530:
is associated with better outcome in stage II colon cancer following surgery, and this result is consistent with reports in the literature, including studies by the NSABP. Cell cycle genes are well-known to produce various effects in different biological contexts, ranging from promotion of proliferation to induction of cell senescence or apoptosis. Higher expression of the stromal gene group is associated with poor outcome in colon cancer, which is consistent with observations in the literature that stromal genes are associated with induction of tumor cell proliferation, tumor invasion, and metastasis. The cell cycle gene group and the stromal gene group are included in the calculation of the
Recurrence Score result as an average of the three genes in each group. GADD45B is an individual gene used for calculation of the Recurrence Score result and is known to be a marker of genotoxic stress which may be indicative of tumor-stroma interactions and thus more aggressive tumor behavior.
489:
the NSABP studies C-01/C-02, C-04, and C-06 and a cohort of patients treated at the
Cleveland Clinic were utilized for identifying genes that were consistently associated with risk of recurrence. 761 candidate genes were studied in the NSABP C01/C02 (surgery alone) and NSABP C04 (surgery+5FU/LV) development studies. Based on the results of these studies, the gene list was refined to 375 genes, which were then studied in the Cleveland Clinic study (surgery alone) and NSABP C06 (surgery+5FU/LV). Of the initial large pool of candidate genes, 48 genes were found to have a consistent and statically significant association with recurrence-free interval in three of the four development studies. Importantly, the multiple large independent studies enabled identification of clinically relevant genes with confidence, with fewer than two of the 48 recurrence-associated genes expected to be false discoveries. The 7 cancer related genes are
561:
risk of recurrence (p=0.004), disease-free survival (p=0.01) and overall survival (p=0.04). In a protocol-specified multivariate analysis, the
Recurrence Score result remained significantly associated with recurrence after simultaneously controlling for the prognostic effects of MMR status, T stage, tumor grade, number of nodes examined, and lymphovascular invasion. The Recurrence Score result retaining a similar hazard ratio and a similar significance level to those observed in the univariate analyses (HR per Interquartile range=1.43, p=0.006). Taken together, these findings demonstrate that the Recurrence Score result provides quantitative information regarding recurrence risk in stage II colon cancer beyond other existing tumor markers.
579:
where proportional benefit with treatment is similar across a population, absolute benefit with treatment is expected to be smaller at low levels of baseline risk and rise as baseline risk increases. Stage II colon cancer patients with a lower recurrence risk, as predicted by
Recurrence Score result, would be expected to derive relatively small absolute benefit with adjuvant therapy, which may prompt stronger consideration of observation following surgery. On the other hand, patients with a higher risk of recurrence would be expected to derive larger absolute benefit with adjuvant therapy, which may warrant stronger consideration of post-operative chemotherapy.
570:
factors, such as tumor grade, number of nodes examined, and lymphovascular invasion. Among stage II patients with no observable high risk features, the
Recurrence Score result identified 22% of patients with an average risk of recurrence at 5 years above 20%. A high Recurrence Score result reveals an underlying biology indicative of more aggressive disease for which adjuvant therapy may be considered.
179:
222:
557:
in patients with resected stage II colon cancer, and demonstrated that adjuvant 5-FU/LV treatment benefits a small but significant population of stage II patients. This study demonstrated an approximate 3-4% absolute benefit of adjuvant 5-FU/LV treatment within the stage II population, which is consistent with meta-analyses of adjuvant 5FU/LV trials involving stage II patients.
132:
66:
25:
327:
529:
The seven cancer-related genes include two key biologic pathways (cell cycle genes and stromal genes) associated with recurrence in the development studies, as well as an individual gene GADD45B (associated with cellular response to stress). Higher expression of the cell cycle group, including Ki67,
488:
DX Colon Cancer Assay, four large, independent development studies were conducted which included patients treated with surgery alone and patients treated with surgery followed by adjuvant 5-FU/LV chemotherapy. Colon tumor samples from a total of 1,851 stage II and stage III colon cancer patients from
560:
In the pre-specified primary analysis for the QUASAR validation study, a Cox proportional hazards regression model was fitted to the clinical endpoint of recurrence-free interval for the 711 patients who were randomized to surgery alone. The
Recurrence Score result was significantly associated with
556:
Following development and analytical validation of the assay, a clinical validation study was conducted in a sample of 1,436 confirmed stage II colon cancer patients from the landmark QUASAR trial. The QUASAR trial is the largest reported randomized study of observation versus adjuvant chemotherapy
578:
In a pre-specified analysis from the QUASAR validation study, the
Recurrence Score result did not demonstrate a significant interaction with treatment (p=0.69). The proportional benefit of adjuvant 5FU/LV was not significantly different across the range of Recurrence Score results. In the setting
525:
Analyses across these four development studies enabled the definition of a multi-gene assay for prediction of tumor recurrence in stage II colon cancer patients following surgery. Based on modeling and assessment of laboratory analytical performance, a 12-gene assay, including seven cancer-related
475:
and measuring gene expression by quantitative RT-PCR technology, (2) the requirement for review of each case by a pathologist for manual microdissection to remove normal colon tissue adjacent to the tumor, and (3) reference genes for normalization of gene expression. The use of carefully selected
1162:
Meropol N, Lyman GH, Chien R. Use of a multigene prognostic assay for selection of adjuvant chemotherapy in patients with stage II colon cancer: Impact on quality-adjusted life expectancy and costs. Poster presented at the
American Society Clinical Oncology Gastrointestinal Cancers Symposium; San
533:
Following gene identification and algorithm development, a process for conducting the assay, including all steps from receipt of the tumor specimen to generation of the assay result, was finalized and analytically validated prior to conducting clinical validation studies. Analytical validation of
470:
DX Colon Cancer Assay, feasibility studies were conducted to optimize the
Genomic Health platform for quantitative assessment of gene expression from fixed paraffin-embedded (FPE) colon tumor tissue. These studies in FPE colon tumor tissue identified (1) the optimal method for reliably extracting
569:
Supporting the original QUASAR study, additional results from a second clinical validation study of stage II colon cancer patients enrolled in CALGB 9581 further confirmed that the
Recurrence Score result improves the ability to differentiate higher from lower recurrence risk beyond conventional
445:
DX assay is a non-invasive test that is performed on a small amount of the tissue removed during surgery, which means no additional invasive procedure is required. After the surgical procedure, the tissue sample is fixed (usually in formalin) and embedded in paraffin so it can be preserved for
413:
in stage II colon cancer following surgery. The result from the assay is a continuous recurrence score value from 0 to 100 that corresponds to a specific likelihood of colon cancer recurrence 3 years after surgery. A lower score corresponds to a lower risk of recurrence, and a higher score
595:
DX Recurrence Score result to assess risk of recurrence in T3 stage II colon cancers with MMR proficient status may improve quality-adjusted life expectancy and be cost-saving from a societal perspective. In this model, patient age and disutility associated with chemotherapy were important
476:
reference genes to normalize gene expression in the context of sources of pre-analytical variability such as time of fixation and block age is a critical feature of this technology. The findings from these feasibility studies provided the technical foundation for subsequent studies.
678:
Garrity MM, Burgart LJ, Mahoney MR, et al. Prognostic value of proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression in patients with resected Dukes' B2 or C colon cancer: a North Central Cancer Treatment Group Study.
1152:
Venook A, Niedzwiecki D, Lopatin M, et al. Validation of a 12-gene colon cancer recurrence score (RS) in patients (pts) with stage II colon cancer (CC) from CALGB 9581. Presented at: American Society of Clinical Oncology; June 2011; Chicago,
647:
O’Connell MJ, Lavery I, Yothers G, et al. Relationship between tumor gene expression and recurrence in four independent studies of stage II/III colon cancer patients treated with surgery alone or surgery plus adjuvant 5-FU/LV.
617:, Gray RG, Quirke P, Handley K, et al. Validation study of a quantitative multigene reverse transcriptase–polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer.
538:
DX test ensures that the assay will give accurate, precise and reproducible results across different reagent lots, operators, and patient samples. Standardization of the assay is critical to ensuring that the
746:"Prognostic value of thymidylate synthase, Ki-67, and p53 in patients with Dukes' B and C colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project collaborative study"
526:
genes and five reference genes, was defined, yielding a colon cancer Recurrence Score result, scaled from 0 to 100, based upon reference-normalized expression of the seven cancer-related genes.
414:
corresponds to a higher risk of recurrence. The Recurrence Score result provides additional information on recurrence risk beyond traditional clinical and pathological characteristics such as
1139:
Sargent D, Sobrero A, Grothey A, et al. Evidence for cure by adjuvant therapy in colon cancer: observations based on individual patient data from 20,898 patients on 18 randomized trials.
409:, since January 2010. The test is a validated diagnostic assay based on an individual patient’s colon tumor expression of 12 genes, which quantifies the likelihood of
38:
1124:
Gill S, Loprinzi CL, Sargent DJ, et al. Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?
956:
Mesker WE, Liefers GJ, Junggeburt JM, van Pelt GW, Alberici P, Kuppen PJ, Miranda NF, van Leeuwen KA, Morreau H, Szuhai K, Tollenaar RA, Tanke HJ (2009).
663:
Anjomshoaa A, Lin Y, Black MA, et al. Reduced expression of a gene proliferation signature is associated with enhanced malignancy in colon cancer.
454:
will send the tumor block or several thin sections of the tissue sample to Genomic Health. Genomic Health uses a laboratory process known as
289:
261:
76:
695:"Increased proliferation activity measured by immunoreactive Ki67 is associated with survival improvement in rectal/recto sigmoid cancer"
205:
44:
268:
199:
95:
1007:"The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage"
380:
308:
113:
52:
153:
790:"Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds"
958:"Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients"
275:
1096:
Quasar Collaborative Group. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study"
246:
1122:
257:
1137:
438:
DX Colon Cancer Assay has the greatest utility for the stage II colon cancer patients with T3 and MMR proficient tumors.
195:
1094:
91:
880:"Analysis of differential gene expression patterns in colon cancer and cancer stroma using microdissected tissues"
632:
Clark-Langone KM, Wu JY, Sangli C, et al. Biomarker discovery for colon cancer using a 761 gene RT-PCR assay.
543:
DX assay yields reliable results which clinicians can use to informing patient management treatment decisions.
774:
Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
431:
282:
1205:
1109:
Figueredo A, Coombes ME, Mukherjee S. Adjuvant Therapy for completely resected Stage II Colon Cancer"
879:
834:
406:
356:
191:
337:
231:
410:
1057:
1077:
1058:"Distinct mechanisms are utilized to induce stress sensor gadd45b by different stress stimuli"
1038:
987:
938:
899:
860:
726:
661:
87:
1069:
1028:
1018:
977:
969:
930:
918:
891:
850:
842:
801:
757:
716:
706:
490:
419:
1005:
Mesker WE, Junggeburt JM, Szuhai K, de Heer P, Morreau H, Tanke HJ, Tollenaar RA (2007).
405:, is a genomic test that has been clinically available for patients with newly diagnosed
838:
1033:
1006:
982:
957:
855:
822:
721:
694:
591:
DX assay in stage II colon cancer management demonstrated that clinical use of the Onco
402:
236:
1199:
645:
615:
895:
806:
789:
676:
745:
451:
427:
423:
415:
221:
630:
506:
502:
711:
761:
346:
1081:
1042:
991:
942:
903:
864:
730:
326:
1023:
973:
846:
514:
1073:
455:
1190:
934:
510:
498:
494:
151:
parameter to this template to explain the issue with the article.
1185:
472:
320:
215:
172:
125:
59:
18:
1176:
823:"Stromal fibroblasts in cancer initiation and progression"
788:
Chang HY, Sneddon JB, Alizadeh AA, et al. (2004).
351:
341:
242:
83:
744:
Allegra CJ, Paik S, Colangelo LH, et al. (2003).
878:
Sugiyama Y, Farrow B, Murillo C, et al. (2005).
693:
Salminen E, Palmu S, Vahlberg T, et al. (2005).
94:, and by adding encyclopedic content written from a
249:. Unsourced material may be challenged and removed.
596:considerations in adjuvant treatment decisions.
458:to measure the expression of the 12-gene panel.
229:An editor has performed a search and found that
8:
1056:Zumbrun SD, Hoffman B, Libermann DA (2009).
53:Learn how and when to remove these messages
821:Bhowmick NA, Neilson EG, Moses HL (2004).
141:needs attention from an expert in Medicine
1032:
1022:
981:
854:
805:
720:
710:
381:Learn how and when to remove this message
309:Learn how and when to remove this message
114:Learn how and when to remove this message
1111:Cochrane Database of Systematic Reviews
605:
611:
609:
446:diagnostic testing. To perform an Onco
156:may be able to help recruit an expert.
75:contains content that is written like
466:Prior to selecting genes for the Onco
7:
247:adding citations to reliable sources
484:To identify the genes for the Onco
16:Genomic test for cancer recurrence
14:
194:to comply with Knowledge (XXG)'s
34:This article has multiple issues.
587:An economic study assessing Onco
325:
258:"Oncotype DX Colon Cancer Assay"
220:
177:
130:
64:
23:
42:or discuss these issues on the
917:Kalluri R, Zeisberg M (2006).
204:Please discuss further on the
1:
1163:Francisco, CA; January 2011.
896:10.1053/j.gastro.2004.11.010
807:10.1371/journal.pbio.0020039
420:mismatch repair (MMR) status
235:to establish the subject's
1222:
521:Development and validation
712:10.3748/wjg.v11.i21.3245
232:sufficient sources exist
919:"Fibroblasts in cancer"
762:10.1200/jco.2003.05.044
652:, 2010; 28(25):3937-44.
583:Health economic studies
432:lymphovascular invasion
340:, as no other articles
1128:. 2004;22(10):1797-806
778:. 1986;315(26):1650-9.
186:This article contains
1191:My Colon Cancer Coach
1100:2007;370(9604):2020-9
974:10.3233/CLO-2009-0478
699:World J Gastroenterol
683:2004;22(9):1572-1582.
462:Technical feasibility
407:stage II colon cancer
399:DX Colon Cancer Assay
200:neutral point of view
96:neutral point of view
243:improve this article
154:WikiProject Medicine
1186:Genomic Health Inc.
1024:10.1155/2007/175276
847:10.1038/nature03096
839:2004Natur.432..332B
547:Clinical validation
188:paid contributions.
88:promotional content
1143:. 2009;27(6):872-7
667:2008;99(6):966-73.
621:.; 2011:4611-4619.
359:for suggestions.
349:to this page from
90:and inappropriate
1074:10.1002/jcb.22354
636:2007;(8): 270-97.
391:
390:
383:
373:
372:
319:
318:
311:
293:
214:
213:
171:
170:
124:
123:
116:
57:
1213:
1164:
1160:
1154:
1150:
1144:
1135:
1129:
1120:
1114:
1107:
1101:
1092:
1086:
1085:
1053:
1047:
1046:
1036:
1026:
1002:
996:
995:
985:
953:
947:
946:
914:
908:
907:
884:Gastroenterology
875:
869:
868:
858:
818:
812:
811:
809:
785:
779:
772:
766:
765:
741:
735:
734:
724:
714:
690:
684:
674:
668:
659:
653:
643:
637:
628:
622:
613:
574:Absolute benefit
386:
379:
368:
365:
354:
352:related articles
329:
321:
314:
307:
303:
300:
294:
292:
251:
224:
216:
209:
196:content policies
181:
180:
173:
166:
163:
157:
143:. Please add a
134:
133:
126:
119:
112:
108:
105:
99:
77:an advertisement
68:
67:
60:
49:
27:
26:
19:
1221:
1220:
1216:
1215:
1214:
1212:
1211:
1210:
1196:
1195:
1173:
1168:
1167:
1161:
1157:
1151:
1147:
1136:
1132:
1121:
1117:
1108:
1104:
1093:
1089:
1055:
1054:
1050:
1004:
1003:
999:
955:
954:
950:
935:10.1038/nrc1877
916:
915:
911:
877:
876:
872:
833:(7015): 332–7.
820:
819:
815:
787:
786:
782:
773:
769:
743:
742:
738:
705:(21): 3245–49.
692:
691:
687:
675:
671:
660:
656:
644:
640:
629:
625:
614:
607:
602:
585:
576:
567:
554:
549:
523:
482:
464:
401:, developed by
387:
376:
375:
374:
369:
363:
360:
350:
347:introduce links
330:
315:
304:
298:
295:
252:
250:
240:
225:
210:
203:
198:, particularly
190:It may require
182:
178:
167:
161:
158:
152:
135:
131:
120:
109:
103:
100:
81:
69:
65:
28:
24:
17:
12:
11:
5:
1219:
1217:
1209:
1208:
1198:
1197:
1194:
1193:
1188:
1183:
1172:
1171:External links
1169:
1166:
1165:
1155:
1145:
1130:
1115:
1113:2008, Issue 3.
1102:
1087:
1068:(5): 1220–31.
1062:J Cell Biochem
1048:
997:
948:
929:(5): 392–401.
923:Nat Rev Cancer
909:
870:
813:
780:
767:
736:
685:
669:
654:
638:
623:
604:
603:
601:
598:
584:
581:
575:
572:
566:
563:
553:
550:
548:
545:
522:
519:
481:
478:
463:
460:
403:Genomic Health
389:
388:
371:
370:
357:Find link tool
333:
331:
324:
317:
316:
228:
226:
219:
212:
211:
185:
183:
176:
169:
168:
138:
136:
129:
122:
121:
92:external links
72:
70:
63:
58:
32:
31:
29:
22:
15:
13:
10:
9:
6:
4:
3:
2:
1218:
1207:
1206:Medical tests
1204:
1203:
1201:
1192:
1189:
1187:
1184:
1182:
1180:
1175:
1174:
1170:
1159:
1156:
1149:
1146:
1142:
1138:
1134:
1131:
1127:
1123:
1119:
1116:
1112:
1106:
1103:
1099:
1095:
1091:
1088:
1083:
1079:
1075:
1071:
1067:
1063:
1059:
1052:
1049:
1044:
1040:
1035:
1030:
1025:
1020:
1017:(5): 387–98.
1016:
1012:
1008:
1001:
998:
993:
989:
984:
979:
975:
971:
968:(3): 169–78.
967:
963:
959:
952:
949:
944:
940:
936:
932:
928:
924:
920:
913:
910:
905:
901:
897:
893:
889:
885:
881:
874:
871:
866:
862:
857:
852:
848:
844:
840:
836:
832:
828:
824:
817:
814:
808:
803:
799:
795:
791:
784:
781:
777:
771:
768:
763:
759:
756:(2): 241–50.
755:
751:
747:
740:
737:
732:
728:
723:
718:
713:
708:
704:
700:
696:
689:
686:
682:
677:
673:
670:
666:
662:
658:
655:
651:
646:
642:
639:
635:
631:
627:
624:
620:
616:
612:
610:
606:
599:
597:
594:
590:
582:
580:
573:
571:
564:
562:
558:
551:
546:
544:
542:
537:
531:
527:
520:
518:
516:
512:
508:
504:
500:
496:
492:
487:
479:
477:
474:
469:
461:
459:
457:
453:
449:
444:
439:
437:
433:
429:
425:
421:
417:
412:
408:
404:
400:
398:
385:
382:
367:
358:
353:
348:
344:
343:
339:
334:This article
332:
328:
323:
322:
313:
310:
302:
291:
288:
284:
281:
277:
274:
270:
267:
263:
260: –
259:
255:
254:Find sources:
248:
244:
238:
234:
233:
227:
223:
218:
217:
207:
201:
197:
193:
189:
184:
175:
174:
165:
155:
150:
146:
142:
139:This article
137:
128:
127:
118:
115:
107:
97:
93:
89:
85:
79:
78:
73:This article
71:
62:
61:
56:
54:
47:
46:
41:
40:
35:
30:
21:
20:
1178:
1158:
1148:
1141:J Clin Oncol
1140:
1133:
1126:J Clin Oncol
1125:
1118:
1110:
1105:
1097:
1090:
1065:
1061:
1051:
1014:
1010:
1000:
965:
961:
951:
926:
922:
912:
890:(2): 480–6.
887:
883:
873:
830:
826:
816:
797:
793:
783:
776:N Engl J Med
775:
770:
753:
750:J Clin Oncol
749:
739:
702:
698:
688:
681:J Clin Oncol
680:
672:
664:
657:
650:J Clin Oncol
649:
641:
634:BMC Genomics
633:
626:
619:J Clin Oncol
618:
592:
588:
586:
577:
568:
559:
555:
540:
535:
532:
528:
524:
485:
483:
467:
465:
447:
442:
440:
435:
422:, number of
396:
394:
392:
377:
361:
335:
305:
296:
286:
279:
272:
265:
253:
241:Please help
230:
187:
159:
148:
144:
140:
110:
101:
86:by removing
82:Please help
74:
50:
43:
37:
36:Please help
33:
1011:Cell. Oncol
962:Cell. Oncol
665:Br J Cancer
452:pathologist
450:DX test, a
428:tumor grade
424:lymph nodes
418:(T-stage),
416:tumor stage
1181:DX Website
600:References
565:CALGB 9581
434:. The Onco
426:examined,
411:recurrence
355:; try the
342:link to it
269:newspapers
237:notability
84:improve it
39:improve it
800:(2): E7.
794:PLOS Biol
364:June 2024
345:. Please
206:talk page
45:talk page
1200:Category
1082:19834918
1043:17726261
992:19478385
943:16572188
904:15685558
865:15549095
731:15929175
441:The Onco
299:May 2024
162:May 2012
104:May 2012
1034:4617992
983:4618830
856:3050735
835:Bibcode
722:4316056
515:GADD45B
283:scholar
192:cleanup
1098:Lancet
1080:
1041:
1031:
990:
980:
941:
902:
863:
853:
827:Nature
729:
719:
552:QUASAR
513:, and
456:RT-PCR
338:orphan
336:is an
285:
278:
271:
264:
256:
145:reason
511:INHBA
499:MYBL2
495:C-MYC
491:Ki-67
480:Genes
290:JSTOR
276:books
147:or a
1179:type
1177:Onco
1078:PMID
1039:PMID
988:PMID
939:PMID
900:PMID
861:PMID
727:PMID
593:type
589:type
541:type
539:Onco
536:type
534:Onco
486:type
468:type
448:type
443:type
436:type
430:and
397:type
395:Onco
393:The
262:news
149:talk
1153:IL.
1070:doi
1066:108
1029:PMC
1019:doi
978:PMC
970:doi
931:doi
892:doi
888:128
851:PMC
843:doi
831:432
802:doi
758:doi
717:PMC
707:doi
507:BGN
503:FAP
473:RNA
245:by
1202::
1076:.
1064:.
1060:.
1037:.
1027:.
1015:29
1013:.
1009:.
986:.
976:.
966:31
964:.
960:.
937:.
925:.
921:.
898:.
886:.
882:.
859:.
849:.
841:.
829:.
825:.
796:.
792:.
754:21
752:.
748:.
725:.
715:.
703:11
701:.
697:.
608:^
517:.
509:,
505:,
501:,
497:,
493:,
48:.
1084:.
1072::
1045:.
1021::
994:.
972::
945:.
933::
927:6
906:.
894::
867:.
845::
837::
810:.
804::
798:2
764:.
760::
733:.
709::
384:)
378:(
366:)
362:(
312:)
306:(
301:)
297:(
287:·
280:·
273:·
266:·
239:.
208:.
202:.
164:)
160:(
117:)
111:(
106:)
102:(
98:.
80:.
55:)
51:(
Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.
