Chapter 40: Tissue-Agnostic Therapies

INTRODUCTION

Tissue-agnostic cancer therapeutics treat cancers based on the mutations they harbor, and it is this genetic change and not the tissue of origin that has led to their regulatory approvals. To date, tissue-agnostic therapeutics have been developed for tumors harboring NTRK mutations, those with mismatch repair deficiencies, and those with high tumor mutational burden. Tissue-agnostic cancer therapeutics are the ultimate goal of precision oncology, and it is hoped additional targets will be added and the number of such drugs will grow

Expert Opinion

NTRK Fusions

• NTRK gene fusions, also called neurotrophic tyrosine receptor kinase gene fusions, lead to abnormal proteins called TRK fusion proteins. NTRK gene fusions involve either NTRK1, NTRK2, or NTRK3—the genes that encode the neurotrophin receptors TRKA, TRKB, and TRKC, respectively

• Usually intra- and inter-chromosomal rearrangements result in hybrid genes with the 3′ sequences of NTRK1, NTRK2, or NTRK3 containing the kinase domain juxtaposed to the 5′ sequences of a different gene. The fusion results in a chimeric oncoprotein characterized by ligand-independent constitutive activation of the TRK kinase

• The fusions result in oncogenic drivers in both adult and pediatric tumors

• NTRK fusions were originally identified in colorectal and papillary thyroid carcinomas but have since been found in multiple tumors from both adult and pediatric patients. These cancers can be grouped into two general categories according to the frequency at which these fusions are detected. For example, in select series of patients the prevalence of the ETV6–NTRK3 fusion exceeds 90% in mammary analogue secretory carcinoma (MASC), secretory breast carcinoma, congenital mesoblastic nephroma (cellular or mixed subtypes), and infantile fibrosarcomas. NTRK fusions are also found at lower and much lower frequencies in other cancers

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  Frequency of NTRK Fusions in Cancer
  Tumor Type	NTRK Gene Fusions Involved	Frequency
  Breast secretory carcinoma	NTRK3	96%
  Infantile fibrosarcoma	NTRK3	95.5%
  Mammary analogue secretory carcinoma (MASC)’	NTRK3	89.1%
  (Cellular and mixed) Congenital mesoblastic nephroma	NTRK3	72%
  Spitz tumors and spitzoid melanoma	NTRK1	16.4%
  Papillary thyroid carcinoma	NTRK1,3	8.8%
  Intrahepatic cholangiocarcinoma	NTRK1	3.6%
  Astrocytoma	NTRK2	3.1%
  High-grade glioma	NTRK1,2,3	2.1%
  Uterine sarcoma	NTRK1,3	2.1%
  GIST (pan-negative)	NTRK3	1.9%
  Lung cancer	NTRK1,2	1.7%
  Thyroid carcinoma	NTRK1,3	1.2%
  Glioblastoma	NTRK1,2	1.2%
  Sarcoma	NTRK1	1.0%
  Ph-like ALL	NTRK3	0.7%
  Colorectal cancer	NTRK1,3	0.61%
  Melanoma	NTRK3	0.3%
  Head and neck cancer	NTRK2,3	0.24%
  Invasive breast cancer	NTRK3	<0.1%
  Other: Renal cell carcinoma, pancreatic cancer, breast cancer, histiocytosis, multiple myeloma, and dendritic cell neoplasms	Various	<1%
  Adapted from: https://oncologypro.esmo.org/oncology-in-practice/anti-cancer-agents-and-biological-therapy/targeting-ntrk-gene-fusions/overview-of-cancers-with-ntrk-gene-fusion/ntrk-gene-fusions-as-oncogenic-drivers/epidemiology-of-cancers-with-ntrk-gene-fusion

• These fusions can be detected using a variety of methods, including tumor DNA and RNA sequencing and plasma cell–free DNA profiling

• The clinical detection of NTRK fusions has predominantly been based on NGS

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  ...

  Techniques to Detect NTRK Gene Fusions
  Technique	Use
  NGS	Detects known and novel fusions with breakpoints in DNA or RNA