Gene expression markers for predicting response to chemotherapy

• US 7,871,769 B2
• Filed: 04/07/2005
• Issued: 01/18/2011
• Est. Priority Date: 04/09/2004
• Status: Active Grant

• Current Assignee: Genomic Health Incorporated (Exact Sciences Corporation), Instituto Nazionale Tumori
• Original Assignee: Genomic Health Incorporated (Exact Sciences Corporation), Instituto Nazionale Tumori
• Inventors: Shak, Steven, Gianni, Luca, Baker, Joffre B.
• Primary Examiner(s): WOOLWINE, SAMUEL C
• Application Number:
  US11/102,228
• Publication Number:
  US 20050260646A1
• Time in Patent Office: 2,112 Days
• Field of Search: None
• 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 1/6886 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: G01N 2474/20 Immunohistochemistry assay

Abstract

The present invention provides sets of genes the expression of which is important in the prognosis of cancer. In particular, the invention provides gene expression information useful for predicting whether cancer patients are likely to have a beneficial treatment response to chemotherapy FHIT; MTA1; ErbB4; FUS; BBC3; IGF1R; CD9; TP53BP1; MUC1; IGFBP5; rhoC; RALBP1; STAT3; ERK1; SGCB; DHPS; MGMT; CRIP2; ErbB3; RAP1GDS1; CCND1; PRKCD; Hepsin; AK055699; ZNF38; SEMA3F; COL1A1; BAG1; AKT1; COL1A2; Wnt.5a; PTPD1; RAB6C; GSTM1, BCL2, ESR1; or the corresponding expression product, is determined, said report includes a prediction that said subject has a decreased likelihood of response to chemotherapy.

Claims

1. A method for predicting the likelihood of pathologic complete response to chemotherapy that comprises administration of both anthracycline and taxane in a human patient diagnosed with breast cancer comprising:

(a) assaying the level of an CEGP1 RNA or protein in a tissue sample obtained from a breast tumor of said human patient;

(b) normalizing said level against a level of at least one reference RNA or protein in said tissue sample to provide a normalized CEGP1 expression level; and

(c) predicting the likelihood of pathologic complete response of the human patient to chemotherapy that comprises administration of anthracycline and taxane, wherein said prediction is based on said normalized CEGP1 expression level, wherein CEGP1 expression is negatively correlated with the likelihood of pathologic complete response to chemotherapy comprising administration of anthracycline and taxane.

2. The method of claim 1, wherein said breast tumor is an invasive breast tumor.

3. The method of claim 2, wherein said breast tumor is a stage II or stage III breast tumor.

4. The method of claim 1, wherein said chemotherapy is adjuvant chemotherapy.

5. The method of claim 1, wherein said chemotherapy is neoadjuvant chemotherapy.

6. The method of claim 1, wherein said taxane is docetaxel or paclitaxel.

7. The method of claim 6, wherein said taxane is docetaxel.

8. The method of claim 1, wherein said chemotherapy further comprises the administration of an additional anti-cancer agent.

9. The method of claim 1, wherein said anthracycline is doxorubicin.

10. The method of claim 8, wherein said additional anti-cancer agent is a topoisomerase inhibitor.

11. The method of claim 1, wherein said tissue sample is fixed, paraffin-embedded, fresh, or frozen.

12. The method of claim 1, wherein the tissue sample is a needle or core biopsy.

13. The method of claim 1, wherein the tissue sample is obtained by fine needle aspiration.

14. The method of claim 1, wherein said assaying is done by reverse transcriptase polymerase chain reaction (RT-PCR) or another PCR-based method.

15. The method of claim 1, wherein said assaying is done by immunohistochemistry.

16. The method of claim 1, further comprising assaying the level of an RNA transcript or protein product of one or more of the following genes:

TBP, ILT.2, ABCC5, CD18, GATA3, DICER1, MSH3, GBP1, IRS1, CD3z, fasl, TUBB, BAD, ERCC1, MCM6, PR, APC, GGPS1, KRT18, ESRRG, E2F1, AKT2, A.Catenin, NPD009, MAPK14, RUNX1, ID2, G.Catenin, FBXO5, FHIT, MTA1, ERBB4, FUS, BBC3, IGF1R, CD9, TP53BP1, MUC1, IGFBP5, rhoC, RALBP1, CDC20, STAT3, ERK1, HLA.DPB1, SGCB, CGA, DHPS, MGMT, CRIP2, MMP12, ErbB3, RAP1GDS1, CDC25B, IL6, CCND1, CYBA, PRKCD, DR4, Hepsin, CRABP1, AK055699, Contig.51037, VCAM1, FYN, GRB7, AKAP.2, RASSF1, MCP1, ZNF38, MCM2, GBP2, SEMA3F, CD31, COL1A1, ER2, BAG1, AKT1, COL1A2, STAT1, Wnt.5a, PTPD1, RAB6C, TK1, ErbB2, CCNB1, BIRC5, STK6, MKI67, MYBL2, MMP11, CTSL2, CD68, GSTM1, BCL2, and ESR1.

17. The method of claim 16, further comprising normalizing said level of an RNA transcript of said one or more genes, or a protein product thereof, against a level of at least one reference RNA transcript or a protein product thereof in said tissue sample to provide a normalized expression level of said one or more genes, wherein

(a) the normalized expression level of one or more of ILT.2, CD18, GBP1, CD3z, fasl, MCM6, E2F1, ID2, FBXO5, CDC20, HLA.DPB1, CGA, MMP12, CDC25B, IL6, CYBA, DR4, CRABP1, Contig.51037, VCAM1, FYN, GRB7, AKAP.2, RASSF1, MCP1, MCM2, GBP2, CD31, ER2, STAT1, TK1, ERBB2, CCNB1, BIRC5, STK6, MKI67, MYBL2, MMP11, CD68 and CTSL2 positively correlates with the likelihood of a pathologic complete response;

and

(b) the normalized expression level of one or more of TBP, ABCC5, GATA3, DICER1, MSH3, IRS1, TUBB, BAD, ERCC1, PR, APC, GGPS1, KRT18, ESRRG, AKT2, A.Catenin, NPD009, MAPK14, RUNX1, G.Catenin, FHIT, MTA1, ErbB4, FUS, BBC3, IGF1R, CD9, TP53BP1, MUC1, IGFBP5, rhoC, RALBP1, STAT3, ERK1, SGCB, DHPS, MGMT, CRIP2, ErbB3, RAP1GDS1, CCND1, PRKCD, Hepsin, AK055699, ZNF38, SEMA3F, COL1A1, BAG1, AKT1, COL1A2, Wnt.5a, PTPD1, RAB6C, GSTM1, BCL2 and ESR1, negatively correlates with the likelihood of a pathologic complete response.

18. The method of claim 8, wherein said additional anti-cancer agent is a cyclophosphamide.

19. The method of claim 1, wherein said assaying comprises determining the level of an RNA transcript of CEGP1.

20. The method of claim 1, wherein said assaying comprises determining the level of CEGP1 protein.

21. The method of claim 1, further comprising creating a report indicating the likelihood of pathologic complete response of the patient to said chemotherapy.

22. The method of claim 1, further comprising calculating a quantitative score indicating the likelihood of a pathologic complete response to chemotherapy that comprises administration of both anthracycline and taxane, wherein said quantitative score is calculated using said normalized CEGP1 expression level and the negative correlation between the normalized CEGP1 level and the likelihood of a pathological complete response to chemotherapy that comprises administration of both anthracycline and taxane.