THE NATIONAUS009890430B2 O UN ALT MAN HAR MAN DI (12 ) United States Patent (10 ) Patent No. : US 9 ,890 ,430 B2 Ellis et al. ( 45 ) Date of Patent: Feb . 13 , 2018 (54 ) COPY NUMBER ABERRATION DRIVEN ( 58) Field of Classification Search ENDOCRINE RESPONSE GENE SIGNATURE None ( 71 ) Applicant : Washington University , Saint Louis , See application file for complete search history . MO (US ) (56 ) References Cited ( 72 ) Inventors: Matthew Ellis , Houston , TX (US ) ; U . S . PATENT DOCUMENTS Jingqin Luo , Saint Louis , MO (US ) 7 , 504 ,214 B2 3 / 2009 Erlander et al . ( 73 ) Assignee : Washington University , St. Louis , MO 7 , 569 ,345 B2 8 /2009 Cobleigh et al . (US ) ( Continued ) ( * ) Notice : Subject to any disclaimer , the term of this FOREIGN PATENT DOCUMENTS patent is extended or adjusted under 35 U . S . C . 154 (b ) by 322 days . Wo 2011120984 Al 10 /2011 (21 ) Appl . No. : 14 /407 , 913 OTHER PUBLICATIONS (22 ) PCT Filed : Jun . 12 , 2013 M Dowsett et al. Meta - Analysis of Breast Cancer Outcomes in Adjuvant Trials of Aromatase Inhibitors Versus Tamoxifen . Journal ( 86 ) PCT No .: PCT/ US2013 / 045525 of Clinical Oncology, Jan . 2010 , vol . 28 , No. 3 , p . 509 -518 . * $ 371 ( c ) ( 1 ) , (Continued ) ( 2 ) Date : Dec. 12 , 2014 Primary Examiner — John S . Brusca ( 87 ) PCT Pub . No. : WO2013 / 188600 Assistant Examiner - Olivia M Wise PCT Pub. Date : Dec . 19 , 2013 (57 ) ABSTRACT (65 ) Prior Publication Data Disclosed are methods of predicting the likelihood of long term survival without recurrence of breast cancer for a US 2015 /0240312 A1 Aug. 27, 2015 subject having estrogen receptor -positive (ER + ) breast can Related U . S . Application Data cer treated with adjuvant endocrine monotherapy . In various embodiments , these methods comprise performing a gene (60 ) Provisional application No . 61/ 658 , 517 , filed on Jun . expression profile of a breast tissue sample of substantially 12 , 2012 . all of the genes of the “CADER set” described herein ; (51 ) Int. Ci. calculating a risk score using a regression model; and G06F 19 / 20 applying a double median cutoff classification to assign the ( 2011 . 01 ) subject to a sensitive , indeterminate or resistant group , C12Q 1 /68 ( 2006 . 01 ) wherein assignment to a sensitive group predicts longer ( Continued ) relapse - free survival compared to the median relapse - free (52 ) U . S . CI. survival of ER + breast cancer patients treated with adjuvant ??? .. C12Q 1 /6886 (2013 .01 ) ; B01J 19 /0046 endocrine monotherapy . ( 2013 .01 ) ; GOIN 33 /57415 ( 2013 .01 ) ; (Continued ) 11 Claims, 5 Drawing Sheets * Therapy * sensitive indeterminate ODOON Therapy indeterminate resistant X -axis : resistant gene centroid Y - axis : sensitive gene centroid US 9 ,890 , 430 B2 Page 2 ( 51 ) Int. Cl. Loi, S ., et al. , Definition of clinically distinct molecular subtypes in GOIN 33 /574 estrogen receptor- positive breast carcinomas through genomic ( 2006 .01 ) grade . , J . Clin . Oncol. , 25 ( 10 ) , 1239 - 1246 ( Apr. 2007 ) . B01J 19 / 00 (2006 . 01 ) Nielsen , T . O . , et al. , A comparison of PAM50 intrinsic subtyping G06F 19 /24 ( 2011. 01 ) with immunohistochemistry and clinical prognostic factors in G06F 19 / 00 ( 2011. 01 ) tamoxifen - treated estrogen receptor- positive breast cancer . , Clin . Cancer Res. , 16 ( 21) , 5222 - 5232 (Nov . 2010 ) . (52 ) U .S . CI. Olson , J . A . Jr . , et al. Improved surgical outcomes for breast cancer ??? 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U ., et al ., Ki67 Index , HER2 Status, and Prognosis of Zhang, Y . , et al. , The 76 - gene signature defines high - risk patients Patients with Luminal B Breast Cancer. , J . Natl . Cancer Inst . , that benefit from adjuvant tamoxifen therapy. , Breast Cancer Res. 101 ( 10 ) : 736 - 750 ( 2009 ) . Treat. , 116 , 303 -309 (2009 ) . Galanina , N . , et al . , Molecular Predictors of Response to Therapy for Breast Cancer. , Cancer J . , 17 ( 2 ), 96 - 103 (Mar . / Apr. 2011 ) . * cited by examiner atent Feb . 13 , 2018 Sheet 1 of 5 US 9 ,890 ,430 B2 FIG . 1 FL????? ???? ???????? [ reme= 1 (? .= meled ?????qa } of cost after?????? ? ? { { ?? 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