Tumor grading and cancer prognosis
The disclosure includes the identification and use of gene expression profiles, or patterns, with clinical relevance to cancer. In particular, the disclosure includes the identities of genes that are expressed in correlation with tumor grade. The levels of gene expression are disclosed as a molecular index for determining tumor grade in a patient and predicting clinical outcome, and so prognosis, for the patient. The molecular grading of cancer may optionally be used in combination with a second molecular index for diagnosing cancer and its prognosis. The disclosure further includes methods for predicting cancer recurrence, and/or predicting occurrence of metastatic cancer. For diagnosis or prognosis, the disclosure further includes methods for determining or selecting the treatment of cancer based upon the likelihood of life expectancy, cancer recurrence, and/or cancer metastasis.
1. A method for selecting a treatment for a breast cancer patient, said method comprising
assaying a breast tumor sample from the subject for gene expression levels of Bub1B, CENPA, NEK2, RACGAP1, and RRM2,
normalizing expression levels of Bub1B, CENPA, NEK2, RACGAP1, and RRM2,
summing the expression levels of Bub1B, CENPA, NEK2, RACGAP1, and RRM2 thereby obtaining a molecular grade index (MGI);
comparing the MGI value to a MGI cutoff, wherein the MGI cutoff is determined by the expression of Bub1B, CENPA, NEK2, RACGAP1, and RRM2, wherein the MGI cutoff is at or about 0.05, 0.10, 0.15, 0.20, 0.25, −0.05, −0.10, −0.15, −0.20, −0.25, −0.30, −0.35, −0.40, −0.45, −0.50, −0.55, −0.60, −0.65, −0.70, −0.75, −0.80, −0.85, −0.90, −0.95, −1.0, −1.1, −1.2, −1.3, −1.4, −1.5, −1.6, −1.7, −1.8, −1.9, or −2.0; and
treating the patient with breast conserving surgery if the MGI is at or below the cutoff, or treating the patient with mastectomy if the MGI is above the cutoff.
2. The method of claim 1 , wherein the method further comprises recommending a reduction in post-operative therapies if the MGI is below the cutoff.
3. The method of claim 2 , wherein the reduction in post-operative therapy comprises omission of one or more of a radiation therapy, an endocrine therapy, and a chemotherapy.
4. The method of claim 3 , wherein the endocrine therapy is selected from a selective estrogen receptor modulator (SERM), a selective estrogen receptor down-regulator (SERD), and an aromatase inhibitor (AI).
5. The method of claim 3 , wherein the chemotherapy is selected from paclitaxel, 5-fluorouracil, doxorubicin and cyclophosphamide.
6. The method of claim 1 , wherein the method further comprises recommending a post-operative therapy.
7. The method of claim 6 , wherein the post-operative therapy is one or more of a radiation therapy, an endocrine therapy and a chemotherapy.
8. The method of claim 1 , further comprising classifying Grade I, Grade II or Grade III tumors as Grade I or Grade III, wherein the breast cancer is Grade I if the MGI is at or below the cutoff, and classifying the breast cancer as a Grade III tumor if the MGI is above the cutoff.
9. A method for prognosing a risk of cancer recurrence in a patient who is being treated with a first therapy for breast cancer, said method comprising
assaying a breast tumor sample from the subject for gene expression levels of Bub 1B, CENPA, NEK2, RACGAP1, and RRM2;
normalizing expression levels of Bub 1B, CENPA, NEK2, RACGAP1, and RRM2,
calculating a molecular grade index (MGI) comprising summing the normalized expression levels of Bub 1B, CENPA, NEK2, RACGAP1, and RRM2 thereby obtaining a molecular grade index (MGI);
comparing the MGI value to a MGI cutoff, wherein the MGI cutoff is determined by the expression of Bub 1B, CENPA, NEK2, RACGAP1, and RRM2 and wherein the MGI cutoff is at or about 0.05, 0.10, 0.15, 0.20, 0.25, −0.05, −0.10, −0.15, −0.20, −0.25, −0.30, −0.35, −0.40, −0.45, −0.50, −0.55, −0.60, −0.65, −0.70, −0.75, −0.80, −0.85, −0.90, −0.95, −1.0, −1.1, −1.2, −1.3, −1.4, −1.5, −1.6, −1.7, −1.8, −1.9, or −2.0; and
discontinuing the first therapy if the MGI is at or below the cutoff, or treating the patient with a second therapy if the MGI is above the cutoff; wherein the first therapy is an endocrine monotherapy or tamoxifen; and wherein the second therapy is chemotherapy, radiation therapy, a combination of chemotherapy and radiation therapy, an endocrine therapy, a selective estrogen receptor modulator (SERM), a selective estrogen receptor down-regulator (SERD), or an aromatase inhibitor (Al).
10. The method of claim 9 , wherein the method comprises recommending treating the patient with the second therapy in addition to the first therapy if the MGI is above the cutoff.
11. The method of claim 9 , wherein the method further comprises recommending ceasing the first therapy if the MGI is above the cutoff, and wherein the second therapy is more aggressive than the first therapy.
12. The method of claim 9 , wherein the cancer is ductal carcinoma in situ (DCIS) and said cancer recurrence comprises local recurrence.
13. The method of claim 9 , wherein the cancer recurrence comprises distal recurrence.
14. The method of claim 9 , wherein the method further comprises assaying for H:I ratio in the sample.
15. The method of claim 9 , wherein the sample is dissected from tissue removed from the patient.
16. The method of claim 9 , wherein the sample is a formalin fixed paraffin embedded (FFPE) sample.