Integration of tumor characteristics with breast cancer index
Methods of determining risk of recurrence of a breast cancer of a subject are provided. Also provided are methods of predicting responsiveness to a therapy of a breast cancer of a subject. Additionally, methods of recommending treatment for a subject that has breast cancer are provided. Further provided are methods of treating a subject that has breast cancer. Systems for performing described methods are also provided.
1. A method of treating breast cancer of a subject who is lymph node-positive, the method comprising
(i) determining that the subject has a BCIN+numerical score above 7 by:
assaying or having assayed a sample of breast cancer cells from the subject for the expression levels of BUB1B, CENPA, NEK2, RACGAP1 and RRM2;
summing or having summed the expression levels of BUB1B, CENPA, NEK2, RACGAP1 and RRM2 as a single index into a subject's MGI index;
assaying or having assayed the sample of breast cancer cells from the subject for the expression levels of HOXB13 and IL17BR;
calculating or having calculated the ratio of the expression levels of HOXB13/IL17BR to obtain the subject's H/I ratio;
summing or having summed the subject's H/I ratio with the subject's MGI index to obtain a subject's BCI numerical score;
determining or having determined one or more clinicopathological factor selected from tumor size and grade of the subject's breast cancer; and
calculating or having calculated the BCIN+numerical score of the subject by combining the BCI numerical score with the one or more clinicopathological factor of the subject using a multivariate Cox-proportional model; and
(ii) treating the subject with
(a) endocrine therapy, if the subject has previously been treated for breast cancer, or
(b) paclitaxel with 5-fluorouracil, doxorubicin and cyclophosphamide, if the subject has not previously been treated for breast cancer.
2. A method of treating breast cancer of a subject who is lymph node-positive, the method comprising
(i) determining that the subject has a BCIN+numerical score above a BCIN+numerical score cut point by:
assaying or having assayed a sample of breast cancer cells from the subject for the expression levels of BUB1B, CENPA, NEK2, RACGAP1 and RRM2;
summing or having summed the expression levels of BUB1B, CENPA, NEK2, RACGAP1 and RRM2 as a single index into a subject's MGI index;
assaying or having assayed the sample of breast cancer cells from the subject for the expression levels of HOXB13 and IL17BR;
calculating or having calculated the ratio of the expression levels of HOXB13/IL17BR to obtain the subject's H/I ratio;
summing or having summed the subject's H/I ratio with the subject's MGI index to obtain a subject's BCI numerical score;
determining or having determined one or more clinicopathological factor selected from tumor size and grade of the subject's breast cancer;
calculating or having calculated the BCIN+numerical score of the subject by combining the BCI numerical score with the one or more clinicopathological factor of the subject using a multivariate Cox-proportional model;
comparing or having compared the BCIN+numerical score of the subject to the BCIN+numerical score cut point pre-determined based on the BCIN+numerical scores calculated for a training set of samples containing breast cancer tissues from patients that were responsive to endocrine therapy and patients that were not responsive to endocrine therapy; and
(ii) treating the subject with endocrine therapy.
3. The method of claim 1 , wherein the one or more clinicopathological factor is tumor size and grade of the subject's breast cancer.
4. The method of claim 1 , wherein the subject's breast cancer is ER+.
5. The method of claim 3 , wherein 1 to 3 lymph nodes are positive.
6. The method of claim 1 , wherein the subject has previously been treated for breast cancer.
7. The method of claim 6 , wherein the subject has had 5 years of endocrine therapy.
8. The method of claim 6 , wherein the subject has had chemotherapy.
9. The method of claim 8 , wherein the previous chemotherapy comprised treatment with paclitaxel.
10. The method of claim 8 , wherein the previous chemotherapy comprised treatment with 5-fluorouracil, doxorubicin and cyclophosphamide.
11. The method of claim 1 , wherein the endocrine therapy comprises tamoxifen or anastrozole.
12. The method of claim 2 , wherein the subject has not been treated for breast cancer.
13. The method of claim 1 , wherein combining or having combined the subject's expression levels of BUB1B, CENPA, NEK2, RACGAP1 and RRM2 as a single index into the subject's MGI index uses or has used coefficients determined from a Cox proportional hazards regression, an accelerated failure time model, a parametric survival model, a logistic model, or a linear discriminant analysis.
14. The method of claim 13 , wherein the coefficients are or have been determined from a Cox proportional hazards regression.
15. A method of treating breast cancer of a subject who is lymph node-positive, the method comprising
(i) determining that the subject has a BCIN+numerical score above a BCIN+numerical score cut point by:
assaying or having assayed a sample of breast cancer cells from the subject for the expression levels of BUB1B, CENPA, NEK2, RACGAP1 and RRM2;
summing or having summed the expression levels of BUB1B, CENPA, NEK2, RACGAP1 and RRM2 as a single index into a subject's MGI index;
assaying or having assayed the sample of breast cancer cells from the subject for the expression levels of HOXB13 and IL17BR;
calculating or having calculated the ratio of the expression levels of HOXB13/IL17BR to obtain the subject's H/I ratio;
summing or having summed the subject's H/I ratio with the subject's MGI index to obtain a subject's BCI numerical score;
determining or having determined one or more clinicopathological factor selected from tumor size and grade of the subject's breast cancer;
calculating or having calculated the BCIN+numerical score of the subject by combining the BCI numerical score with the one or more clinicopathological factor of the subject using a multivariate Cox-proportional model;
comparing or having compared the BCIN+numerical score of the subject to the BCIN+numerical score cut point pre-determined based on the BCIN+numerical scores calculated for a training set of samples containing breast cancer tissues from patients that had breast cancer recurrence and patients that did not have breast cancer recurrence; and
(ii) treating the subject with endocrine therapy if.
16. The method of claim 15 , wherein the patients from the training set with BCIN+numerical scores below the cut point have minimal 5-year breast cancer recurrence.
17. The method of claim 15 , wherein the patients from the training set with BCIN+numerical scores below the cut point have minimal 10-year residual disease.
18. The method of claim 16 , wherein the recurrence is distant recurrence.
19. The method of claim 16 , wherein the recurrence is local recurrence.