Method for predicting response to breast cancer therapeutic agents and method of treatment of breast cancer
View Patent ↗Methods for treating triple negative breast cancer with an androgen receptor inhibitor are provided, as well as methods for screening for the likelihood of the effectiveness of such treatment.
1. A method of treating triple negative breast cancer in a subject, said subject having a breast cancer comprising breast cancer cells that have been classified as other than basal-like subtype, said method comprising:
testing the subject to determine the Weighted Basal and Luminal A classifier score of breast cancer cells of the subject; and
administering a breast cancer treatment to the subject comprising an androgen receptor inhibitor, thereby treating the triple negative breast cancer in the subject;
wherein the breast cancer cells of the subject are characterized by a Weighted Basal and Luminal A classifier score greater than −0.3 according to the formula:
Weighted Basal and Luminal A classifier score=−0.25(Basal Centroid classifier score)+0.27(Luminal A Centroid classifier score)
wherein said Basal Centroid classifier score and said Luminal A Centroid classifier score are determined for the breast cancer cells of the subject from the expression by said cells of the set of intrinsic genes listed in Table 1.
2. The method according to claim 1 , wherein the breast cancer cells of the subject are characterized by a Weighted Basal and Luminal A classifier score greater than −0.2.
3. The method according to claim 1 , wherein the breast cancer cells of the subject are characterized by a Weighted Basal and Luminal A classifier score greater than −0.25.
4. The method according to claim 1 , wherein the breast cancer of the subject is characterized by the presence of androgen receptor-positive tumor cells.
5. The method according to claim 1 , wherein the androgen receptor inhibitor is selected from the group consisting of enzalutamide, bicalutamide, flutamide, nilutamide, ARN509, ketoconazole, abiraterone acetate, VN/124-1 (TOK-001), orteronel (TAK-700), finasteride, galeterone, cyproterone acetate, andarine, and combinations thereof.
6. The method according to claim 5 , wherein the androgen receptor inhibitor is enzalutamide.
7. The method according to claim 1 , wherein the androgen receptor inhibitor is enzalutamide.
8. The method according to claim 2 , wherein the androgen receptor inhibitor is enzalutamide.
9. The method according to claim 3 , wherein the androgen receptor inhibitor is enzalutamide.
10. The method according to claim 6 , wherein the enzalutamide is orally administered once daily at a dose of 160 mg.
11. The method according to claim 10 , wherein the enzalutamide is administered as a single capsule comprising 160 mg enzalutamide.
12. The method according to claim 10 , wherein the enzalutamide is administered as four capsules, each capsule comprising 40 mg enzalutamide.
13. The method according to claim 1 , wherein the breast cancer treatment comprising an androgen receptor inhibitor further comprises one or more other anti-cancer agents that is not an androgen receptor inhibitor.
14. The method according to claim 13 , wherein the other anti-cancer agent that is not an androgen receptor inhibitor is selected from the group consisting of cyclophosphamide, fluorouracil, 5-fluorouracil, methotrexate, thiotepa, carboplatin, cisplatin, taxanes, paclitaxel, protein-bound paclitaxel, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, gemcitabine, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserelin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb, bevacizumab, and combinations thereof.
15. The method according to claim 14 wherein the other anti-cancer agent hat is not an androgen receptor inhibitor is paclitaxel.
16. The method according to claim 1 , further comprising a step of testing the subject to determine whether the subject has a breast cancer comprising breast cancer cells that are other than basal-like subtype.
17. The method according to claim 3 , wherein the subject has received zero or one round of prior treatment with an anti-cancer agent, other than an androgen receptor inhibitor, for treatment of triple negative breast cancer.
18. A method of treating triple negative breast cancer in a subject in need of such treatment comprising:
(a) providing a biological sample from the subject;
(b) assaying the biological sample to determine whether the biological sample is classified as a basal-like subtype or another subtype; and
(c) if the biological sample is classified as other than a basal-like subtype, administering a breast cancer treatment to the subject comprising an androgen receptor inhibitor, thereby treating the breast cancer in the subject.
19. The method of claim 18 , wherein assaying the biological sample to determine whether the biological sample is classified as a basal-like subtype or another subtype is performed by detecting the expression of the intrinsic genes listed in Table 1.
20. The method according to claim 19 , comprising:
(a) determining the Basal Centroid classifier score and the Luminal A Centroid classifier score of the sample from the expression of the set of intrinsic genes listed in Table 1; and
(b) calculating a Weighted Basal and Luminal A classifier score from the Basal Centroid classifier score and the Luminal A Centroid classifier score according to the following equation:
Weighted Basal and Luminal A classifier score =−0.25(Basal Centroid classifier score)+0.27(Luminal A Centroid classifier score); and
wherein the breast cancer treatment is administered to the subject if the Weighted Basal and Luminal A classifier score is greater than −0.3.
21. The method according to claim 20 , wherein the breast cancer treatment is administered if the Weighted Basal and Luminal A classifier score is greater than −0.2.
22. The method according to claim 20 , wherein the breast cancer treatment is administered if the Weighted Basal and Luminal A classifier score is greater than −0.25.
23. The method according to claim 19 , comprising determining the Basal Centroid classifier score of the sample from the expression of the set of intrinsic genes listed in Table 1, wherein the breast cancer treatment is administered if the Basal Centroid classifier score is less than or equal to 0.9.
24. The method according to claim 23 wherein the breast cancer treatment is administered if the Basal Centroid classifier score is less than or equal to 0.6.
25. The method according to claim 23 , wherein a breast cancer treatment is administered to the subject if the Basal Centroid classifier score is in the range from 0.2 to 0.8.
26. The method according to claim 22 , wherein a breast cancer treatment is administered to the subject if the Basal Centroid classifier score is in the range from 0.4 to 0.7.
27. The method according to claim 18 , wherein the breast cancer of the subject is characterized by the presence of androgen receptor-positive tumor cells.
28. The method according to claim 18 , wherein the androgen receptor inhibitor is selected from the group consisting of enzalutamide, bicalutamide, flutamide, nilutamide, ARN509, ketoconazole, abiraterone acetate, VN/124-1 (TOK-001), orteronel (TAK-700) finasteride, galeterone, cyproterone acetate, andirine, and combinations thereof.
29. The method according to claim 28 , wherein the androgen receptor inhibitor is enzalutamide.
30. The method according to claim 20 wherein the androgen receptor inhibitor is enzalutamide.
31. The method according to claim 21 , wherein the androgen receptor inhibitor is enzalutamide.
32. The method according to claim 22 , wherein the androgen receptor inhibitor is enzalutamide.
33. The method according to claim 29 , wherein the enzalutamide is orally administered once daily at a dose of 160 mg.
34. The method according to claim 33 , wherein the enzalutamide is administered as a single capsule comprising 160 mg enzalutamide.
35. The method according to claim 33 , wherein the enzalutamide is administered as four capsules, each capsule comprising 40 mg enzalutamide.
36. The method according to claim 18 , wherein the breast cancer treatment comprising an androgen receptor inhibitor further comprises one or more other anti-cancer agents that is not an androgen receptor inhibitor.
37. The method according to claim 36 , wherein the other anti-cancer agent that is not an androgen receptor inhibitor is selected from the group consisting of cyclophosphamide, fluorouracil, 5-fluorouracil, methotrexate, ethotrexate, thiotepa, carboplatin, cisplatin, taxanes, paclitaxel, protein; bound paclitaxel, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, gemcitabine, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinlblastine, eribulin, irautamycin, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserelin, goserelin, megestrol acetate, risedronate, parnidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb, bevacizumab, and combinations thereof.
38. The method according to claim 37 wherein the other anti-cancer agent that is not an androgen receptor inhibitor is paclitaxel.
39. The method according to claim 18 , wherein the biological sample is selected from the group consisting of a cell, tissue, and bodily fluid.
40. The method according to claim 39 , wherein the biological sample comprises breast tissue or cells.
41. The method of claim 40 , wherein the tissue is obtained from a biopsy.
42. The method of claim 40 , wherein the bodily fluid is selected from the group consisting of blood, lymph, urine, saliva, fluid from ductal lavage, and nipple aspirate.
43. The method according to claim 22 , wherein the subject has received zero or one round of prior treatment with an anti-cancer agent, other than an androgen receptor inhibitor, for treatment of triple negative breast cancer.
44. The method according to claim 20 , wherein the androgen receptor inhibitor is selected from the group consisting of enzalutamide, bicalutamide flutamide, nilutamide, ARN509, ketoconazole, abiraterone acetate, VN/124-1 (TOK-001), orteronel (TAK-700), finasteride, galeterone, cyproterone acetate, andarine, and combinations thereof.
45. The method according to claim 21 , wherein the androgen receptor inhibitor is selected from the group consisting of enzalutamide, bicalutamide, flutamide, nilutamide, ARN509, ketoconazole, abiraterone acetate, VN/124-1 (TOK-001), orteronel (TAK-700), finasteride, galeterone, cyproterone acetate, andarine, and combinations thereof.
46. The method according to claim 23 , wherein the androgen receptor inhibitor is selected from the group consisting of enzalutainide, bicalutamide, fiutamide, nilutamide, ARN509, ketoconazole, abiraterone acetate, VN/124-1 (TOK-001), orteronel (TAK-700), finasteride, galeterone, cyproterone acetate, andarine, and combinations thereof.
47. The method according to claim 23 , wherein the androgen receptor inhibitor is enzalutamide.
48. The method according to claim 26 , wherein the androgen receptor inhibitor is selected from the group consisting of enzalutamide, hicalutamide, flutamide, nilutamide, ARN509, ketoconazole, abiraterone acetate, VN/124-1 (TOK-001), orteronel (TAK-700), finasteride, galeterone, cyproterone acetate, andarine, and combinations thereof.
49. The method according to claim 26 , wherein the androgen receptor inhibitor is enzalutamide.
50. The method according to claim 20 , wherein the breast cancer treatment comprising an androgen receptor inhibitor further comprises one or more other anti-cancer agents that is not an androgen receptor inhibitor.
51. The method according to claim 21 , wherein the breast cancer treatment comprising an androgen receptor inhibitor further comprises one or more other anti-cancer agents that is not an androgen receptor inhibitor.
52. The method according to claim 23 , wherein the breast cancer treatment comprising an androgen receptor inhibitor further comprises one or more other anti-cancer agents that is not an androgen, receptor inhibitor.
53. The method according to claim 26 , wherein the breast cancer treatment comprising an androgen receptor inhibitor further comprises one or more other anti-cancer agents that is not an androgen receptor inhibitor.
54. The method according to claim 50 , wherein the other anti-cancer agent that is not an androgen receptor inhibitor is selected from the group consisting cyclophosphamide, fluorouracil, 5-fluorouracil, methotrexate, thiotepa, carboplatin, cisplatin, taxanes, paclitaxel, protein-bound paclitaxel, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, gemcitabine, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserelin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb, bevacizumab, and combinations thereof.
55. The method according to claim 51 , wherein the other anti-cancer agent that is not an androgen receptor inhibitor is selected from the group consisting of cyclophosphamide, fluorouracil, 5-fluorouracil, methotrexate, thiotepa, carboplatin, cisplatin, taxanes, paclitaxel, protein-bound paclitaxel, docetaxel, vinorelbine, tamoxifen, raloxifene, toremifene, fulvestrant, gemeitabine, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserelin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb, bevacizumab, and combinations thereof.
56. The method according to claim 52 , wherein the other anti-cancer agent that is not an androgen receptor inhibitor is selected from the group consisting of cyclophosphamide, fluorouracil, 5-fluorouracil, methotrexate, thiotepa, carboplatin, cisplatin, taxanes, paclitaxel, protein-bound paclitaxel, docetaxel, vinorelbine, tamoxifen, raloxifene, torernifene, fulvestrant, gemcitabine, irinotecan, ixabepilone, ternozolmide, topotecan, vincristine, vinblastine, eribulin, mutamycin, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserelin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trastuzumab, tykerb, bevacizumab, and combinations thereof.
57. The method according to claim 53 , wherein the other anti-cancer agent that is not an androgen receptor inhibitor is selected from the group consisting of cyclophosphamide, fluorouracil, 5-fluorouracil, methotrexate, thiotepa, carboplatin, cisplatin, taxanes, paclitaxel, protein-bound paclitaxel, docetaxel, vinoreibine, tamoxifen, raloxifene, toremifene, fulvestrant, gemcitabine, irinotecan, ixabepilone, temozolmide, topotecan, vincristine, vinblastine, mutamycin, capecitabine, anastrozole, exemestane, letrozole, leuprolide, abarelix, buserelin, goserelin, megestrol acetate, risedronate, pamidronate, ibandronate, alendronate, denosumab, zoledronate, trasutzumab, tykerb, bevacizumab, and combinations thereof.
58. The method according to claim 20 , wherein the breast cancer treatment comprising an androgen receptor inhibitor further comprises one or more other anti-cancer agents that is not an androgen receptor inhibitor, wherein the androgen receptor inhibitor is enzalutamide.
59. The method according to claim 21 , wherein the breast cancer treatment comprising an androgen receptor inhibitor further comprises one or more other anti-cancer agents that is not an androgen receptor inhibitor, wherein the androgen receptor inhibitor is enzalutamide.
60. The method according to claim 23 , wherein the breast cancer treatment comprising an androgen receptor inhibitor further comprises one or more other anti-cancer agents that is not an androgen receptor inhibitor, wherein the androgen receptor inhibitor is enzalutamide.
61. The method according to claim 26 , wherein the breast cancer treatment comprising an androgen receptor inhibitor further comprises one or more other anti-cancer agents that is not an, androgen receptor inhibitor, wherein the androgen receptor inhibitor is enzalutamide.