Predicting response to chemotherapy using gene expression markers
View Patent ↗The present invention provides gene expression information useful for predicting whether a cancer patient is likely to have a beneficial response to treatment with chemotherapy, comprising measuring, in a biological sample comprising a breast tumor sample obtained from the patient, the expression levels of gene subsets to obtain a risk score associated with a likelihood of a beneficial response to chemotherapy, wherein the score comprises at least one of the following variables: (i) Recurrence Score, (ii) ESRI Group Score; (iii) Invasion Group Score; (iv) Proliferation Group Score; and (v) the expression level of the RNA transcript of at least one of MYBL 2 and SCUBE 2 , or the corresponding expression product. The invention further comprises a molecular assay-based algorithm to calculate the likelihood that the patient will have a beneficial response to chemotherapy based on the risk score.
1. A method for determining a likelihood that a breast cancer patient will have a beneficial response to treatment with chemotherapy, comprising:
measuring expression levels of RNA transcripts of at least two genes selected from BIRC5, MKi67, MYBL2, CCNB1, STK6, MMP11, SCUBE2, ERBB2, GRB7, ESR1, PGR, BCL2, CTSL2, GSTM1, CD68, and BAG1 in a biological sample obtained from a breast tumor of the patient;
calculating a risk score (RS) based on said expression levels, wherein said expression levels comprise one or more of the following variables:
(i) Recurrence Score;
(ii) ESR1 Group Score;
(iii) Invasion Group Score;
(iv) Proliferation Group Score;
(v) MYBL2 expression level; and
(vi) SCUBE2 expression level,
wherein each group score, MYBL2 expression level, and SCUBE2 expression level is weighted by its respective contribution to chemotherapy benefit,
wherein the Recurrence Score, the Proliferation Group Score, the Invasion Group Score, and the MYBL2 expression level are positively correlated with the likelihood that the patient will have a beneficial response to chemotherapy, and
wherein the ESR1 Group Score and the SCUBE2 expression level is negatively associated with the likelihood that the patient will have a beneficial response to chemotherapy; and
creating a report based on the RS, comprising an estimate of the likelihood that the patient will have a beneficial response to chemotherapy.
2. The method of claim 1 , wherein said treatment is administered as adjuvant chemotherapy.
3. The method of claim 1 , wherein said chemotherapy comprises an anthracycline-based therapy.
4. The method of claim 3 wherein said anthracycline-based therapy is doxorubicin or adriamycin.
5. The method of claim 1 , wherein said chemotherapy comprises a taxane derivative.
6. The method of claim 5 wherein said taxane derivative is paclitaxel or docetaxel.
7. The method of claim 1 , wherein said chemotherapy comprises a topoisomerase inhibitor.
8. The method of claim 7 wherein said topoisomerase inhibitor is selected from the group consisting of camptothecin, topotecan, irinotecan, 20-S camptothecin, 9-nitro-camptothecin, 9-amino-camptothecin and GI147211.
9. The method of claim 1 , wherein said chemotherapy comprises an inhibitor of nucleotide biosynthesis.
10. The method of claim 9 , wherein said inhibitor of nucleotide biosynthesis is methotrexate and/or 5-fluorouracil (5-FU).
11. The method of claim 1 , wherein said biological sample is fixed, paraffin-embedded, fresh, or frozen.
12. The method of claim 11 where the biological sample is from fine needle biopsy or core biopsy.
13. The method of claim 1 , wherein measurement of said expression levels includes quantitative reverse transcription polymerase chain reaction (RT-PCR).
14. The method of claim 1 , wherein the expression levels of the RNA transcripts are normalized relative to the expression levels of at least one reference gene, or its expression product.
15. The method of claim 14 , wherein the at least one reference gene is selected from the group consisting of ACTB, GAPD, GUSB, RPLPO, and TFRC.
16. The method of claim 14 , wherein the breast tumor sample is ESR1-positive.
17. The method of claim 1 , further comprising:
applying a threshold to the Proliferation Group Score to obtain a Proliferation Group Threshold Score, wherein the Proliferation Group Threshold Score equals 6.5, if the Proliferation Group Score is less than 6.5; and equals the Proliferation Group Score, if the Proliferation Group Score is greater than or equal to 6.5.
18. The method of claim 17 , wherein the ESR1 Group Score and SCUBE2 expression level are weighted by a factor of 0.34; the Proliferation Group Threshold Score and MYBL2 expression level by a factor of 1.04; and the Invasion Group Score by a factor of 0.10.
19. A method of preparing a personalized genomics profile for a human subject diagnosed with breast cancer, comprising
assaying, in a biological sample comprising a breast tumor sample obtained from said subject, expression levels of RNA transcripts of at least two genes selected from BIRC5, MKi67, MYBL2, CCNB1, STK6, MMP11, SCUBE2, ERBB2, GRB7, ESR1, PGR, BCL2, CTSL2, GSTM1, CD68, and BAG1;
calculating a risk score (RS) based on said expression levels, wherein said expression levels comprise one or more of the following variables:
(i) Recurrence Score;
(ii) ESR1 Group Score;
(iii) Invasion Group Score;
(iv) Proliferation Group Score;
(v) MYBL2 expression level; and
(vi) SCUBE2 expression level,
wherein each group score, the MYBL2 expression level, and the SCUBE2 expression level is weighted by its respective contribution to chemotherapy benefit,
wherein the Recurrence Score, the Proliferation Group Score, the Invasion Group Score, and the MYBL2 expression level are positively correlated with the likelihood that the patient will have a beneficial response to chemotherapy, and
wherein the ESR1 Group Score and the SCUBE2 expression level is negatively associated with the likelihood that the patient will have a beneficial response to chemotherapy; and
creating a report based on the RS, comprising an estimate of the likelihood that the patient will have a beneficial response to chemotherapy.
20. The method of claim 19 , wherein said expression levels used to calculate said variables are normalized relative to expression levels of at least one reference gene, or its expression product.
21. The method of claim 20 , wherein the at least one reference gene is selected from the group consisting of ACTB, GAPD, GUSB, RPLPO, and TFRC.
22. The method of claim 19 , wherein the breast tumor sample is ESR1-positive.
23. The method of claim 1 , further comprising:
applying a threshold to the Proliferation Group Score to obtain a Proliferation Group Threshold Score, wherein the Proliferation Group Threshold Score equals 6.5, if the Proliferation Group Score is less than 6.5; and equals the Proliferation Group Score, if the Proliferation Group Score is greater than or equal to 6.5.
24. The method of claim 23 , wherein the ESR1 Group Score and SCUBE2 expression level are weighted by a factor of 0.34; the Proliferation Group Threshold Score and MYBL2 expression level by a factor of 1.04; and the Invasion Group Score by a factor of 0.10.