US 12,760,372 B2Granted

Methods and kits for determining the risk of breast cancer recurrence

AssigneeIstituto Europeo di Oncologia S.r.l.

InventorsPier Paolo Di Fiore, Salvatore Pece

Life of this patent

Estimating the term…

Abstract

The present invention relates to methods and kits for the evaluation of risk and treatment of distant recurrence of breast cancer in a subject. The methods and kits can comprise combining the measured expression levels of a subset of genes selected from a 20-gene signature with tumor size and nodal status to determine the risk of distant recurrence.

Claims20

Dependent claims

A method comprising:

(a) determining, in a sample from a subject having at least one ER+/HER2− breast cancer tumor, mRNA expression levels of the following genes:
H2AFZ, CDK1, EXOSC4, PHLDA2, APOBEC3B, EIF4EBP1, SFN, PHB, EPB41L5, RACGAP1, MRPS23, TOP2A, H2AFJ, NOL3, MIEN1, CENPW, LY6E, ALYREF, MMP1, and NDUFB10;
(b) determining the tumor size (pT) of the at least one ER+/HER2− breast cancer tumor;
(c) determining the nodal status (pN) of the at least one ER+/HER2− breast cancer tumor;
and
(d) calculating a risk score for ER+/HER2− breast cancer recurrence based upon the mRNA expression levels of H2AFZ, CDK1, EXOSC4, PHLDA2, APOBEC3B, EIF4EBP1, SFN, PHB, EPB41L5, RACGAP1, MRPS23, TOP2A, H2AFJ, NOL3, MIEN1, CENPW, LY6E, ALYREF, MMP1, and NDUFB10, the pT and the pN;
and
(e) administering at least one treatment to the subject based on the risk score, wherein the treatment comprises surgery, radiation, anthracycline agents, alkylating agents, nucleoside analogs, platinum agents, vinca agents, anti-estrogen drugs, aromatase inhibitors, ovarian suppression agents, endocrine/hormonal agents, bisphophonate therapy agents, cyclophosphamide, fluorouracil (or 5-fluorouracil or 5-FU), methotrexate, thiotepa, carboplatin, cisplatin, gemcitabine, anthracycline, taxanes, paclitaxel, protein-bound paclitaxel, doxorubicin, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserlin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb or bevacizumab, or combinations thereof,
wherein the risk score is calculated according to the following formula:
Risk
⁢
Score
=
(
0
.
0
⁢
3
⁢
6
⁢
0
⁢
4
)
×
(
∑
i
β
i
×
C
⁢
q
normalized
)
+
p
⁢
T
+
p
⁢
N
5
.
6
⁢
4
⁢
0
⁢
3
⁢
2
wherein
i is the summation index for the genes for which the mRNA expression level was measured;
β is the ridge penalized Cox model coefficient for each gene as set forth below:
H2AFZ-0.03833591325196550, CDK1-0.06132455806571770, EXOSC4-0.02105976326055420, PHLDA2-0.06295739658169650, APOBEC3B 0.02341881674020150, EIF4EBP1-0.13911217901125500, SFN 0.05788269046891110, PHB-0.03538557745953510, EPB41L5-0.04675539403890050, RACGAP1-0.05097505893853430, MRPS23-0.14201022110072700, TOP2A-0.11290078348786600, H2AFJ-0.04975471358452700, NOL3-0.04193802459521500, MIEN1 0.01133668644106850, CENPW-0.03717918353187610, LY6E-0.02829256296234230, ALYREF-0.09541915699494330, MMP1-0.00911370427072023, NDUFB10 0.00626166874136819;
and Cqnormalized is the normalized average quantification cycle (Cq) for each of the genes for which the mRNA expression level was measured;
wherein
pT is 0.45542 when the tumor size of the at least one ER+/HER2− breast cancer tumor is determined to be pT1c;
or
pT is 0.96572 when the tumor size of the ER+/HER2− breast cancer tumor is determined to be any of pT2, pT3 and pT4;
and
wherein
pN is 0.46293 when the nodal status of the at least one ER+/HER2− breast cancer tumor is determined to be pN1 or
pN is 1.24922 when the nodal status of the at least one ER+/HER2− breast cancer tumor is determined to be pN2.

67 more elements

A method for stratifying a subject having at least one ER+/HER2− breast cancer tumor into a low or high risk group of ER+/HER2− breast cancer recurrence, the method comprising:

(a) determining, in a sample from the subject, mRNA expression levels of the following genes:
H2AFZ, CDK1, EXOSC4, PHLDA2, APOBEC3B, EIF4EBP1, SFN, PHB, EPB41L5, RACGAP1, MRPS23, TOP2A, H2AFJ, NOL3, MIEN1, CENPW, LY6E, ALYREF, MMP1, and NDUFB10;
(b) determining the tumor size (pT) of the at least one ER+/HER2− breast cancer tumor;
(c) determining the nodal status (pN) of the at least one ER+/HER2− breast cancer tumor;
(d) calculating a risk score based upon the mRNA expression levels of H2AFZ, CDK1, EXOSC4, PHLDA2, APOBEC3B, EIF4EBP1, SFN, PHB, EPB41L5, RACGAP1, MRPS23, TOP2A, H2AFJ, NOL3, MIEN1, CENPW, LY6E, ALYREF, MMP1, and NDUFB10, the pT and the pN;
(e) stratifying the subject based upon the calculated risk score;
and
(f) administering at least one treatment to the subject based on the risk score, wherein the treatment comprises surgery, radiation, anthracycline agents, alkylating agents, nucleoside analogs, platinum agents, vinca agents, anti-estrogen drugs, aromatase inhibitors, ovarian suppression agents, endocrine/hormonal agents, bisphophonate therapy agents, cyclophosphamide, fluorouracil (or 5-fluorouracil or 5-FU), methotrexate, thiotepa, carboplatin, cisplatin, gemcitabine, anthracycline, taxanes, paclitaxel, protein-bound paclitaxel, doxorubicin, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserlin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb or bevacizumab, or combinations thereof,
wherein the risk score is calculated according to the following formula:
Risk
⁢
Score
=
(
0
.
0
⁢
3
⁢
6
⁢
0
⁢
4
)
×
(
∑
i
⁢
β
i
×
C
⁢
q
normalized
)
+
pT
+
pN
5
.
6
⁢
4
⁢
0
⁢
3
⁢
2
wherein
i is the summation index for the genes for which the mRNA expression level was measured;
β is the ridge penalized Cox model coefficient for each gene as set forth below:
H2AFZ-0.03833591325196550, CDK1-0.06132455806571770, EXOSC4-0.02105976326055420, PHLDA2-0.06295739658169650, APOBEC3B 0.02341881674020150, EIF4EBP1-0.13911217901125500, SEN 0.05788269046891110, PHB-0.03538557745953510, EPB41L5-0.04675539403890050, RACGAP1-0.05097505893853430, MRPS23-0.14201022110072700, TOP2A-0.11290078348786600, H2AFJ-0.04975471358452700, NOL3-0.04193802459521500, MIEN1 0.01133668644106850, CENPW-0.03717918353187610, LY6E-0.02829256296234230, ALYREF-0.09541915699494330, MMP1-0.00911370427072023, NDUFB10 0.00626166874136819;
and Cqnormalized is the normalized average quantification cycle (Cq) for each of the genes for which the mRNA expression level was measured;
wherein
pT is 0.45542 when the tumor size of the at least one ER+/HER2− breast cancer tumor is determined to be pT1c;
or
pT is 0.96572 when the tumor size of the ER+/HER2− breast cancer tumor is determined to be any of pT2, pT3 and pT4;
and
wherein
pN is 0.46293 when the nodal status of the at least one ER+/HER2− breast cancer tumor is determined to be pN1 or
pN is 1.24922 when the nodal status of the at least one ER+/HER2− breast cancer tumor is determined to be pN2.

64 more elements

A method for stratifying a subject having at least one ER+/HER2− breast cancer tumor into a low, intermediate, or high risk group of ER+/HER2− breast cancer recurrence, the method comprising:

(a) determining, in a sample from the subject, mRNA expression levels of the following genes:
H2AFZ, CDK1, EXOSC4, PHLDA2, APOBEC3B, EIF4EBP1, SFN, PHB, EPB41L5, RACGAP1, MRPS23, TOP2A, H2AFJ, NOL3, MIEN1, CENPW, LY6E, ALYREF, MMP1, and NDUFB10;
(b) determining the tumor size (pT) of the at least one ER+/HER2− breast cancer tumor;
(c) determining the nodal status (pN) of the at least one ER+/HER2− breast cancer tumor;
(d) calculating a risk score based upon the mRNA expression levels of H2AFZ, CDK1, EXOSC4, PHLDA2, APOBEC3B, EIF4EBP1, SFN, PHB, EPB41L5, RACGAP1, MRPS23, TOP2A, H2AFJ, NOL3, MIEN1, CENPW, LY6E, ALYREF, MMP1, and NDUFB10, the pT and the pN;
(e) stratifying the subject based upon the calculated risk score;
and
(f) administering at least one treatment to the subject based on the risk score, wherein the treatment comprises surgery, radiation, anthracycline agents, alkylating agents, nucleoside analogs, platinum agents, vinca agents, anti-estrogen drugs, aromatase inhibitors, ovarian suppression agents, endocrine/hormonal agents, bisphophonate therapy agents, cyclophosphamide, fluorouracil (or 5-fluorouracil or 5-FU), methotrexate, thiotepa, carboplatin, cisplatin, gemcitabine, anthracycline, taxanes, paclitaxel, protein-bound paclitaxel, doxorubicin, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserlin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb or bevacizumab, or combinations thereof,
wherein the risk score is calculated according to the following formula:
Risk
⁢
Score
=
(
0
.
0
⁢
3
⁢
6
⁢
0
⁢
4
)
×
(
∑
i
⁢
β
i
×
Cq
normalized
)
+
pT
+
pN
5
.
6
⁢
4
⁢
0
⁢
3
⁢
2
wherein
i is the summation index for the genes for which the mRNA expression level was measured;
β is the ridge penalized Cox model coefficient for each gene as set forth below:
H2AFZ-0.03833591325196550, CDK1-0.06132455806571770, EXOSC4-0.02105976326055420, PHLDA2-0.06295739658169650, APOBEC3B 0.02341881674020150, EIF4EBP1-0.13911217901125500, SEN 0.05788269046891110, PHB-0.03538557745953510, EPB41L5-0.04675539403890050, RACGAP1-0.05097505893853430, MRPS23-0.14201022110072700, TOP2A-0.11290078348786600, H2AFJ-0.04975471358452700, NOL3-0.04193802459521500, MIEN1 0.01133668644106850, CENPW-0.03717918353187610, LY6E-0.02829256296234230, ALYREF-0.09541915699494330, MMP1-0.00911370427072023, NDUFB10 0.00626166874136819;
and Cqnormalized is the normalized average quantification cycle (Cq) for each of the genes for which the mRNA expression level was measured;
wherein
pT is 0.45542 when the tumor size of the at least one ER+/HER2− breast cancer tumor is determined to be pT1c;
or
pT is 0.96572 when the tumor size of the ER+/HER2− breast cancer tumor is determined to be any of pT2, pT3 and pT4;
and
wherein
pN is 0.46293 when the nodal status of the at least one ER+/HER2− breast cancer tumor is determined to be pN1 or
pN is 1.24922 when the nodal status of the at least one ER+/HER2− breast cancer tumor is determined to be pN2.

62 more elements

Dependencies are inferred from the claim text.

Facts

Application: 17/907,601Filed 7 May 2021
Priority: EP 201736128 May 2020
Published: US 2023/0143295 A111 May 2023
Granted: 13 Oct 2026
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C12Q 1/6886
For diseases caused by alterations of genetic material: for cancer
G16H 50/30
ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or…: for…
C12Q 2600/118
Oligonucleotides characterized by their use: prognosis of disease development
C12Q 2600/158
Oligonucleotides characterized by their use: expression markers

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US 2023/0143295 A1Pre-grant publication · published 11 May 2023
US 12,760,372 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A method comprising:

(a) determining, in a sample from a subject having at least one ER+/HER2− breast cancer tumor, mRNA expression levels of the following genes:
H2AFZ, CDK1, EXOSC4, PHLDA2, APOBEC3B, EIF4EBP1, SFN, PHB, EPB41L5, RACGAP1, MRPS23, TOP2A, H2AFJ, NOL3, MIEN1, CENPW, LY6E, ALYREF, MMP1, and NDUFB10;
(b) determining the tumor size (pT) of the at least one ER+/HER2− breast cancer tumor;
(c) determining the nodal status (pN) of the at least one ER+/HER2− breast cancer tumor;
and
(d) calculating a risk score for ER+/HER2− breast cancer recurrence based upon the mRNA expression levels of H2AFZ, CDK1, EXOSC4, PHLDA2, APOBEC3B, EIF4EBP1, SFN, PHB, EPB41L5, RACGAP1, MRPS23, TOP2A, H2AFJ, NOL3, MIEN1, CENPW, LY6E, ALYREF, MMP1, and NDUFB10, the pT and the pN;
and
(e) administering at least one treatment to the subject based on the risk score, wherein the treatment comprises surgery, radiation, anthracycline agents, alkylating agents, nucleoside analogs, platinum agents, vinca agents, anti-estrogen drugs, aromatase inhibitors, ovarian suppression agents, endocrine/hormonal agents, bisphophonate therapy agents, cyclophosphamide, fluorouracil (or 5-fluorouracil or 5-FU), methotrexate, thiotepa, carboplatin, cisplatin, gemcitabine, anthracycline, taxanes, paclitaxel, protein-bound paclitaxel, doxorubicin, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserlin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb or bevacizumab, or combinations thereof,
wherein the risk score is calculated according to the following formula:
Risk
⁢
Score
=
(
0
.
0
⁢
3
⁢
6
⁢
0
⁢
4
)
×
(
∑
i
β
i
×
C
⁢
q
normalized
)
+
p
⁢
T
+
p
⁢
N
5
.
6
⁢
4
⁢
0
⁢
3
⁢
2
wherein
i is the summation index for the genes for which the mRNA expression level was measured;
β is the ridge penalized Cox model coefficient for each gene as set forth below:
H2AFZ-0.03833591325196550, CDK1-0.06132455806571770, EXOSC4-0.02105976326055420, PHLDA2-0.06295739658169650, APOBEC3B 0.02341881674020150, EIF4EBP1-0.13911217901125500, SFN 0.05788269046891110, PHB-0.03538557745953510, EPB41L5-0.04675539403890050, RACGAP1-0.05097505893853430, MRPS23-0.14201022110072700, TOP2A-0.11290078348786600, H2AFJ-0.04975471358452700, NOL3-0.04193802459521500, MIEN1 0.01133668644106850, CENPW-0.03717918353187610, LY6E-0.02829256296234230, ALYREF-0.09541915699494330, MMP1-0.00911370427072023, NDUFB10 0.00626166874136819;
and Cqnormalized is the normalized average quantification cycle (Cq) for each of the genes for which the mRNA expression level was measured;
wherein
pT is 0.45542 when the tumor size of the at least one ER+/HER2− breast cancer tumor is determined to be pT1c;
or
pT is 0.96572 when the tumor size of the ER+/HER2− breast cancer tumor is determined to be any of pT2, pT3 and pT4;
and
wherein
pN is 0.46293 when the nodal status of the at least one ER+/HER2− breast cancer tumor is determined to be pN1 or
pN is 1.24922 when the nodal status of the at least one ER+/HER2− breast cancer tumor is determined to be pN2.

67 more elements

Facts

Application

17/907,601Filed 7 May 2021

Priority

EP 201736128 May 2020

Published

US 2023/0143295 A111 May 2023

Granted

13 Oct 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification6 codes

C12Q 1/6886
For diseases caused by alterations of genetic material: for cancer
G16H 50/30
ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or…: for…
C12Q 2600/118
Oligonucleotides characterized by their use: prognosis of disease development
C12Q 2600/158
Oligonucleotides characterized by their use: expression markers