Method for modifying a treatment regimen of a human female subject
The present disclosure relates to methods and systems for assessing the risk of a human female subject for developing breast cancer. In particular, the present disclosure relates to combining clinical risk assessment and genetic risk assessment to improve risk analysis.
1. A method for modifying a treatment regimen of a human female subject in accordance with the subject's risk of developing breast cancer, the method comprising:
I) determining a genetic risk score of the human female subject by:
a) obtaining the identity of alleles present in the genome of the human female subject at at least 72 single nucleotide polymorphisms associated with breast cancer, of which at least 67 of the single nucleotide polymorphisms are selected from the group consisting of rs616488, rs11552449, rs11249433, rs6678914, rs4245739, rs12710696, rs4849887, rs2016394, rs1550623, rs1045485, rs13387042, rs16857609, rs6762644, rs4973768, rs12493607, rs9790517, rs6828523, rs10069690, rs10941679, rs10472076, rs1353747, rs1432679, rs11242675, rs204247, rs17529111, rs2046210, rs720475, rs9693444, rs6472903, rs2943559, rs13281615, rs11780156, rs1011970, rs10759243, rs865686, rs2380205, rs7072776, rs11814448, rs10995190, rs704010, rs7904519, rs2981579, rs11199914, rs3817198, rs3903072, rs554219, rs75915166, rs11820646, rs12422552, rs10771399, rs17356907, rs1292011, rs11571833, rs2236007, rs999737, rs2588809, rs941764, rs3803662, rs17817449, rs11075995, rs13329835, rs6504950, rs527616, rs1436904, rs8170, rs4808801, rs3760982, rs2823093, rs132390, and rs6001930, and the remaining single nucleotide polymorphisms are selected from the group consisting of rs616488, rs11552449, rs11249433, rs6678914, rs4245739, rs12710696, rs4849887, rs2016394, rs1550623, rs1045485, rs13387042, rs16857609, rs6762644, rs4973768, rs12493607, rs9790517, rs6828523, rs10069690, rs10941679, rs10472076, rs1353747, rs1432679, rs11242675, rs204247, rs17529111, rs2046210, rs720475, rs9693444, rs6472903, rs2943559, rs13281615, rs11780156, rs1011970, rs10759243, rs865686, rs2380205, rs7072776, rs11814448, rs10995190, rs704010, rs7904519, rs2981579, rs11199914, rs3817198, rs3903072, rs554219, rs75915166, rs11820646, rs12422552, rs10771399, rs17356907, rs1292011, rs11571833, rs2236007, rs999737, rs2588809, rs941764, rs3803662, rs17817449, rs11075995, rs13329835, rs6504950, rs527616, rs1436904, rs8170, rs4808801, rs3760982, rs2823093, rs132390, rs6001930, rs7696175, rs4415084, rs7726159, rs2736108, rs889312, rs2067980, rs2180341, rs9485370, RS12662670, rs3757318, rs17157903, rs10822013, rs2981582, rs614367, rs78540526, rs2363956, rs2284378, and rs17879961;
b) determining an adjusted risk score for each of the at least 72 SNPs, where:
(i) if two major alleles are present at the SNP, then the adjusted risk score for the SNP is 1/μ,
(ii) if one major and one minor allele are present at the SNP, then the adjusted risk score for the SNP is OR/μ,
(iii) if two minor alleles are present at the SNP, then the adjusted risk score for the SNP is OR 2 /μ, and
(iv) if the genotype is missing for the SNP, then the adjusted risk score for the SNP is 1,
where μ=(1−p) 2 +2p(1−p)OR+p 2 OR 2 , wherein OR is the odds ratio of association with breast cancer of a minor allele at the given SNP and p is the frequency of the minor allele in the population to which the human female subject belongs; and
c) multiplying together the adjusted risk score for each of the at least 72 SNPs of the human female subject to produce a genetic risk score of the human female subject,
II) obtaining a clinical risk score of the human female subject,
III) multiplying the genetic risk score determined in step I by the human female subject's clinical risk score to obtain the human female subject's risk for developing breast cancer,
IV) administering a chemopreventative treatment appropriate for the risk of developing breast cancer determined in step III.
2. The method of claim 1 , wherein the clinical risk score is provided by a clinical evaluation.
3. A method for routinely screening for breast cancer in a human female subject identified as having a greater than about 20% lifetime risk of developing breast cancer comprising:
I) determining a genetic risk score of a human female subject by:
a) obtaining the identity of alleles present in the genome of the human female subject at at least 72 single nucleotide polymorphisms associated with breast cancer, of which at least 67 of the single nucleotide polymorphisms are selected from the group consisting of rs616488, rs11552449, rs11249433, rs6678914, rs4245739, rs12710696, rs4849887, rs2016394, rs1550623, rs1045485, rs13387042, rs16857609, rs6762644, rs4973768, rs12493607, rs9790517, rs6828523, rs10069690, rs10941679, rs10472076, rs1353747, rs1432679, rs11242675, rs204247, rs17529111, rs2046210, rs720475, rs9693444, rs6472903, rs2943559, rs13281615, rs11780156, rs1011970, rs10759243, rs865686, rs2380205, rs7072776, rs11814448, rs10995190, rs704010, rs7904519, rs2981579, rs11199914, rs3817198, rs3903072, rs554219, rs75915166, rs11820646, rs12422552, rs10771399, rs17356907, rs1292011, rs11571833, rs2236007, rs999737, rs2588809, rs941764, rs3803662, rs17817449, rs11075995, rs13329835, rs6504950, rs527616, rs1436904, rs8170, rs4808801, rs3760982, rs2823093, rs132390, and rs6001930, and the remaining single nucleotide polymorphisms are selected from the group consisting of rs616488, rs11552449, rs11249433, rs6678914, rs4245739, rs12710696, rs4849887, rs2016394, rs1550623, rs1045485, rs13387042, rs16857609, rs6762644, rs4973768, rs12493607, rs9790517, rs6828523, rs10069690, rs10941679, rs10472076, rs1353747, rs1432679, rs11242675, rs204247, rs17529111, rs2046210, rs720475, rs9693444, rs6472903, rs2943559, rs13281615, rs11780156, rs1011970, rs10759243, rs865686, rs2380205, rs7072776, rs11814448, rs10995190, rs704010, rs7904519, rs2981579, rs11199914, rs3817198, rs3903072, rs554219, rs75915166, rs11820646, rs12422552, rs10771399, rs17356907, rs1292011, rs11571833, rs2236007, rs999737, rs2588809, rs941764, rs3803662, rs17817449, rs11075995, rs13329835, rs6504950, rs527616, rs1436904, rs8170, rs4808801, rs3760982, rs2823093, rs132390, rs6001930, rs7696175, rs4415084, rs7726159, rs2736108, rs889312, rs2067980, rs2180341, rs9485370, RS12662670, rs3757318, rs17157903, rs10822013, rs2981582, rs614367, rs78540526, rs2363956, rs2284378, and rs17879961;
b) determining an adjusted risk score for each of the at least 72 SNPs, where:
(i) if two major alleles are present at the SNP, then the adjusted risk score for the SNP is 1/μ,
(ii) if one major and one minor allele are present at the SNP, then the adjusted risk score for the SNP is OR/μ,
(iii) if two minor alleles are present at the SNP, then the adjusted risk score for the SNP is OR 2 /μ, and
(iv) if the genotype is missing for the SNP, then the adjusted risk score for the SNP is 1,
where μ=(1−p) 2 +2p(1−p)OR+p 2 OR 2 , wherein OR is the odds ratio of association with breast cancer of a minor allele at the given SNP and p is the frequency of the minor allele in the population to which the human female subject belongs; and
c) multiplying together the adjusted risk score for each of the at least 72 SNPs of the human female subject to produce a genetic risk score of the human female subject,
II) obtaining a clinical risk score of the human female subject,
III) multiplying the genetic risk score determined in step I by the human female subject's clinical risk score to obtain the human female subject's lifetime risk for developing breast cancer,
IV) selecting the human female subject identified as having a greater than about 20% lifetime risk of developing breast cancer based on the human female subject's lifetime risk for developing breast cancer obtained in step III,
V) enrolling the human female subject identified as having a greater than about 20% lifetime risk of developing breast cancer in a screening breast MRI and mammography program.
4. The method of claim 3 , wherein the clinical risk score is provided by a clinical evaluation.
5. A method for screening for breast cancer in a human female subject, the method comprising enrolling the human female subject in a screening breast MRI and mammography program if the human female subject is identified as having a greater than about 20% lifetime risk of developing breast cancer, the subject's lifetime risk having been identified by:
I) determining a genetic risk score of the human female subject by:
a) obtaining the identity of alleles present in the genome of the human female subject at at least 72 single nucleotide polymorphisms associated with breast cancer, of which at least 67 of the single nucleotide polymorphisms are selected from the group consisting of rs616488, rs11552449, rs11249433, rs6678914, rs4245739, rs12710696, rs4849887, rs2016394, rs1550623, rs1045485, rs13387042, rs16857609, rs6762644, rs4973768, rs12493607, rs9790517, rs6828523, rs10069690, rs10941679, rs10472076, rs1353747, rs1432679, rs11242675, rs204247, rs17529111, rs2046210, rs720475, rs9693444, rs6472903, rs2943559, rs13281615, rs11780156, rs1011970, rs10759243, rs865686, rs2380205, rs7072776, rs11814448, rs10995190, rs704010, rs7904519, rs2981579, rs11199914, rs3817198, rs3903072, rs554219, rs75915166, rs11820646, rs12422552, rs10771399, rs17356907, rs1292011, rs11571833, rs2236007, rs999737, rs2588809, rs941764, rs3803662, rs17817449, rs11075995, rs13329835, rs6504950, rs527616, rs1436904, rs8170, rs4808801, rs3760982, rs2823093, rs132390, and rs6001930, and the remaining single nucleotide polymorphisms are selected from the group consisting of rs616488, rs11552449, rs11249433, rs6678914, rs4245739, rs12710696, rs4849887, rs2016394, rs1550623, rs1045485, rs13387042, rs16857609, rs6762644, rs4973768, rs12493607, rs9790517, rs6828523, rs10069690, rs10941679, rs10472076, rs1353747, rs1432679, rs11242675, rs204247, rs17529111, rs2046210, rs720475, rs9693444, rs6472903, rs2943559, rs13281615, rs11780156, rs1011970, rs10759243, rs865686, rs2380205, rs7072776, rs11814448, rs10995190, rs704010, rs7904519, rs2981579, rs11199914, rs3817198, rs3903072, rs554219, rs75915166, rs11820646, rs12422552, rs10771399, rs17356907, rs1292011, rs11571833, rs2236007, rs999737, rs2588809, rs941764, rs3803662, rs17817449, rs11075995, rs13329835, rs6504950, rs527616, rs1436904, rs8170, rs4808801, rs3760982, rs2823093, rs132390, rs6001930, rs7696175, rs4415084, rs7726159, rs2736108, rs889312, rs2067980, rs2180341, rs9485370, RS12662670, rs3757318, rs17157903, rs10822013, rs2981582, rs614367, rs78540526, rs2363956, rs2284378, and rs17879961;
b) determining an adjusted risk score for each of the at least 72 SNPs, where:
(i) if two major alleles are present at the SNP, then the adjusted risk score for the SNP is 1/μ,
(ii) if one major and one minor allele are present at the SNP, then the adjusted risk score for the SNP is OR/μ,
(iii) if two minor alleles are present at the SNP, then the adjusted risk score for the SNP is OR 2 /μ, and
(iv) if the genotype is missing for the SNP, then the adjusted risk score for the SNP is 1,
where μ=(1−p) 2 +2p(1−p)OR+p 2 OR 2 , wherein OR is the odds ratio of association with breast cancer of a minor allele at the given SNP and p is the frequency of the minor allele in the population to which the human female subject belongs; and
c) multiplying together the adjusted risk score for each of the at least 72 SNPs of the human female subject to produce a genetic risk score of the human female subject,
II) obtaining a clinical risk score of the human female subject,
III) multiplying the genetic risk score determined in step I by the human female subject's clinical risk score to obtain the human female subject's risk for developing breast cancer.
6. The method of claim 5 , wherein the clinical risk score is provided by a clinical evaluation.