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BRAF Mutation Status Tied to Papillary Thyroid Cancer Mortality

BRAF Mutation Status Tied to Papillary Thyroid Cancer Mortality

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Action Points

  • Note that this observational study found that older age is a risk factor for aggressive papillary thyroid cancer, but only among those with BRAF V600E mutations.
  • With further confirmation, this may allow older individuals with wild-type BRAF thyroid cancer to avoid some of the most toxic therapies.

While age is a strong, and independent, mortality risk factor in papillary thyroid cancer (PTC) patients with BRAF V600E mutation, that is not the case in patients with wild-type BRAF, investigators have found in a retrospective study.

This finding challenges the long-held belief that the general use of patient age at diagnosis is a high-risk factor in PTC.

These findings were from a comparative study led by Xiaopei Shen, PhD, Johns Hopkins University School of Medicine in Baltimore, and published in the Journal of Clinical Oncology.

PTC is the most common type of thyroid cancer, accounting for >85% of all thyroid malignancies. As pointed out by Shen and his colleagues, risk stratification — based on clinicopathologic risk factors such as patient age — is an important component of standard management of thyroid cancer.

In fact, use of age as a major risk factor in thyroid cancer has been accepted since 1953, when a study in Annals of Surgery made the connection. And other studies have suggested that mortality in thyroid cancer goes up with increasing patient age.

“However, critical questions remain unanswered as to why older patient age has such a remarkable adverse effect on PTC-specific mortality and whether age is a risk factor universally applicable to all patients with PTC,” Shen and his colleagues wrote.

The investigators noted that the BRAF V600E mutation is known to be a main driver of PTC and is associated with older patient age and poor clinical outcomes. With this in mind they hypothesized that not only does BRAF V600E play an important role in the effect of patient age on PTC-specific mortality, but that in the absence of that mutation age may not be a risk factor.

To test that hypothesis Shen and his colleagues compared data on 2,638 patients (623 men and 2,015 women) with PTC from 11 medical centers in six countries. Patients had a median age of 46 (interquartile range 35-58), and a median follow-up of 58 months (IQR 26-107 months).

Shen and his colleagues found that after the age of 45 mortality rates increased as patient age increased overall — but the subgroup analysis by BRAF V600E mutation status showed the increase was entirely confined to those with the mutation.

And after adjusting for sex, tumor size, extrathyroidal extension, lymph node metastasis, distant metastasis, and administered activities of radioactive iodine, the linear relationship between PTC mortality and BRAF V600E remained, but was not seen in patients with wild-type BRAF.

These findings should have a major impact on the clinical management of PTC, the investigators suggested, considering the prevalence of BRAF V600E mutation in PTC is about 45%.

“As such, many older patients will be able to avoid more aggressive treatment that would otherwise be administered as a result of the conventional concept of older patient age being a general high-risk factor,” Shen and his colleagues wrote.

In an editorial accompanying the study, Megan Haymart, MD, of the University of Michigan in Ann Arbor, said that while the study’s findings provide insight into the relationship between age and thyroid cancer prognosis, the study was limited by the fact the authors only studied the absence or presence of one mutation.

“A necessary next step is evaluating age-related prognostication and other molecular markers, including evaluating the relationship between age, death, and coexistence of BRAF V600E and TERT promoter mutations,” she wrote.

She also pointed out that this study focused solely on papillary thyroid cancer. While that is the most common type of differentiated thyroid cancer, she noted that follicular thyroid cancer and Hürthle cell cancer are also staged by age.

Further studies are needed to confirm the concept of designing distinct staging systems on the basis of BRAF, “and whether our future staging systems will incorporate a molecular-based approach to risk stratification remains to be determined,” Haymart concluded. “Yet, this is a worthy area of investigation that offers potential opportunities to further tailor prognostication through a better understanding of pathogenesis.”

Supported by National Institutes of Health (NIH) Grants No. R01CA113507 and R01CA189224 (M.X.); Polish National Center of Research and Development MILESTONE Project Grant No. STRATEGMED2/267398/4/NCBR/2015 (Poland, A.C., B.J.); grants from Menzies Health Institute, Griffith University, Queensland Cancer Council and Queensland Smart State Fellowship (Australia; A.K.L.); Grants No. SAF2013-44709-R and SAF2016-75531-R (MINECO and FEDER), RD12/0036/0030, PI14/01980 (ISCIII), and GCB14142311CRES (AECC Foundation) (Spain; P.S. and G.R-E); Grants No. AZV 16-32665A and MH CZ-DRO (Institute of Endocrinology-EU, 00023761; Czech Republic; B.B., V.S.); grants from the New South Wales Cancer Institute (C.J.O.) and Cancer Council of New South Wales (Australia; R.C.-B.); NIH/National Institute on Aging Grant No. 5R03AG042334-02 (L.Y.); and grants from the Ministero della Istruzione Universitaria e Ricerca Scientifica, the Associazione Italiana per la Ricerca sul Cancro, the Istituto Toscano Tumori, and the Ministero della Salute (Italy; D.V., R.E.).

  • Reviewed by
    F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner


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