Classification of breast cancer patients using a combination of clinical criteria and informative genesets
View Patent ↗The present invention provides prognostic methods for conditions such as cancer, for example, breast cancer, comprising classifying an individual by a plurality of phenotypic, genotypic or clinical characteristics of the condition into a plurality of patient subsets, and analyzing the pattern of expression of prognosis-informative genes identified for that subset in a sample from the individual. The present invention also provides methods for constructing such patient subsets and of identifying prognosis-informative genesets for such subsets. The invention further provides methods of assigning a therapeutic regimen to an individual, microarrays useful for performing prognosis, kits comprising these microarrays, and computer systems and programs for implementing the methods of the invention.
1. A method for predicting a human breast cancer patient as having a good prognosis or a poor prognosis, comprising:
(a) classifying said breast cancer patient into one of the following classes:
(a1) ER − and sporadic;
(a2) ER − and BRCA1;
(a3) ER+ and ER/AGE high;
(a4) ER+, ER/AGE low and LN+; or
(a5) ER+, ER/AGE low and LN − ;
wherein ER + designates a high ER level and ER − designates a low ER level, wherein said ER/AGE is a metric of said ER level relative to the age of said patient, and wherein LN + designates a greater than 0 lymph nodes status in said patient and LN − designates a 0 lymph nodes status in said patient, and wherein said ER/AGE is classified as high if said ER level is greater than c·(AGE−d), and wherein said ER/AGE is classified as low if said ER level is equal to or less than c·(AGE−d), wherein c is a coefficient, AGE is the age of said patient, and d is an age threshold;
(b) determining a profile comprising measurements of levels of transcripts of, or proteins encoded by, respective genes in a plurality of genes in a cell sample taken from said breast cancer patient, said respective genes comprising:
(b1) at least five of the genes for which markers are listed in Table 1 if said breast cancer patient is classified as ER − and sporadic;
(b2) at least two of the genes for which markers are listed in Table 2 if said breast cancer patient is classified as ER − and BRCA1,
(b3) at least two of the genes for which markers are listed in Table 3 if said breast cancer patient is classified as ER+ and ER/AGE high;
(b4) at least two of the genes for which markers are listed in Table 4 if said breast cancer patient is classified as ER+, ER/AGE low and LN+; or
(b5) at least two of the genes for which markers are listed in Table 5 if said breast cancer patient is classified as ER+, ER/AGE low and LN − ; and
(c) comparing, on a computer, said profile to a good prognosis template and/or a poor prognosis template, wherein said good prognosis template comprises measurements of average levels of transcripts of, or proteins encoded by, said respective genes in a plurality of good outcome patients, and said poor prognosis template comprises measurements of average levels of transcripts of, or proteins encoded by, said respective genes in a plurality of poor outcome patients, and wherein a good outcome patient is a breast cancer patient who has non-reoccurrence of metastases within a first period of time after initial diagnosis and a poor outcome patient is a patient who has reoccurrence of metastases within a second period of time after initial diagnosis; and
(d) classifying said breast cancer patient (i) as having a good prognosis if said profile has a high similarity to said good prognosis template, has a low similarity to said poor prognosis template, or has a higher similarity to said good prognosis template than to said poor prognosis template, wherein said profile has a high similarity to said good prognosis template if the similarity to said good prognosis template is above a predetermined threshold or has a low similarity to said poor prognosis template if the similarity to said poor prognosis template is below said predetermined threshold, or (ii) as having a poor prognosis if said profile has a high similarity to said poor prognosis template, has a low similarity to said good prognosis template, or has a higher similarity to said poor prognosis template than to said good prognosis template, wherein said profile has a high similarity to said poor prognosis template if the similarity to said poor prognosis template is above said predetermined threshold, or has a low similarity to said good prognosis template if the similarity to said good prognosis template is below said predetermined threshold.
2. The method of claim 1 , wherein said individual is ER − and sporadic, and said plurality of genes comprises at least ten of the genes for which markers are listed in Table 1.
3. The method of claim 1 , wherein said individual is ER − and sporadic, and said plurality of genes comprises all of the genes for which markers are listed in Table 1.
4. The method of claim 1 , wherein said individual is ER − and BRCA1, and said plurality of genes comprises at least five of the genes for which markers are listed in Table 2.
5. The method of claim 1 , wherein said individual is ER − and BRCA1, and said plurality of genes comprises all of the genes for which markers are listed in Table 2.
6. The method of claim 1 , wherein said individual is ER+ and ER/AGE high, and said plurality of genes comprises at least five of the genes for which markers are listed in Table 3.
7. The method of claim 1 , wherein said individual is ER+ and ER/AGE high, and said plurality of genes comprises all of the genes for which markers are listed in Table 3.
8. The method of claim 1 , wherein said individual is ER+, ER/AGE low and LN+, and said plurality of genes comprises at least five of the genes for which markers are listed in Table 4.
9. The method of claim 1 , wherein said individual is ER+, ER/AGE low and LN+, and said plurality of genes comprises all of the genes for which markers are listed in Table 4.
10. The method of claim 1 , wherein said individual is ER+, ER/AGE low and LN − , and said plurality of genes comprises at least five of the genes for which markers are listed in Table 5.
11. The method of claim 1 , wherein said individual is ER+, ER/AGE low and LN − , and said plurality of genes comprises all of the genes for which markers are listed in Table 5.
12. A computer-implemented method for predicting a human breast cancer patient as having a good prognosis or a poor prognosis, comprising:
(a) classifying, on a computer, said patient as having a good prognosis or a poor prognosis based on a profile comprising measurements of levels of transcripts of, or proteins encoded by, respective genes in a plurality of genes in a cell sample taken from said patient, said plurality of genes comprising:
(b1) at least five of the genes for which markers are listed in Table 1 if said patient is ER − and sporadic;
(b2) at least two of the genes for which markers are listed in Table 2 if said patient is ER − and BRCA1;
(b3) at least two of the genes for which markers are listed in Table 3 if said patient is ER+ and ER/AGE high;
(b4) at least two of the genes for which markers are listed in Table 4 if said patient is ER+, ER/AGE low and LN+; or
(b5) at least two of the genes for which markers are listed in Table 5 if said patient is ER+, ER/AGE low and LN − ,
wherein ER+ designates a high ER level and ER − designates a low ER level, wherein said ER/AGE is a metric of said ER level relative to the age of said patient, wherein LN + designates a greater than 0 lymph nodes status in said patient and LN − designates a 0 lymph nodes status in patient, and wherein said ER/AGE is classified as high if said ER level is greater than c·(AGE−d), and wherein said ER/AGE is classified as low if said ER level is equal to or less than c·(AGE−d), wherein c is a coefficient, AGE is the age of said patient, and d is an age threshold,
wherein said classifying is carried out by a method comprising comparing said profile to a good prognosis template and/or a poor prognosis template, wherein said good prognosis template comprises measurements of average levels of transcripts of, or proteins encoded by, said respective genes in a plurality of good outcome patients, and said poor prognosis template comprises measurements of average levels of transcripts of, or proteins encoded by, said respective genes in a plurality of poor outcome patients, and wherein a good outcome patient is a breast cancer patient who has non-reoccurrence of metastases within a first period of time after initial diagnosis and a poor outcome patient is a breast cancer patient who has reoccurrence of metastases within a second period of time after initial diagnosis, and wherein:
(i) said individual is classified as having a good prognosis if said profile has a high similarity to said good prognosis template, has a low similarity to said poor prognosis template, or has a higher similarity to said good prognosis template than to said poor prognosis template, wherein said profile has a high similarity to said good prognosis template if the similarity to said good prognosis template is above a predetermined threshold, or has a low similarity to said poor prognosis template if the similarity to said poor prognosis template is below said predetermined threshold, or
(ii) said individual is classified as having a poor prognosis if said profile has a high similarity to said poor prognosis template, has a low similarity to said good prognosis template, or has a higher similarity to said poor prognosis template than to said good prognosis template, wherein said profile has a high similarity to said poor prognosis template if the similarity to said poor prognosis template is above said predetermined threshold, or has a low similarity to said good prognosis template if the similarity to said good prognosis template is below said predetermined threshold.
13. The method of claim 12 , wherein said individual has been classified as ER − and sporadic, and said plurality of genes comprises at least ten of the genes for which markers are listed in Table 1.
14. The method of claim 12 , wherein said individual has been classified as ER − and sporadic, and said plurality of genes comprises all of the genes for which markers are listed in Table 1.
15. The method of claim 12 , wherein said individual has been classified as ER − and BRCA1, and said plurality of genes comprises at least five of the genes for which markers are listed in Table 2.
16. The method of claim 12 , wherein said individual has been classified as ER − and BRCA1, and said plurality of genes comprises all of the genes for which markers are listed in Table 2.
17. The method of claim 12 , wherein said individual has been classified as ER+ and ER/AGE high, and said plurality of genes comprises at least five of the genes for which markers are listed in Table 3.
18. The method of claim 12 , wherein said individual has been classified as ER+ and ER/AGE high, and said plurality of genes comprises all of the genes for which markers are listed in Table 3.
19. The method of claim 12 , wherein said individual has been classified as ER+; ER/AGE low and LN+, and said plurality of genes comprises at least five of the genes for which markers are listed in Table 4.
20. The method of claim 12 , wherein said individual has been classified as ER+, ER/AGE low and LN+, and said plurality of genes comprises all of the genes for which markers are listed in Table 4.
21. The method of claim 12 , wherein said individual has been classified as ER+, ER/AGE low and LN − , and said plurality of genes comprises at least five of the genes for which markers are listed in Table 5.
22. The method of claim 12 , wherein said individual has been classified as ER+, ER/AGE low and LN − , and said plurality of genes comprises all of the genes for which markers are listed in Table 5.