Method for Assessing and Predicting Efficacy of Breast Cancer Treatment with a Long-Acting Topoisomerase I Inhibitor

Abstract

Provided is a method of treating an individual suffering from a cancer such as breast cancer by administering to the individual a long-acting topoisomerase I inhibitor, and correlating the level of one or more tumor markers in the individual with response of the cancer to treatment with the long-acting topoisomerase I inhibitor, to thereby provide a method for predicting and assessing the therapeutic efficacy of the treatment.

What is claimed is: 
     
         1 . A method for assessing response to treatment with a long-acting topoisomerase-I inhibitor selected from SN-38 and irinotecan in a subject having breast cancer, the method comprising:
 (i) determining the level of a tumor marker in a bodily fluid sample of the subject to provide a reference level of the tumor marker, where the tumor marker is selected from CA27.29, CA15-3 and CEA,   (ii) treating said subject over a duration of time of at least 2 weeks by administering a dosage amount of the long-acting topoisomerase-I inhibitor on a given dosing schedule,   (iii) determining the level of the tumor marker in a bodily fluid sample of the subject following said treating in step (ii), wherein the bodily fluid is the same as in step (i),   (iv) correlating the level of the tumor marker in step (iii) with response of the breast cancer to treatment with the long-acting topoisomerase-I inhibitor, wherein in the event of a level of the tumor marker in step (iii) that is either unchanged or reduced from the reference level in step (i), a positive response to treatment is determined, and in the event of a level of tumor marker in step (iii) that is increased from the reference level in step (i), a negative response to treatment is determined.   
     
     
         2 . The method of  claim 1 , wherein exposure of the breast cancer to SN-38 resulting from said treating step correlates with the level of the tumor marker in the subject and the efficacy of the treatment regimen. 
     
     
         3 . The method of  claim 1 , wherein the long-acting topoisomerase-I inhibitor comprises SN-38 modified by releasable covalent attachment to one or more water-soluble polymers. 
     
     
         4 . The method of  claim 1 , wherein the long-acting topoisomerase-I inhibitor comprises irinotecan modified by releasable covalent attachment to one or more water-soluble polymers. 
     
     
         5 . The method of  claim 3  or  claim 4 , wherein the one or more water-soluble polymers comprise polyethylene glycol. 
     
     
         6 . The method of  claim 5 , wherein the long-acting topoisomerase-I inhibitor is pentaerythritolyl-4-arm-(polyethyleneglycol-1-methylene-2 oxo-vinylamino acetate-linked-irinotecan). 
     
     
         7 . The method of  claim 5 , wherein the long-acting topoisomerase-I inhibitor has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of any one of  claims 1 - 7 , wherein in step (i), the level of the tumor marker is determined prior to treatment with the long-acting topoisomerase-I inhibitor. 
     
     
         9 . The method of any one of  claims 1 - 7 , wherein the bodily fluid sample in steps (i) and (iii) is selected from plasma, serum, and blood. 
     
     
         10 . The method of any one of  claims 1 - 7 , wherein the reference level of the tumor marker in step (i) is elevated over normal baseline levels. 
     
     
         11 . The method of  claim 10 , wherein the tumor marker is CA27.29 and the reference level of CA27.29 is greater than 38 U/ml. 
     
     
         12 . The method of  claim 10 , wherein the tumor marker is CA15-3 and the reference level of CA15-3 is greater than 30 U/ml. 
     
     
         13 . The method of any one of  claims 1 - 12 , wherein the duration of treatment is at least 3 weeks. 
     
     
         14 . The method of  claim 13 , wherein the duration of treatment is at least 6 weeks. 
     
     
         15 . The method of  claim 14 , wherein the duration of treatment is at least 12 weeks. 
     
     
         16 . The method of any one of  claims 1 - 15 , wherein the level of the tumor marker is determined by an immunoassay. 
     
     
         17 . The method of any one of the foregoing claims, wherein a reduction in the level of the tumor marker of at least 25% by week 6 shows a positive correlation with progression-free survival in the subject of at least 4 months. 
     
     
         18 . The method of any one of  claims 1 - 16 , wherein step (iii) is optionally repeated, either following additional treatment with the long-acting topoisomerase inhibitor I or following the cessation of treatment. 
     
     
         19 . The method of any one of  claims 1 - 16 , where in the event of determining a negative response to treatment in step (iv), either the dosage amount or dosing schedule in step (ii) or both are altered. 
     
     
         20 . Use of the level of a tumor marker selected from CA27.29, CA15-3 and CEA in a bodily fluid selected from blood, serum, and plasma, for predicting efficacy of treatment with a long-acting topoisomerase-I inhibitor in a subject diagnosed with breast cancer, wherein the long-acting topoisomerase-I inhibitor is selected from long-acting irinotecan and long-acting SN-38. 
     
     
         21 . Use of the level of a tumor marker selected from CA27.29, CA15-3 and CEA in a bodily fluid selected from blood, serum, and plasma, for predicting exposure of breast cancer to levels of SN-38 resulting from treatment of the breast cancer with a long-acting topoisomerase-I inhibitor in a subject diagnosed with breast cancer, wherein the long-acting topoisomerase-I inhibitor is selected from long-acting irinotecan and long-acting SN-38, and exposure of the breast cancer to SN-38 correlates with efficacy of treatment. 
     
     
         22 . The method of any one of  claims 1 - 19  or the use of  claim 20  or  claim 21 , wherein the subject has metastatic breast cancer. 
     
     
         23 . The method of any one of  claims 1 - 19  or the use of  claim 20  or  21 , wherein prior to the method or use, the subject has failed to respond to taxane-based treatment for the breast cancer.