METHODS OF ASSESSING RISK OF DEVELOPING BREAST CANCER

Abstract

Methods and systems for assessing the risk of a human female subject for developing breast cancer. In particular, the present disclosure relates to combining a first clinical risk assessment, a second clinical assessment based at least on breast density, and a genetic risk assessment, to obtain an improved risk analysis.

Claims

1. A method for assessing the risk of a human female subject for developing breast cancer comprising: performing a first clinical risk assessment of the female subject; performing a second clinical risk assessment of the female subject, wherein the second clinical assessment is based at least on breast density; performing a genetic risk assessment of the female subject, wherein the genetic risk assessment involves detecting, in a biological sample derived from the female subject, the presence at least two polymorphisms known to be associated with breast cancer; and combining the first clinical risk assessment, the second clinical risk assessment, and the genetic risk assessment to obtain the overall risk of a human female subject for developing breast cancer.

2. The method of claim 1, wherein the second clinical risk assessment is based only on breast density.

3. The method of claim 1 or claim 2, wherein performing the first clinical risk assessment uses a model selected from a group consisting of the Gail model, the Claus model, Claus Tables, BOADICEA, the Jonker model, the Claus Extended Formula, the Tyrer-Cuzick model, and the Manchester Scoring System.

4. The method of claim 3, wherein the first clinical risk assessment is obtained using the Gail model or BOADICEA or the Tyrer-Cuzick model.

5. The method according to any one of claims 1 to 4, wherein performing the first clinical risk assessment includes obtaining information from the female on one or more of the following: medical history of breast cancer, ductal carcinoma or lobular carcinoma, age, age of first menstrual period, age at which she first gave birth, family history of breast cancer, results of previous breast biopsies and race/ethnicity.

6. The method of claim 5, wherein the first clinical risk assessment is based only on two or all of the female subject's age, family history of breast cancer and ethnicity.

7. The method of claim 5 or claim 6, wherein the first clinical risk assessment is based only on the female subject's age and family history of breast cancer.

8. The method according to any one of claims 1 to 7 which comprises detecting the presence of at least three, four, five, six, seven, eight, nine, ten, 20, 30, 40, 50, 60, 70, 80, 100, 120, 140, 160, 180, or 200 polymorphisms known to be associated with breast cancer.

9. The method according to any one of claims 1 to 8, wherein the polymorphisms are selected from Table 12 or a polymorphism in linkage disequilibrium with one or more thereof.

10. The method according to any one of claims 1 to 9, comprising detecting at least 50, 80, 100, 150 of the polymorphisms shown in Table 12, or a polymorphism in linkage disequilibrium with one or more thereof.

11. The method according to any one of claims 1 to 10, comprising detecting all of the 203 polymorphisms shown in Table 12, or a polymorphism in linkage disequilibrium with one or more thereof.

12. The method according to any one of claims 1 to 8, wherein the polymorphisms are selected from Table 6 or a polymorphism in linkage disequilibrium with one or more thereof.

13. The method according to any one of claims 1 to 8, which comprises detecting at least 72 polymorphisms associated with breast cancer, wherein at least 67 of the polymorphisms are selected from Table 7, or a polymorphism in linkage disequilibrium with one or more thereof, and the remaining polymorphisms are selected from Table 6, or a polymorphism in linkage disequilibrium with one or more thereof.

14. The method according to any one of claims 1 to 8, wherein when the female subject is Caucasian, the method comprises detecting at least 72 polymorphisms shown in Table 9, or a polymorphism in linkage disequilibrium with one or more thereof.

15. The method of claim 14, wherein when the female subject is Caucasian, the method comprises detecting all of the 77 polymorphisms shown in Table 9, or a polymorphism in linkage disequilibrium with one or more thereof.

16. The method according to any one of claims 1 to 8, wherein when the female subject is Negroid or African-American, the method comprises detecting at least 74 polymorphisms shown in Table 10, or a polymorphism in linkage disequilibrium with one or more thereof.

17. The method according to any one of claims 1 to 8, wherein when the female subject is Negroid or African-American, the method comprises detecting all of the 74 polymorphisms shown in Table 13, or a polymorphism in linkage disequilibrium with one or more thereof.

18. The method according to any one of claims 1 to 8, wherein when the female subject is Hispanic, the method comprises detecting at least 71 polymorphisms shown in Table 11, or a polymorphism in linkage disequilibrium with one or more thereof.

19. The method according to any one of claims 1 to 8, wherein when the female subject is Hispanic, the method comprises detecting all of the 71 polymorphisms shown in Table 14, or a polymorphism in linkage disequilibrium with one or more thereof.

20. The method according to any one of claims 1 to 19, wherein combining the first clinical risk assessment, the second clinical risk assessment, and the genetic risk assessment comprises multiplying the risk assessments.

21. The method according to any one of claim 1 to 15 or 20, wherein the female is Caucasian.

22. The method according to any one of claims 1 to 21, wherein if it is determined the subject has a risk of developing breast cancer, the subject is more likely to be responsive oestrogen inhibition than non-responsive.

23. The method according to any one of claims 1 to 22, wherein the breast cancer is estrogen receptive positive or estrogen receptor negative.

24. A method for determining the need for routine diagnostic testing of a human female subject for breast cancer comprising assessing the overall risk of the subject for developing breast cancer using the method according to any one of claims 1 to 23.

25. The method of claim 24, wherein a risk score greater than about 20% lifetime risk indicates that the subject should be enrolled in a screening breast MRIc and mammography program.

26. A method of screening for breast cancer in a human female subject, the method comprising assessing the overall risk of the subject for developing breast cancer using the method according to any one of claims 1 to 23, and routinely screening for breast cancer in the subject if they are assessed as having a risk for developing breast cancer.

27. A method for determining the need of a human female subject for prophylactic anti-breast cancer therapy comprising assessing the overall risk of the subject for developing breast cancer using the method according to any one of claims 1 to 23.

28. The method of claim 27, wherein a risk score greater than about 1.66% 5-year risk indicates that estrogen receptor therapy should be offered to the subject.

29. A method for preventing or reducing the risk of breast cancer in a human female subject, the method comprising assessing the overall risk of the subject for developing breast cancer using the method according to any one of claims 1 to 23, and administering an anti-breast cancer therapy to the subject if they are assessed as having a risk for developing breast cancer.

30. The method of claim 29, wherein the therapy inhibits oestrogen.

31. An anti-breast cancer therapy for use in preventing breast cancer in a human female subject at risk thereof, wherein the subject is assessed as having a risk for developing breast cancer according to the method of any one of claims 1 to 23.

32. A method for stratifying a group of human female subject's for a clinical trial of a candidate therapy, the method comprising assessing the individual overall risk of the subject's for developing breast cancer using the method according to any one of claims 1 to 23, and using the results of the assessment to select subject's more likely to be responsive to the therapy.

33. A computer implemented method for assessing the risk of a human female subject for developing breast cancer, the method operable in a computing system comprising a processor and a memory, the method comprising: receiving first clinical risk data, second clinical risk data, and genetic risk data for the female subject, wherein the first clinical risk data, second clinical risk data and genetic risk data were obtained by a method according to any one of claims 1 to 23; processing the data to combine the clinical risk data with the genetic risk data to obtain the risk of a human female subject for developing breast cancer; outputting the risk of a human female subject for developing breast cancer.

34. A system for assessing the risk of a human female subject for developing breast cancer comprising: system instructions for performing a first clinical risk assessment, a second clinical risk assessment and a genetic risk assessment of the female subject according to any one of claims 1 to 23; and system instructions for combining the first clinical risk assessment, second clinical risk assessment, and the genetic risk assessment to obtain the risk of a human female subject for developing breast cancer.

Description

EXAMPLES

Example 1

Combination of a First Clinical Risk Assessment, a Second Clinical Risk Assessment at Least Based on Breast Density, and a Genetic Risk Assessment

[0209] The present inventors have found that a breast cancer risk model which combines a first clinical risk assessment, a second clinical risk assessment based at least on breast density, and a genetic risk assessment provides better risk discrimination than any of the currently available individual risk models.

[0210] The model has been developed using 800 breast cancer subjects and 2,000 controls and is cross-validated using a second independent cohort comprising 1,259 breast cancer subjects and 1,800 controls.

[0211] From a public health perspective, a key issue is how well a risk factor differentiates breast cancer subjects from controls in a given population. This can be determined from the risk gradient, best expressed in terms of the change in odds per adjusted standard deviation (OPERA) of the risk factor in the population about which the inference is being made (Hopper, 2015). OPERA allows risk factorsadjusted for all other factors taken into account by design and analysis, which is the correct way to interpret risk estimatesto be compared for quantitative and binary exposures and thereby puts risk factors into perspective.

[0212] The accuracy and clinical validity of the risk scores is determined and validated using approximately 800 breast cancer subjects and 2,000. However, the gold standard in assessing the performance of a new model is a cross-validation in a study population that is independent from that used to build the risk model.

[0213] The following specific data fields are included in the model: [0214] A first clinical risk assessment based on age, ethnicity, height, weight, menarche, menopause details, childbirth history, contraceptive usage, hormone replacement therapy usage, family history of breast and ovarian cancer, smoking, alcohol consumption, and mammography history; [0215] A second clinical risk assessment based on breast density measures (Cumulus percent dense area and non-dense area as well as percent density); and [0216] A genetic risk assessment based on genotype data for breast cancer susceptibility loci.

[0217] The developed model is cross-validated in a second independent cohort of breast cancer subjects and controls. The critical importance of using an independent dataset is to eliminate bias in the estimates of test performance.

Example 2

Absolute Risk Estimation

[0218] In the case of cancer risk assessment it is often more useful to provide an absolute estimate of cancer risk (ie the risk as it pertains to an individual rather than a population relative risk). The absolute risk is usually described as a remaining lifetime risk or a shorter-term risk such as 5-year risk or 10-year risk (which describe the risk of developing cancer within the next 5 or 10 years respectively).

[0219] An absolute risk of developing breast cancer may be derived from the risk model by incorporating the specific incidence of breast cancer in the population under consideration and the competing mortality, which provides an estimate of the risk of dying from causes other than breast cancer.

[0220] The following specific data fields can be included in a model to determine the absolute risk of developing breast cancer: [0221] A first clinical risk assessment based on age, ethnicity, height, weight, menarche, menopause details, childbirth history, contraceptive usage, hormone replacement therapy usage, family history of breast and ovarian cancer, smoking, alcohol consumption, and mammography history; [0222] A second clinical risk assessment based on breast density measures (Cumulus percent dense area and non-dense area as well as percent density); [0223] A genetic risk assessment based on genotype data for breast cancer susceptibility loci; [0224] The cumulative incidence of breast cancer from birth to baseline; [0225] The cumulative incidence of breast cancer from birth to baseline plus 5 (or 10) years; [0226] The cumulative incidence of breast cancer from birth to age 85 years; [0227] The survival from baseline age to baseline age plus 5 (or 10) years; and [0228] The survival from baseline age to age 85 years.

[0229] It will be appreciated by persons skilled in the art that numerous variations and/or modifications may be made to the invention as shown in the specific embodiments without departing from the spirit or scope of the invention as broadly described. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive.

[0230] All publications discussed and/or referenced herein are incorporated herein in their entirety.

[0231] Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

[0232] The present application claims priority from AU 2017904153 filed 13 Oct. 2017, the entire contents of which are incorporated herein by reference.

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