Methods for determining breast cancer risk

Abstract

The present disclosure relates generally to determining the risk of developing breast cancer. In particular, the present disclosure provides materials and methods for determining whether a subject diagnosed with a non-cancerous breast tumor will develop cancer based on expression of multiple oncogenic biomarkers in the non-cancerous breast tumor. The present disclosure also provides a cancer risk score to determine whether a subject has low risk, intermediate risk, or high risk of developing cancer, thereby permitting selection of appropriate therapies to treat the subject. The present disclosure addresses the need for improved diagnostic assessment of early hyperplastic lesions, the presence of which in a subject is a significant indicator that a subject will eventually develop invasive breast cancer.

1 .- 36 . (canceled) 
     
     
         37 . A biomarker panel for determining breast cancer risk in a subject, the panel comprising at least two of the following oncogenic biomarkers or fragments thereof: HEC1 (Highly Expressed in Cancer protein), CEACAM6 (Carcino Embryonic Antigen Cell Adhesion Molecule 6), HYAL1 (Hyaluronoglucosaminidase 1), and MMP-1 (Matrix Metalloproteinase-1);
 wherein quantification of levels of the at least two oncogenic biomarkers or fragments thereof from a hyperplastic tissue sample from a subject is used to calculate a risk score predictive of a low, intermediate, or high risk of developing breast cancer.   
     
     
         38 . The biomarker panel of  claim 37 , wherein the panel comprises at least HEC1 or fragments thereof. 
     
     
         39 . The biomarker panel of  claim 37 , wherein the panel comprises at least three of the following biomarkers: HEC1, CEACAM6, HYAL1, and MMP-1, or fragments thereof. 
     
     
         40 . The biomarker panel of  claim 37 , wherein the panel comprises at least the four following biomarkers: HEC1, CEACAM6, HYAL1, and MMP-1, or fragments thereof. 
     
     
         41 . The biomarker panel of  claim 37 , wherein a risk score equal to or less than 1 indicates a low risk of the subject developing cancer, a risk score greater than 1 but equal to or less than 5 indicates an intermediate risk of the subject developing cancer, and a risk score of greater than 5 indicates a high risk of the subject developing cancer. 
     
     
         42 . The biomarker panel of  claim 37 , wherein a risk score equal to or less than 1 indicates that the subject has a breast cancer free survival rate of at least 95% for at least 19 years, a risk score greater than 1 but equal to or less than 5 indicates that the subject has a breast cancer free survival rate of at most 95% for at least 5 years and at least 75% for at least 10 years, and a risk score of greater than 5 indicates a high risk that the subject has a breast cancer free survival rate of at most 45% for at least 5 years and at least 20% for at least 10 years. 
     
     
         43 . The biomarker panel of  claim 37 , wherein quantifying levels of the at least two oncogenic biomarkers or fragments thereof from the hyperplastic tissue sample from the subject comprises an assay having a sensitivity of at least 80% and a specificity of at least 70%. 
     
     
         44 . The biomarker panel of  claim 37 , wherein quantifying levels of the at least two oncogenic biomarkers or fragments thereof from the hyperplastic tissue sample from the subject comprises an assay having a negative predictive value (NPV) of at least 90% and a positive predictive value (PPV) of at least 70%. 
     
     
         45 . The biomarker panel of  claim 37 , wherein quantifying the levels of the at least two oncogenic biomarkers comprises one or more of Western blot analysis, a protein/peptide function assay, immunohistochemistry analysis, ELISA analysis, DNA chip analysis, or mRNA analysis by one or more of reverse transcription-polymerase chain reaction (RT-PCR), competitive RT-PCR, real-time RT-PCR, digital PCR, RNase protection assay (RPA), Next Generation RNA sequencing, and Northern blotting. 
     
     
         46 . The biomarker panel of  claim 37 , wherein the hyperplastic tissue sample is obtained using at least one of a core biopsy, a surgical biopsy, a fine needle aspiration procedure, ductal lavage, a nipple aspirate fluid procedure, and nipple discharge collection. 
     
     
         47 . The biomarker panel of  claim 37 , wherein the subject is a human mammal without a history of breast cancer. 
     
     
         48 . A method of assessing a patient at risk for breast cancer, the method comprising:
 quantifying levels of at least two oncogenic biomarkers or fragments thereof from a first hyperplastic tissue sample from a subject and subsequently from a second hyperplastic tissue sample from the subject, wherein the at least two oncogenic biomarkers or fragments thereof comprise HEC1 (Highly Expressed in Cancer protein), CEACAM6 (Carcino Embryonic Antigen Cell Adhesion Molecule 6), HYAL1 (Hyaluronoglucosaminidase 1), and MMP-1 (Matrix Metalloproteinase-1);   calculating a risk score based on the levels of the at least two oncogenic biomarkers or fragments thereof from each of the first and the second hyperplastic tissue samples; and   determining that the subject has a low, intermediate or high risk of developing cancer based on the calculated risk scores.   
     
     
         49 . The method of  claim 48 , wherein a risk score equal to or less than 1 indicates that the subject has a breast cancer free survival rate of at least 95% for at least 19 years, a risk score greater than 1 but equal to or less than 5 indicates that the subject has a breast cancer free survival rate of at most 95% for at least 5 years and at least 75% for at least 10 years, and a risk score of greater than 5 indicates a high risk that the subject has a breast cancer free survival rate of at most 45% for at least 5 years and at least 20% for at least 10 years. 
     
     
         50 . The method of  claim 48 , further comprising comparing the first risk score with the second risk score and determining whether to: (i) discontinue use of the anti-cancer agent in the subject; (ii) continue treatment with the anti-cancer agent in the subject; or (iii) administer a different anti-cancer agent to the subject based on the comparison of the first and second risk scores. 
     
     
         51 . The method of  claim 48 , wherein treatment with the anti-cancer agent is discontinued because the second risk score is lower than the first risk score. 
     
     
         52 . The method of  claim 48 , wherein the treatment with the anti-cancer agent is continued because the first and second risk scores are identical. 
     
     
         53 . The method of  claim 48 , wherein the treatment with the anti-cancer agent is discontinued and treatment with a new anti-cancer agent is administered to the patient because the second risk score is higher than the first risk score. 
     
     
         54 . The method of  claim 48 , wherein the at least two oncogenic biomarkers or fragments thereof comprise at least HEC1 or fragments thereof. 
     
     
         55 . The method of  claim 48 , wherein the at least two oncogenic biomarkers or fragments thereof comprise at least three of the following biomarkers: HEC1, CEACAM6, HYAL1, and MMP-1, or fragments thereof. 
     
     
         56 . The method of  claim 48 , wherein the at least two oncogenic biomarkers or fragments thereof comprise at least the four following biomarkers: HEC1, CEACAM6, HYAL1, and MMP-1, or fragments thereof. 
     
     
         57 . A method of predicting breast cancer in a subject, the method comprising:
 quantifying levels of at least two oncogenic biomarkers or fragments thereof from a hyperplastic tissue sample from a subject, wherein the at least two oncogenic biomarkers comprise HEC1 (Highly Expressed in Cancer protein), CEACAM6 (Carcino Embryonic Antigen Cell Adhesion Molecule 6), HYAL1 (Hyaluronoglucosaminidase 1), and MMP-1 (Matrix Metalloproteinase-1); and   calculating a risk score based on the levels of the at least two oncogenic biomarkers or fragments thereof, wherein a risk score equal to or less than 1 indicates that the subject has a cancer free survival rate of at least 95% for at least 19 years, a risk score greater than 1 but equal to or less than 5 indicates that the subject has a cancer free survival rate of at most 95% for at least 5 years and at least 75% for at least 10 years, and a risk score of greater than 5 indicates a high risk of that the subject has a cancer free survival rate of at most 45% for at least 5 years and at least 20% for at least 10 years.