Method and kit for the detection of genes associated with pik3ca mutation and involved in pi3k/akt pathway activation in the er-postitive and her2-positive subtypes with clinical implications

Abstract

A method to determine the clinical outcome of breast tumour affecting a patient if treated with an antitumoural agent against breast tumour, the said method comprising the step of assaying a sample of a breast tumour from said patient for an expression level of selected genes, by contacting mRNA sequences from the cells of this breast tumour with a set of more than 3 nucleotide sequences related to human mutated PIK3CA.

1 . A method to determine a signature of PIK3CA for treatment of early stage breast cancer in a patient, the method comprising:
 measuring an expression level of genes from a biopsy of a breast cancer tumour from the patient by contacting mRNA sequences from the cells of the said biopsy with a gene set of at least 3 capture nucleotide sequences that specifically hybridizes to RNA encoded by PFN2, ORC5L, MYC, E2F5, ARPP19, MNAT1 SCGB2A2, NOTCH2, TNIK, GOLPH2, ARHGDIB, GALNT2, SPTLC2 and SCGDAD2 of a breast cell;   determining the PIK3CA signature for said tumour, wherein under-expression of SCGB2A2, NOTCH2, TNIK, GOLPH2, ARHGDIB, GALNT2, SPTLC2 and SCGDAD2 and/or overexpression of PFN2, ORC5L, MYC, E2F5, ARPP19 and MNAT1 corresponds to a wild-type PIK3CA signature; and   administering to a patient comprising a breast cancer tumour having a wild-type PIK3CA signature a PI3-kinase inhibitor or a PI3-kinase pathway inhibitor.   
     
     
         2 . The method of  claim 1 , wherein the gene set further comprises one or more capture nucleotide sequences selected from the sequences of Table 6. 
     
     
         3 . The method of  claim 1 , wherein the nucleotide sequences related to human mutated PIK3CA, mutated AKT-1 sequences and/or sequences involved in PI3K/AKT further comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all the sequences of Table 5 that are not present in Table 6. 
     
     
         4 . The method of  claim 1 , wherein the nucleotide sequences related to human mutated PIK3CA, mutated AKT-1 sequences and/or sequences involved in PI3K/AKT further comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all the sequences of Table 4 that are not present in Table 6. 
     
     
         5 . The method of  claim 1 , wherein the nucleotide sequences related to human mutated PIK3CA, mutated AKT-1 sequences and/or sequences involved in PI3K/AKT further comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or all the sequences of Table 2a or 2b that are not present in Table 6. 
     
     
         6 . The method of  claim 1 , wherein the nucleotide sequences related to human mutated PIK3CA, mutated AKT-1 sequences and/or sequences involved in PI3K/AKT further comprises capture probes for a detection of an expression level of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or the 12 corresponding target mRNA sequences selected from the group consisting of PML, PP2A, IRS2 PIK3R1, ESR1, FOXO3A, P21 (PAK2), RPS6K, EIF4E, RHEB, P27 and PI3K sequences. 
     
     
         7 . The method of  claim 1  further comprising a step of sequencing of the PIK3CA gene. 
     
     
         8 . The method of  claim 1  further comprising a step of determining a clinical outcome of breast tumour affecting a patient if treated with an antitumoural agent against breast tumour. 
     
     
         9 . The method according to  claim 8  wherein the breast tumour is ER+. 
     
     
         10 . The method according to the  claim 9  wherein the breast tumour is obtained from a high proliferative tumour sample. 
     
     
         11 . The method according to the  claim 9  wherein the breast tumour is a luminal B ER+ tumour. 
     
     
         12 . The method of  claim 11 , wherein the breast tumor harbours overexpression of SCGB2A2, NOTCH2, TNIK, GOLPH2, ARHGDIB, GALNT2, SPTLC2 and SCGDAD2 and/or under-expression of PFN2, ORC5L, MYC, E2F5, ARPP19 and MNAT1 and which further comprises a step of administering to the patient, an anti-oestrogen agent selected from the group consisting of tamoxifen, raloxifene, faslodex or a mixture thereof. 
     
     
         13 . The method according to  claim 9 , further comprising a step of administering to the patient, an anti oestrogen agent selected from a group consisting of a selective oestrogen receptor modulator, a selective oestrogen receptor down regulator, a GnRH analog or an aromatase inhibitor. 
     
     
         14 . The method of  claim 9 , wherein the breast tumor harbours overexpression of SCGB2A2, NOTCH2, TNIK, GOLPH2, ARHGDIB, GALNT2, SPTLC2 and SCGDAD2 and/or under-expression of PFN2, ORC5L, MYC, E2F5, ARPP19 and MNAT1 and which further comprises a step of administering to the patient an anti-oestrogen agent selected from the group consisting of tamoxifen, raloxifene, faslodex or a mixture thereof. 
     
     
         15 . The method according to  claim 9 , wherein the breast tumor harbours overexpression of SCGB2A2, NOTCH2, TNIK, GOLPH2, ARHGDIB, GALNT2, SPTLC2 and SCGDAD2 and/or under-expression of PFN2, ORC5L, MYC, E2F5, ARPP19 and MNAT1 and wherein the breast tumor is Her2+, and which further comprises a step of administering to the patient an antitumoral agent selected from a group consisting of a selective oestrogen receptor modulator, a selective oestrogen receptor down regulator, a GnRH analog or an aromatase inhibitor. 
     
     
         16 . The method of  claim 15  wherein the antitumoral agent further comprise an anti Her2 compound. 
     
     
         17 . The method of  claim 16 , wherein the anti Her2 compound is an anti Her2 antibody. 
     
     
         18 . The method of  claim 17 , wherein the anti Her2 compound is Trastuzumab. 
     
     
         19 . The method of  claim 1 , wherein the inhibitor of the PI3-kinase pathway is a mTOR inhibitor. 
     
     
         20 . The method of  claim 19 , wherein the mTOR inhibitor is Everolimus. 
     
     
         21 . The method according to  claim 8 , wherein the breast tumor harbours overexpression of SCGB2A2, NOTCH2, TNIK, GOLPH2, ARHGDIB, GALNT2, SPTLC2 and SCGDAD2 and/or under-expression of PFN2, ORC5L, MYC, E2F5, ARPP19 and MNAT1 and wherein the breast tumor is Her2+, and which further comprises a step of administering to the patient an antitumoral agent being an anti Her2 compound, preferably an anti Her2 antibody. 
     
     
         22 . The method of  claim 19 , wherein the anti Her2 compound is an anti Her2 antibody. 
     
     
         23 . The method of  claim 22 , wherein the anti Her2 antibody is Trastuzumab. 
     
     
         24 . The method of  claim 1 , wherein the expression level of up to 81 genes is measured. 
     
     
         25 . The method of  claim 1 , wherein the breast cancer tumor is less than 2 cm and/or the patient has a negative lymph node status.