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WO 2012/066451 Al 24 May 2012 (24.05.2012) P O P CT (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2012/066451 Al 24 May 2012 (24.05.2012) P O P CT (51) International Patent Classification: (74) Agent: BENSON, Gregg C ; Pfizer Inc. Eastern Point C12Q 1/68 (2006.01) Road, MS 9 114, Groton, Connecticut 06340 (US). (21) International Application Number: (81) Designated States (unless otherwise indicated, for every PCT/IB201 1/054962 kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, (22) Date: International Filing CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, 7 November 201 1 (07.1 1.201 1) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, (25) Filing Language: English HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (26) Publication Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (30) Priority Data: OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, 61/413,806 15 November 2010 (15. 11.2010) US SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, 61/470,381 31 March 201 1 (3 1.03.201 1) US TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (71) Applicants (for all designated States except US): PFIZER (84) Designated States (unless otherwise indicated, for every INC. [US/US]; 235 East 42nd Street, New York, New kind of regional protection available): ARIPO (BW, GH, York 10017 (US). CENTRE HOSPITALIER UNI- GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, VERSITAIRE VAUDOIS [CH/CH]; Rue du Bugnon 21, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, CH-101 1 Lausanne (CH). SWISS INSTITUTE OF TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, BIOINFORMATICS [CH/CH]; Quartier Unil Sorge-Bati- DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, ment Genopode, CH-1015 Lausanne (CH). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventors; and GW, ML, MR, NE, SN, TD, TG). (75) Inventors/Applicants (for US only): BUDINSKA, Eva [SK/FR]; 2 bis Rue du Jura, F-01 630 St. Genis Pouilly Declarations under Rule 4.17 : (FR). DELORENZI, Mauro Claudio [CH/CH]; Route du — as to the identity of the inventor (Rule 4.1 7(Ϊ)) jorat 118, CH-1000 Lausanne 26 (CH). PAVLICEK, — as to applicant's entitlement to apply for and be granted a Adam [CZ/US]; Pfizer Global Research & Development, patent (Rule 4.1 7(H)) 10777 Science Center Drive, San Diego, California 92121 (US). POPOVICI, Vlad Calin [RO/CH]; Rue du Bugnon — as to the applicant's entitlement to claim the priority of the 37, CH-1020 Renens, Vaud (CH). TEJPAR, Sabine earlier application (Rule 4.1 7(in)) [BE/BE]; Groenlaan 22, B-1560 Hoeilaart (BE). WEIN- — of inventorship (Rule 4.17(iv)) RICH, Scott Lawrence [US/US]; Pfizer Global Research & Development, 10777 Science Center Drive, San Diego, Published: California 92121 (US). — with international search report (Art. 21(3)) © (54) Title: PROGNOSTIC AND PREDICTIVE GENE SIGNATURE FOR COLON CANCER (57) Abstract: The application provides methods of prognosing and classifying colon cancer patients into poor survival groups or good survival groups and for determining the benefit of adjuvant chemotherapy by way of a multigene signature. The application S also includes kits and computer products for use in the methods of the application. Prognostic and Predictive Gene Signature for Colon Cancer This application claims priority to U.S. Provisional Application No. 61/413,806 filed on November 15, 2010, and to U.S. Provisional Application No. 61/470,381 filed on March 3 1, 201 1, both of which are incorporated herein by reference in their entireties. Field The application relates to compositions and methods for prognosing and classifying colon cancer and for determining the benefit of adjuvant chemotherapy. Background As the third most common form of cancer, over 1 million new cases of colorectal cancer (CRC) are diagnosed worldwide each year. Despite significant advances in detection, surgery, and chemotherapeutic treatment, CRC is the fourth most common cause of cancer death worldwide, and second most common cause of cancer death in the United States (Tenesa & Dunlop, Nat Rev Genet 10:353-358 (2009); Jemal et al., Methods Mol. Biol. 471 :3-29 (2009)). CRC that is confined within the wall of the colon (TNM (tumor-node metastasis) stages I and II) are typically curable with surgery. However, if left untreated, such tumors may spread to regional lymph nodes (stage III), where up to 73% are curable by surgery and chemotherapy. Once CRC metastasizes to distant sites within the body (stage IV), the disease is typically not curable, although chemotherapy can extend the rate of survival. Clinical benefit in CRC patients has recently been observed with drugs that target vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR). In particular, monoclonal antibodies that target EGFR (e.g. cetuximab and panitumumab) and VEGF (bevacizumab) are approved for clinical use to treat CRC. The constitutive activation of the mitogen-activated protein kinase (MAPK) pathway is a key driver of CRC tumorigenesis. The extracellular signal-regulated kinase (ERK) pathway plays a key role in cell proliferation and its aberrant activation is often due to oncogenic mutations in KRAS or BRAF genes (Fang and Richardson, Lancet Oncol. 6:322-327 (2005); Tejpar et al., Oncologist 15:390-404 (2010)). RAF is a serine-threonine-specific protein kinase that is activated downstream of the small G-protein RAS and which activates the MAP kinase (MEK) pathway, which in turn activates ERK. BRAF is one of the three highly conserved RAF genes in mammals (the other two being ARAF and CRAF) and its somatic mutations have been reported in approximately 7% of human cancers (Davies et al., Nature 417:949-954 (2002); Dhomen & Marais, Curr. Opin. Genet. Dev. 17:31-39 (2007)). In CRC, the BRAF mutations occur in 8-10% of sporadic cancers and generally are markers of poor prognosis. For example, the V600E mutation in BRAF, is believed to be associated with microsatellite instability (MSI), and may confer resistance to anti-EGFR therapy (Richman et al. J. Clin. Oncol. 27(35):5931-5937 (2009)). Furthermore, KRAS mutations are known to lead to EGFR-independent activation of the MAPK pathway, suggesting that therapies targeting EGFR will not be effective in patients with KRAS mutations (Benvenuti et al. Cancer Res 67: 2643-2648 (2007); Di Fiore et al., Br. J. Cancer 96:1 166-1 169 (2007)). Accordingly, there is an ongoing need to develop biomarkers that can effectively identify CRC patients that are best suited for certain therapeutic modalities. Summary As will be discussed in more detail herein, the present disclosure relates to the identification, from historical CRC patient data, several gene signatures that identify a subpopulation of patients that may be sensitive to novel targeted treatments. In particular, the present disclosure provides several gene signatures that are characteristic of BRAF mutated CRC tumors. The present disclosure provides methods and kits useful for obtaining and utilizing expression information for the genes identified herein, to obtain prognostic and diagnostic information for patients with CRC. The methods of the present disclosure generally involve obtaining relative expression data from a patient, at the DNA, messenger RNA (mRNA), or protein level, for each of the genes identified herein, processing the data and comparing the resulting information to one or more reference values. Relative expression levels are expression data normalized according to techniques known to those skilled in the art. Expression data may be normalized with respect to one or more genes with invariant expression, such as "housekeeping" genes. In some embodiments, expression data may be processed using standard techniques, such as transformation to a z-score, and/or software tools, such as RMAexpress v0.3. In one aspect, a multi-gene signature is provided for prognosing or classifying patients with CRC. In some embodiments, a 39-gene pair signature is provided, comprising reference values for each of 39 pairs of different genes based on relative expression data for each gene from a historical data set with a known outcome, such as good or poor survival, and/or known treatment, such as adjuvant chemotherapy. In one aspect, relative expression data from a patient are combined with the gene-specific reference values on a gene-by-gene basis for each of the genes identified herein, to generate a test value which allows prognosis or therapy recommendation. In some embodiments, relative expression data are subjected to an algorithm that yields a single test value, or combined score, which is then compared to a control value obtained from the historical expression data for a patient or pool of patients. In some embodiments, the control value is a numerical threshold for predicting outcomes, for example good and poor outcome, or making therapy recommendations, for example adjuvant therapy in addition to surgical resection or surgical resection alone. In some embodiments, a test value or combined score greater than the control value is predictive, for example, of high risk (poor outcome) or benefit from adjuvant therapy, whereas a combined score falling below the control value is predictive, for example, of low risk (good outcome) or lack of benefit from adjuvant therapy.
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