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Cancer biomarkers

a biomarker and cancer technology, applied in the field of molecular classification of diseases, can solve the problems of significant morbidity, unneeded treatment and their associated side effects, and often different severity of side effects, and achieve the effects of improving predictive power, increasing likelihood of recurrence, and increasing the likelihood of recurren

Inactive Publication Date: 2012-02-16
MYRIAD GENETICS
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013]Thus one aspect of the invention provides an in vitro diagnostic method comprising determining at least one clinical parameter for a cancer patient and determining the status of at least one CCG in a sample obtained from the patient. In some embodiments the status of a plurality of CCGs (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 40, 50 or more) is determined. In some embodiments abnormal status indicates an increased likelihood of recurrence or progression. In some embodiments the patient has prostate cancer. In some embodiments the patient has lung cancer. Often the clinical parameter is at least somewhat independently predictive of recurrence or progression and the addition of CCG status improves the predictive power. Exemplary CCGs include those in Panels A through G. In some embodiments more than one clinical parameter is assessed along with the expression level of at least one CCG. In some embodiments more than one clinical parameter is assessed and the combination of parameters, along with the expression level of at least one CCG, predicts the likelihood of cancer recurrence or progression.
[0019]PTEN status can add predictive value to clinical parameters in predicting prostate recurrence. Thus another aspect of the invention provides an in vitro diagnostic method comprising determining PTEN status and determining at least one clinical parameter for a prostate cancer patient. Often the clinical parameter is at least somewhat independently predictive of recurrence and the addition of PTEN status improves the predictive power. In some embodiments the invention provides a method of determining whether a cancer patient has an increased likelihood of recurrence comprising determining the status of PTEN in a sample obtained from the patient and determining a clinical nomogram score for the patient, wherein low or negative PTEN status and a high nomogram score indicate the patient has an increased likelihood of recurrence. In some embodiments the invention provides a method of determining whether a cancer patient has an increased likelihood of recurrence comprising determining the status of PTEN in a sample obtained from the patient, determining a clinical nomogram score for the patient and determining the status of at least one CCG in a sample obtained from the patient, wherein low or negative PTEN status, a high nomogram score and an elevated CCG status indicate the patient has an increased likelihood of recurrence.

Problems solved by technology

Cancer is a major public health problem, accounting for roughly 25% of all deaths in the United States.
Though many treatments have been devised for various cancers, these treatments often vary in severity of side effects.
For many of these patients, however, these treatments and their associated side effects and costs are unnecessary because the cancer in these patients is not aggressive (i.e., grows slowly and is unlikely to cause mortality or significant morbidity during the patient's lifetime).
Despite these advances, however, many patients are given improper cancer treatments and there is still a serious need for novel and improved tools for predicting cancer recurrence.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0131]The following cell cycle gene (CCG) signature was tested for predicting time to chemical recurrence after radical prostatectomy.

31-CCG Prostate RecurrenceSignatureAURKABUB1CCNB1CCNB2CDC2CDC20CDC45LCDCA8CENPACKS2DLG7DTLFOXM1HMMRKIF23KPNA2MAD2L1MELKMYBL2NUSAP1PBKPRC1PTTG1RRM2TIMELESSTPX2TRIP13TTKUBE2CUBE2SZWINT

[0132]Mean mRNA expression for the above 31 CCGs was tested on 440 prostate tumor FFPE samples using a Cox Proportional Hazard model in Splus 7.1 (Insightful, Inc., Seattle Wash.). The p-value for the likelihood ratio test was 3.98×10−5.

[0133]The mean of CCG expression is robust to measurement error and individual variation between genes. In order to determine the optimal number of cell cycle genes for the signature, the predictive power of the mean was tested for randomly selected sets of from 1 to 30 of the CCGs listed above. This simulation showed that there is a threshold number of CCGs in a panel that provides significantly improved predictive power.

example 2

[0134]In a univariate analysis a set of 31 CCGs (Table 3) was found to be a significant predictor of biochemical recurrence (p-value=1.8×10−9) after RP in prostate cancer patients. This signature was further evaluated to determine whether it added to an established clinical nomogram for prostate cancer recurrence (the Kattan-Stephenson nomogram). In summary, the nomogram was a highly significant predictor of recurrence (p-value 1.6×10−10) and, after adjusting for the nomogram, the CCG signature was a significant predictor of biochemical recurrence (p-value 4.8×10−5, Table 6).

Patients and Methods

[0135]Eight hundred four consecutive RP patients were followed for a median of 9.5 years. The patient characteristics and the treatment outcomes of the entire cohort have been previously reported (Swanson et al., UROL ONCOL. (2007) 25:110-114). Tissue blocks and / or slides from the final pathological evaluation with enough tissue for analysis were available for 430 patients. The cohort was div...

example 3

[0142]The following study aimed at determining the optimal number of CCGs to include in the signature. As mentioned above, CCG expression levels are correlated to each other so it was possible that measuring a small number of genes would be sufficient to predict disease outcome. In fact, single CCGs from the 31-gene set in Table 3 (Panel C) add significantly to the Kattan-Stephenson nomogram, as shown in Table 9 below (after adjustment for the nomogram and an interaction term between the nomogram and CCG expression):

TABLE 9Genep-value*Genep-value*Genep-value*NUSAP12.8 × 10−7BUB18.3 × 10−5KPNA22.0 × 10−2DLG75.9 × 10−7PBK1.2 × 10−4UBE2C2.2 × 10−2CDC26.0 × 10−7TTK3.2 × 10−4MELK2.5 × 10−2FOXM11.1 × 10−6CDC45L7.7 × 10−4CENPA2.9 × 10−2MYBL21.1 × 10−6PRC11.2 × 10−3CKS25.7 × 10−2CDCA83.3 × 10−6DTL1.4 × 10−3MAD2L11.7 × 10−1CDC203.8 × 10−6CCNB11.5 × 10−3UBE2S2.0 × 10−1RRM27.2 × 10−6TPX21.9 × 10−3AURKA4.8 × 10−1PTTG11.8 × 10−5ZWINT9.3 × 10−3TIMELESS4.8 × 10−1CCNB25.2 × 10−5KIF231.1 × 10−2HMMR5...

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Abstract

Biomarkers and methods using the biomarkers for the prediction of the recurrence risk of cancer in a patient are provided.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is the U.S. national phase entry of International Application no. PCT / US2010 / 020397 filed Jan. 7, 2010 (publication no. WO / 2010 / 080933A1) and further claims the priority benefit of U.S. Provisional Application Ser. Nos. 61 / 143,077 (filed Jan. 7, 2009), 61 / 179,650 (filed May 19, 2009), 61 / 185,901 (filed Jun. 10, 2009), 61 / 241,748 (filed Sep. 11, 2009), 61 / 256,443 (filed Oct. 30, 2009), which are each hereby incorporated by reference in their entirety.FIELD OF THE INVENTION[0002]The invention generally relates to a molecular classification of disease and particularly to molecular markers for cancer and methods of use thereof.BACKGROUND OF THE INVENTION[0003]Cancer is a major public health problem, accounting for roughly 25% of all deaths in the United States. Though many treatments have been devised for various cancers, these treatments often vary in severity of side effects. It is useful for clinicians to know how aggressi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61B5/00C12Q1/68A61P35/00C40B60/12C40B40/06C07G15/00C40B30/00C12M1/34G16B20/10G16B20/20G16B40/30
CPCC12Q1/6886C12Q2600/106G06F19/24C12Q2600/158G06F19/18C12Q2600/118G16B20/00G16B40/00A61P35/00G16B40/30G16B20/20G16B20/10
Inventor STONE, STEVENGUTIN, ALEXANDERWAGNER, SUSANNEREID, JULIA
Owner MYRIAD GENETICS
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