Download RET Aberrations in Diverse Cancers

Published OnlineFirst September 28, 2016; DOI: 10.1158/1078-0432.CCR-16-1679
Personalized Medicine and Imaging
RET Aberrations in Diverse Cancers:
Next-Generation Sequencing of 4,871 Patients
Clinical
Cancer
Research
Shumei Kato1, Vivek Subbiah2, Erica Marchlik3, Sheryl K. Elkin3, Jennifer L. Carter3,
and Razelle Kurzrock1
Abstract
Purpose: Aberrations in genetic sequences encoding the tyrosine
kinase receptor RET lead to oncogenic signaling that is targetable
with anti-RET multikinase inhibitors. Understanding the comprehensive genomic landscape of RET aberrations across multiple
cancers may facilitate clinical trial development targeting RET.
Experimental Design: We interrogated the molecular portfolio
of 4,871 patients with diverse malignancies for the presence of
RET aberrations using Clinical Laboratory Improvement Amendments–certified targeted next-generation sequencing of 182 or
236 gene panels.
Results: Among diverse cancers, RET aberrations were identified in 88 cases [1.8% (88/4, 871)], with mutations being
the most common alteration [38.6% (34/88)], followed
by fusions [30.7% (27/88), including a novel SQSTM1-RET]
and amplifications [25% (22/88)]. Most patients had coexisting
aberrations in addition to RET anomalies [81.8% (72/88)],
with the most common being in TP53-associated genes [59.1%
(52/88)], cell cycle–associated genes [39.8% (35/88)], the PI3K
signaling pathway [30.7% (27/88)], MAPK effectors [22.7%
(20/88)], or other tyrosine kinase families [21.6% (19/88)].
RET fusions were mutually exclusive with MAPK signaling
pathway alterations. All 72 patients harboring coaberrations
had distinct genomic portfolios, and most [98.6% (71/72)]
had potentially targetable coaberrations with either an FDAapproved or an investigational agent. Two cases with lung
(KIF5B-RET) and medullary thyroid carcinoma (RET M918T)
that responded to a vandetanib (multikinase RET inhibitor)containing regimen are shown.
Conclusions: RET aberrations were seen in 1.8% of diverse
cancers, with most cases harboring actionable, albeit distinct, coexisting alterations. The current report suggests that
optimal targeting of patients with RET anomalies will
require customized combination strategies. Clin Cancer Res;
Introduction
RET aberrations can result in gain of function via amplification or mutations and rearrangements that result in ligandindependent kinase activation. These alterations have been
reported in different types of malignancies and in hereditary
conditions.
Mutations in RET have been reported in patients with medullary thyroid carcinoma. They are seen in 43% to 71% of
sporadic cases, with the most common mutation being RET
M918T (5–8). Of note, germline mutations of RET are a hallmark of multiple endocrine neoplasia (MEN), including type
2A, 2B, and familial medullary thyroid carcinoma, with all three
subtypes being associated with a high risk of developing a
medullary thyroid carcinoma (70%–100% risk by age 70 years;
ref. 9). Clinically, MEN 2A is also associated with pheochromocytoma and parathyroid hyperplasia, whereas MEN 2B is
associated with mucosal neuromas, pheochromocytomas, intestinal ganglioneuromas and marfanoid habitus; familial medullary thyroid carcinoma is not associated with other conditions
(9). Interestingly, different RET mutations are associated with
distinct subtypes of MEN: (i) RET C634R, which leads to ligandindependent receptor dimerization, is most commonly associated with MEN 2A; (ii) RET M918T, which leads to decreased
auto-inhibition and increased kinase activity, as well as ATP
binding, is associated with MEN 2B; and (iii) various mutations
at codons 609, 618, 620, 768, 804, and 891 are reported in both
MEN 2A and familial medullary thyroid carcinoma (9, 10).
These observations suggest that different RET-activating mutations have dissimilar oncogenic effects.
The RET proto-oncogene encodes a transmembrane receptor
tyrosine kinase composed of an extracellular cadherin domain,
cysteine-rich region, transmembrane domain, and an intracellular kinase domain (1, 2). It functions as the receptor for the
growth factors of the glial cell line–derived neurotropic factor
family (3). Binding of ligand facilitates RET kinase activation,
which leads to activation of multiple downstream effectors,
including MAPK and PI3K pathways (3). Physiologically, RET is
crucial for neural crest development (1, 2); loss-of-function
mutations in RET are associated with aganglionic megacolon in
Hirschsprung disease (4).
1
Department of Medicine, Center for Personalized Cancer Therapy and Division
of Hematology and Oncology, University of California, San Diego, Moores Cancer
Center, San Diego, California. 2Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. 3N-ofOne, Inc., Lexington, Massachusetts.
Note: Supplementary data for this article are available at Clinical Cancer
Research Online (http://clincancerres.aacrjournals.org/).
Corresponding Author: Shumei Kato, UC San Diego Moores Cancer Center,
3855 Health Sciences Drive, La Jolla, CA 92093. Phone: 858-822-2372; Fax: 858822-6186; E-mail: [email protected]
doi: 10.1158/1078-0432.CCR-16-1679
2016 American Association for Cancer Research.
1–10. 2016 AACR.
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Kato et al.
Translational Relevance
To optimize clinical trials targeting RET aberrations,
understanding the relevant genomic landscape in diverse
cancers is critical. Here, we report the molecular portfolio,
including coexisting alterations, of RET-altered cancers
in 4,871 patients who were evaluated using clinical grade
next-generation sequencing. Among 88 cases with RET
aberrations, the most common alterations included mutations [38.6% (34/88)], fusions [30.7% (27/88)], and amplification [25% (22/88)]. In the 72 patients harboring coaberrations along with RET alterations, there were no two
patients with identical molecular portfolios. Among 292
coexisting molecular aberrations, 200 were molecularly
distinct. The median number of coaberrations per patient
was three (range, 0–16). In 71 of the 72 tumors with more
than one alteration, at least one coexisting genomic alteration was potentially pharmacologically tractable, suggesting the need for customized combination treatments.
On the other hand, fusions in RET have been described in
patients with papillary thyroid carcinoma, accounting for approximately 20% to 40% of sporadic cases (2, 11), with a higher
frequency of RET fusions observed after radioiodine exposure
(60%; ref. 12). Diverse RET fusions have been identified, but more
than 90% of fusions involve the coiled–coil domain-containing
protein 6 (CCDC6)-RET or nuclear receptor coactivator 4
(NCOA4)-RET (also referred in the literature as RET/PTC1 and
RET/PTC3, respectively; ref. 2).
Although less frequent, several activating RET fusions have
been reported in 1% to 2% of patients with non–small cell lung
cancer (NSCLC). These include CCDC6-RET (13, 14), NCOA4RET (14), kinesin family member 5b (KIF5B)-RET (13–18), and
tripartite motif-containing 33 (TRIM33)-RET (15).
Identification of RET aberrations is therapeutically important
as they are targetable with several FDA-approved multikinase
inhibitors that have anti-RET activity, including vandetanib
(RET/EGFR/VEGFR2 inhibitor, approved for medullary thyroid
carcinoma), cabozantinib (RET/MET/VEGFR2 inhibitor, approved for medullary thyroid carcinoma), lenvatinib (RET/FGFR/
VEGFR/KIT/PDGFR inhibitor, approved for differentiated thyroid carcinoma and renal cell carcinoma), ponatinib (RET/
FGFR/VEGFR/KIT/PDGFR/BCR-ABL inhibitor, approved for
chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia), sunitinib [RET/VEGFR/KIT/
PDGFR/FLT3 inhibitor, approved for renal cell carcinoma and
imatinib-resistant gastrointestinal stromal tumor (GIST)], regorafenib (RET/VEGFR/KIT/BRAF/CRAF inhibitor, approved for
colorectal cancer and GIST), and sorafenib (RET/VEGFR/KIT/
BRAF/CRAF inhibitor, approved for differentiated thyroid carcinoma, renal cell carcinoma and hepatocellular carcinoma;
refs. 19, 20). However, none of these inhibitors are FDA approved on the basis of targeting RET aberrations. Meanwhile, there
are a series of reports suggesting that matched therapies against
RET aberrations can yield significant responses (8, 15, 21–27).
Further clinical trials with a focus on RET-aberrant advanced
cancer are being conducted to determine impact on outcome
(Supplementary Table S1).
OF2 Clin Cancer Res; 2017
To facilitate the clinical trials targeting RET, a comprehensive
understanding of RET aberrations among diverse cancer types
is essential. Therefore, we examined the genomic landscape of
RET alterations using targeted next-generation sequencing
(NGS) in 4,871 patients with diverse malignancies, and we
also show two illustrative cases of lung and medullary thyroid
carcinoma with KIF5B-RET and RET M918T alterations, respectively, who both responded to vandetanib (multikinase RET
inhibitor) containing regimen.
Materials and Methods
Patients
We investigated the RET gene status of patients with
diverse malignancies that were referred for NGS from October
2011 to November 2013 (N ¼ 4,871; Table 1 and Supplementary
Tables S2 and S3; Fig. 1). The submitting physicians provided
specification of tumor types. The database was deidentified with
only diagnosis available. NGS data were collected and interpreted
by N-of-One, Inc. The dataset of 4,871 sequenced tumors was
queried for RET and coexisting gene alterations. Clinical impact
was demonstrated by selected case studies. This study was performed in accordance with the guidelines of the UCSD and the
MD Anderson Internal Review Board.
Tissue samples and mutational analysis
We collected sequencing information from 4,871 cancers
whose formalin-fixed, paraffin-embedded (FFPE) tumor samples
were submitted to a Clinical Laboratory Improvement Amendments–certified laboratory for genomic profiling (Foundation
Medicine). Samples were required to have a surface area 25
mm2, volume 1 mm3, nucleated cellularity 80%, and tumor
content 20% (28). The methods used in this assay have been
validated and reported previously (28–30). In short, 50 to 200 ng
of genomic DNA was extracted and purified from the submitted
FFPE tumor samples. This whole-genome DNA was subjected to
shotgun library construction and hybridization-based capture
before paired-end sequencing on the Illumina HiSeq2000 platform. Hybridization selection is performed using individually
synthesized baits targeting the exons of 182 or 236 cancer-related
genes and the introns of 14 or 19 genes frequently rearranged in
cancer (Supplementary Table S4). Sequence data were processed
using a customized analysis pipeline (28). Sequencing was performed with an average sequencing depth of coverage greater than
250, with >100 at >99% of exons. This method of sequencing
allows for detection of copy number alterations, gene rearrangements, and somatic mutations with 99% specificity and >99%
sensitivity for base substitutions at 5 mutant allele frequency
and >95% sensitivity for copy number alterations. A threshold of
8 copies for gene amplification with 6 copies considered
equivocal (except for ERRB2, which is considered equivocally
amplified with 5 copies) was used.
cBio Cancer Genomics Portal data
For comparison purposes, we evaluated the RET aberration status using the cBio Cancer Genomics Portal data
(cBioPortal; http://cbioportal.org, accessed May 2016; refs.
31, 32), which provides access to publicly available datasets
with genomic information from a diverse array of cancer
types (please refer to Supplementary Methods for additional
information).
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RET Aberrations in Cancer
Results
Analysis of RET aberrations among diverse cancers (N ¼ 4,871)
Among the 4,871 diverse cancer patients, the most common
diagnosis was breast carcinoma [10.4% (506/4,871)], followed
by lung adenocarcinoma [8.5% (412/4,871)], and sarcoma
[7.1% (348/4,871); Table 1 and Supplementary Table S2].
Overall, RET aberrations were identified in 88 cases [1.8%
(88/4,871)]. Among 88 cases with RET aberrations, 38.6%
(34/88) were mutations, 30.7% (27/88) were fusions (defined
as RET rearrangement with known fusion partner. e.g., KIF5BRET), 25% (22/88) were amplifications, and 3.4% (3/88) were
rearrangements without specific identified fusion partner (e.g.,
RET rearrangement, exon 11). In addition, RET duplication
and loss were each observed in 1 of 88 cases. (Fig. 1). According
to cBioPortal, RET aberrations have been reported in 3.0%
(181/6,011) of diverse cancers (Supplementary Table S5;
Supplementary Fig. S1). In the current report, most RET aberrations were activating alterations [71.6% (63/88)] and
one inactivating RET alteration was observed (RET loss). The
functional significance of 27.3% (24/88) of RET aberrations,
including RET R163Q, M255I, R525Q, V706M, A756V,
M1109I, and SQSTM1-RET, fusion was unknown (Supplementary Table S3).
Overview of cancer diagnoses and RET aberrations
RET aberrations were most commonly seen in patients with
medullary thyroid carcinoma [80% (4/5)], followed by anaplastic thyroid carcinoma [16.7% (2/12)], lung carcinosarcoma
[16.7% (1/6)], and ureter urothelial carcinoma [16.7% (1/6)];
however, these cancer diagnoses were not reported in cBioPortal, and thus, direct comparisons were not feasible (Table 1 and
Supplementary Table S5; Fig. 2 and Supplementary Fig. S1).
Although there was only one patient each for hemangiopericytoma and pheochromocytoma, they both harbored RET
aberrations (Table 1 and Supplementary Table S3). In some
cancer diagnoses, including cholangiocarcinoma (n ¼ 159),
neuroendocrine carcinoma (n ¼ 97), renal cell carcinoma
(n ¼ 92), and glioblastoma (n ¼ 84), we did not observe RET
aberrations (Supplementary Table S2). In contrast, data from
cBioPortal showed rare RET alterations in cholangiocarcinoma
Table 1. RET aberrations and associated cancer diagnosis (N ¼ 88)
Diagnosis
Hemangiopericytoma (n ¼ 1)
Pheochromocytoma (n ¼ 1)
Medullary thyroid carcinoma (n ¼ 5)
Paraganglioma (n ¼ 4)
Anaplastic thyroid carcinoma (n ¼ 12)
Lung carcinosarcoma (n ¼ 6)
Ureter urothelial carcinoma (n ¼ 6)
Uterine carcinosarcoma (n ¼ 19)
Papillary thyroid carcinoma (n ¼ 23)
Basal cell carcinoma (n ¼ 8)
Merkel cell carcinoma (n ¼ 10)
Atypical lung carcinoid (n ¼ 11)
Fallopian tube adenocarcinoma (n ¼ 12)
Ovarian epithelial carcinoma (n ¼ 54)
Salivary gland adenocarcinoma (n ¼ 31)
Lung adenocarcinoma (n ¼ 412)
Meningioma (n ¼ 18)
Duodenal adenocarcinoma (n ¼ 20)
Cervical adenocarcinoma (n ¼ 24)
Adrenal carcinoma (n ¼ 27)
Gastroesophageal junction carcinoma (n ¼ 29)
GIST (n ¼ 30)
Non–small cell lung carcinoma (n ¼ 125)
Cutaneous squamous cell carcinoma (n ¼ 36)
Hepatocellular carcinoma (n ¼ 44)
Pancreatic ductal adenocarcinoma (n ¼ 160)
Prostate adenocarcinoma (n ¼ 64)
Melanoma (n ¼ 136)
Esophageal adenocarcinoma (n ¼ 69)
Endometrial adenocarcinoma (n ¼ 79)
Ovarian serous carcinoma (n ¼ 169)
Carcinoma unknown primary (n ¼ 270)
Bladder urothelial (transitional cell) carcinoma (n ¼ 91)
Lung squamous cell carcinoma (n ¼ 93)
Colorectal adenocarcinoma (n ¼ 300)
HNSCC (n ¼ 108)
Sarcoma (n ¼ 348)
Gastric adenocarcinoma (n ¼ 134)
Breast carcinoma (n ¼ 506)
Any aberrations
n (%)
1 (100)
1 (100)
4 (80.0)
1 (25.0)
2 (16.7)
1 (16.7)
1 (16.7)
3 (15.8)
3 (13.0)
1 (12.5)
1 (10)
1 (9.1)
1 (8.3)
4 (7.4)
2 (6.5)
23 (5.6)
1 (5.6)
1 (5.0)
1 (4.2)
1 (3.7)
1 (3.4)
1 (3.3)
4 (3.2)
1 (2.8)
1 (2.3)
3 (1.9)
1 (1.6)
2 (1.5)
1 (1.4)
1 (1.3)
2 (1.2)
3 (1.1)
1 (1.1)
1 (1.1)
3 (1.0)
1 (0.9)
3 (0.9)
1 (0.7)
3 (0.6)
Fusiona
n (%)
0
0
0
0
0
1 (16.7)
0
0
2 (8.7)
0
0
0
0
1 (1.9)
1 (3.2)
16 (3.9)
0
0
0
0
0
0
4 (3.2)
0
0
0
0
0
0
0
0
2 (0.7)
0
0
0
0
0
0
0
Mutation
n (%)
1 (100)
1 (100)
4 (80.0)
1 (25.0)
2 (16.7)
0
1 (16.7)
1 (5.3)
1 (4.3)
1 (12.5)
1 (10.0)
1 (9.1)
0
2 (3.7)
0
3 (0.7)
1 (5.6)
0
1 (4.2)
1 (3.7)
0
1 (3.3)
0
0
1 (2.3)
1 (0.6)
0
1 (0.7)
1 (1.4)
1 (1.3)
0
0
0
0
2 (0.7)
0
1 (0.3)
1 (0.7)
1 (0.2)
Rearrangementa
n (%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
2 (0.5)
0
0
0
0
0
0
0
0
0
1 (0.6)
0
0
0
0
0
0
0
0
0
0
0
0
0
Amplification
n (%)
0
0
0
0
0
0
0
1 (5.3)
0
0
0
0
1 (8.3)
1 (1.9)
1 (3.2)
2 (0.5)
0
1 (5.0)
0
0
1 (3.4)
0
0
0
0
1 (0.6)
1 (1.6)
1 (0.7)
0
0
2 (1.2)
1 (0.4)
1 (1.1)
1 (1.1)
1 (0.3)
1 (0.9)
2 (0.6)
0
2 (0.4)
Duplication
n (%)
0
0
0
0
0
0
0
1 (5.3)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Loss
n (%)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
1 (2.8)
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
Abbreviation: HNSCC, head and neck squamous cell carcinoma.
The term fusion was used when RET was rearranged with known fusion partner (e.g., KIF5B-RET). On the other hand, the term rearrangement was used when there
was no specific identified fusion partner (e.g., RET rearrangement, exon 11).
a
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Duplicaon (1.1%)
Loss (1.1%)
Rearrangement (3.4%)
RET Aberraons
(1.8%)
Amplificaon
(25%)
No RET aberraons (98.2%)
N = 4,871
[5.7% (2/35)] and glioblastoma [0.7% (2/281); Supplementary
Table S5; Supplementary Fig. S1].
Overview of cancer diagnosis and specific RET aberrations
As mentioned, the most common type of RET aberrations were
mutations [38.6% (34/88)], followed by fusions [30.7% (27/88)]
and amplifications [25.0% (22/88); Fig. 1]. This observation was
similar to cBioPortal data in relative frequencies, although the
actual percentages for cBioPortal mutations, fusions, and amplifications differed a bit from our data [60.2% (109/181), 15.5%
(28/181), and 12.7% (23/181), respectively; Supplementary
Table S5; Supplementary Fig. S1]. In the current report, RET
mutations were most commonly seen in patients with medullary
thyroid carcinoma [80% (4/5)], followed by paraganglioma [25%
(1/4)], anaplastic thyroid carcinoma [16.7% (2/12)], and ureter
urothelial carcinoma [16.7% (1/6); Table 1; Fig. 2]. RET fusions
were seen in patients with lung carcinosarcoma [16.7% (1/6)],
followed by papillary thyroid carcinoma [8.7% (2/23)] and lung
adenocarcinoma [3.9% (16/412)]. RET amplifications were
detected in patients with fallopian tube adenocarcinoma [8.3%
(1/12)], uterine carcinosarcoma [5.3% (1/19)], and duodenal
adenocarcinoma [5.0% (1/20); Table 1; Fig. 2].
Coaberrant oncogenic pathways associated with RET
aberrations
Among 88 patients with RET aberrations, 72 also harbored
coaberrations (Supplementary Table S3). Those include coaberrations with TP53-associated genes [59.1% (52/88)], cell cycle–
associated genes [39.8% (35/88)], aberrations in the PI3K signaling pathway [30.7% (27/88)], MAPK effectors [22.7%
(20/88)], and other tyrosine kinases families [21.6% (19/88);
Fig. 3; Supplementary Table S5]. Coaberrant oncogenic pathways
were all readily observed (greater than 20%) among RET mutations, amplifications, and fusions, except the coaberrations with
tyrosine kinase families and MAPK signaling pathway were
both infrequently associated with RET fusions [7.4% (2/27) and
0% (0/27), respectively; Supplementary Table S5].
Number of cogenetic aberrations associated with RET
aberrations and possible cognate targeted therapies
As mentioned, among 88 cases with RET aberrations, 72
patients also had cogenetic aberrations along with RET aberrations (Supplementary Table S3). Among these 72 cases, a total of
OF4 Clin Cancer Res; 2017
Mutaon (38.6%)
Fusion (30.7%)
N = 88
Figure 1.
Overview of RET aberrations among
diverse cancers (N ¼ 4,871). Among
diverse cancers (N ¼ 4,871), 88 cases
(1.8%) harbored RET aberrations.
Among 88 cases with RET aberrations,
38.6% (34/88) were mutations, 30.7%
(27/88) were fusions (defined as RET
rearrangement with known fusion
partner, e.g., KIF5B-RET), 25% (22/88)
were amplifications, 3.4% (3/88) were
rearrangements (defined as RET
rearrangement without specific
identified fusion partner, e.g., RET
rearrangement, exon 11), 1.1% (1/88)
were duplication, and 1.1% (1/88)
were loss.
292 coaberrations were identified. Among 292 coaberrations,
80.8% (236/292) were potentially targetable with FDA-approved
agents as off-label use, and an additional 8.2% (24/292) were
theoretically targetable with therapies that are currently in clinical
trials. Altogether, among all coaberrations, 89.0% (260/292) were
potentially actionable either with therapies that are approved by
the FDA (albeit off label) or with therapies that are in clinical trials
(Supplementary Tables S3 and S7).
Among 292 coexisting aberrations, 200 were molecularly distinct alterations, occurring either in separate genes or distinct
alterations within the same gene. However, there were 16 cases of
CDKN2A/B loss, and those were considered as single aberration.
Among these molecularly distinct aberrations, 80.0% (160/200)
were targetable by an FDA-approved drug, and an additional 7.5%
(15/200) were targetable by drugs that are under investigation in
clinical trials (Supplementary Tables S3 and S7).
Among 88 patients with RET aberrations, the median number
of coaberrations per patient was three (range, 0–16; excluding RET
alterations). The median number of coaberrations was similar
among patients who were tested with the 182-gene panel (n ¼ 16
patients, median of 3 coaberrations, range 0–6) and 236-gene
panel (n ¼ 72 patients, median of 3 coaberrations, range 0–16;
Supplementary Table S4 for list of genes). The median number of
potentially targetable coaberrations per patient was two (range,
0–16; Fig. 4). Among all 88 patients with RET aberrations, 78.4%
(69/88) of patients had theoretically actionable coaberrations
by an FDA-approved agent, and an additional 2.3% (2/88)
patients had coaberrations targetable with investigational agents
in clinical trial. Altogether, 80.6% (71/88) patients had actionable coaberrations either with FDA-approved or with investigational agents. However, if we only focus on 72 patients who
had coaberrations along with RET aberrations, almost all patients had actionable coaberrations [98.6% (71/72)] either with
FDA-approved or with investigational agents (Fig. 4; Supplementary Tables S3 and S7).
Distinctness of genomic aberrations among 88 patients with
RET aberrations
Among 88 patients with RET aberrations, 12 patients had
identical genomic portfolios [RET C634R (ID #1 and #2), RET
M918T (patient ID #6, #8, #9, #11, and #12), RET-NCOA4 fusion
(ID #37 and #38), and RET-CCDC6 fusion (ID #57, #58, and
#60); Supplementary Table S3]. However, among 72 patients
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RET Aberrations in Cancer
≈
All
Medullary thyroid carcinoma
Anaplastic thyroid carcinoma
Lung carcinosarcoma
Ureter urothelial carcinoma
Uterine carcinosarcoma
Papillary thyroid carcinoma
Basal cell carcinoma
Merkel cell carcinoma
Atypical lung carcinoid
Fallopian tube adenocarcinoma
Ovarian epithelial carcinoma
Salivary gland adenocarcinoma
Lung adenocarcinoma
Duodenal adenocarcinoma
0%
0%
Fusion
Mutation
5%
5%
10%
10%
Rearrangement
15%
15%
20%
20%
Amplification
≈
Meningioma
75%
25%
Duplication
80%
30%
85%
35%
Loss
Figure 2.
Frequencies and distributions of RET aberrations. RET aberrations were frequently seen in patients with medullary thyroid carcinoma [80% (4/5)], all being
mutations. This was followed by anaplastic thyroid carcinoma [16.7% (2/12)], lung carcinosarcoma [16.7% (1/6)], and ureter urothelial carcinoma [16.7% (1/6)].
Included when RET was aberrant in 5% of cases and if at least 5 cancer diagnoses were tested for the aberration. Please see Table 1 for a complete
list of cancer diagnoses found to be positive for RET aberrations. The term fusion was used when RET was rearranged with known fusion partner (e.g., KIF5BRET). On the other hand, the term rearrangement was used when there was no specific identified fusion partner (e.g., RET rearrangement, exon 11).
harboring coaberrations along with RET aberrations, there were
no two patients with identical genomic portfolios (Supplementary Table S3). If we consider the genetic alterations at the level of
the gene (and not the specific molecular aberration), then five
patients had coaberrations identical to at least one other patient.
Those include patient ID #32 and #87 with KRAS and TP53 and ID
#39, #41, and #45 with RB1, STK11, and TP53 coaberrations
(Supplementary Table S3).
Clinical impact of multikinase inhibitors with anti-RET activity
in patients with RET aberrations
To demonstrate the impact of therapies with anti-RET activity in
cancer patients harboring RET aberrations, we report two patients
with RET alterations who were treated with multikinase inhibitors
that possess anti-RET activity. The first is a 43-year-old woman
with adenocarcinoma of the lung and a KIF5B-RET fusion, refractory to multiple lines of therapies including the multikinase RET/
MET/VEGFR2 inhibitor cabozantinib. Treatment with another
multikinase inhibitor, vandetanib (RET/EGFR/VEGFR2 inhibitor) in combination with everolimus (an mTOR inhibitor), led
www.aacrjournals.org
to a major response (Fig. 5A); the second patient was a 35-year-old
man with sporadic medullary thyroid carcinoma and a RET
M918T mutation as well as ATM L804fs 4 and ATM S978fs 12
alterations. Additional tumor evaluation with an IHC panel also
showed strong positivity of phospho-AKT. The patient was initially treated with single-agent vandetanib with prolonged stable
disease; however, the addition of everolimus led to significant
tumor shrinkage (Fig. 5B).
Discussion
We report a comprehensive landscape of RET aberrations
among 4,871 patients with diverse cancers. RET aberrations were
identified in 1.8% (88/4,871) of tumors, with mutations being
the most frequent aberration [38.6% (34/88)], followed by
fusions [e.g., KIF5B-RET; 30.7% (27/88)], amplifications
[25.0% (22/88)], rearrangements without specific identified
fusion partner [e.g., RET rearrangement, exon 11; 3.4% (3/88)]
and n ¼ 1 each of duplication and loss (Fig. 1). The overall
frequency of RET aberrations in this current report is similar to the
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Tyrosine kinases families (21.6%)
Cell-cycle–associated genes (39.8%)
CDKN2A/B (18.2%)
CDKN2A (8.0%)
CDKN2C (1.1%)
CCND1 (3.4%)
CCND2 (3.4%)
FGFR1 (3.4%)
FGFR2 (2.3%)
FGFR3 (3.4%)
FGFR4 (1.1%)
DDR2 (1.1%)
EGFR (2.3%)
ERBB2 (2.3%)
KDR (2.3%)
ALK (1.1%)
PDGFRA (2.3%)
PDGFRB (1.1%)
KIT (2.3%)
CDK6 (2.3%)
RB1 (6.8%)
NF1 (6.8%)
Cell-cycle progression
TP53 (52.3%)
SRC (1.1%)
PTEN (5.7%)
AKT2 (1.1%)
TSC1 (2.3%)
TSC2 (2.3%)
STK11 (4.5%)
ATM (4.5%)
MDM2 (5.7%)
PIK3CA (10.2%)
PIK3R1 (1.1%)
KRAS (10.2%)
NRAS (3.4%)
BRAF (4.5%)
TP53-associated genes (59.1%)
JAK2 (2.3%)
PI3K Signaling (30.7%)
MAPK Signaling (22.7%)
CCNE1 (6.8%)
FLT3 (3.4%)
FLT4 (1.1%)
MTOR (1.1%)
RPTOR (1.1%)
NF2 (2.3%)
RICTOR (3.4%)
Figure 3.
Coaberrant oncogenic pathways
associated with RET aberrations.
Among 88 patients with RET
aberrations, some patients also
harbored coaberrations that can lead
to tumorigenesis. Those coaberrations
include TP53-associated genes [e.g.,
MDM2, ATM, or TP53; 59.1% (52/88)],
cell-cycle–associated genes [e.g.,
CDKN2A/B, CDK6, or RB1; 39.8%
(35/88)], PI3K signaling pathway [e.g.,
PIK3CA, PTEN, AKT, or MTOR; 30.7%
(27/88)], MAPK effectors [e.g., KRAS,
NF1, or BRAF; 22.7% (20/88)], and
other tyrosine kinase families [e.g.,
FGFR, EGFR, ERBB2, ALK, or KIT; 21.6%
(19/88)]. Please see Supplementary
Tables S3 and S5 for a complete list of
co-occurring aberrations associated
with RET aberrations.
Cell survival and proliferaon
Cell survival and proliferaon
frequency reported in the cBioPortal dataset 3.0% (181/6,011;
Supplementary Table S5; Supplementary Fig. S1).
RET mutations are a hallmark of medullary thyroid cancer (both sporadic and familial cases); they are reported in
43% to 71% of sporadic medullary thyroid carcinomas (5–8).
RET M918T is the most common mutation reported in
sporadic disease (5, 6, 8), which is consistent with the current
report, wherein four of five medullary thyroid cancers
16
≈
11
Number of aberrations
10
9
8
Figure 4.
Number of all reported coaberrations
and possibly actionable coaberrations
per patient. Among 88 patients with
RET aberrations, there was a median
of 3 coaberrations per patient (range,
0–16) and a median of 2 (range, 0–16)
possibly actionable coaberrations per
patient. Please see Supplementary
Table S6 for a complete list of
co-occurring aberrations and rationale
for possible targeted therapies.
7
6
5
4
3
2
1
0
0
2
4
6
8
10
12
14
16
18
Number of patients
All reported coaberrations
Possibly actionable coaberrations
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RET Aberrations in Cancer
B
Pretreatment
Posttreatment
Posttreatment
100 mm
Pretreatment
100 mm
A
Figure 5.
Case reports of patients with RET aberrations treated with anti-RET multikinase inhibitors. A, Never-smoker lung adenocarcinoma with KIF5B-RET
fusion. Posttreatment PET scan was performed at 8 weeks and showed improvement in the right lung hypermetabolic tumor. A 43-year-old female
never-smoker was diagnosed with stage IV poorly differentiated adenocarcinoma of the lung with focal signet features. Comprehensive genomic profiling
revealed a KIF5B-RET fusion with CDK4 and MDM2 amplification. She was started on treatment with a multikinase RET/MET/VEGFR2 inhibitor,
cabozantinib. She responded initially to treatment and derived clinical benefit for 12 months. On progression, she was then enrolled on a trial with
carboplatin/paclitaxel plus a heat shock protein 90 inhibitor. She progressed after 7 months and was started on pemetrexed plus bevacizumab. Because
of progression, she was enrolled on vandetanib, a multikinase inhibitor of RET/EGFR/VEGFR2 inhibitor, in combination with everolimus (an mTOR
inhibitor; ClinicalTrials.gov; NCT01582191). Her performance status and pain improved while on therapy. After two cycles, FDG PET scans showed interval
improvement in the right lung hypermetabolic tumor (A) and improvement in metastases to the bones and liver. She had a 76% decrease per RECIST
version 1.1. However, she developed new sites of disease after four cycles and was taken off the trial and is now enrolled on another RET inhibitor trial.
B, Recurrent medullary thyroid carcinoma sporadic type with RET M918T mutation. Posttreatment CT scan was performed at 8 weeks, which showed
improvement of lymphadenopathy. A 45-year-old man without known family history of endocrine malignancy initially underwent thyroidectomy for
localized medullary thyroid carcinoma. The patient subsequently developed multiple areas of lymphadenopathy and liver metastasis that was biopsy
proven to be recurrent disease. Comprehensive genomic profiling revealed RET M918T as well as ATM L804fs 4 and ATM S978fs 12. The patient
was treated with vandetanib for 12 months with overall stable disease with eventual slow increase in size. Meanwhile, the patient had further evaluation of
the tumor sample with an IHC panel, including phospho-AKT, which showed positive intensity (3þ) in 100% of cells, suggesting coactivation
of the PI3K pathway. He was subsequently enrolled on a trial with vandetanib, a multikinase inhibitor of RET/EGFR/VEGFR inhibitor, in combination
with everolimus (an mTOR inhibitor; ClinicalTrials.gov; NCT01582191) with improvement in lymphadenopathy (B). His tumor demonstrated a 25%
decrease per RECIST version 1.1 that lasted eight cycles.
harbored RET mutations [M918T (n ¼ 3) and C634R (N ¼
1); Table 1 and Supplementary Table S3; Fig. 2]. Activating
RET mutations lead to enhanced downstream signaling with
multiple effectors, including those in the MAPK and PI3K
pathways, resulting in increased cell proliferation and
anchorage-independent cell growth (33–35). Clinically, RET
mutations are associated with poor clinical outcomes, including larger tumor size, metastasis, and poorer survival, when
compared with RET wild-type cases among patients with
medullary thyroid carcinoma (7).
www.aacrjournals.org
Various FDA-approved multikinase inhibitors that possess
anti-RET activity have recently become available: vandetanib,
cabozantinib, lenvatinib, ponatinib, sunitinib, regorafenib, and
sorafenib (19, 20). Among these agents, one of the earliest studies
that demonstrated clinical activity against RET-mutated tumors
was a phase I trial with cabozantinib (RET/MET/VEGFR2 inhibitor), which enrolled 37 patients with medullary thyroid carcinoma (8). In that study, 81% (25/31) of analyzed tumors harbored activating RET mutations (including 3 patients with germline RET mutations). Stable disease of at least 6 months or a partial
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response (PR) was observed in 68% (25/37) of patients [PR,
25.9% (17/37)]. Tumor regression was also observed among
medullary thyroid carcinomas without identified RET mutations,
which could be due to anti-VEGFR2 and anti-MET activities
(2 patients had MET amplification) of cabozantinib or because
of other unknown aberrations in the RET pathway (8). Cabozantinib was further studied in a double-blind, phase III trial in
patients with advanced medullary thyroid carcinoma and demonstrated statistically significant progression-free survival (PFS)
when compared with placebo (PFS, 11.2 months versus 4.0
months; HR, 0.28; P < 0.001), with a subgroup analysis demonstrating statistically significant HR only seen among the RET
mutation–positive group (22). On the basis of these studies,
cabozantinib is currently approved for patients with advanced
medullary thyroid carcinoma. In this current report, RET-activating mutations were also found in diverse cancers other than
medullary thyroid carcinoma with variable frequencies: anaplastic thyroid [16.7% (2/12)], Merkel cell [10% (1/10)], GIST [3.3%
(1/30)], hepatocellular [2.3% (1/44)], endometrial [1.3%
(1/79)], colorectal [0.7% (2/300)], and breast [0.2% (1/506)]
carcinomas (Table 1 and Supplementary Table S3; Fig. 2). Additional clinical trials targeting diverse cancer types with RET mutations in so-called basket trials may yield insights as to the
relevance of histology in the presence of RET mutations (Supplementary Table S1). It is important to also note that medullary
thyroid carcinoma patients being targeted with multikinase
inhibitors can have frequent initial declines in tumor measurements and markers (calcitonin and carcinoembryonic antigen),
followed by short-lived cycling patterns that include an increase
in tumor measurements more than 20% above nadir values
(which is defined as progressive disease per RECIST version
1.1) with or without increases in tumor markers (36). However,
we have previously demonstrated that these fluctuations can be
transient, and continued RET inhibition was associated with
durable tumor regression (36).
RET fusions were the second most common RET aberrations
identified [30.7% (27/88); Table 1 and Supplementary Table
S3; Fig. 1]. Most fusion partners contain coiled–coil or leucine
zipper domains that drive the dimerization or oligomerization
of the fusion kinase and lead to ligand-independent RET activation (20). RET fusions have been described in approximately
20% to 40% of papillary thyroid cancers (2, 11), with even
higher frequency when associated with radioiodine exposure
(60%; ref. 12). More than 10 RET fusion partners have been
reported (2). In our study, 8.7% of papillary thyroid carcinomas
(2/23) harbored RET fusions (Table 1; Fig. 2). The differences in
frequency between previous reports and the current study may
be due to small sample size and/or differing detection methods.
Recent studies also demonstrated RET fusions in about 1% to
2% of patients with NSCLC, with several of the fusion partners
overlapping with those identified in papillary thyroid carcinoma
(e.g., CCDC6, KIF5B, NCOA4, and TRIM33; refs. 13–18, 24),
which is consistent with findings in this current report (Table 1
and Supplementary Table S3; Fig. 2). Studies analyzing case
series have reported that individual patients with NSCLC harboring a CCDC6-RET fusion treated with vandetanib (n ¼ 1;
ref. 21) as well as NSCLC bearing TRIM33-RET (n ¼ 1) or KIF5BRET (n ¼ 1) treated with cabozantinib have achieved PRs (15).
Herein, we also show a patient with lung adenocarcinoma and
a KIF5B-RET fusion, refractory to multiple lines of therapy,
who attained a major response (76% regression) with vande-
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tanib (RET/EGFR/VEGFR2 inhibitor)-based therapy (Fig. 5A).
Along with these promising reports (15, 21, 24), there are
multiple ongoing phase I and II trials targeting RET fusions in
patients with NSCLC and other advanced solid tumors (Supplementary Table S1).
Of note, we have identified a patient (papillary thyroid; case
#61, Supplementary Table S3) with a sequestosome 1
(SQSTM1)-RET fusion, which, to our knowledge, has not been
previously reported (2, 12–18, 20). The functional and clinical
relevance of SQSTM1-RET is worth investigating as the SQSTM1
fusion with other partners, such as ALK (37), showed transforming activity in vitro, and there is a case report of a patient
with NSCLC and a SQSTM1-NTRK1 fusion demonstrating a
durable response to entrectinib (a multikinase inhibitor with
targets including TrkA, B, and C; ref. 38).
We have also evaluated aberrations that cooccurred with
RET. Indeed, 81.8% (72/88) of cases harboring RET aberrations had additional alterations. The most common pathways
altered involved TP53-associated genes [59.1% (52/88)], followed by cell cycle–associated genes [39.8% (35/88)], the
PI3K signaling pathway [30.7% (27/88)], MAPK effectors
[22.7% (20/88)], and other tyrosine kinase families [21.6%
(19/88); Fig. 3]. In fact, among 292 coexisting aberrations
detected in this report, 80.8% (236/292) were potentially
targetable with FDA-approved agents (albeit off label) and
an additional 8.2% (24/292) with experimental agents that
are under investigation in clinical trials (Supplementary
Tables S3 and S7). Moreover, almost all patients [98.6%
(71/72)] harboring coaberrations with RET had potentially
actionable coaberrations with either FDA-approved or with
investigational agents (Supplementary Tables S3 and S7).
Although targeting RET aberrations has been reported to be
successful, especially when RET was the only identifiable
target (15, 21), the current report suggests that therapeutic
combination approaches may be necessary to move beyond
PRs with limited durability. Several such trials have been
suggested or described previously (39–42). Consistent with
this notion, we show a patient with sporadic medullary
thyroid carcinoma harboring a RET M918T alteration, who
had prolonged stable disease on vandetanib (12 months)
and had strong positivity for phospho-AKT by IHC. The
patient's tumor demonstrated 25% reduction with the addition of everolimus (an mTOR inhibitor; Fig. 5B).
Interestingly, RET fusions were mutually exclusive with
MAPK signaling pathway (which includes NF1, KRAS, NRAS,
and BRAF that were seen with RET mutations/amplifications)
and infrequently associated with aberrations in other tyrosine
kinase families [7.4% (2/27); Fig. 3; Supplementary Table S6],
which is consistent with a previous report (15). However,
coaberrations in effectors of MAPK signaling or other tyrosine
kinases were readily (greater than 20%) seen among tumors
with either RET mutations or amplifications (Fig. 3; Supplementary Table S6). The extent to which this holds true in larger
groups of patients merits investigation.
There are several limitations to the current data. First, correlations with overall disease outcome were not feasible, as the
data were not clinically annotated. Second, the impact of
germline mutations [especially important for medullary thyroid carcinoma and pheochromocytoma that can be associated
with MEN (9, 10)] was not evaluable. Third, the possibility of
sample size bias exists as the number of cases in each
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RET Aberrations in Cancer
malignancy relied on the number of specimens submitted by
physicians for NGS. Finally, the diagnosis was determined on
the basis of the submitting physician's designation. However,
despite these limitations, the current report provides a large and
comprehensive analysis of RET aberrations in diverse cancers.
In conclusion, we have evaluated 4,871 patients with diverse
cancers and shown that aberrations in RET are found in 1.8% (88/
4,871) of cases. We have also identified a novel SQSTM1-RET
fusion (n ¼ 1) in a papillary thyroid tumor. Most patients [81.8%
(72/88)] had coexisting genomic aberrations that accompanied
their RET alterations. In the vast majority of individuals [98.6%
(71/72)], at least one of the coalterations was pharmacologically
tractable. Although various trials targeting RET aberrations are
ongoing (Supplementary Table S1), the current report suggests
that individualized cotargeting of multiple aberrant genes along
with RET inhibition may be required for optimal clinical
outcome.
Disclosure of Potential Conflicts of Interest
V. Subbiah reports receiving commercial research grants from Novartis.
S.K. Elkin and J.L. Carter have ownership interest (including patents) in
N-of-One. R. Kurzrock is an employee of and has ownership interests
(including patents) in Novena Inc. and Curematch, Inc.; is a consultant/
advisory board member for Actuate Therapeutics, Squenom, and Xbiotech;
and reports receiving commercial research grants from Foundation Medi-
cine, Genentech, Guardant, Merck, Pfizer, and Squenom. No potential
conflicts of interest were disclosed by the other authors.
Authors' Contributions
Conception and design: S. Kato, E. Marchlik, S.K. Elkin, J.L. Carter, R. Kurzrock
Development of methodology: S. Kato, E. Marchlik, S.K. Elkin
Acquisition of data (provided animals, acquired and managed patients,
provided facilities, etc.): V. Subbiah, E. Marchlik, S.K. Elkin
Analysis and interpretation of data (e.g., statistical analysis, biostatistics,
computational analysis): S. Kato, V. Subbiah, E. Marchlik, S.K. Elkin,
R. Kurzrock
Writing, review, and/or revision of the manuscript: S. Kato, V. Subbiah,
E. Marchlik, S.K. Elkin, J.L. Carter, R. Kurzrock
Administrative, technical, or material support (i.e., reporting or organizing
data, constructing databases): V. Subbiah
Study supervision: R. Kurzrock
Grant Support
This study was funded in part by the Joan and Irwin Jacobs fund.
The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked
advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate
this fact.
Received July 7, 2016; revised August 22, 2016; accepted September 4, 2016;
published OnlineFirst September 28, 2016.
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RET Aberrations in Diverse Cancers: Next-Generation
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