Copy number aberration driven endocrine response gene signature
Disclosed are methods of predicting the likelihood of long-term survival without recurrence of breast cancer for a subject having estrogen receptor-positive (ER+) breast cancer treated with adjuvant endocrine monotherapy. In various embodiments, these methods comprise performing a gene expression profile of a breast tissue sample of substantially all of the genes of the “CADER set” described herein; calculating a risk score using a regression model; and applying a double median cutoff classification to assign the subject to a sensitive, indeterminate or resistant group, wherein assignment to a sensitive group predicts longer relapse-free survival compared to the median relapse-free survival of ER+ breast cancer patients treated with adjuvant endocrine monotherapy.
1. A method of predicting the likelihood of long-term survival without recurrence of cancer for a subject having estrogen receptor positive (ER+) breast cancer treated with endocrine monotherapy, the method comprising:
a) obtaining a breast cancer tissue sample from a human subject;
b) generating cDNA from the sample;
c) detecting expression levels of a set of genes consisting of (i) endocrine therapy sensitivity genes PARP3, AZGP1, EPHX2, IGFBP4, NUDT18, FOM5, C1orf66, COL14A1, PLAT, PCM1, ABTB20, NFKB1, TK2, ABAT, ANF18, PHYHD1, and CHDH and (ii) endocrine monotherapy resistance genes CENPE, CCNB1, KIFC1, CCT6A, EIF2C2, RAD54B, VDAC2, MCM10, ZWINT, KIF18A, RACGAP1, TDG, NUP107, TMPO, XPOT, BIRC5, TOP2A, DSC2, EIP2S2, UBEC2C, TPX2, C20orf24, KIF4A, CDC2, CDCA5, C8orf76, and FBXO45 from the cDNA; and
d) assigning the subject to a sensitive, indeterminate or resistant group, wherein assignment to the sensitive group predicts longer relapse-free survival compared to the resistant group, wherein the assigning the subject to a sensitive, indeterminate or resistant group comprises determining the gene centroid of the endocrine therapy sensitivity genes and the gene centroid of the endocrine therapy resistance genes.
2. The method of claim 1 , wherein the assigning the subject to a sensitive, indeterminate or resistant group comprises representing the expression levels as a coordinate in a quadrant in a 2-dimensional space comprising the resistant gene centroid and the sensitive gene centroid and determining a Euclidean distance of the expression levels to a gene centroid of each of the sensitive, resistant and indeterminate groups, wherein the subject is assigned to the group with the shortest distance.
3. The method of claim 1 , wherein the endocrine monotherapy comprises a therapy selected from the group consisting of tamoxifen treatment and aromatase inhibitor treatment.
4. The method of claim 1 , further consisting of detecting expression levels of one or more housekeeping genes.
5. The method of claim 4 , wherein the one or more housekeeping genes are selected from the group consisting of MRPL19, SF3A1, and PUM1.
6. A The method of claim 4 , wherein the one or more housekeeping genes are selected from the group consisting of MRPL19, SF3A1, PUM1, ACTB, GAPD, GUSB, RPLP0, and TFRC.
7. A method of predicting the likelihood of long-term survival without recurrence of cancer for a subject having estrogen receptor positive (ER+) breast cancer treated with endocrine monotherapy, the method comprising:
a) obtaining a breast cancer tissue sample from a human subject;
b) generating cDNA from the sample;
c) detecting expression levels of a set of genes consisting of (i) endocrine therapy sensitivity genes PARP3, AZGP1, EPHX2, IGFBP4, NUDT18, FOM5, C1orf66, COL14A1, PLAT, PCM1, ABTB20, NFKB1, TK2, ABAT, ANF18, PHYHD1, and CHDH and (ii) endocrine monotherapy resistance genes CENPE, CCNB1, KIFC1, CCT6A, EIF2C2, RAD54B, VDAC2, MCM10, ZWINT, KIF18A, RACGAP1, TDG, NUP107, TMPO, XPOT, BIRC5, TOP2A, DSC2, EIP2S2, UBEC2C, TPX2, C20orf24, KIF4A, CDC2, CDCA5, C8orf76, and FBXO45 from the cDNA;
d) scaling the expression levels to have similar distribution of a matching prototype dataset in which patients belong to a sensitive, an indeterminate or a resistant group based on the centroids of the sensitive genes and the resistant genes; and
e) assigning the subject to the sensitive, indeterminate or resistant group, wherein assignment to the sensitive group predicts longer relapse-free survival compared to the resistant group, wherein the assigning the subject to a sensitive, indeterminate or resistant group comprises determining the gene centroid of the endocrine therapy sensitivity genes and the gene centroid of the endocrine therapy resistance genes.
8. The method of claim 7 , wherein detecting the expression levels comprises performing a quantitative RT-PCR assay.
9. The method of claim 7 , further comprising providing a microarray consisting of probes for (i) endocrine therapy sensitivity genes PARP3, AZGP1, EPHX2, IGFBP4, NUDT18, FMO5, C1orf66, COL14A1, PLAT, PCM1, ZBTB20, NFKB1, TK2, ABAT, ACP6, TSPAN7, TNFRSF10B, OSBPL1A, KCTD9, EVL, MAP2K4, RPL21, STC2, ZNF18, PHYHD1, and CHDH, and (ii) endocrine therapy resistance genes CENPE, CCNB1, KIFC1, CCT6A, EIF2C2, RAD54B, VDAC2, MCM10, ZWINT, KIF18A, RACGAP1, TDG, NUP107, TMPO, XPOT, BIRC5, TOP2A, DSC2, EIF2S2, UBE2C, TPX2, C20orf24, KIF4A, CDC2, CDCA5, C8orf76, and FBXO45.
10. The method of claim 7 , wherein the assigning the subject to a sensitive, indeterminate or resistant group comprises representing the expression levels as a coordinate in a quadrant in a 2-dimensional space comprising the resistant gene centroid and the sensitive gene centroid and determining a Euclidean distance of the expression levels to a gene centroid of each of the sensitive, resistant and indeterminate groups, wherein the subject is assigned to the group with the shortest distance.
11. The method of claim 7 , wherein the endocrine monotherapy comprises a therapy selected from the group consisting of tamoxifen treatment and aromatase inhibitor treatment.