esmo advanced course on ntrk gene fusion · esmo advanced course on ntrk gene fusion. epidemiology...

ESMO ADVANCED COURSE ON NTRK GENE FUSION

Epidemiology and distribution of NTRK gene fusions in human tumors

Dr Elise DELUCHE, MD, PhD Gustave Roussy , FRANCELyon, 13-14 September 2019

DISCLOSURE OF INTEREST

No disclosure

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General information about distribution of NTRK Gene Fusions

Incidence of NTRK Gene Fusions : In which tumor type … In which age …

… can we highlight NTRK gene fusions ?

Relation between NTRK gene fusions and the other oncogenic drivers

What is the prognosis ?

OUTLINE OF THE PRESENTATION

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General information of NTRK Gene Fusions

Incidence of NTRK Gene Fusions : In which tumor type ? In which age ?

… can we highlight NTRK gene fusions ?

Relation between NTRK gene fusions and the other oncogenic drivers

What is the prognosis ?

OUTLINE OF THE PRESENTATION

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DISCOVER OF NTRK GENE FUSIONS IN CANCER

Amatu A, et al. ESMO Open 2016;1:e000023Cocco E. et al. NaTure Reviews, december 2018

The discovery of gene fusions dates back to the 1980s.

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Are NTRKs detected in primary tumors or metastases?

Do they have several fusion partners ?

TWO QUESTIONS …..

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ARE NTRKS DETECTED IN PRIMARY TUMORSOR METASTASES?

7 Cocco E. et al. NaTure Reviews, december 2018

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A.Retrospective study751 metastatic melanomas were analyzed by next generationsequencing4 metastatic melanomas presented NTRK fusions; expressionconfirmed by immunohistochemistryNTRK1 (n = 3)NTRK2 (n= 1)

Metastatic melanoma in dermiswith immunoreaction for NTRK

ALSO IN METASTASIS …

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A. 751 metastatic melanomas were analyzed by next generationsequencing4 metastatic melanomas were identified with NTRK fusionsNTRK1 (n = 3)NTRK2 ( n= 1)

The melanoma in situ isimmunoreactive for NTRK.

B. Analysis of the only two primary tumors of metastasesavailable They were immunoreactive for NTRK.

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conclusion : this study shows that tumors and their metastasis canexpress the same NTRK gene fusion but there are a lack of data onthis subject.

Among metastatic cancers, gene fusions were reportedin 1,597 individuals

The most famous gene fusions: ALK, RET, ROS

Behind them : NTRK3 and NTRK1

(15%)

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1/ NTRK1,2,3 have both 61 Partners across tumor types in adult and paediatric cancers

2/ NTRK1 has more fusionpartners than NTRK2 and NTRK3which have a limited number offusion partners

3/ Different types of cancer

DO THEY HAVE SEVERAL FUSION PARTNERS ?

Kummar. S et al., Targeted Oncology (2018)/ Amatu A, et al. ESMO Open 2016/ Marchiò C. et al, Ann Oncol, 201912

General informations of NTRK Gene Fusions

Incidence of NTRK Gene Fusions : In which tumor type ? In which age ?

… can we highlight NTRK gene fusions ?

Is their presence mutually exclusive of the other oncogenic drivers ?

What is the prognosis ?

OUTLINE OF THE PRESENTATION

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IDENTIFICATION OF 3 DIFFERENT GROUPS FORTHE INCIDENCE OF NTRK.

1/Tumors with HIGH FREQUENCY >75%

2/ Tumors with INTERMEDIATE FREQUENCY : 5%-25%

3/ Tumors with LOWER FREQUENCY < 5%

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Tumors with high frequency of NTRK > 90%

Mammary analog secretory carcinoma of thesalivary gland (MASC)

Amatu A, et al. ESMO Open 2016;1:e000023Cocco E et al. NaTure Reviews, december 2018

Secretory breast cancerrare subtype of breast cancer (0.02% ofpatients)

ADULT CANCERS15

NTRK3 gene fusion

Secretory breast cancerNTRK3 fusion

Infantile fibrosarcomaMost common soft tissue sarcoma in children younger than1 year old (20%)7% in people younger than 20 yearsNTRK3 and NTRK1 fusions

Tumors with high frequency of NTRK > 75%

Cellular congenital mesoblastic nephroma= Most kidney tumor in the first month of life NTRK3 fusions > 75%

PAEDIATRIC CANCERS

Albert et al. J Clin Oncol 37:513-524; 2018Cocco E et al. Nature Reviews, december 2018

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NTRK wereidentified inmore than90%

Which are fusion partners ?

Adult cancers NTRK1 NTRK2 NTRK3Carcinoma of the salivary

gland ETV6

Secretory breast cancer ETV6

Penault-Llorca F, et al. J Clin Pathol 2019 / Albert et al. J Clin Oncol; 2018 / Cocco E et al. Nature Reviews, december 2018

Paediatric cancers NTRK1 NTRK2 NTRK3Secretory breast cancer ETV6Infantile fibrosarcoma SQSTM1

TPM3 LMNA

EML4ETV6

Cellular and mixed congenital mesoblastic

nephroma

TPRLMNA

ETV6

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TAKE HOME MESSAGE

In adult cancers No common tumors

Two rare tumors : Salivary gland carcinoma Secretory breast cancer

In paediatric cancers Two common tumors in infancy : Infantile fibrosarcoma Cellular congenital mesoblastic nephroma

One rare tumor : secretory breast cancer

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1/ If you want to analyse tumors with a high frequency of NTRK gene fusions....

2/ Type of NTRK gene fusion : ETV6-NTRK3 > LMNA-NTRK1NTRK2

Tumors with intermediate frequency of NTRK fusions : 5%-25%

Albert et al. J Clin Oncol 37:513-524; 2018Amatu A, et al. ESMO Open 2016;1Cocco E et al. Nature Reviews, december 2018

ADULT CANCERS

Papillary thyroid cancer

« Wild-Type » Gastrointestinalstromal tumor(without cKIT /PDFRA /RAS alterations)

Spitzoid tumors(an uncommon

melanocytic lesion)

High-grade glioma

PAEDIATRIC CANCERS

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Which are fusion partners ?

Penault-Llorca F, et al. J Clin Pathol 2019

Adult/Paediatric cancers NTRK1 NTRK2 NTRK3Papillary thyroid cancer TPR

IRF2BP2 TPM3

ETV6

« Wild-Type » Gastrointestinal stromal

tumor

ETV6

Spitz tumors TP53LMNA

ETV6MYH9

MYO5APaediatric high-grade

gliomasTPM3 AGBL4

VCLETV6BTB1

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TAKE HOME MESSAGE

In adult cancer Papillary thyroid cancer « Wild-Type » Gastrointestinal stromal tumor Spitz tumor

In paediatric cancers Papillary thyroid cancer Spitz tumor High-grade glioma

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1/ If you test NTRK gene fusion ....

2/ Type of NTRK fusion gene : ETV6-NTRK3 > NTRK1 > NTRK2 (only in paediatric cancers)

…you will find them in 5-25% of the time

Head and neck cancer

High-grade glioma

Lung cancerBreast cancer

CholangiocarcinomaMelanoma Colorectal cancer

Pancreatic cancerRenal cell carcinoma

Sarcoma

Acute lymphoblastic leukaemia

Tumors with lower frequency of NTRK < 5%

ADULT CANCERS

Amatu A, et al. ESMO Open 2016Cocco E et al. NaTure Reviews, december 2018

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23Penault-Llorca F, et al. J Clin Pathol 2019

Tumors with lower frequency of NTRK < 5%PAEDIATRIC CANCERS

Albert et al. J Clin Oncol 37:513-524; 2018Cocco E et al. NaTure Reviews, december 2018

Inflammatory myofibroblastic tumor

Sarcoma

Low-grade gliomas

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Penault-Llorca F, et al. J Clin Pathol 201925

TAKE HOME MESSAGE

In common adult cancer like breast cancer, colorectal cancer…

In paediatric cancers Low-grade gliomas Sarcoma Inflammatory myofibroblastic tumor

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1/ If you want to detect NTRK gene fusion ....

2/ Type of NTRK fusion gene : NTRK1 > NTRK3 > NTRK2

…you'll have little chance of finding them.

General information of NTRK Gene Fusions

Incidence of NTRK Gene Fusions in Cancer In which tumor type ? In which age ?

Relation between NTRK gene fusions and the other oncogenic drivers

What is the prognosis ?

OUTLINE OF THE PRESENTATION

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They are mutually exclusive of other genomic alterations (cKIT, PDFRA, BRAF V600 and RAS mutations…)

For example :

RELATION BETWEEN NTRK GENE FUSIONS AND THE OTHER ONCOGENIC DRIVERS

Cocco et al. Cancer Research 2019Pietrantonio, F et al. JNCI 2017

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RELATION BETWEEN NTRK GENE FUSIONS AND THE OTHER ONCOGENIC DRIVERS

Cocco et al. Cancer Research 2019

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2,314 colorectal carcinomas

NTRK gene fusions areassociated to MSI-hightumors

NTRK gene fusions aremutually exclusive of othergenomic alterations

NTRK have been reported as more frequently expressed inMSI-high tumors in colorectal carcinoma patients

Pietrantonio, F et al. JNCI 201730

Relation between MLH1 hypermethylation status and the presence of gene fusions mismatch repair deficient mismatch repair proficient

31Wang et al. Modern Pathology (2019)

Oncogenic fusions are associated to hypermethylation of theMLH1 promoter and lacked activating mutations in BRAF andKRAS

Lynch syndrome

Proposed strategy for screening oncogenic fusions such as ALK, NTRK, and RET rearrangements in CRCs.

Cocco et al. Cancer Research 2019/ Wang et al. Modern Pathology (2019)32

No test for gene fusion

No test for gene fusion

General information of NTRK Gene Fusions

Incidence of NTRK Gene Fusions in Cancer In which tumor type ? In which age ?

Relation between NTRK gene fusions and the other oncogenic drivers

What is the prognosis ?

OUTLINE OF THE PRESENTATION

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WHICH PROGNOSIS ?

1/Tumors with HIGH FREQUENCY >75%

2/ Tumors with INTERMEDIATE FREQUENCY : 5%-25%

3/ Tumors with LOWER FREQUENCY < 5%

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secretory breast carcinoma

Amatu A, et al. ESMO Open 2016 Boon et al. Oral Oncology 82 (2018) 29–33

Generally associated with worst prognosis and aggressiveness

Secretory carcinoma of the breast is a rare and indolent tumor

The age at presentation varies from 3 to 87 years with a median age of 25 years

Distant metastases from secretory carcinoma are extremely rare with only four casesreported.

Shukla et al. JCO 2017

Case Report

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Shukla et al. JCO 2017

8-year-old girl at diagnosisBangladeshSecretory breast carcinomaAfter 6 years of unsuccessfultreatmentleft chestwall lesion and lungmetastasis

Rare case of refractory secretory breast carcinoma

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Typical histopathology of thesecretory breast

Shukla et al. JCO 2017

Her treating oncologist presented hercase at a virtual multidisciplinarytumor board organized by the GlobalCancer Institute

the board recommendedmolecular testing for an ETV6-NTRK3fusion

Rare case of refractory secretory breast carcinoma

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Immunohistochemical stainingfor pan-Trk expression revealeddiffuse, strong positive stainingin a nuclear pattern (Abcam,mAb EPR17341, 1:250).

Presence of an ETV6-NTRK3fusion

Shukla et al. JCO 201738

Treatment : larotrectinib (pan-Trk inhibitor)

Successful targetedtherapy for this refractorypediatric secretory breastcarcinoma

Radiographic response of chest wall lesion and lung metastases39

WHICH PROGNOSIS ?

1/Tumors with HIGH FREQUENCY >75%

2/ Tumors with INTERMEDIATE FREQUENCY : 5%-25%

3/ Tumors with LOWER FREQUENCY < 5%

40Amatu A, et al. ESMO Open 2016 Boon et al. Oral Oncology 82 (2018) 29–33

Colorectal cancer

41 Wang et al. Modern Pathology (2019)

Relationship between MLH1 hypermethylation status and the presence of NTRK

NTRK rearranged tumors had short OS independent from MSI status

Survival in metastatic colorectalcancer patients carrying ALK, ROS1,and NTRK rearranged tumors.

Pietrantonio, F et al. JNCI 201742

LAST TAKE ON MESSAGESNTRK1 NTRK2 NTRK3

FUSION PARTNERS(> 61 ) +++ + ++

HIGH FREQUENCY >75% Infantile fibrosarcoma

ADULT CANCERS :Rare tumorsPAEDIATRIC CANCERSCommon tumors in infancyOne rare tumorETV6-NTRK3

INTERMEDIATE FREQUENCY > 5%-25%

(adult and paediatric cancers)

Rare tumors (3 types) ++ Rare tumors (1type) + only in paediatric cancers

Rare tumors (4 types) +++

LOWER FREQUENCY < 5%

ADULT CANCERS : Several common cancers

+++Need to develop algorithms

to screen patients

ADULT CANCERS : common and rare cancers

PAEDIATRIC CANCERS : only with rare tumors

+

ADULT CANCERS : Common cancers

Rare tumors++

LAST TAKE ON MESSAGES

NTRK1 NTRK2 NTRK3

Oncogenic driver Mutually exclusive of other genomic alterations (BRAF, RAS…)

Prognosis Associated with worst prognosis and aggressiveness

Development of TRK inhibitors treatment

Contacts ESMO

European Society for Medical Oncology Via L. Taddei 4, CH-6962 Viganello – LuganoT. +41 (0)91 973 19 00F. +41 (0)91 973 19 02esmo@esmo.org

esmo.org

elise.deluche@gustaveroussy.fr

THANK YOU FOR YOUR ATTENTION

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