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WO 2013/070521 Al O (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 2013/070521 Al 16 May 2013 (16.05.2013) P O P C T (51) International Patent Classification: (74) Agent: GARRETT, Arthur S.; Finnegan, Henderson, G01N 33/50 (2006.01) C12Q 1/68 (2006.01) Farabow, Garrett & Dunner, LLP, 901 New York Avenue, N.W., Washington, DC 20001-4413 (US). (21) International Application Number: PCT/US2012/0633 13 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, 2 November 2012 (02.1 1.2012) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (25) Filing Language: English DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (26) Publication Language: English KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (30) Priority Data: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 61/557,238 8 November 201 1 (08. 11.201 1) US NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, 61/597,426 10 February 2012 (10.02.2012) US RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (71) Applicant: GENOMIC HEALTH, INC. [US/US]; 301 ZM, ZW. Penobscott Drive, Redwood City, CA 94063 (US). (84) Designated States (unless otherwise indicated, for every (72) Inventors: BAKER, Joffre B.; 301 Penobscot Drive, Red kind of regional protection available): ARIPO (BW, GH, wood City, CA 94063 (US). SINICROPI, Dominick V.; GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 301 Penobscot Drive, Redwood City, CA 94063 (US). UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, PELHAM, Robert J.; 301 Penobscot Drive, Redwood TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, City, CA 94063 (US). CRAGER, Michael; 301 Penobscot EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, Drive, Redwood City, CA 94063 (US). COLLIN, Fran¬ MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, cois; 301 Penobscot Drive, Redwood City, CA 94063 TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, (US). STEPHANS, James C ; 301 Penobscot Drive, Red ML, MR, NE, SN, TD, TG). wood City, CA 94063 (US). LIU, Mei-Lan; 301 Penob Published: scot Drive, Redwood City, CA 94063 (US). MORLAN, John; 301 Penobscot Drive, Redwood City, CA 94063 — with international search report (Art. 21(3)) (US). QU, Kunbin; 301 Penobscot Drive, Redwood City, — before the expiration of the time limit for amending the CA 94063 (US). claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) o © o (54) Title: METHOD OF PREDICTING BREAST CANCER PROGNOSIS (57) Abstract: The present invention relates to biomarkers associated with breast cancer prognosis. These biomarkers include coding transcripts and their expression products, as well as non-coding transcripts, and are useful for predicting the likelihood of breast can cer recurrence in a breast cancer patient, The present invention also relates to a novel method of identifying intergenic sequences that correlate with a clinical outcome. [0001] This application claims the benefit of U.S. Provisional Application Nos. 61/557,238, filed November 8, 201 1, and 61/597,426, filed February 0, 2012, which are hereby incorporated by reference in their entirety. LD OF [0002] The present invention relates to biomarkers associated with breast cancer prognosis. These biomarkers include coding transcripts and their expression products, as well as non-coding transcripts, an are useful for predicting the likelihood of breast cancer recurrence in a breast cancer patient. INTRODUCTION [0003] For over a decade, technologies such as DNA microarray and reverse transcription polymerase chain reaction (RT-PCR) have demonstrated that levels of certain RNA transcripts ("gene expression profiles") relate to patient stratification and disease outcomes, especially in a variety of cancers. Several validated and now widely used clinical tests make use of gene expression profiling, such as the Oncotype DX* RT-PCR test, which measures the levels of 2 1 biomarker RNAs in archival formalin-fixed paraffin-embedded (FFPE) tissue. The Oncotype DX® RT-PCR test predicts the risk of recurrence of early estrogen receptor (ER)- positive breast cancer, as well as the likelihood of response to chemotherapy, and is now used to guide treatment decisions for about half of ER+ breast cancer patients in the U.S. [0004] However, RT-PCR is constrained by the number of transcripts and sequence complexity that can be interrogated especially given the limited amount of patient FFPE RNA available from many tumor specimens. Recent major advances in DNA sequencing ("next generation sequencing") provide massively parallel throughput and data volumes that eclipse the nucleic acid information content possible with other technologies, such as RT-PCR. Next generation sequencing makes feasible unprecedented extensive genome analysis of groups of individuals, including analyses of sequence differences, polymorphisms, mutations, copy number variations epigenetic variations and transcript abundance (RNA-Seq). SUMMARY [0005] A multiplexed, whole genome sequencing methodology was developed to enable whole transcriptome-wide breast cancer biomarker discovery using low amounts of FFPE tissue. The present invention provides biomarkers that associate, positively or negatively, with a particular clinical outcome in breast cancer. These biomarkers are listed in Tables 1-5 and 15. For example, the clinical outcome could be no cancer recurrence or cancer recurrence. The clinical outcome may be defined by clinical endpoints, such as disease or recurrence free survival, metastasis free survival, overall survival, etc [0006] The present invention accommodates the use of archived paraffin-embedded biopsy material for assay of all markers in the set, and therefore is compatible with the most widely available type of biopsy material. It is also compatible with other different methods of tumor tissue harvest, fo example, via core biopsy or fine needle aspiration [0007] In one aspect, the present invention provides a method of predicting a likelihood of long-term survival without recurrence of breast cancer in a breast cancer patient. The method comprises determining a level of one or more RN A transcripts, or its expression product, in a breast cancer tumor sample obtained from the patient. The RNA transcript or its expression product may be selected from Tables 1 and 5. The likelihood of long-term survival without breast cancer recurrence is then predicted based on the negative or positive correlation of the RNA transcript or its expression product with increased likelihood of long-term survival without breast ca cer recurrence. An RNA transcript is negatively correlated with increased long-term survival without recurrence of breast cancer if its direction of association is marked in Tables 1 and 15, and is positively correlated with increased long-term survival without recurrence of breast cancer if its direction of association is marked -lin Tables and 15, [0008] In another aspect, the present invention provides a method of predicting a likelihood of long-term survival without recurrence of breast cancer in an estrogen receptor (ER)-positive breast cancer patient. The method comprises determining a level of one o more RNA transcripts, or its expression product, in a breast cancer tumor sample obtained from the patient. The RNA transcript or its expression product may be selected fro Table 2. The likelihood of long-term survi val without breast cancer recurrence is then predicted based on the negative or positive correlation of the RNA transcript or its expression product with increased likelihood of long-term survival without breast cancer recurrence. An RNA transcript is negatively correiaied with increased long-term survival without recurrence of breast cancer if its direction of association is marked 1 in Table 2, and is positively correlated with increased long- term survival without recurrence of breast cancer if its direction of association is marked - 1 in Table 2. [0009] The R A transcripts, or the expression products, ay be grouped into gene networks based on the current understanding of their cellular function. For example, the gene networks include a cell cycle network, ESR1 network, Clxr9q22network, Chrl7q23-24 network, Chr8q21-24 network, olfactory receptor network, and metabolic-like networks. The present invention therefore also provides a method of predicting a likelihood of long-term survival without breast cancer recurrence in a breas cancer patient by determining a quantitative value, such as a likelihood score, for one or more gene networks based on the level of at least one RNA transcript, or expression product thereof within the gene network, in a breast cancer tumor sample obtained from the patient The quantitative value for the gene network may be determined by weighting the contribution of one or more RNA transcripts or their expression products, to clinical outcome such as risk of recurrence. [0010] In yet another aspect, the present invention provides a method of predicting a likelihood of long-term survival without recurrence of breast cancer in a breast cancer patient by determining a level of one or more non-coding sequences in a breast cancer tissue sample obtained from the patient. In one embodiment, the non-coding sequence is one or more intronic RNAs selected from Table 3. In another embodiment, the non-coding sequence is one or more long intergenic non-coding regions (IincRNAs) selected from Table 4. In a further embodiment, the non-coding sequence is one or more intergenic sequences selected from Table 5.
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