MN/CA IX and breast cancer therapy
View Patent ↗Herein disclosed are methods that are predictive of resistance to endocrine therapy in an estrogen receptor-positive (ER-positive) breast cancer patient. An exemplary method comprises detecting the overexpression of MN/CA9 gene expression product(s) in a sample from an affected subject, wherein if MN/CA9 is overexpressed, then the subject is considered to have a greater probability of resistance to endocrine therapy, particularly tamoxifen, and a corresponding poorer prognosis if undergoing endocrine therapy, than if MN/CA9 is not overexpressed. MN/CA9 gene expression products useful in the predictive/prognostic methods include MN/CA IX, MN proteins/polypeptides, MN nucleic acids and soluble MN/CA IX antigen (s-CA IX). The methods are useful as an aid in the selection of treatment for a patient with an ER-positive breast tumor. The methods of the invention can be used, for example, to identify those patients requiring additional/alternative therapies, preferably, but not necessarily, therapies that are not affected by acidic pH. The methods also comprise the use of diagnostic/prognostic imaging to detect MN/CA IX in a patient tumor, wherein the presence of MN/CA IX in one or more tumors is indicative of probable resistance to antiestrogen therapy, particularly to tamoxifen.
1. A method of predicting resistance to endocrine therapy in a breast cancer patient with an ER-positive breast tumor, comprising:
(a) obtaining a breast tumor tissue sample from said ER-positive breast cancer patient;
(b) determining immunologically whether said sample is MN/CA IX-positive, wherein MN/CA IX positivity is indicated by any conventionally detectable MN/CA IX-specific immunohistochemical staining of cells in said sample; and
(c) correlating a finding of combined ER-positivity in said tumor and MN/CA IX-positivity in said sample with a greater probability of resistance to said endocrine therapy for said ER-positive breast cancer patient than if said tumor were ER-positive and said sample were MN/CA IX-negative.
2. The method of claim 1 , wherein said endocrine therapy comprises or consists of the use of an antiestrogen or estrogen lowering drug, or drug that modifies endocrine environment.
3. The method of claim 1 , wherein said endocrine therapy is a selective estrogen receptor modulator (SERM), a pure antiestrogen, a steroidal aromatase inhibitor, a nonsteroidal aromatase inhibitor, or estrogen.
4. The method of claim 1 , wherein said endocrine therapy is selected from the group consisting of tamoxifen, raloxifene, toremifene, fulvestrant, exemestane, letrozole or anastrozole.
5. The method of claim 2 , wherein said antiestrogen is tamoxifen.
6. A method of predicting resistance to endocrine therapy in a breast cancer patient with an ER-positive breast tumor, comprising:
(a) obtaining a body fluid sample from said ER-positive breast cancer patient;
(b) immunologically detecting the presence or absence of soluble MN/CA IX in said body fluid sample; and
(c) correlating a finding of combined ER-positivity in said tumor and detectable soluble MN/CA IX in said body fluid sample with a greater probability of resistance to said endocrine therapy for said ER-positive breast cancer patient than if said tumor were ER-positive and said body fluid sample were MN/CA IX-negative.
7. The method of claim 6 , wherein said endocrine therapy comprises or consists of the use of an antiestrogen.
8. The method of claim 7 , wherein said antiestrogen is tamoxifen.
9. A method of predicting resistance to an antiestrogen therapy in a breast cancer patient with an ER-positive breast tumor, comprising:
(a) employing diagnostic/prognostic imaging to detect the presence or absence of MN/CA IX in one or more tumors in said ER-positive breast cancer patient, wherein said imaging comprises the use of labeled MN/CA IX-specific antibodies; and
(b) correlating a finding of combined ER-positivity in said breast tumor and the presence of MN/CA IX in said one or more tumors with a greater probability of resistance to said antiestrogen therapy for said ER-positive breast cancer patient than if said breast tumor were ER-positive and said one or more tumors were MN/CA IX-negative.
10. The method of claim 9 , wherein said one or more tumors is or are metastatic tumor(s).
11. A method for selecting an appropriate therapy for a breast cancer patient with an ER-positive breast tumor, comprising:
(a) immunologically detecting the presence or absence of MN/CA IX in said ER-positive tumor or in a metastasis of said tumor;
(b) correlating a finding of combined ER-positivity in said breast tumor and the presence of MN/CA IX in said tumor or said metastasis with a greater probability of resistance to antiestrogen therapy for said ER-positive breast cancer patient, than if said breast tumor were ER-positive and said tumor or said metastasis were MN/CA IX-negative; and
(c) selecting an additional or alternative therapy to antiestrogen therapy for said ER-positive, MN/CA IX-positive breast cancer patient identified in step (b) as having a greater probability of resistance to antiestrogen therapy.
12. The method of claim 11 , wherein said antiestrogen therapy is tamoxifen.
13. The method of claim 11 , wherein said MN/CA IX comprises soluble MN/CA IX antigen (s-CA IX), a MN protein or a MN polypeptide.
14. The method of claim 11 , wherein said additional or alternative therapy is an anthracycline.
15. The method of claim 14 , wherein said anthracycline is epirubicin or doxorubicin.
16. The method of claim 11 , wherein said additional or alternative therapy is not substantially inhibited by acidic pH.
17. The method of claim 11 , wherein said additional or alternative therapy is selected from adjuvant chemotherapy, alternative endocrine therapy, or MN-targeted therapy.
18. The method of claim 17 , wherein said adjuvant chemotherapy is a taxane.
19. The method of claim 18 , wherein said taxane is paclitaxel or docetaxel.
20. The method of claim 12 , wherein if MN/CA IX is present in said tumor or said metastasis, said method further comprises deciding not to use chemotherapy or alternative endocrine therapy substantially inhibited by acidic pH.
21. A method of predicting resistance to tamoxifen in a breast cancer patient with an ER-positive breast tumor, comprising:
(a) obtaining a breast tumor tissue sample from said ER-positive breast cancer patient;
(b) immunologically detecting MN/CA IX overexpression in said sample, wherein any conventionally detectable MN/CA IX-specific immunohistochemical staining of cells in said sample indicates MN/CA IX overexpression; and
(c) correlating a finding of combined ER-positivity in said tumor and MN/CA IX overexpression in said sample with a greater probability of resistance to tamoxifen for said ER-positive breast cancer patient than if said sample were MN/CA IX-negative, and identifying said ER-positive, MN/CA IX-positive breast cancer patient as a candidate for an additional or alternative therapy to tamoxifen.
22. The method of claim 9 , wherein said imaging is positron emission tomography (PET) imaging.
23. The method of claim 22 , wherein the MN/CA IX-specific antibodies are labeled using the fluorine isotope 18 F.
24. A method of predicting resistance to endocrine therapy in a breast cancer patient with an ER-positive breast tumor, comprising:
(a) obtaining a breast tumor tissue sample from said ER-positive breast cancer patient;
(b) determining by MN/CA IX-specific immunohistochemical staining of cells in said sample an MN/CA IX immunoreactivity score of said sample, wherein said sample is assigned an immunoreactivity score with
a value of 0 (zero) if no staining,
a value of 1 if weak staining, or
a value of 2 if strong staining;
and
(c) correlating a finding of combined ER-positivity in said tumor and an MN/CA IX immunoreactivity score of the sample greater than 0 (zero), with a greater probability of resistance to said endocrine therapy for said ER-positive breast cancer patient, than if said tumor were ER-positive and said sample had an MN/CA IX immunoreactivity score of 0 (zero).