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

• US 20060147959A1
• Filed: 12/05/2005
• Published: 07/06/2006
• 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., Johnson, Bruce E., Bell, Daphne Winifred, Settleman, Jeffrey E.
• Granted Patent: US 7,294,468 B2
• Time in Patent Office: Days
• US Class Current: 435/6
• 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 predicting an individual'"'"'s sensitivity to gefitinib or erlotinib in an individual affected with cancer comprising:

a. obtaining a test and control sample from said individual;

b. obtaining DNA from the test and control sample;

c. amplifying exons 18, 19, 20 and 21 of the epidermal growth factor receptor (EGFR) gene by performing a polymerase chain reaction (PCR) to amplify a portion of the exons; and

d. determining the nucleotide sequence of the amplified nucleic acid by sequencing at least one portion of the amplified exon 18, 19, 20 and 21, wherein the presence of at least one nucleotide variance in exon 18, 19, 20 or 21 compared to the control indicates that the individual is sensitive to gefitinib or erlotinib.

2. The method of claim 1, wherein said cancer is lung cancer, non-small cell lung cancer or pancreatic cancer.

3. The method of claim 1, wherein said cancer is non-small cell lung cancer.

4. The method of claim 1, wherein the control sample is isolated from the individual'"'"'s blood or mouth aspirate.

5. The method of claim 1, wherein said test sample is a tissue sample.

6. The method of claim 5, wherein the tissue sample is a tumor biopsy.

7. The method of claim 1, wherein the nucleotide variance of the epidermal growth factor receptor (EGFR) gene is an in frame deletion, substitution, or insertion.

8. The method of claim 1, wherein the nucleotide variance comprises an in frame deletion in exon 19 of the epidermal growth factor receptor (EGFR) gene, wherein the in frame deletion comprises a deletion of at least amino acids leucine, arginine, glutamic acid and alanine, at codons 747, 748, 749, and 750 of SEQ. ID. NO.:

512.

9. The method of claim 1, wherein the nucleotide variance comprises a substitution in exon 21 of the epidermal growth factor receptor (EGFR) gene, wherein the substitution comprises a substitution of guanine for a thymine at nucleotide 2573 of SEQ ID NO:

511.

10. The method of claim 1, wherein the nucleotide variance comprises an in frame deletion in exon 19 of the epidermal growth factor receptor (EGFR) gene, wherein the in frame deletion comprises a deletion of nucleotides selected from the group consisting of nucleotides 2235 to 2249, 2240 to 2251, and 2240 to 2257 of SEQ ID NO:

511.