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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
3
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
33
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 [email protected]
esmo.org
THANK YOU FOR YOUR ATTENTION
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