Testing for RET Alterations Gains Traction Across Tumor Types

Ariela Katz
Published: Thursday, Aug 30, 2018
Lynette M. Sholl, MD
Lynette M. Sholl, MD
Testing for RET aberrations is starting to gain importance in clinical practice along with the awareness that RET fusions and mutations are drivers in multiple tumor types. In recent years, tyrosine kinase inhibitors that specifically target RET have entered the pipeline. Although none have yet received FDA approval, the promise of these agents has spurred interest in diagnostic assays that can accurately and efficiently detect RET abnormalities.

The RET receptor tyrosine kinase plays a crucial role in cell growth and differentiation. RET rearrangements are observed in 1% to 2% of non–small cell lung cancers (NSCLCs). RET mutations are found in 60% of sporadic cases of medullary thyroid cancer (MTC) and 90% of hereditary MTC (Figure 1). They are also observed in papillary renal cell carcinoma, breast, colon, and pancreatic cancers (Figure 2).1

Testing for RET aberrations is challenging because multiple different assays may be required to detect the range of possible alterations in different tumor types.

RET aberrations in NSCLC are usually the result of a gene fusion, most commonly between RET and KIF5B. Additionally, a host of gatekeeper mutations typically denote resistance to therapy, particularly V804L and V804M.2

RET [in NSCLC] is like other driver oncogenes, such as EGFR, ROS1, and ALK, in that something essentially leads to an abnormal event—for instance, when a fusion occurs—and that allows the tumor to propagate irrespective of external signals,” said Lynette M. Sholl, MD, an associate pathologist at Brigham and Women’s Hospital and associate professor at Harvard Medical School in Boston, Massachusetts.

Figure 1. RET Mutations are Common in Medullary Thyroid Cancer1

RET Mutations are Common in Medullary Thyroid Cancer

Figure 2. RET Fusions Occur in a Small Proportion of Tumors1

RET Fusions Occur in a Small Proportion of Tumors

In patients with NSCLC, RET fusions are more common in younger individuals, both smokers and never-smokers, and regardless of gender. In this setting, they occur just in patients with adenocarcinoma with a predominantly lepidic or papillary growth pattern in their tumor.2 On the other hand, MTC often involves RET-activating point mutations, according to Jacob S. Van Naarden, chief business officer of Loxo Oncology, which is developing the RET-targeting agent LOXO-292.

In NSCLC in particular, it is usually more important in a clinical setting to determine whether a patient has an EGFR, ALK, RET, NTRK, BRAF, or ROS1 mutation, each of which has a cognate targeted therapy either in clinical development or approved by the FDA. RET is seldom at the top of the list.

The molecular testing guidelines for lung cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology recommend that RET testing not be performed as a routine standalone assay outside the context of a clinical trial. In the expert consensus opinion, the guidelines further state that it is appropriate to include RET as part of larger testing panels, either initially or when routine tests for EGFR, ALK, and ROS1 mutations are negative.3

When testing for RET rearrangements, 3 main options exist: fluorescence in situ hybridization (FISH), immunohistochemical (IHC) testing, and next-generation sequencing (NGS).

Traditionally, FISH has been used to detect RET rearrangements, but as a single-gene assay, it is not practical when seeking to test for multiple aberrations. “FISH is a very robust assay, but it is limited, like other single-gene target assays, in that if you are interested in a range of different potential genomic alterations that could be amenable to targeted therapies, you are generally reluctant to serially test every single possibility in a small biopsy specimen,” Sholl said. She explained that multiple driver mutations are of interest in lung cancer, and it can be cumbersome to do sequential testing for them all.

FISH is also relatively expensive, requires technical expertise for interpretation, and is usually available just in larger centers and reference laboratories. It also cannot determine the RET fusion partner gene, and no standard cutoffs define positivity—estimates range from 10% to 20% of cells with RET split signals.4

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