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

• US 20080096212A1
• Filed: 08/20/2007
• Published: 04/24/2008
• 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: Johnson, Bruce, Lynch, Thomas, Paez, Juan, Haber, Daniel, Settleman, Jeffrey, Bell, Daphne, Sordella, Raffaella, Janne, Pasi, Meyerson, Matthew, Sellers, William
• Granted Patent: US 8,105,769 B2
• Time in Patent Office: Days
• US Class Current: 435/6.16
• 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 to determine the likelihood of response to treatment with gefitinib or erlotinib in an individual affected with non-small cell lung cancer (NSCLC) 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 obtained from a biopsy of said NSCLC, wherein said at least one nucleotide variance is 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;

wherein the presence of said at least one nucleotide variance indicates that said individual is likely to respond to treatment with gefitinib or erlotinib.

2. The method of claim 1, wherein the presence or absence of said at least one nucleotide variance is determined by DNA sequencing, allele-specific amplification, single strand conformation polymorphisms, mismatch cleavage analysis, denaturing Gradient gel electrophoresis or temperature gradient gel electrophoresis analysis.

6. The method of claim 1 wherein said at least one nucleotide variance is an in-frame deletion in exon 19 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 said at least one nucleotide variance is a substitution in exon 21 that results in 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 said at least one nucleotide variance is a substitution in exon 18 that results in a substitution of cysteine for glycine at position 719 (G719C) of SEQ ID NO:

512.

3-5. -5. (canceled)

9. A method to determine the likelihood of response to treatment with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor in an individual affected with cancer comprising:

determining the presence or absence of at least one nucleotide variance in exon 18, 19, or 21 of the EGFR gene in DNA obtained from a biopsy of said NSCLC, wherein said at least one nucleotide variance is 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;

wherein the presence of said at least one nucleotide variance indicates that said individual is likely to respond to treatment with an EGFR tyrosine kinase inhibitor.

10. The method of claim 9 wherein the cancer is selected from the group consisting of gastrointestinal cancer, prostate cancer, ovarian cancer, breast cancer, head and neck cancer, lung cancer, non-small cell lung cancer, cancer of the nervous system, kidney cancer, retina cancer, skin cancer, liver cancer, pancreatic cancer, genital-urinary cancer and bladder cancer.

11. The method of claim 9 wherein the EGFR tyrosine kinase inhibitor is gefitinib or erlotinib.