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(12) Patent Application Publication (10) Pub. No.: US 2012/0053253 A1 Stone Et Al US 20120053253A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0053253 A1 Stone et al. (43) Pub. Date: Mar. 1, 2012 (54) GENESIGNATURES FOR CANCER Related U.S. Application Data PROGNOSIS (60) Provisional application No. 61/362,209, filed on Jul. 7, 2010, now abandoned. (75) Inventors: Steven Stone, Salt Lake City, UT O O (US); Alexander Gutin, Salt Lake Publication Classification City, UT (US); Susanne Wagner, (51) Int. Cl. Salt Lake City, UT (US); Julia A6II 45/00 (2006.01) Reid, Salt Lake City, UT (US) C40B 30/04 (2006.01) C4DB 60/2 (2006.01) (73) Assignee: Myriad Genetics, Incorporated, A6IP35/00 (2006.01) Salt Lake City, UT (US) (52) U.S. Cl. ................................ 514/789; 506/9; 506/39 (21) Appl. No.: 13/178,380 (57) ABSTRACT Biomarkers and methods using the biomarkers for the predic (22) Filed: Jul. 7, 2011 tion of the recurrence risk of cancer in a patient are provided. Patent Application Publication Mar. 1, 2012 Sheet 1 of 17 US 2012/0053253 A1 ?un61-I| º||||||||||||enem-dolfo Patent Application Publication Mar. 1, 2012 Sheet 2 of 17 US 2012/0053253 A1 000qãIH 9 MOH? qfij?– %0.01 Ofeire Patent Application Publication Mar. 1, 2012 Sheet 3 of 17 US 2012/0053253 A1 3. 53 crogo 3 y D . 9) s g : s s eouelunoe ou Patent Application Publication Mar. 1, 2012 Sheet 4 of 17 US 2012/0053253 A1 eun61-I#7 OG * ejooSuojejeold le) Patent Application Publication Mar. 1, 2012 Sheet 5 of 17 US 2012/0053253 A1 G?un61-I %0.01 %0. are O Patent Application Publication Mar. 1, 2012 Sheet 6 of 17 US 2012/0053253 A1 600 606 // Secondary Memory Module Communication Infrastructure 620 Input Interface 622 Output Interface 624 Output Module Input Module Figure 6 Patent Application Publication Mar. 1, 2012 Sheet 7 of 17 US 2012/0053253 A1 "30LIÐI.Inoe.J /eun61-I Patent Application Publication Mar. 1, 2012 Sheet 8 of 17 US 2012/0053253 A1 eIOOSOO ----+---+---+-------------|--?– Patent Application Publication Mar. 1, 2012 Sheet 9 of 17 US 2012/0053253 A1 >uoseaI5)-uefiuo?01>vsaºg2d30ufij?+aseesippauguos 'Z90468 ?ouailnoeuoùsueek %9/ Ore O Patent Application Publication Mar. 1, 2012 Sheet 10 of 17 US 2012/0053253 A1 Yo N 3 o - t 35 CSh 9 He to ym f T o o co st CN o ran o o d o c eouenoe leouetooga o Alqeqoad reef-0. Patent Application Publication Mar. 1, 2012 Sheet 11 of 17 US 2012/0053253 A1 N s y ? ru C. 9 O s 9 - d co co st c e C o es 80ueline peoguetoolq o Aqeqold reef-g Patent Application Publication Mar. 1, 2012 Sheet 12 of 17 US 2012/0053253 A1 i Aouenbe Patent Application Publication Mar. 1, 2012 Sheet 14 of 17 US 2012/0053253 A1 ___ETOAOTTEOMOT *-ETOAOTTEJOHSIH 2829=|SºÐHEIONVOMERCICIVT£ Q3,?8 SHINDH izI?unº!— Patent Application Publication Patent Application Publication Mar. 1, 2012 Sheet 16 of 17 -ETOAOTTEOMOT Patent Application Publication Mar. 1, 2012 Sheet 17 of 17 US 2012/0053253 A1 seue6pºo??uopaseqeuoosdoojoeoueo.?ubis - - - - - - - - - - - - - - - - x - - - - - - - - - - - - - - eneA-d 60 US 2012/0053253 A1 Mar. 1, 2012 GENESIGNATURES FOR CANCER prostate cancer, lung cancer, bladder cancer or brain cancer, PROGNOSIS (2) determining the expression of a panel of genes in said tumor sample including at least 4 cell-cycle genes; and (3) CROSS REFERENCE TO RELATED providing a test value by (a) weighting the determined expres APPLICATIONS sion of each of a plurality of test genes selected from said 0001. This application claims the priority benefit of U.S. panel of genes with a predefined coefficient, and (b) combin Provisional Application Ser. No. 61/362.209 (filed on Jul. 7, ing the weighted expression to provide said test value, 2010), which is hereby incorporated by reference in its wherein at least 50%, at least 75% or at least 90% of said entirety. plurality of test genes are cell-cycle genes. 0008. In preferred embodiments, the plurality of test genes FIELD OF THE INVENTION includes at least 8 cell-cycle genes, or at least 10, 15, 20, 25 or 30 cell-cycle genes. Preferably, all of the test genes are cell 0002 The invention generally relates to a molecular clas cycle genes. sification of disease and particularly to molecular markers for 0009. Also in preferred embodiments, the step of deter cancer prognosis and methods of use thereof. mining the expression of the panel of genes in the tumor sample comprises measuring the amount of mRNA in the BACKGROUND OF THE INVENTION tumor sample transcribed from each of from 4 to about 200 0003 Cancer is a major public health problem, accounting cell-cycle genes; and measuring the amount of mRNA of one for roughly 25% of all deaths in the United States. Though or more housekeeping genes in the tumor sample. many treatments have been devised for various cancers, these 0010. In another aspect of the present invention, a method treatments often vary in severity of side effects. It is useful for is provided for determining the prognosis of prostate cancer, clinicians to know how aggressive a patient's cancer is in lung cancer, bladder cancer or brain cancer, which comprises order to determine how aggressively to treat the cancer. determining in a tumor sample from a patient diagnosed of 0004 For example, most patients with early-stage asymp prostate cancer, lung cancer, bladder cancer or brain cancer, tomatic prostate cancer are treated with radical prostatectomy the expression of at least 6, 8 or 10 cell-cycle genes, wherein or radiotherapy and optionally adjuvant therapy (e.g., hor overexpression of said at least 6, 8 or 10 cell-cycle genes mone or chemotherapy), all of which have severe side effects. indicates a poor prognosis oran increased likelihood of recur For many of these patients, however, these treatments and rence of cancer in the patient. their associated side effects and costs are unnecessary 0011. In one embodiment, the prognosis method com because the cancer in these patients is not aggressive (i.e., prises (1) determining in a tumor sample from a patient diag grows slowly and is unlikely to cause mortality or significant nosed of prostate cancer, lung cancer, bladder cancer or brain morbidity during the patient's lifetime). In other patients the cancer, the expression of a panel of genes in said tumor cancer is virulent (i.e., more likely to recur) and aggressive sample including at least 4 or at least 8 cell-cycle genes; and treatment is necessary to save the patient's life. (2) providing a test value by (a) weighting the determined 0005. Some tools have been devised to help physicians in expression of each of a plurality of test genes selected from deciding which patients need aggressive treatment and which the panel of genes with a predefined coefficient, and (b) do not. In fact, several clinical parameters are currently in use combining the weighted expression to provide the test value, for this purpose in various different cancers. In prostate can wherein at least 50%, at least 75% or at least 85% of the cer, for example, Such clinical parameters include serum plurality of test genes are cell-cycle genes, and wherein an prostate-specific antigen (PSA), Gleason grade, pathologic increased level of overall expression of the plurality of test stage, and Surgical margins. In recent years clinical param genes indicates a poor prognosis, whereas if there is no eters have been made more helpful through their incorpora increase in the overall expression of the test genes, it would tion into continuous multivariable postoperative nomograms indicate a good prognosis or a low likelihood of recurrence of that calculate apatient's probability of having cancer progres cancer in the patient. sion/recurrence. See, e.g., Kattan et al., J. CLIN. ONCOL. 0012. In preferred embodiments, the prognosis method (1999) 17:1499-1507; Stephenson et al., J. CLIN. ONCOL. further includes a step of comparing the test value provided in (2005) 23:7005-7012. Despite these advances, however, step (2) above to one or more reference values, and correlat many patients are given improper cancer treatments and there ing the test value to a risk of cancer progression or risk of is still a serious need for novel and improved tools for pre cancer recurrence. Optionally an increased likelihood of poor dicting cancer recurrence. prognosis is indicated if the test value is greater than the reference value. SUMMARY OF THE INVENTION 0013. In yet another aspect, the present invention also 0006. The present invention is based in part on the surpris provide a method of treating cancer in a patient identified as ing discovery that the expression of those genes whose having prostate cancer, lung cancer, bladder cancer or brain expression closely tracks the cell cycle (“cell-cycle genes' or cancer, comprising: (1) determining in a tumor sample from a "CCGs” as further defined below) is particularly useful in patient diagnosed of prostate cancer, lung cancer, bladder classifying selected types of cancer and determining the prog cancer or brain cancer, the expression of a panel of genes in nosis of these cancers. the tumor sample including at least 4 or at least 8 cell-cycle 0007 Accordingly, in a first aspect of the present inven genes; (2) providing a test value by (a) weighting the deter tion, a method is provided for determining gene expression in mined expression of each of a plurality of test genes selected a tumor sample from a patient identified as having prostate from said panel of genes with a predefined coefficient, and (b) cancer, lung cancer, bladder cancer or brain cancer.
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