in 52% (ie, the best reported specificity of the GEC) (2) of patients with truly benign pathology outweigh the potentially negative effects of delaying diagnosis in one of 12 malignant nodules. Assessment of costs, the other component in the value paradigm, must include all relevant costs associated with the important outcomes over an appropriate time horizon for each stakeholder’s perspective. In the case of the GEC, the cost of routinely performing the GEC must not exceed the cost savings from correctly avoiding surgery minus the costs of a delayed diagnosis of malignancy. Several costeffectiveness studies have been performed, with variable results. Li et al (18) used a mathematical model to estimate the costs and outcomes over a 5-year period from the US healthcare system perspective. Outcomes were measured using quality-adjusted life years, which incorporate multiple outcomes (each outcome is weighted by its relative “preference” on a 0 –1 scale, with 0 representing death and 1 representing perfect health) over time into a single summary measure. They demonstrated that the use of a GEC resulted in 74% fewer surgeries for benign nodules, which amounted to overall savings of $1453 per patient over 5 years (assuming a GEC cost of $3200). The improvement in quality-adjusted life years with the GEC was minimal and not clinically significant. Our group has also investigated the cost effectiveness of different molecular diagnostic strategies over a lifetime time horizon, but we reported that the GEC was associated with increased costs ($201 higher) compared to standard management without molecular diagnostics (19). Improvements in long-term outcomes in our study were also minimal and should not be considered clinically meaningful. The findings of min-

J Clin Endocrinol Metab, November 2014, 99(11):4062– 4065

imal differences in simulated outcomes are not unsurprising because the benefit of avoiding surgery is predicated on the basis of avoiding surgical complications, especially recurrent laryngeal nerve injury, which is rare in expert hands. However, both of these studies were modeled using the diagnostic performance characteristics of GEC reported by Alexander et al (2). Any decrease in the diagnostic performance characteristics will likely adversely affect the cost-effectiveness results. A simulation study estimated that a molecular test would have to have a sensitivity and specificity of 95% and cost less than $1087 to result in cost savings over standard management (20), characteristics for which the GEC compares unfavorably. As it stands, the literature tenuously supports the cost effectiveness of the GEC, and these data must be interpreted with caution, given the results of McIver et al (5). A potential strategy is to combine the GEC (high sensitivity) with a gene mutation panel (high specificity), which would in theory further limit the number of unnecessary surgeries. This combined strategy is potentially cost effective (19). However, the addition of BRAF mutation testing to the GEC (thereby combining the GEC with some elements of gene mutation testing) did not increase overall sensitivity or specificity of the test (21), thereby calling into question the effectiveness of selected additional gene mutation testing. Given the current evidence, does the GEC add value to the standard management of patients with indeterminate thyroid nodules? Using Porter’s definition of value, the short answer is “no” because its outcomes assessment is incomplete and its cost efficiency is equivocal. The study of McIver et al (5) further adds to the uncertainty. The potential of molecular diagnostics for thyroid nodules with indeterminate cytology is promising, but they should be used judiciously until further data guide us as to their precise value as well as their limitations.

Acknowledgments Address all correspondence and requests for reprints to: Lawrence Lee, MD, MSc, Steinberg-Bernstein Centre for Minimally Invasive Surgery and Innovation, Department of Surgery, McGill University Health Centre, 1650 Cedar Avenue, E19-125, Montreal, QC, Canada H3G 1A4. E-mail: [email protected]. Disclosure Summary: The authors have nothing to declare.

References 1. Cibas ES, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Am J Clin Pathol. 2009;132:658 – 665. 2. Alexander EK, Kennedy GC, Baloch ZW, et al. Preoperative diag-

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 December 2014. at 09:31 For personal use only. No other uses without permission. . All rights reserved.

doi: 10.1210/jc.2014-3650

3.

4.

5.

6.

7.

8. 9.

10.

11.

nosis of benign thyroid nodules with indeterminate cytology. N Engl J Med. 2012;367:705–715. Nikiforov YE, Ohori NP, Hodak SP, et al. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: a prospective analysis of 1056 FNA samples. J Clin Endocrinol Metab. 2011;96:3390 –3397. National Comprehensive Cancer Network. NCCN Guidelines and Compendium Updated. http://www.nccn.org/about/news/ebulletin/ebulletindetail.aspx?ebulletinid⫽65. Accessed September 12, 2014. McIver B, Castro MR, Morris JC, et al. An independent study of a gene expression classifier (Afirma) in the evaluation of cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. 2014;99: 4069-4077. Cochand-Priollet B, Schmitt FC, Tötsch M, Vielh P, European Federation of Cytology Societies’ Scientific Committee. The Bethesda terminology for reporting thyroid cytopathology: from theory to practice in Europe. Acta Cytol. 2011;55:507–511. Broome JT, Solorzano CC. The impact of atypia/follicular lesion of undetermined significance on the rate of malignancy in thyroid fineneedle aspiration: evaluation of the Bethesda system for reporting thyroid cytopathology. Surgery. 2011;150:1234 –1241. Krane JF. Lessons from early clinical experience with the Afirma gene expression classifier. Cancer Cytopathol. 2014;122:715–719. Harrell RM, Bimston DN. Surgical utility of Afirma: effects of high cancer prevalence and oncocytic cell types in patients with indeterminate thyroid cytology. Endocr Pract. 2014;20:364 –369. Lastra RR, Pramick MR, Crammer CJ, LiVolsi VA, Baloch ZW. Implications of a suspicious afirma test result in thyroid fine-needle aspiration cytology: an institutional experience. Cancer Cytopathol. 2014;122:737–744. Duick DS, Klopper JP, Diggans JC, et al. The impact of benign gene expression classifier test results on the endocrinologist-patient decision to operate on patients with thyroid nodules with indetermi-

jcem.endojournals.org

12. 13.

14. 15.

16.

17.

18.

19.

20.

21.

4065

nate fine-needle aspiration cytopathology. Thyroid. 2012;22:996 – 1001. Porter ME. What is value in health care? N Engl J Med. 2010;363: 2477–2481. Watt T, Hegedüs L, Rasmussen AK, et al. Which domains of thyroid-related quality of life are most relevant? Patients and clinicians provide complementary perspectives. Thyroid. 2007;17:647– 654. Groenvold M. Health-related quality of life in early breast cancer. Dan Med Bull. 2010;57:B4184. Watt T, Cramon P, Hegedüs L, et al. The thyroid-related quality of life measure ThyPRO has good responsiveness and ability to detect relevant treatment effects. J Clin Endocrinol Metab. 2014;99:3708 – 3717. Williamson PR, Altman DG, Blazeby JM, et al. Developing core outcome sets for clinical trials: issues to consider. Trials. 2012;13: 132. Yeh MW, Demircan O, Ituarte P, Clark OH. False-negative fineneedle aspiration cytology results delay treatment and adversely affect outcome in patients with thyroid carcinoma. Thyroid. 2004; 14:207–215. Li H, Robinson KA, Anton B, Saldanha IJ, Ladenson PW. Costeffectiveness of a novel molecular test for cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. 2011;96:E1719 – E1726. Lee L, How J, Tabah RJ, Mitmaker EJ. Cost-effectiveness of molecular testing for thyroid nodules with atypia of undetermined significance cytology. J Clin Endocrinol Metab. 2014;99:2674 –2682. Najafzadeh M, Marra CA, Lynd LD, Wiseman SM. Cost-effectiveness of using a molecular diagnostic test to improve preoperative diagnosis of thyroid cancer. Value Health. 2012;15:1005–1013. Kloos RT, Reynolds JD, Walsh PS, et al. Does addition of BRAF V600E mutation testing modify sensitivity or specificity of the Afirma Gene Expression Classifier in cytologically indeterminate thyroid nodules? J Clin Endocrinol Metab. 2013;98:E761–E768.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 December 2014. at 09:31 For personal use only. No other uses without permission. . All rights reserved.

The value of molecular diagnostics for indeterminate thyroid nodules.

The value of molecular diagnostics for indeterminate thyroid nodules. - PDF Download Free
49KB Sizes 2 Downloads 6 Views