Method for breast cancer recurrence prediction under endocrine treatment

Abstract

The present invention relates to methods, kits and systems for the prognosis of the disease outcome of breast cancer, said method comprising: (a) determining in a tumor sample from said patient the RNA expression levels of at least 2 of the following 9 genes: UBE2C, BIRC5, RACGAP1, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP (b) mathematically combining expression level values for the genes of the said set which values were determined in the tumor sample to yield a combined score, wherein said combined score is indicative of a prognosis of said patient; and kits and systems for performing said method.

1 . A method for predicting an outcome of breast cancer in an estrogen receptor positive and HER2 negative tumor of a breast cancer patient, said method comprising:
 (a) determining in a tumor sample from said patient the RNA expression levels of at least 2 of the following 9 genes: UBE2C, BIRC5, RACGAP1, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP; and   (b) mathematically combining expression level values for the genes of the said set which values were determined in the tumor sample to yield a combined score, wherein said combined score is indicative of a prognosis of said patient.   
     
     
         2 . The method of  claim 1  comprising:
 determining in a tumor sample from said patient the RNA expression levels of at least 3 of the following 9 genes: UBE2C, BIRC5, RACGAP1, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP. 
 
     
     
         3 . The method of  claim 1  comprising:
 (a) determining in a tumor sample from said patient the RNA expression levels of the following 8 genes: UBE2C, RACGAP1, DHCR7 , STC2, AZGP1, RBBP8, IL6ST, and MGP; and 
 (b) mathematically combining expression level values for the genes of the said set which values were determined in the tumor sample to yield a combined score, wherein said combined score is indicative of a prognosis of said patient. 
 
     
     
         4 . The method of  claim 1  comprising:
 (a) determining in a tumor sample from said patient the RNA expression levels of the following 8 genes: UBE2C, BIRC5, DHCR7 , STC2, AZGP1, RBBP8, IL6ST, and MGP; and 
 (b) mathematically combining expression level values for the genes of the said set which values were determined in the tumor sample to yield a combined score, wherein said combined score is indicative of a prognosis of said patient. 
 
     
     
         5 . The method according to  claim 4  wherein
 BIRC5 may be replaced by UBE2C or TOP2A or RACGAP1 or AURKA or NEK2 or E2F8 or PCNA or CYBRD1 or DCN or ADRA2A or SQLE or CXCL12 or EPHX2 or ASPH or PRSS16 or EGFR or CCND1 or TRIM29 or DHCR7 or PIP or TFAP2B or WNT5A or APOD or PTPRT with the proviso that after a replacement 8 different genes are selected; and 
 UBE2C may be replaced by BIRC5 or RACGAP1 or TOP2A or AURKA or NEK2 or E2F8 or PCNA or CYBRD1 or ADRA2A or DCN or SQLE or CCND1 or ASPH or CXCL12 or PIP or PRSS16 or EGFR or DHCR7 or EPHX2 or TRIM29 with the proviso that after a replacement 8 different genes are selected; and 
 DHCR7 may be replaced by AURKA, BIRC5, UBE2C or by any other gene that may replace BIRC5 or UBE2C with the proviso that after a replacement 8 different genes are selected; and 
 STC2 may be replaced by INPP4B or IL6ST or SEC14L2 or MAPT or CHPT1 or ABAT or SCUBE2 or ESR1 or RBBP8 or PGR or PTPRT or HSPA2 or PTGER3 with the proviso that after a replacement 8 different genes are selected; and 
 AZGP1 may be replaced by PIP or EPHX2 or PLAT or SEC14L2 or SCUBE2 or PGR with the proviso that after a replacement 8 different genes are selected; and 
 RBBP8 may be replaced by CELSR2 or PGR or STC2 or ABAT or IL6ST with the proviso that after a replacement 8 different genes are selected; and 
 IL6ST may be replaced by INPP4B or STC2 or MAPT or SCUBE2 or ABAT or PGR or SEC14L2 or ESR1 or GJA1 or MGP or EPHX2 or RBBP8 or PTPRT or PLAT with the proviso that after a replacement 8 different genes are selected; and 
 MGP may be replaced by APOD or IL6ST or EGFR with the proviso that after a replacement 8 different genes are selected. 
 
     
     
         6 . The method according to  claims 1 , wherein said patient has received endocrine therapy or is contemplated to receive endocrine treatment. 
     
     
         7 . The method of  claim 6 , wherein said endocrine therapy comprises tamoxifen or an aromatase inhibitor. 
     
     
         8 . The method according to  claim 1  wherein a risk of developing breast cancer recurrence or cancer related death is predicted. 
     
     
         9 . The method according to  claim 1 , wherein said expression level is determined as a Messenger-RNA expression level. 
     
     
         10 . The method according to  claim 8 , wherein said expression level is determined by at least one of
 a PCR based method,   a microarray based method, or   a hybridization based method.   
     
     
         11 . The method of  claim 1 , wherein said determination of expression levels is in a formalin-fixed paraffin embedded tumor sample or in a fresh-frozen tumor sample. 
     
     
         12 . The method of  claim 1 , wherein the expression level of at least one marker gene is determined as a pattern of expression relative to at least one reference gene or to a computed average expression value. 
     
     
         13 . The method of  claim 1 , wherein said step of mathematically combining comprises a step of applying an algorithm to values representative of expression levels of given genes. 
     
     
         14 . The method of  claim 13 , wherein said algorithm is a linear combination of said values representative of expression levels of given genes. 
     
     
         15 . The method of  claim 14  wherein a value for a representative value of an expression level of a given gene is multiplied with a coefficient. 
     
     
         16 . The method of  claim 1 , wherein one or more thresholds are determined for said combined score, that discriminate into high and low risk, high, intermediate and low risk, or more risk groups by applying the threshold on the combined score. 
     
     
         17 . The method of  claim 1 , wherein a high combined score is indicative of benefit from cytotoxic chemotherapy. 
     
     
         18 . The method of  claim 1 , wherein information regarding nodal status of the patient is processed in the step of mathematically combining expression level values for the genes to yield a combined score. 
     
     
         19 . The method of  claim 17 , wherein said information regarding nodal status is a numerical value if said nodal status is negative and said information is a different numerical value if said nodal status positive and a different or identical number if said nodal status is unknown. 
     
     
         20 . A kit for performing a method of  claim 1 , said kit comprising a set of oligonucleotides capable of specifically binding sequences or to sequences of fragments of the genes in a combination of genes, wherein said combination comprises at least the two of the 9 genes UBE2C, BIRC5, RACGAP1, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP. 
     
     
         21 . A computer program product capable of processing values representative of expression levels of a set of genes, mathematically combining said values to yield a combined score, wherein said combined score is indicative of efficacy from endocrine therapy of said patient, according to the method of  claim 1 . 
     
     
         22 . The method of  claim 1 , comprising:
 determining in a tumor sample from said patient the RNA expression levels of at least 6 of the following 9 genes: UBE2C, BIRC5, RACGAP1, DHCR7, STC2, AZGP1, RBBP8, IL6ST, and MGP.   
     
     
         23 . The method of  claim 1 , wherein two or more thresholds are determined for said combined score, that discriminate into high and low risk, high, intermediate and low risk, or more risk groups by applying the threshold on the combined score.