braf mutation and cancer recurrence

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BRAFMutation and Thyroid Cancer RecurrenceMark Yarchoan, Virginia A. LiVolsi, and Marcia S. Brose, Abramson Cancer Center at University of Pennsylvania, Philadelphia, PA

Thyroidcancer is themostcommonendocrine malignancy,with

an incidence that has been increasing rapidly since the mid-1990s.

Papillary thyroid cancer (PTC) accountsfor more than 85%to 90%of

all thyroid malignancies.1 In general, PTC has an excellent prognosis,

witha 5-year survivalrate of approximately 98%.2 However,although

most PTC can be treated successfully with surgery, radioiodine

ablation, and thyroid suppression therapy, tumor recurrence oc-

curs in 5% to 20% of patients.3 If distant tumor recurrences occur,

the 10-year survival rate of PTC is reduced to approximately 40%.

The development of molecular determinants of disease recurrence

has the potential to improve the clinical management of patients

with PTC by assisting in risk stratification and pairing the use of

more aggressive treatments with patients who are at higher risk of

recurrence.

TheBRAFV600E mutation is the most common genetic muta-

tion detected in patientswith PTC4 and occurs in approximately 45%

of patients. However, thus far, itsusefulnessas a prognostic marker in

PTC has been controversial. Previous work has shown that patients

with aBRAFmutation may be more likely to have clinicopathologic

characteristics of more aggressive disease, suchas extrathyroidal inva-

sion, lymph node metastasis, and advanced tumor stage at initialsurgery.5,6 Furthermore, a recent large multicenter retrospective study

byXinget al7 foundthat in an unadjusted analysis, thepresenceof the

BRAFV600E mutation was significantly associated with PTC-related

mortality. However, this association lost statistical significance after

adjusting for clinical and clinicopathologic risk factors such as patient

age, lymph node metastasis, extrathyroidal invasion, and distant me-

tastasis. The prognostic value of theBRAFV600E mutation in PTC

was subsequently questioned in an accompanying editorial.8 There-

fore, until now, ithas been debated whether theBRAFmutation status

provides any useful prognostic value beyond that obtained from tra-

ditional pathologist and radiologic evaluation.

Inthearticlethat accompaniesthis editorial, Xing et al9

reportthelargest study to date to suggest that theBRAFV600E mutation has

prognostic value for recurrence in PTC. In a collaborative effort in-

volving data from 2,099 patients from 16 medical centers in eight

countries, the authors showed that the presence of aBRAFV600E

mutation is significantly associated with an increased risk of PTC

recurrence, even after adjusting for several traditional clinicopatho-

logic risk factors including tumor size, extrathyroidal extension,

lymph node metastases, and multifocality. Within the subtypes of

classic papillary thyroid carcinoma and follicular-variant papillary

thyroid carcinoma, recurrence rates were statistically higher inBRAF

mutationpositive PTC compared with BRAF mutationnegative

PTC. These differences remained statistically significant after adjust-

ing for the traditional clinicopathologic risk factors listed.

Notably absent from the pathologic risk factors accounted for in

this analysis are lymphatic or vascular invasion or the presence of foci

withadverse histology (ie, tall-cell features10); it would be worthwhile

to know whether BRAFmutation is independent of these known risk

factors. Despite the worse outcome in recurrence-free survival

(shown in Figs 2A and 2B of the article by Xing et al9), the effect of

theBRAFmutation seems to be small when a direct comparison ismade with the corresponding subset that lacks the mutation, and

may be further diminished if additional clinicopathologic factors

are taken into account.

The vast majority of patients who were included in this study9

seem to have also been evaluated in this groups previous study7 that

examined the relationship betweenBRAFmutation status and PTC-

related mortality. Therefore, it is noteworthy that BRAF mutation

status has emerged as a more robust prognostic factor for PTC recur-

rence thanfor PTC-related mortality. Should the relationship holdup

after additional known clinicopathologic factors are included, it will

raise the question of where in clinical practice BRAFmutation testing

should be applied.Although the clinical role of testing for the BRAFmutation con-

tinues to intrigue, prospective data will be required to support that

BRAFmutation testing can improve outcomes when incorporated

into clinical decision making. Until the completion of a study that

providessuch data, it is unknownwhether BRAFmutation testing can

improve the management of patients with PTC. Given the costs and

the potential for significant psychological and emotional harmrelated

to theanxiety that mayaccompanyBRAFmutation testing,we believe

that there is insufficient evidence to support widespread use ofBRAF

mutation testing for patients with PTC at this time. However, ulti-

mately, there may be a few subgroups of patients for whom BRAF

mutation testing is eventually shown to improvemanagement of PTC

whenused incombination withtraditional clinical andpathologic riskfactors to most accurately risk stratify patients.

Onesuch subgroupmay be patients with conventionally low-risk

PTC. In this study by Xing et al,9 recurrence rates were 12.1% in

patients with BRAFmutationpositive and 7.3% in patients with

BRAFmutationnegative low-riskPTC. In a separate, previous cohort

of 319 patients with low-risk intrathyroidal PTC,BRAF-mutated tu-

mors had a recurrence rate of 7.5% compared with a rate of 1% for

BRAFmutationnegative tumors after 5 years of follow-up.11 There-

fore, BRAFmutation testing may eventually be shown to be helpful in

identifying patients with conventionally low-risk disease who are at

truly low risk of recurrence (eg,BRAF-negative intrathyroidal PTC)

JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L

2014 by American Society of Clinical Oncology 1Journal of Clinical Oncology, Vol 32, 2014

http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.59.3657The latest version is atPublished Ahead of Print on November 24, 2014 as 10.1200/JCO.2014.59.3657

Copyright 2014 by American Society of Clinical Oncology

http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.59.3657The latest version is atPublished Ahead of Print on November 24, 2014 as 10.1200/JCO.2014.59.3657

Copyright 2014 by American Society of Clinical Oncology

Downloaded from jco.ascopubs.org on June 16, 2015. For personal use only. No other uses without permission.Copyright 2014 American Society of Clinical Oncology. All rights reserved.
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and can be treated with a more conservative approach. BRAFmuta-

tion testing may also prove to be helpfulfor patientswithPTC whofall

between clear recurrence-risk categories or for whom conventional

pathologic markers are unclear. Prospective clinical trials are now

warranted to evaluate the predictive significance ofBRAFmutation

testing in these subpopulations and whether testing improves clinical

outcomes. Advanced metastatic radioactive iodinerefractory disease

is the only entity thus far for which identification ofBRAFmutations

hasdefinitely beenshown to be useful,resulting intheidentification of

patients who may benefit from BRAFV600Etargeted kinases.12

This is the beginning of an era in which molecularly based tests

are being developed to accompany or even supplant conventional

clinicopathologic riskfactorsin the riskstratification of many cancers.

Forexample,in breast cancer,theOncotype DXtest(GenomicHealth,

Redwood City, CA) has bothprognostic and predictive significancein

early-stage, estrogenreceptorpositive breastcancer13andisnowused

by cliniciansto determine whether chemotherapy should be added to

hormonal therapy in otherwise low-risk disease. In PTC, Xing et al9

haveprovided new evidence thatthe prevalent BRAFV600E mutation

may have prognostic value in the assessment of PTC recurrence risk.

We believe that prospective studies are now warranted to evaluatewhether BRAFmutation testing, in conjunction withevaluation of all

conventional clinicopathologic risk factors including histologic sub-

type, partial or complete encapsulation, and lymphatic and vascular

invasion, as well as the presence of tall-cell features, adds predictive

significance and canimprovemanagement and outcomes for patients

with PTC.

AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Disclosures provided by the authors are available with this article atwww.jco.org.

AUTHOR CONTRIBUTIONS

Manuscript writing:All authorsFinal approval of manuscript: All authors

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cancer. Nature 417:949-954, 2002

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J Clin Oncol 24:3726-3734, 2006

DOI: 10.1200/JCO.2014.59.3657; published online ahead of print at

www.jco.org on November 24, 2014

Editorial

2 2014 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

http://www.jco.org/http://www.jco.org/http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013http://dx.doi.org/10.1200/JCO.2014.56.8253http://dx.doi.org/10.1200/JCO.2014.56.8253http://dx.doi.org/10.1200/JCO.2014.59.3657http://dx.doi.org/10.1200/JCO.2014.59.3657http://dx.doi.org/10.1200/JCO.2014.56.8253http://dx.doi.org/10.1200/JCO.2014.56.8253http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013http://www.cancer.org/research/cancerfactsfigures/cancerfactsfigures/cancer-facts-figures-2013http://www.jco.org/


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AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

BRAFMutation and Thyroid Cancer Recurrence

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships areself-held unless noted. I Immediate Family Member, InstMy Institution. Relationships may not relate to the subject matter of this manuscript. For moreinformation about ASCOs conflict of interest policy, please refer towww.asco.org/rwcorjco.ascopubs.org/site/ifc.

Mark Yarchoan

No relationship to disclose

Virginia A. Livolsi

No relationship to disclose

Marcia S. BroseHonoraria:Bayer Healthcare Pharmaceuticals, Onyx, Exelixis

Consulting or Advisory Role: Bayer HealthCare Pharmaceuticals,Exelixis, Onyx, AstraZeneca, EisaiResearch Funding:Bayer HealthCare Pharmaceuticals (Inst), Eisai(Inst), Novartis (Inst), Roche/Genentech (Inst), Exelixis (Inst)

Editorial

www.jco.org 2014 by American Society of Clinical Oncology

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