Predictive markers for ovarian cancer

US 9,274,118 B2
Filed: 02/04/2014
Issued: 03/01/2016
Est. Priority Date: 06/29/2007
Status: Active Grant

First Claim

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1. A set of reagents to measure the levels of biomarkers in a specimen, wherein the biomarkers are selected from the group consisting of the following panels of biomarkers or measurable fragments thereof:

(a) myoglobin, CRP, FGF basic protein and CA 19-9;

(b) Hepatitis C NS4, Ribosomal P Antibody and CRP;

(c) CA 19-9, TGF alpha, EN-RAGE, EGF and HSP 90 alpha antibody,(d) EN-RAGE, EGF, CA 125, Fibrinogen, Apolipoprotein CIII, Cholera Toxin and CA 19-9;

(e) Proteinase 3 (cANCA) antibody, Fibrinogen, CA 125, EGF, CD40, TSH, Leptin, CA 19-9 and lymphotactin;

(f) CA125, EGFR, CRP, IL-18, Apolipoprotein CIII, Tenascin C and Apolipoprotein A1;

(g) CA125, Beta-2 Microglobulin, CRP, Ferritin, TIMP-1, Creatine Kinase-MB and IL-8;

(h) CA125, EGFR, IL-10, Haptoglobin, CRP, Insulin, TIMP-1, Ferritin, Alpha-2 Macroglobulin, Leptin, IL-8, CTGF, EN-RAGE, Lymphotactin, TNF-alpha, IGF-1, TNF RII, von Willebrand Factor and MDC;

(i) CA-125, CRP, EGF-R, CA-19-9, MIP-1, IL-18 and VCAM-1;

j) CA-125, CRP, EGF-R, CA-19-9, MIP-1, vWF and VCAM-1;

(k) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, IL-6 and MIP-1;

(1) CA-125, CRP, EGF-R, CA-19-9, IL-6, MIP-1 and vWF;

(m) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, ApoCIII and IL-18;

(n) CA-125, CRP, EGF-R, CA-19-9, Apo A1, MIP-1 and vWF;

(o) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, Apo A1, and MIP-1;

(p) CA-125, CRP, EGF-R, IL-6, myoglobin, MIP-1 and myeloperoxidase;

(q) CA-125, CRP, EGF-R, CA-19-9, myoglobin MIP-1 and Growth Hormone;

(r) CA-125, CRP, EGF-R, CA-19-9, MIP-1, Growth Hormone and myeloperoxidase;

(s) CA-125, CRP, EGF-R, CA-19-9, MIP-1, Growth Hormone and IL-18;

(t) CA-125, CRP, EGF-R, CA-19-9, myoglobin, Growth Hormone and VCAM-1;

(u) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and Leptin;

(v) CA-125, CRP, EGF-R, CA-19-9, myoglobin, Leptin and Growth Hormone;

(w) CA-125, CRP, EGF-R, CA-19-9, IL-6, myoglobin and Growth Hormone;

(x) CA-125, CRP, EGF-R, CA-19-9, myoglobin, Leptin and myeloperoxidase;

(y) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and insulin;

(z) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and ferritin;

(aa) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and myeloperoxidase;

(bb) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, myoglobin, and MIP-1;

(cc) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and haptoglobulin;

(dd) CA-125, CRP, EGF-R, CA-19-9, ApoA1, myoglobin, MIP-1 and leptin;

(ee) CA-125, CRP, EGF-R, CA-19-9, IL-6, vWF and ApoCIII;

(ff) CA-125, CRP, EGF-R, Serum Amyloid P, IL-6, MIP-1 and ferritin;

(gg) CA-125, CRP, EGF-R, CA-19-9, vWF, ApoCIII and ferritin;

(hh) CA-125, CRP, EGF-R, CA-19-9, IL-6, MIP-1 and ferritin;

(ii) CA-125, CRP, EGF-R, CA-19-9, MIP-1, vWF and ApoCIII;

(jj) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, ApoCIII and ferritin;

(kk) CA-125, CRP, EGF-R, CA-19-9, IL-6, CK-MB and vWF; and

(ll) CA-125, CRP, EGF-R, CA-19-9, MIP-1, IL-10 and ferritin.

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Abstract

Methods are provided for predicting the presence, subtype and stage of ovarian cancer, as well as for assessing the therapeutic efficacy of a cancer treatment and determining whether a subject potentially is developing cancer. Associated test kits, computer and analytical systems as well as software and diagnostic models are also provided.

Citations

20 Claims

1. A set of reagents to measure the levels of biomarkers in a specimen, wherein the biomarkers are selected from the group consisting of the following panels of biomarkers or measurable fragments thereof:
- (a) myoglobin, CRP, FGF basic protein and CA 19-9;
  
  (b) Hepatitis C NS4, Ribosomal P Antibody and CRP;
  
  (c) CA 19-9, TGF alpha, EN-RAGE, EGF and HSP 90 alpha antibody,(d) EN-RAGE, EGF, CA 125, Fibrinogen, Apolipoprotein CIII, Cholera Toxin and CA 19-9;
  
  (e) Proteinase 3 (cANCA) antibody, Fibrinogen, CA 125, EGF, CD40, TSH, Leptin, CA 19-9 and lymphotactin;
  
  (f) CA125, EGFR, CRP, IL-18, Apolipoprotein CIII, Tenascin C and Apolipoprotein A1;
  
  (g) CA125, Beta-2 Microglobulin, CRP, Ferritin, TIMP-1, Creatine Kinase-MB and IL-8;
  
  (h) CA125, EGFR, IL-10, Haptoglobin, CRP, Insulin, TIMP-1, Ferritin, Alpha-2 Macroglobulin, Leptin, IL-8, CTGF, EN-RAGE, Lymphotactin, TNF-alpha, IGF-1, TNF RII, von Willebrand Factor and MDC;
  
  (i) CA-125, CRP, EGF-R, CA-19-9, MIP-1, IL-18 and VCAM-1;
  
  j) CA-125, CRP, EGF-R, CA-19-9, MIP-1, vWF and VCAM-1;
  
  (k) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, IL-6 and MIP-1;
  
  (1) CA-125, CRP, EGF-R, CA-19-9, IL-6, MIP-1 and vWF;
  
  (m) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, ApoCIII and IL-18;
  
  (n) CA-125, CRP, EGF-R, CA-19-9, Apo A1, MIP-1 and vWF;
  
  (o) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, Apo A1, and MIP-1;
  
  (p) CA-125, CRP, EGF-R, IL-6, myoglobin, MIP-1 and myeloperoxidase;
  
  (q) CA-125, CRP, EGF-R, CA-19-9, myoglobin MIP-1 and Growth Hormone;
  
  (r) CA-125, CRP, EGF-R, CA-19-9, MIP-1, Growth Hormone and myeloperoxidase;
  
  (s) CA-125, CRP, EGF-R, CA-19-9, MIP-1, Growth Hormone and IL-18;
  
  (t) CA-125, CRP, EGF-R, CA-19-9, myoglobin, Growth Hormone and VCAM-1;
  
  (u) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and Leptin;
  
  (v) CA-125, CRP, EGF-R, CA-19-9, myoglobin, Leptin and Growth Hormone;
  
  (w) CA-125, CRP, EGF-R, CA-19-9, IL-6, myoglobin and Growth Hormone;
  
  (x) CA-125, CRP, EGF-R, CA-19-9, myoglobin, Leptin and myeloperoxidase;
  
  (y) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and insulin;
  
  (z) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and ferritin;
  
  (aa) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and myeloperoxidase;
  
  (bb) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, myoglobin, and MIP-1;
  
  (cc) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and haptoglobulin;
  
  (dd) CA-125, CRP, EGF-R, CA-19-9, ApoA1, myoglobin, MIP-1 and leptin;
  
  (ee) CA-125, CRP, EGF-R, CA-19-9, IL-6, vWF and ApoCIII;
  
  (ff) CA-125, CRP, EGF-R, Serum Amyloid P, IL-6, MIP-1 and ferritin;
  
  (gg) CA-125, CRP, EGF-R, CA-19-9, vWF, ApoCIII and ferritin;
  
  (hh) CA-125, CRP, EGF-R, CA-19-9, IL-6, MIP-1 and ferritin;
  
  (ii) CA-125, CRP, EGF-R, CA-19-9, MIP-1, vWF and ApoCIII;
  
  (jj) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, ApoCIII and ferritin;
  
  (kk) CA-125, CRP, EGF-R, CA-19-9, IL-6, CK-MB and vWF; and
  
  (ll) CA-125, CRP, EGF-R, CA-19-9, MIP-1, IL-10 and ferritin.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
- - 2. The set of reagents of claim 1, wherein the reagents are binding molecules.
  - 3. The set of reagents of claim 2, wherein the binding molecules are antibodies.
  - 4. A test kit comprising the set of reagents of claim 1.
  - 5. A multianalyte panel assay comprising the set of reagents of claim 1.
  - 6. A method of predicting the likelihood of cancer in a subject, comprising:
    - detecting the levels of biomarkers in a specimen using the set of reagents of claim 1, wherein a change in the levels of the biomarkers, as compared with a control group of patients who do not have cancer, is predictive of cancer in that subject.
  - 7. The method of claim 6, wherein the cancer is ovarian cancer.
  - 8. The method of claim 7, wherein a change in the relative levels of the biomarkers is determined.
  - 9. The method of claim 7, wherein the specimen is selected from the group consisting of blood, serum, plasma, lymph, cerebrospinal fluid, ascites, urine and tissue biopsy.
  - 10. The method of claim 7, wherein the ovarian cancer is selected from the group consisting of serous, endometrioid, mucinous, and clear cell cancer.
  - 11. The method of claim 7, wherein the prediction of ovarian cancer includes a stage selected from the group consisting of Stage IA, IB, IC, II, III and IV tumors.
  - 12. The method of claim 7, further comprising creating a report of the relative levels of the biomarkers.
  - 13. The method of claim 12, wherein the report includes the prediction as to the presence or absence of ovarian cancer in the subject or the stratified risk of ovarian cancer for the subject, optionally by stage of cancer.
  - 14. The method of claim 7, wherein the sample is taken from a subject selected from the group consisting of subjects who are symptomatic for ovarian cancer and subjects who are at high risk for ovarian cancer.
  - 15. The method of claim 7, wherein the method has a sensitivity of at least about 85 percent and a specificity of at least about 85 percent.
  - 16. The method of claim 15, wherein the sensitivity and specificity are determined for a population of women who are symptomatic for ovarian cancer and have ovarian cancer as compared with a control group of women who are symptomatic for ovarian cancer but who do not have ovarian cancer.
  - 17. A predictive or diagnostic model based on levels of the panels of biomarkers of claim 1.
  - 18. A method to assess the therapeutic efficacy of a cancer treatment, comprising:
    - comparing the biomarker profiles in specimens taken from a subject before and after the treatment or during the course of treatment with a set of reagents according to claim 1, wherein a change in the biomarker profile over time toward a non-cancer profile or to a stable profile is interpreted as efficacy.
  - 19. A method for determining whether a subject potentially is developing cancer, comprising:
    - comparing the biomarker profiles in specimens taken from a subject at two or more points in time with a set of reagents according to claim 1, wherein a change in the biomarker profile toward a cancer profile, is interpreted as a progression toward developing cancer.

20. A set of antibodies fixed to a microsphere to measure the levels of biomarkers in a specimen, wherein the biomarkers are selected from the group consisting of the following panels of biomarkers and their measurable fragments:
- (a) myoglobin, CRP, FGF basic protein and CA 19-9;
  
  (b) Hepatitis C NS4, Ribosomal P Antibody and CRP;
  
  (c) CA 19-9, TGF alpha, EN-RAGE, EGF and HSP 90 alpha antibody;
  
  (d) EN-RAGE, EGF, CA 125, Fibrinogen, Apolipoprotein CIII, Cholera Toxin and CA 19-9;
  
  (e) Proteinase 3 (cANCA) antibody, Fibrinogen, CA 125, EGF, CD40, TSH, Leptin, CA 19-9 and lymphotactin;
  
  (f) CA125, EGFR, CRP, IL-18, Apolipoprotein CIII, Tenascin C and Apolipoprotein A1;
  
  (g) CA125, Beta-2 Microglobulin, CRP, Ferritin, TIMP-1, Creatine Kinase-MB and IL-8;
  
  (h) CA125, EGFR, IL-10, Haptoglobin, CRP, Insulin, TIMP-1, Ferritin, Alpha-2 Macroglobulin, Leptin, IL-8, CTGF, EN-RAGE, Lymphotactin, TNF-alpha, IGF-1, TNF RII, von Willebrand Factor and MDC;
  
  (i) CA-125, CRP, EGF-R, CA-19-9, MIP-1, IL-18 and VCAM-1;
  
  (j) CA-125, CRP, EGF-R, CA-19-9, MIP-1, vWF and VCAM-1;
  
  (k) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, IL-6 and MIP-1;
  
  (l) CA-125, CRP, EGF-R, CA-19-9, IL-6, MIP-1 and vWF;
  
  (m) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, ApoCIII and IL-18;
  
  (n) CA-125, CRP, EGF-R, CA-19-9, Apo A1, MIP-1 and vWF;
  
  (o) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, Apo A1, and MIP-1;
  
  (p) CA-125, CRP, EGF-R, IL-6, myoglobin, MIP-1 and myeloperoxidase;
  
  (q) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and Growth Hormone;
  
  (r) CA-125, CRP, EGF-R, CA-19-9, MIP-1, Growth Hormone and myeloperoxidase;
  
  (s) CA-125, CRP, EGF-R, CA-19-9, MIP-1, Growth Hormone and IL-18;
  
  (t) CA-125, CRP, EGF-R, CA-19-9, myoglobin, Growth Hormone and VCAM-1;
  
  (u) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and Leptin;
  
  (v) CA-125, CRP, EGF-R, CA-19-9, myoglobin, Leptin and Growth Hormone;
  
  (w) CA-125, CRP, EGF-R, CA-19-9, IL-6, myoglobin and Growth Hormone;
  
  (x) CA-125, CRP, EGF-R, CA-19-9, myoglobin, Leptin and myeloperoxidase;
  
  (y) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and insulin;
  
  (z) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and ferritin;
  
  (aa) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and myeloperoxidase;
  
  (bb) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, myoglobin, and MIP-1;
  
  (cc) CA-125, CRP, EGF-R, CA-19-9, myoglobin, MIP-1 and haptoglobulin;
  
  (dd) CA-125, CRP, EGF-R, CA-19-9, ApoA1, myoglobin, MIP-1 and leptin;
  
  (ee) CA-125, CRP, EGF-R, CA-19-9, IL-6, vWF and ApoCIII;
  
  (ff) CA-125, CRP, EGF-R, Serum Amyloid P, IL-6, MIP-1 and ferritin;
  
  (gg) CA-125, CRP, EGF-R, CA-19-9, vWF, ApoCIII and ferritin;
  
  (hh) CA-125, CRP, EGF-R, CA-19-9, IL-6, MIP-1 and ferritin;
  
  (ii) CA-125, CRP, EGF-R, CA-19-9, MIP-1, vWF and ApoCIII;
  
  (jj) CA-125, CRP, EGF-R, CA-19-9, Serum Amyloid P, ApoCIII and ferritin;
  
  (kk) CA-125, CRP, EGF-R, CA-19-9, IL-6, CK-MB and vWF; and
  
  (ll) CA-125, CRP, EGF-R, CA-19-9, MIP-1, IL-10 and ferritin.

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Current Assignee
Aspira Women's Health, Inc.
Original Assignee
Vermillion, Inc.
Inventors
Mansfield, Brian C., Yip, Ping F., Amonkar, Suraj, Bertenshaw, Greg P.
Primary Examiner(s)
Shen, Bin

Application Number

US14/172,237
Publication Number

US 20140221240A1
Time in Patent Office

756 Days
Field of Search
US Class Current

1/1
CPC Class Codes

G01N 2800/50   Determining the risk of dev...

G01N 2800/52   Predicting or monitoring th...

G01N 2800/60   Complex ways of combining m...

G01N 33/57449   of ovaries

Y02A 90/10   Information and communicati...

Predictive markers for ovarian cancer

First Claim

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Predictive markers for ovarian cancer

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