Method to determine responsiveness of cancer to epidermal growth factor receptor targeting treatments

• US 7,294,468 B2
• Filed: 12/05/2005
• Issued: 11/13/2007
• Est. Priority Date: 03/31/2004
• Status: Active Grant

• Current Assignee: The General Hospital Corporation (Mass General Brigham, Inc.)
• Original Assignee: Dana-Farber Cancer Institute, The General Hospital Corporation (Mass General Brigham, Inc.)
• Inventors: Lynch, Thomas J., Sordella, Raffaella, Paez, Juan Guillermo, Janne, Pasi Antero, Haber, Daniel A., Meyerson, Matthew, Sellers, William R., Bell, Daphne Winifred, Settleman, Jeffrey E., Johnson, Bruce E.
• Primary Examiner(s): Ungar; Susan
• Assistant Examiner(s): Goddard; Laura B
• Application Number:
  US11/294,621
• Publication Number:
  US 20060147959A1
• Time in Patent Office: 708 Days
• Field of Search: 435/6
• US Class Current: 435/6.14
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12Q 1/485 involving kinase
• CPC Class Codes: C12Q 1/6886 for cancer immunoassay for cancer G01N33/574
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/136 Screening for pharmacological compounds
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: C12Q 2600/16 Primer sets for multiplex assays
• CPC Class Codes: G01N 2333/485 Epidermal growth factor [EGF] (urogastrone)
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/574 for cancer
• CPC Class Codes: G01N 33/74 involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

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

1. A method for determining an increased likelihood of pharmacological effectiveness of treatment by gefitinib or erlotinib in an individual diagnosed with non-small cell lung cancer comprising:

obtaining DNA from a non-small cell lung cancer tumor sample from the individual; and

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 the DNA, 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 gefitinib or erlotinib in the individual.

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

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

4. 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.

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

6. 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.

7. 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.

8. 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.