PROTEIN MARKERS FOR ESTROGEN RECEPTOR (ER)-POSITIVE-LIKE AND ESTROGEN RECEPTOR (ER)-NEGATIVE-LIKE BREAST CANCER
The present invention relates to protein markers for ER-positive-like and ER-negative-like breast cancer. Methods for differentiating ER-positive-like and ER-negative-like breast cancer in a subject having breast cancer are provided, such methods including the detection of levels of a variety of biomarkers for ER-positive-like and ER-negative-like breast cancer. Compositions in the form of kits and panels of reagents for detecting the biomarkers of the invention are also provided.
1 . A method for determining a molecular subtype of a breast cancer in a subject, comprising,
(a) detecting the level of a breast cancer marker in a biological sample from the subject, wherein the breast cancer marker comprises one or more markers selected from Tables 1 and 2; and
(b) comparing the level of the breast cancer marker in the biological sample with a predetermined threshold value;
wherein the molecular subtype of the breast cancer is determined based on the level of the breast cancer marker above or below the predetermined threshold value.
2 . The method of claim 1 ,
(a) wherein the breast cancer is an estrogen receptor (ER)-positive breast cancer;
optionally, wherein the estrogen receptor (ER)-positive breast cancer comprises luminal A (LA) breast cancer, luminal B1 (LB1 breast cancer), or LA and LB1 breast cancer; and/or
wherein the estrogen receptor (ER)-positive breast cancer does not comprise ER-low breast cancer; or
(b) wherein the breast cancer is an estrogen receptor (ER)-negative breast cancer;
optionally, wherein the estrogen receptor (ER)-negative breast cancer is triple-negative breast cancer.
3 - 6 . (canceled)
7 . The method of claim 1 , wherein the biological sample comprises a breast tissue sample or a breast tumor tissue sample; or
wherein the biological sample comprises circulating tumor cells or disseminated tumor cells in bone marrow, exosomes, and/or breast ductal fluid exudents.
8 . (canceled)
9 . The method of claim 1 ,
(a) wherein the breast cancer marker comprises at least two or more markers, wherein each of the two of more markers are selected from the proteins set forth in Tables 1 and 2;
(b) wherein the breast cancer marker comprises one or more markers set forth in Table 1;
optionally, wherein the one or more markers set forth in Table 1 is present at a decreased level or an increased level when compared to the predetermined threshold value in the subject;
wherein a decreased level of the one or markers in Table 1 when compared to the predetermined threshold value indicates that the molecular subtype of the breast cancer is ER-negative-like; and/or
wherein an increased level of the one or markers in Table 1 when compared to the predetermined threshold value indicates that the molecular subtype of the breast cancer is ER-positive-like;
(c) wherein the breast cancer marker comprises one or more markers set forth in Table 2;
optionally, wherein the one or more markers set forth in Table 2 is present at an increased level or a decreased level when compared to the predetermined threshold value in the subject;
wherein an increased level of the one or markers in Table 2 when compared to the predetermined threshold value indicates that the molecular subtype of the breast cancer is ER-negative-like; and/or
wherein a decreased level of the one or markers in Table 2 when compared to the predetermined threshold value indicates that the molecular subtype of the breast cancer is ER-positive-like;
(d) wherein the breast cancer marker comprises one or more markers set forth in Table 1 and one or more markers set forth in Table 2;
optionally, (i) wherein the one or more markers set forth in Table 1 is present at a decreased level and the one or more markers set forth in Table 2 is present at an increased level when compared to the predetermined threshold value in the subject; and/or
wherein a decreased level of the one or markers in Table 1 and an increased level of the one or more markers in Table 2 when compared to the predetermined threshold value indicates that the molecular subtype of the breast cancer is ER-negative-like; or
(ii) wherein the one or more markers set forth in Table 1 is present at an increased level and the one or more markers set forth in Table 2 is present at a decreased level when compared to the predetermined threshold value in the subject; and/or
wherein an increased level of the one or markers in Table 1 when compared to the predetermined threshold value and a decreased level of the one or more markers in Table 2 when compared to the predetermined threshold value indicates that the molecular subtype of the breast cancer is ER-positive-like; and/or
(e) wherein the level of the breast cancer marker is detected by one or more of HPLC/UV-Vis spectroscopy, enzymatic analysis, mass spectrometry, NMR, immunoassay, ELISA, chromatography, or any combination thereof, or by determining the level of its corresponding mRNA in the biological sample.
10 - 22 . (canceled)
23 . The method of claim 9 ,
(a) wherein the ER-negative-like molecular subtype of the breast cancer is predictive of poor survival and/or short progression free interval;
(b) wherein the ER-positive-like molecular subtype of the breast cancer is predictive of good survival and/or long progression free interval.
24 . (canceled)
25 . (canceled)
26 . The method of claim 1 , further comprising selecting a treatment regimen based on the type of breast cancer in the subject; optionally, wherein the treatment regimen is selected from radiation, hormone therapy, chemotherapy, or any combination thereof.
27 . (canceled)
28 . A method for diagnosing ER-negative-like molecular subtype of ER-positive breast cancer in a subject, comprising,
(a) detecting the level of a breast cancer marker in a biological sample from the subject, wherein the breast cancer marker comprises one or more markers selected from Tables 1 and 2; and
(b) comparing the level of the breast cancer marker in the biological sample with a predetermined threshold value;
wherein the level of the breast cancer marker above or below the predetermined threshold value indicates a diagnosis that the subject has ER-negative-like molecular subtype of ER-positive breast cancer.
29 . The method of claim 28 ,
(a) wherein the estrogen receptor (ER)-positive breast cancer comprises luminal A (LA) breast cancer, luminal B1 (LB1 breast cancer), or LA and LB1 breast cancer; and/or
(b) wherein the estrogen receptor (ER)-positive breast cancer does not comprise ER-low breast cancer.
30 . (canceled)
31 . The method of claim 28 , wherein the biological sample comprises a breast tissue sample or a breast tumor tissue sample; or
wherein the biological sample comprises circulating tumor cells or disseminated tumor cells in bone marrow, exosomes, and/or breast ductal fluid exudents.
32 . (canceled)
33 . The method of claim 28 ,
(a) wherein the breast cancer marker comprises at least two or more markers, wherein each of the two of more markers are selected from the proteins set forth in Tables 1 and 2;
(b) wherein the breast cancer marker comprises one or more markers set forth in Table 1; optionally, wherein the one or more markers set forth in Table 1 is present at a decreased level when compared to the predetermined threshold value in the subject; and/or
wherein a decreased level of the one or markers in Table 1 when compared to the predetermined threshold value indicates a diagnosis that the subject has ER-negative-like molecular subtype of ER-positive breast cancer;
(c) wherein the breast cancer marker comprises one or more markers set forth in Table 2; optionally, wherein the one or more markers set forth in Table 2 is present at an increased level when compared to the predetermined threshold value in the subject; and/or
wherein an increased level of the one or markers in Table 2 when compared to the predetermined threshold value indicates a diagnosis that the subject has ER-negative-like molecular subtype of ER-positive breast cancer;
(d) wherein the breast cancer marker comprises one or more markers set forth in Table 1 and one or more markers set forth in Table 2;
optionally, wherein the one or more markers set forth in Table 1 is present at a decreased level and the one or more markers set forth in Table 2 is present at an increased level when compared to the predetermined threshold value in the subject; and/or
wherein a decreased level of the one or markers in Table 1 and an increased level of the one or more markers in Table 2 when compared to the predetermined threshold value indicates a diagnosis that the subject has ER-negative-like molecular subtype of ER-positive breast cancer; and/or
(e) wherein the level of the breast cancer marker is detected by one or more of HPLC/UV-Vis spectroscopy, enzymatic analysis, mass spectrometry, NMR, immunoassay, ELISA, chromatography, or any combination thereof, or by determining the level of its corresponding mRNA in the biological sample.
34 - 43 . (canceled)
44 . A method for diagnosing estrogen receptor (ER)-positive-like molecular subtype of ER-negative breast cancer in a subject, comprising,
(a) detecting the level of a breast cancer marker in a biological sample from the subject, wherein the breast cancer marker comprises one or more markers selected from Tables 1 and 2; and
(b) comparing the level of the breast cancer marker in the biological sample with a predetermined threshold value;
wherein the level of the breast cancer marker above or below the predetermined threshold value indicates a diagnosis that the subject has ER-positive-like molecular subtype of ER-negative breast cancer.
45 . The method of claim 44 , wherein the biological sample comprises a breast tissue sample or a breast tumor tissue sample; or
wherein the biological sample comprises circulating tumor cells or disseminated tumor cells in bone marrow, exosomes, and/or breast ductal fluid exudents.
46 . (canceled)
47 . The method of claim 44 ,
(a) wherein the breast cancer marker comprises at least two or more markers, wherein each of the two of more markers are selected from the proteins set forth in Tables 1 and 2;
(b) wherein the breast cancer marker comprises one or more markers set forth in Table 1;
optionally, wherein the one or more markers set forth in Table 1 is present at an increased level when compared to the predetermined threshold value in the subject; and/or
wherein an increased level of the one or markers in Table 1 when compared to the predetermined threshold value indicates a diagnosis that the subject has ER-positive-like molecular subtype of ER-negative breast cancer;
(c) wherein the breast cancer marker comprises one or more markers set forth in Table 2;
optionally, wherein the one or more markers set forth in Table 2 is present at a decreased level when compared to the predetermined threshold value in the subject; and/or
wherein a decreased level of the one or markers in Table 2 when compared to the predetermined threshold value indicates a diagnosis that the subject has ER-positive-like molecular subtype of ER-negative breast cancer;
(d) wherein the breast cancer marker comprises one or more markers set forth in Table 1 and one or more markers set forth in Table 2;
optionally, wherein the one or more markers set forth in Table 1 is present at an increased level and the one or more markers set forth in Table 2 is present at a decreased level when compared to the predetermined threshold value in the subject; and/or
wherein an increased level of the one or markers in Table 1 and a decreased level of the one or more markers in Table 2 when compared to the predetermined threshold value indicates a diagnosis that the subject has ER-positive-like molecular subtype of ER-negative breast cancer; and/or
(e) wherein the level of the breast cancer marker is detected by one or more of HPLC/UV-Vis spectroscopy, enzymatic analysis, mass spectrometry, NMR, immunoassay, ELISA, chromatography, or any combination thereof, or by determining the level of its corresponding mRNA in the biological sample.
48 - 96 . (canceled)
97 . A kit for detecting a molecular subtype of estrogen receptor (ER)-positive-like breast cancer in a biological sample from a subject having breast cancer, comprising one or more reagents for measuring the level of a breast cancer marker in the biological sample from the subject, wherein the breast cancer marker comprises one or more markers selected from Tables 1 and 2 and a set of instructions for measuring the level of the breast cancer marker.
98 . The kit of claim 97 ,
(a) wherein the breast cancer marker comprises one or more markers set forth in Table 1 with an increased level when compared to the predetermined threshold value in the subject;
(b) wherein the breast cancer marker comprises one or more markers set forth in Table 2 with a decreased level when compared to the predetermined threshold value in the subject;
(c) wherein the breast cancer marker comprises one or more markers set forth in Table 1 with an increased level when compared to the predetermined threshold value in the subject and one or more markers set forth in Table 2 with a decreased level when compared to the predetermined threshold value in the subject; and/or
(d) wherein the reagent is an antibody that binds to the marker or an oligonucleotide that is complementary to the corresponding mRNA of the breast cancer marker.
99 - 101 . (canceled)
102 . A kit for detecting a molecular subtype of estrogen receptor (ER)-negative-like breast cancer in a biological sample from a subject having breast cancer, comprising one or more reagents for measuring the level of a breast cancer marker in the biological sample from the subject, wherein the breast cancer marker comprises one or more markers selected from Tables 1 and 2 and a set of instructions for measuring the level of the breast cancer marker.
103 . The kit of claim 102 ,
(a) wherein the breast cancer marker comprises one or more markers set forth in Table 1 with a decreased level when compared to the predetermined threshold value in the subject;
(b) wherein the breast cancer marker comprises one or more markers set forth in Table 2 with an increased level when compared to the predetermined threshold value in the subject;
(c) wherein the breast cancer marker comprises one or more markers set forth in Table 1 with a decreased level when compared to the predetermined threshold value in the subject and one or more markers set forth in Table 2 with an increased level when compared to the predetermined threshold value in the subject; and/or
(d) wherein the reagent is an antibody that binds to the marker or an oligonucleotide that is complementary to the corresponding mRNA of the breast cancer marker.
104 - 109 . (canceled)