NUT carcinoma: an introduction - PowerPoint Presentation

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NUT carcinoma:an introduction

Last updated:

September 2020

Introduction

NUT carcinoma (formerly NUT midline carcinoma)

is a poorly differentiated squamous cell cancer defined by NUT gene rearrangement1,2Malignancy is most commonly triggered by fusion of the BRD4 gene, although BRD3-NUT and other fusions have been reported1,2BRD4-NUT causes malignancy by blocking cellular differentiation and maintaining cells in a proliferative state3NUT carcinoma is a rare and aggressive tumor type1,2 Median

OS

has been reported as ~

6.5 months1 There is currently no consistently effective treatment for NUT carcinoma, and response to initial therapies is generally poor1,4,5

1. Chau NG, et al. JNCI Cancer Spectrum 2020;4(2):pkz094; 2. French CA, et al. Cancer Res 2003;63(2):304–7; 3. French CA. Head Neck Pathol 2013;7(1):11–16; 4. French CA. Pathol Int 2018;68(11):583–95; 5. Huang QW, et al. Biomed Res Int 2019;2019:1018439.

BRD,

bromodomain

protein; NUT, nuclear protein in testis; OS, overall survival.

Epidemiology of NUT carcinoma

NUT carcinoma is rare,

aggressive and difficult to treat

NUT carcinoma (formerly known as NUT midline carcinoma) is a rare, aggressive, squamous cell cancer defined by fusions of the nuclear protein in testis (NUT) gene1,2 Approximately 15–20 cases are seen annually by the International NUT Midline Carcinoma Registry3NUT carcinoma is likely to be under-diagnosed and under-recognized worldwide4,51. Chau NG, et al. JNCI Cancer Spectrum 2020;4(2):pkz094; 2. French CA, et al. Cancer Res 2003;63(2):304–7; 3. International NUT Midline Carcinoma Registry.

https://www.nmcregistry.org/

. (Accessed: July 2020); 4; Chau NG, et al. Cancer 2016;122(23):3632–40; 5. French CA.

Annu Rev Pathol Mech Dis 2012;7:247–65; 6. French CA. Cancer Genet Cytogenet 2010;203(1):16–20; 7. Bauer DE, et al. Clin Cancer Res 2012;18(20):5773–9. NUT, nuclear protein in testis. *Data sourced between 1990

and 2010.† Cases registered with the International Nut Midline Carcinoma Registry between 1993 and 2017.

1999 –

First American patient

with NUT carcinoma reported

6

2010 –

63

cases

of NUT carcinoma

have been identified

*7

2010 – Creation of the

International NUT Midline Carcinoma Registry1

2017

– 141 cases registered worldwide†1

NUT carcinoma is associated with poor

patient outcomes

1. Chau NG, et al. JNCI Cancer Spectrum 2020;4(2):pkz094; 2. Bauer DE, et al. Clin Cancer Res 2012;18(20):5773–9; 3. Chau NG, et al. Cancer 2016;122(23):3632–40. NUT, nuclear protein in testis; OS, overall survival.

M

edian

OS

is ~6.5 months;

1,2

and

9.7

months

for

head and neck

disease

3

26% of patients

present with

regional nodal metastases on diagnosis3

8

4% mortality within first year of diagnosis in adult patients2

59%

mortality within first year of diagnosis in

paediatric patients

2

NUT carcinoma often originates in midline structures, but may occur elsewhere

While not associated with a specific organ, NUT carcinoma often originates in

midline structures1–3>50% of known cases have been of thoracic origin141% have been of the head or neck1Other reported sites include bone, bladder, pancreas, retroperitoneum, and salivary glands1,41. Chau NG, et al. JNCI Cancer Spectrum 2020;4(2):pkz094; 2. Oren N, et al. Insights Imaging 2019;10(1):72; 3. French CA. Head Neck Pathol 2013;7(1):11–16; 4. French CA. Cancer Genet Cytogenet 2010;203(1):16–20.

NUT

, nuclear protein in testis.

Study included 141 patients; one patient had an ‘unknown’ primary tumor site.1*Bone and soft tissue primary

tumors included chest wall soft tissue, soft tissue mass, right hip bone, left scapula or shoulder, right chest soft tissue, soft tissue, occipital scalp soft tissue, iliac bone, and temporal region soft tissue mass.1

NUT carcinoma can occur at any age

NUT, nuclear protein in testis.

Figure adapted from French CA, 2012.2

1.Chau

NG, et al. JNCI Cancer Spectrum 2020;4(2):

pkz094; 2.

French CA.

Annu

Rev

Pathol

Mech

Dis

2012;7:247–65.

As the first known cases were in children, NUT carcinoma was initially considered

a

pediatric

cancer

2

Recent data suggest that prevalence appears to be distributed across age

groups1,2Reported median age at diagnosis is currently 23.6 years (range <0.1–80 years)1

Several factors result in underestimation of the prevalence of NUT carcinoma

1. French CA.

Annu Rev Pathol Mech Dis 2012;7:247–65; 2. Lee T, et al. Head Neck 2020;42(5):924; 3. Chau NG, et al. Cancer 2016;122(23):3632–40; 4. Aizawa H, et al. Int J Oral Maxillofac Surg 2019;48(10):1265–72; 5. International NUT Midline Carcinoma Registry. https://www.nmcregistry.org/. (Accessed: July 2020); 6. French CA. Cancer Genet Cytogenet 2010;203(1):16–20; 7. Huang QW, et al. Biomed Res Int 2019;2019:1018439.NUT, nuclear protein in testis.

Poorly differentiated disease characteristics

1,2

Aggressive disease progression leading to retrospective diagnosis

3,4

Lack of awareness leading to exclusion from differential diagnoses

6,7

Lack of widely available

molecular testing

and/or

understanding of

laboratory

techniques for

diagnosis

5,6

Oncogenesis of NUT carcinoma

Oncogenesis of NUT carcinoma typically occurs via fusion of NUT with a BRD4

gene1

1. Chau NG, et al. JNCI Cancer Spectrum 2020;4(2):pkz094; 2. Chau NG, et al. Cancer 2016;122(23):3632–40; 3. French CA, et al. Cancer Res 2003;63(2):304–7.BRD, bromodomain protein; NUT, nuclear protein in testis. Data taken from retrospective review of patients (N=141) in the International NUT Midline Carcinoma Registry, spanning January 1993–July 2017. A total of 127 patients are reported here. Nine additional patients had a fusion partner tested but not identified, and five patients were not tested.1

Variant

fusions with

a non-BRD4 partner such as

BRD3

,

NSD3

,

ZNF532,

and

ZNF592

, have also been reported

1

NUT carcinoma is most commonly triggered by fusion

of

the BRD4 double bromodomain-containing gene, a regulator of chromatin activity1–3

Impact of subtype on survival outcomes

for patients with NUT carcinoma

Figure shows OS for three statistically distinct risk groups truncated at five years (N=124).2 Inset figure shows OS by risk group across full length of follow-up.2BRD, bromodomain protein; NUT, nuclear protein in testis; OS, overall survival. Figure reproduced with permission from Chau et al. 2020.2COPYRIGHT PERMISSIONS REQUIRED HERE – Chau 2020

1. McEvoy CR, et al. Genes Chromosomes Cancer 2020;59(6):375–85; 2. Chau NG, et al. JNCI Cancer Spectrum 2020;4(2):pkz094.

It has been proposed that the

NUT

fusion partner may be the most suitable way to classify NUT carcinoma, as well as the best way to define clinical

behavior

and response to treatment

1

A recent analysis identified three

risk groups

that may

impact patient survival outcomes:

2

Non-thoracic primary with non-BRD4-NUT

fusion confers the best prognosis, followed bynon-thoracic primary with BRD4-NUT fusionThoracic NUT carcinoma

has the worst survival outcomes, irrespective of fusion partner2

4

8121620

The BRD-NUT fusion oncogene drives undifferentiated cell proliferation

BRD4

fuses with NUT on chromosome 15q14 to form a fusion oncogene, BRD4-NUT1Evidence suggests that the BRD4-NUT fusion gene upregulates MYC oncogene expression2 Targeting oncogenes by BRD bromodomains impairs histoneacetylation, helping to maintain a poorly differentiated state in NUT carcinoma cells3BET, bromodomain and extra-terminal domain; BRD, bromodomain protein; CDK9, cyclin-dependent kinase 9; CTD, C-terminal domain; P, phosphate; mRNA, messenger ribonucleic acid; NUT, nuclear

protein in testis

.

Figure adapted from Tontsch-Grunt U, et al. 2016.4

The bromodomains also tether NUT to chromatin, promoting the histone acetyltransferase, p300, and increasing chromatin acetylation to create

megadomains

and promote

oncoprotein

expression

3

1. French CA, et al. Cancer Res 2003;63(2):304–7; 2. Grayson AR, et al. Oncogene 2014;33:1736–42; 3. Chau NG, et al. Cancer 2016;122(23):3632–40; 4.

Tontsch-Grunt

U, et al. J

Clin

Oncol 2016;34(Suppl. 15):11574.

BET(BRD4)

DNAHistonesCDK9Cyclin T

P

PPRNA polymerase IIITarget genese.g. C-Myc

mRNA

CTD

AC

NUT carcinoma presents as poorly differentiated cells

BRD4-NUT

causes malignancy by blocking cellular differentiation and promoting a proliferative state1NUT carcinomas may present similarly to small round-cell tumors, with:Sheets of monotonous, small to midsize, primitive‐appearing cells largely distributed singly in a discohesive pattern that can exhibit focal abrupt squamous differentiation1,2Round to oval nuclei mostly devoid of cytoplasm1,2 Lack of a pathognomonic appearance, leading to frequent misdiagnosis of NUT carcinoma1BRD, bromodomain protein; NUT, nuclear protein in testis. Figure reproduced with permission from French.

2010.

3

1. French CA. Head and Neck Pathol 2013;7:11–6; 2. Bishop JA, et al. Cancer Cytopathol 2016;124(12):901–8; 3. French C. J Clin

Pathol 2010;63(6):492–6.

COPYRIGHT PERMISSIONS REQUIRED HERE Figure is taken from French

2010, Figure 3 (

https

://pubmed.ncbi.nlm.nih.gov/18552174

/

)

Making a diagnosis of NUT carcinoma

1. French CA.

Annu Rev Pathol Mech Dis 2012;7:247–65; 2, Napolitano M, et al. Onco Targets Ther 2019;12:3235–44; 3 French CA. Head and Neck Pathol 2013;7:11–6; 4. Mao N, et al. Cancer Biol Ther 2019;20:150–6; 5. Huang QW, et al. Biomed Res Int 2019;2019:1018439.FISH, fluorescence in situ hybridization; IHC, immunohistochemistry; NGS, next-generation sequencing; NUT, nuclear protein in testis; RT-PCR, reverse transcription polymerase chain reaction.

‘When to test’

is a continuing area of need in NUT carcinoma:

A lack of awareness, perceived rarity and absence of effective treatment options contribute

to insufficient testing,

3

and diagnosis is not confirmed pre-mortem in many patients

5

In normal adult tissue, NUT is only expressed in the testes;

1,2

thus, diagnosis is made by its presence outside the testes

Diagnosis is comprehensively confirmed by the high-specificity IHC assay (C52B1) for the nuclear NUT protein

2,3

Fusion partner

Location

NGS

IHC

Ancillary karyotype, FISH or

RT-PCR can identify the fusion oncogene3

NGS for the fusion oncogene

is used

in

diagnosis

4

Current therapeutic options for NUT carcinoma

There is currently no approved treatment

for NUT carcinoma1

1. Huang QW, et al. Biomed Res Int 2019;2019:1018439; 2. Chau NG, et al. Cancer 2016;122(23):3632–40; 3. Napolitano M, et al. Onco Targets Ther 2019;12:3235–44; 4. French CA. Annu Rev Pathol Mech Dis 2012;7:247–65; 5. Darvin P, et al. Exp Mol Med 2018;50:165; 6. Xie XH, et al. Orphanet J Rare Dis 2020;15(1):183; 7. Prasad M, et al. Oncologist 2019;24:e1232–5; 8. International NUT Midline Carcinoma Registry. https://www.nmcregistry.org/. (Accessed: July 2020). IO, immuno-oncology; NUT, nuclear protein in testis.

NUT carcinoma has been shown to be largely insensitive to

non-specific chemotherapy

and radiotherapy

2,3

Lack of sensitivity to non-specific therapies

The International NUT Midline Carcinoma Registry provides a repository of data to

help advance

diagnosis and treatment

8

Aggressive surgical resection +/- postoperative chemo-/radiation has been associated with enhanced survival in head and neck cases

2

NUT carcinoma may involve a low number of mutations,

4

which is a factor relevant for IO

response

5

Patient survival outcomes – both adult and pediatric – remain exceptionally poor

6,7

Low mutational burdenMultimodal approach used in clinical practice

Continuing poor patient outcomes

Ongoing patient registry

Inhibiting targets commonly dysregulated in NUT Carcinoma

Targeted therapy may be a promising therapeutic option for

NUT carcinoma

1. Napolitano M, et al. Onco Targets Ther 2019;12:3235–44; 2. Huang QW, et al. Biomed Res Int 2019;2019:1018439.Creation of a therapeutic pathway has been complicated by the small number of cases and lack of prospective, comparative studies1,2Targeted therapy is a focus for current clinical research of treatment for NUT carcinoma2Potential small molecules either as monotherapies or combination partners under investigation include:1,2

HDAC inhibitors

BET, bromodomain and extra-terminal; HDAC, histone deacetylase; NUT, nuclear protein in testis.

BET inhibitors

Spotlight on BET inhibition

A BET inhibitor is an

acetyl-histone mimetic compound that competitively binds to bromodomains to inhibit the BRD–acetylated chromatin tether1 This inhibition induces differentiation and growth arrest of cells and regulates gene expression2 Small-molecule BET bromodomain inhibitors are in early development as monotherapy treatment3–5Prevalence of common treatment issues, such as acquired treatment resistance and tolerability concerns, are yet to be confirmed for BET inhibitors6,7 BET inhibition is also being investigated for its efficacy alongside chemotherapy for advanced NUT carcinoma81. Huang QW, et al. Biomed Res Int 2019;2019:1018439; 2. French CA. Head Neck Pathol 2013;7(1):11–16; 3. Piha-Paul SA, et al. JNCI Cancer Spectr 2019;4(2):pkz093; 4. NCT02259114. https://clinicaltrials.gov/ct2/show/NCT02259114. (Accessed: July 2020); 5. NCT02516553. https://

clinicaltrials.gov

/ct2/show/NCT02516553. (Accessed: July 2020); 6.

Stathis A, Bertoni D. Cancer Discov; 8(1); 24–36; 7. Napolitano M, et al. Onco Targets Ther 2019;12:3235–4; 8. NCT04116359. https://clinicaltrials.gov/ct2/show/NCT04116359. (Accessed: July 2020); 9. Tontsch-Grunt U, et al. J Clin Oncol 2016;34(Suppl. 15):11574.

Ac, acetyl group; BET, bromodomain and extra-terminal domain; BRD,

bromodomain

protein; CDK9, cyclin-dependent kinase 9; CTD, C-terminal domain; P, phosphate; mRNA, messenger ribonucleic acid; NUT, nuclear protein in testis.

Figure adapted from

Tontsch-Grunt

U, et al. 2016.

9

BET

(BRD4)

DNAHistones

CDK9Cyclin TPP

P

RNA polymerase IIITarget genese.g. C MycmRNA

CTD

BET(BRD4)Cyclin TCDK9RNA polymerase III

Target genes

AC

AC

Spotlight on HDAC inhibition

The BRD4-NUT protein

hyperactivates p300 in chromatin regions, unbalancing HDAC activity and repressing genes needed for cellular differentiation1HDAC inhibition could restore normal chromatin acetylation and, thus, cellular differentiation1In preclinical models and individual clinical cases, HDAC inhibition has been shown to inhibit tumor cell growth and promote differentiation1,2However, tolerability issues and recurrent disease have been reported1,2A phase I trial has recently completed* investigating the effects of a dual HDAC–P13K inhibitor therapy3A case report of one enrolled patient showed disease control of 32 months at the time of publication41. Napolitano M, et al.

Onco

Targets

Ther 2019;12:3235–44; 2. Schwartz BE, et al. Cancer Res 2011;71(7):2686–96; 3. NCT02307240. https://clinicaltrials.gov/ct2/show/NCT02307240. (Accessed July 2020); 4. Munster P, et al. Case Rep Clinical Med 2018;7:451–60.

BRD, bromodomain protein; HDAC, histone deacetylase; NUT, nuclear protein in testis. *Results not yet published.

Hyperactivated p300

Repressed cell

differentiation

BRD4-NUT protein

HDAC inhibitor

Normalized chromatin acetylation

Cell

differentiation resumes

Summary

Summary

The incidence of NUT carcinoma – while rare – is underdiagnosed and likely to be higher

than initially reported, with an estimated prevalence of ~1%1,2 There are no approved treatments and no clearly defined treatment pathways for NUT carcinoma:3Surgical resection in appropriate patients is associated with improved outcomes4Survival may also be stratified into risk groups based on NUT fusion type and tumor location5Investigations into targeted therapies and combination strategies are underway to improve patient outcomes in NUT carcinoma, primarily BET inhibitors and HDAC

inhibitors

3

1. Lee T, et al. Head Neck 2020;42(5):924–38; 2. Sholl LM, et al. J Thorac Oncol 2015;10(6):951–9; 3. Huang QW, et al. Biomed Res Int 2019;2019:1018439; 4. Chau NG, et al. Cancer 2016;122(23):3632–40; 5. Chau NG, et al. JNCI Cancer Spectrum 2020;4(2):pkz094.

BET, bromodomain and extra-terminal; HDAC, histone deacetylase; NUT, nuclear protein in testis.