# US 8,465,916 B2 · Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments

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- Number: US 8,465,916 B2
- Document ID: US8465916B2
- Status: Granted
- Kind: B2
- Application number: 11/894,160
- Filed: 2007-08-20
- Published: 2008-09-25
- Granted: 2013-06-18
- Earliest claimed: 2004-03-31
- Assignees: The General Hospital Corporation; Dana-Farber Cancer Institute, Inc.
- Applicants: Daphne Winifred Bell; Daniel A. Haber; Pasi Antero Janne; Bruce E. Johnston; Thomas J. Lynch; Matthew Meyerson; Juan Guillermo Paez; William R. Sellers; Jeffrey E. Settleman; Raffaella Sordella
- Inventors: Daphne Winifred Bell; Daniel A. Haber; Pasi Antero Janne; Bruce E. Johnston; Thomas J. Lynch; Matthew Meyerson; Juan Guillermo Paez; William R. Sellers; Jeffrey E. Settleman; Raffaella Sordella
- Web page: https://patentgrep.com/patent/US8465916B2

## CPC

- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12Q 1/485: {involving kinase}
- G01N 33/575: for cancer
- G01N 33/74: involving hormones {or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors}
- C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
- C12Q 2600/118: Prognosis of disease development
- C12Q 2600/136: Screening for pharmacological compounds
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- C12Q 2600/16: Primer sets for multiplex assays
- G01N 2333/485: Epidermal growth factor [EGF] (urogastrone)
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The present invention is directed to a method for determining the responsiveness of cancer to an epidermal growth factor receptor (EGFR) treatment. In a preferred embodiment, the presence of at least one variance in the kinase domain of the erbB1 gene confers sensitivity to the tyrosine kinase inhibitor gefitinib. Thus, a diagnostic assay for these mutations will allow for the administration of gefitinib, erlotinib and other tyrosine kinase inhibitors to those patients most likely to respond to the drug.

## Claims

### Claim 1

A method for determining an increased likelihood of pharmacological effectiveness of treatment by an EGFR tyrosine kinase inhibitor in an individual diagnosed with non-small cell lung cancer comprising:
determining the presence or absence of at least one nucleotide variance in exon 18, 19, or 21 of the epidermal growth factor receptor (EGFR) gene in DNA from a non-small cell lung cancer tumor sample from the individual, wherein the presence of at least one nucleotide variance selected from:
1) an in-frame deletion in exon 19 of the EGFR gene consisting of a deletion within codons 746 to 753 that results in amino acid changes comprising a deletion of at least amino acids leucine, arginine, and glutamic acid at position 747, 748, and 749 of SEQ ID NO:512;
2) a substitution in exon 21 that results in an amino acid change consisting of a substitution of arginine for leucine at position 858 (L858R) of SEQ ID NO:512, or a substitution in exon 21 that results in an amino acid change consisting of a substitution of glutamine for leucine at position 861 (L861Q) of SEQ ID NO:512; or
3) a substitution in exon 18 that results in an amino acid change consisting of a substitution of cysteine for glycine at position 719 (G719C) of SEQ ID NO:512;
indicates an increased likelihood of pharmacological effectiveness of treatment by an EGFR tyrosine kinase inhibitor in the individual.

### Claim 2 (depends on 1)

The method of claim 1, wherein the presence or absence of the at least one nucleotide variance is determined by DNA sequencing.

### Claim 3 (depends on 1)

The method of claim 1, wherein the presence or absence of the at least one nucleotide variance is determined by allele-specific amplification.

### Claim 4 (depends on 1)

The method of claim 1, wherein the presence or absence of the at least one nucleotide variance is determined by single strand conformation polymorphism, denaturing gradient gel electrophoresis or temperature gradient gel electrophoresis analysis.

### Claim 5 (depends on 1)

The method of claim 1, wherein the presence or absence of the at least one nucleotide variance is determined by mismatch cleavage analysis.

### Claim 6 (depends on 1)

The method of claim 1 wherein the at least one nucleotide variance is an in-frame deletion in exon 19 of the EGFR gene consisting of a deletion within codons 746 to 753 that results in amino acid changes comprising a deletion of at least amino acids leucine, arginine, and glutamic acid at position 747, 748, and 749 of SEQ ID NO:512.

### Claim 7 (depends on 1)

The method of claim 1, wherein the at least one nucleotide variance is a substitution in exon 21 that results in an amino acid change consisting of a substitution of arginine for leucine at position 858 (L858R) of SEQ ID NO:512 or a substitution of glutamine for leucine at position 861 (L861Q) of SEQ ID NO:512.

### Claim 8 (depends on 1)

The method of claim 1, wherein the at least one nucleotide variance is a substitution in exon 18 that results in an amino acid change consisting of a substitution of cysteine for glycine at position 719 (G719C) of SEQ ID NO:512.

### Claim 9 (depends on 1)

The method of claim 1, wherein the EGFR tyrosine kinase inhibitor is a reversible tyrosine kinase inhibitor.

### Claim 10 (depends on 9)

The method of claim 9, wherein the reversible tyrosine kinase inhibitor is an anilinoquinazoline.

### Claim 11 (depends on 1)

The method of claim 1, wherein the EGFR tyrosine kinase inhibitor is an irreversible tyrosine kinase inhibitor.

### Claim 12

A method for determining an increased likelihood of pharmacological effectiveness of treatment by an EGFR tyrosine kinase inhibitor in an individual diagnosed with non-small cell lung cancer comprising:
determining the presence or absence of at least one nucleotide variance in exon 19, or 21 of the epidermal growth factor receptor (EGFR) gene in DNA from a non-small cell lung cancer tumor sample from the individual, wherein the presence of at least one nucleotide variance selected from:
1) an in-frame deletion in exon 19 of the EGFR gene consisting of a deletion within codons 746 to 753 that results in amino acid changes comprising a deletion of at least amino acids leucine, arginine, and glutamic acid at position 747, 748, and 749 of SEQ ID NO:512; or
2) a substitution in exon 21 that results in an amino acid change consisting of a substitution of arginine for leucine at position 858 (L858R) of SEQ ID NO:512, or a substitution in exon 21 that results in an amino acid change consisting of a substitution of glutamine for leucine at position 861 (L861Q) of SEQ ID NO:512;
indicates an increased likelihood of pharmacological effectiveness of treatment by an EGFR tyrosine kinase inhibitor in the individual.

### Claim 13 (depends on 12)

The method of claim 12, wherein the presence or absence of the at least one nucleotide variance is determined by DNA sequencing.

### Claim 14 (depends on 12)

The method of claim 12, wherein the presence or absence of the at least one nucleotide variance is determined by allele-specific amplification.

### Claim 15 (depends on 12)

The method of claim 12, wherein the presence or absence of the at least one nucleotide variance is determined by single strand conformation polymorphism, denaturing gradient gel electrophoresis or temperature gradient gel electrophoresis analysis.

### Claim 16 (depends on 12)

The method of claim 12, wherein the presence or absence of the at least one nucleotide variance is determined by mismatch cleavage analysis.

### Claim 17 (depends on 12)

The method of claim 12 wherein the at least one nucleotide variance is an in-frame deletion in exon 19 of the EGFR gene consisting of a deletion within codons 746 to 753 that results in amino acid changes comprising a deletion of at least amino acids leucine, arginine, and glutamic acid at position 747, 748, and 749 of SEQ ID NO:512.

### Claim 18 (depends on 12)

The method of claim 12, wherein the at least one nucleotide variance is a substitution in exon 21 that results in an amino acid change consisting of a substitution of arginine for leucine at position 858 (L858R) of SEQ ID NO:512 or a substitution of glutamine for leucine at position 861 (L861Q) of SEQ ID NO:512.

### Claim 19 (depends on 12)

The method of claim 12, wherein the EGFR tyrosine kinase inhibitor is a reversible tyrosine kinase inhibitor.

### Claim 20 (depends on 19)

The method of claim 19, wherein the reversible tyrosine kinase inhibitor is an anilinoquinazoline.

### Claim 21 (depends on 12)

The method of claim 12, wherein the EGFR tyrosine kinase inhibitor is an irreversible tyrosine kinase inhibitor.