Using proliferative markers and Oncotype DX in therapeutic decision-making for breast cancer: the B.C. experience

Transcription

1 ORIGINAL ARTICLE Using prolifertive mrkers nd Oncotype DX in therpeutic decision-mking for brest cncer: the B.C. experience E. Bxter bsc,* L. Gondr btech pdc, C. Lohrisch md, S. Chi md, K. Gelmon md, M. Hyes mb chb, A. Dvidson md, nd S. Tyldesley md* ABSTRACT Bckground Prolifertive scoring of brest tumours cn guide tretment recommendtions, prticulrly for estrogen receptor (er) positive, her2-negtive, T1 2, N0 disese. Our objectives were to estimte the proportion of such ptients for whom prolifertive indices [mitotic count (mc), Ki-67 immunostin, nd Oncotype dx (Genomic Helth, Redwood City, CA, U.S.A.) recurrence score (rs)] were obtined. compre the indices preferred by oncologists with the indices vilble to them. correlte Nottinghm grde (ng) nd its subcomponents with Oncotype dx. ssess interobserver vrition. Methods All of the er-positive, her2-negtive, T1 2, N0 brest cncers dignosed from 2007 to 2011 (n = 5110) were linked to dtset of ll provincil brest cncers with rs. A 5% rndom smple of the 5110 cncers ws reviewed to estimte the proportion tht hd mc, Ki-67 index, nd rs. Correltion coefficients were clculted for the rs with ng subcomponent scores. Interobserver vrition in histologic grding between outside nd centrl review pthology reports ws ssessed using weighted kpp test. Results During , most cncers were histologiclly grded nd ssigned mc; few hd Ki-67 index or rs. The ng nd mc were significntly positively correlted with rs. The level of greement in histologic scoring between outside nd centrl pthology reports ws good or very good. Very few cses with low mc hd high rs (1.8%). Conclusions Ptients with low ng nd mc scores re unlikely to hve high rs, nd thus re less likely to benefit from chemotherpy. In the context of limited resources, tht finding cn guide clinicins bout when rs dds the most vlue. Key Words Brest cncer, prolifertive mrkers Curr Oncol June;22(3): INTRODUCTION Prolifertion indices cn provide vluble informtion bout the prognosis nd ggressiveness of brest tumours nd cn guide tretment recommendtions. Ptients with estrogen receptor (er) positive, her2-negtive, T1 2, N0 brest cncers represent group in which the decision to give chemotherpy is often ssocited with n uncertin or smll risk:benefit rtio. Indices of prolifertion help clinicins to ssess the risk of recurrence. As well, high prolifertion rtes in ptients with erly-stge er-positive node-negtive brest tumours imply n incresed potentil benefit from chemotherpy; low prolifertion rtes suggest modest recurrence risk, for which the hrm of chemotherpy might outweigh the benefit 1. Mitotic count (mc) is count of the number of mitotic figures visible in 10 high-power fields of light microscope. A score of 0, 1, 2, or 3 is then ssigned to the smple ccording to the cut-off vlues vlidted in the Nottinghm grding (ng) system 2. The method is inexpensive nd simple, but it lcks the precision nd rnge provided by more modern nd utomted techniques. The ubiquitous ng for brest cncer is composite score for tubule formtion (tf), nucler pleomorphism (np), nd mc 3. The nucler protein Ki-67 is expressed t its highest levels during mitosis; it is not expressed in G0 phse 4. Correspondence to: Scott Tyldesley, Deprtment of Rdition Oncology, BC Cncer Agency, Vncouver Centre, 600 West 10th Avenue, Vncouver, British Columbi V5Z 4E6 E-mil: styldesl@bccncer.bc.c n DOI: Current Oncology, Vol. 22, No. 3, June Multimed Inc.

2 Immunostining of tumour biopsy tissue with monoclonl ntibody (usully mib1) llows for n ssessment of the proportion of neoplstic cells tht re mitoticlly ctive. Tht growth frction is the Ki-67 index, reported s percentge, which cn be correlted with risk ctegories in brest cncer 3. Mny studies hve concluded tht the Ki-67 index cn provide physicins with informtion, beyond tht vilble by conventionl histopthology, bout prognosis nd risk of recurrence for erly brest cncers. There is evidence tht n elevted Ki-67 index is mrker of worse disese-free survivl nd overll survivl 5 7. The Ki-67 index could potentilly guide tretment recommendtions in future, but more reserch is needed to link the Ki-67 index with response to specific therpy nd to stndrdize the scoring system 3. The Oncotype dx (Genomic Helth, Redwood City, CA, U.S.A.) 21-gene ssy genertes recurrence score (rs) tht mesures the reltive expression levels of 16 cncer-relted genes nd 5 reference genes. The rs quntifies the risk of recurrence so tht the benefit of chemotherpy in ptients with erly-stge node-negtive er-positive brest cncers cn be ssessed. Cses re grouped into 3 ctegories low, intermedite, nd high risk of recurrence bsed on the expression levels of the cncer-relted genes. Of the 16 cncer-relted genes, 5 (including MKI67) constitute prolifertion group. In er-positive, her2-negtive, T1 2, N0 brest cncer, the mgnitude of the rs depends minly on the prolifertion group score becuse of its very high weighting in clculting the finl rs nd the reltively low estrogen nd her2 group scores (Tble i). Severl retrospective studies using tumour smples bnked by The Ntionl Surgicl Adjuvnt Brest nd Bowel Project B14 nd B20 trils hve found n ssocition between tumour gene expression, recurrence risk, nd benefit from chemotherpy. Compred with cncers hving low rs, cncers with high rs were found, in significntly greter proportion, to be ssocited with distnt recurrence t 10 yers 8. Recurrence risk ws lso shown to increse s expression levels of genes in the prolifertive group incresed 8. Additionlly, ptients with higher rs cncers nd likely more prolifertive tumour experienced greter benefit from djuvnt chemotherpy 1. In the present study, we exmined the use of indices of prolifertion tht is, ng nd mc, Ki-67 index, nd rs for TABLE I The 21-gene pnel (16 cncer-relted genes nd 5 reference genes) used to clculte the Oncotype DX Recurrence Score Group Genes Weighting Prolifertion MKI67, AURKA, BIRC5, CCNB1, MYBL Invsion MMP11, CTSV HER2 GRB7, ERBB Estrogen ESR, PGR, BCL2, SCUBE Reference FLNB, GAPDH, RPLP0, TFRC Other GSTM CD BAG Genomic Helth, Redwood City, CA, U.S.A. ptients with er-positive, her2-negtive, T1 2, N0 brest cncers in British Columbi during The resulting cohort is one of the lrgest to be exmined with respect to this topic, nd it is unique in tht it specificlly represents her2-negtive popultion. Our objectives were to estimte the proportion of ptients with er-positive, her2-negtive, T1 2, N0 brest cncers for whom the Nottinghm mc, Ki-67 index, nd Oncotype dx rs prolifertive indices were obtined. compre the indices preferred by oncologists with the indices vilble to them. correlte ng nd its subcomponents, prticulrly the mc, with rs. ssess interobserver vrition of mc nd ng between pthologists. METHODS All ptients with er-positive, her2-negtive, T1 2, N0, M0 brest cncers, dignosed nd referred to the BC Cncer Agency (bcc) between 2007 nd 2011 were identified using dt collected by the bcc Brest Cncer Outcomes Unit. The period ws chosen becuse it coincided with the period of recruitment for two lrge Oncotype dx bsed trils tht provided the only public ccess to Oncotype dx testing in British Columbi t the time 9,10. Ptients who hd been treted with neodjuvnt chemotherpy or who hd prior or synchronous invsive or in situ brest cncer dignosis were excluded. To estimte the use of ng, the Ki-67 index, nd Oncotype dx in this ptient popultion, 5% rndom smple of ptient chrts from the period of interest were retrospectively reviewed. The Ki-67 index ws bstrcted from pthology reports. Numerous pthology deprtments perform Ki-67 testing using vrious ssys, nd no uniform ssy or cut-point hd been estblished. During bstrction, the Ki-67 index ws scored s elevted or not elevted bsed on the qulittive description in the pthology report. (The most common cut-points for elevtion were >10% nd >20%.) The ptient nd disese chrcteristics collected were ge; TNM stging; lymphovsculr invsion (lvi) sttus; strength of er, progesterone receptor, nd her2 expression; ng, Ki-67, nd Oncotype dx (when performed) scores; nd the type of brest surgery, rdition tretment, hormonl therpy, nd chemotherpy prescribed. Medicl oncologists t the bcc were surveyed bout the ccessibility nd utility of the prolifertive mrkers in this ptient popultion. To determine the correltions of ng overll, tf, np, nd mc with rs risk group in this ptient popultion, ll ptients with er-positive, her2-negtive, T1 2, N0 brest cncer who were referred to the bcc during nd were known to hve hd n Oncotype dx test performed on clinicl study 9,10 were identified (n = 226). Histologic grding ws ssessed on the specimen used for the Oncotype dx test. Ptient nd tumour chrcteristics were collected from pthology reports. Spermn correltion coefficients nd 95% confidence intervls (cis) were clculted for rs risk Current Oncology, Vol. 22, No. 3, June Multimed Inc. 193

3 group compred with ng overll, tf, np, nd mc. The sme correltions were lso performed for lvi-negtive nd lvipositive cncers. A kpp correltion ws used to ssess the level of interobserver vrition between externl pthology reports nd internl pthology reviews of ng, where vilble. Resons for the reviews included lvi sttus, mrgin sttus, nodl sttus, nd qulity control. RESULTS A survey (Tble ii) distributed to the 31 medicl oncologists who tret ptients with brest cncer t the bcc ssessed TABLE II Survey for medicl oncologists on the utility of prolifertive scoring when determining the potentil benefit of chemotherpy When responding to the following questions, plese consider ptients with invsive ER±, T1 or T2, N0 brest cncers. 1) Do you consider indictors of prolifertion when deciding whether to recommend chemotherpy to your ptients? () Yes (b) No 2) If you nswered yes to question 1, which of the following prolifertive indictors do you consider when deciding if chemotherpy would be beneficil? (select ll tht pply) () Nottinghm mitotic index (b) Ki-67 immunostin (c) Oncotype (d) Other (stte) 3) Select the one prolifertive indictor you most frequently request or use in your decision-mking. () Nottinghm mitotic index (b) Ki-67 immunostin (c) Oncotype (d) Other (stte) 4) Which prolifertive mrkers do you not hve esy or routine ccess to? () Nottinghm mitotic index (b) Ki-67 immunostin (c) Oncotype (d) Other (stte) 5) If there were no brriers to ccessing testing for prticulr mrkers of prolifertion, which would be your preferred test to use 6) Which of the following best describes your level of greement with the following sttement: I hve sufficient ccess to indictors of prolifertion to confidently inform my decision bout chemotherpy when dvising ptients with ER-positive T1 2 N0 brest cncers. () Strongly gree (b) Somewht gree (c) Neither gree nor disgree (d) Somewht disgree (e) Strongly disgree 7) Do you think you would be less likely to overtret these ptients with chemotherpy if you hd more ccess to indictors of prolifertion? () Yes (b) No the preferred nd prcticed methods of mesuring prolifertion rtes in er-positive, her2-negtive, T1 2, N0 disese in British Columbi. The response rte ws 32%. Among responders, 90% stted tht they consider indictors of prolifertion, prticulrly the Nottinghm mc nd the Oncotype dx rs, when mking chemotherpy recommendtions to ptients. However, when sked which indices re esily ccessible, 87.5% nswered the Nottinghm mc only. When sked which mesure of prolifertion would be preferred if there were no brriers to ccess, the unnimous nswer ws the rs. All responders stted they would be less likely to overtret with chemotherpy if they hd better ccess to robust indictors of prolifertion. The impliction of more robust indictors ws tht respondents wnted tests tht hve been vlidted to both consistently nd ccurtely indicte prolifertion. During , 5110 ptients with er-positive, her2- negtive, T1 2, N0 brest cncers were referred to the bcc. Tble iii shows, bsed on the 5% rndom smple of those ptients (n = 256), the cse mix nd proportion of ptients for whom mc, Ki-67 index, nd rs ws obtined. A mc ws reported for 85% of the smple (n = 217), Ki-67 index for 9% (n = 24), nd rs for 5% (n = 14). Of the 5110 identified ptients, 226 hd both rs nd ng bsed on the specimen used for the rs. The medin ge in tht subpopultion ws 52 yers (rnge: yers). Medin tumour size ws 1.7 cm. All ptients underwent nodl procedure (sentinel lymph node biopsy, xillry dissection, or both), nd the medin number of nodes removed ws 3 (rnge: 1 27). Tble iii lso further describes disese nd tretment chrcteristics in the subpopultions. Despite positive er sttus, 7 ptients received no hormonl therpy. Resons included refusl of djuvnt tretment (n = 3), wekly positive er expression on immunohistochemistry (Allred score: 3) nd negtive er reported from Oncotype dx (even though er positivity ws reported on immunohistochemistry, n = 2), severe depression (n = 1), nd development of metsttic lung cncer (n = 1) shortly fter the brest cncer dignosis. The 5% rndom smple cohort (n = 256) nd the Oncotype dx cohort (n = 226) showed severl significnt differences (Tble iii). On verge, women for whom n Oncotype dx test ws performed hd more high-risk fetures for exmple, higher T stge nd grde, nd greter lvi. Ptients in the Oncotype dx cohort lso more often received chemotherpy nd hormonl therpy. Explntions for the differences include specific enrolment criteri for the trils within which the Oncotype dx testing occurred, higher generl complince mong ptients who choose to tke prt in trils, nd lck of vilbility of the trils in ll bcc centres. The ng overll nd the tf, np, nd mc were collected from the pthology reports for the 5% smple of dignosed ptients. Only ptients whose overll ng ws determined using the specimen lso used for the rs were included. When centrl pthology review hd been conducted (n = 136 ptients, 60% of the smple), the histopthologic vlues ssigned during the centrl review, rther thn the vlues from the externl pthology report, were used in our nlysis. 194 Current Oncology, Vol. 22, No. 3, June Multimed Inc.

4 TABLE III Ptient chrcteristics nd tretment fctors in two ptient groups, Chrcteristic 5% Rndom smple of ll referred ptients All ptients with Oncotype DX nd NG results Chi-squre p Vlue (n) (%) (n) (%) Ptients (n) b T Stge T <0.001 T1b T1c T N Stge N0 nd N0 (LVI-negtive) N0 (LVI-positive) Lymphovsculr invsion Positive Negtive Unknown Tumour grde Low Intermedite High Initil definitive surgery Brest-conserving Mstectomy Nodl procedures Affected ptients (n) SLNB lone SLNB xillry dissection Axillry dissection lone Chemotherpy No <0.001 Yes AC CMF AC plus txne FEC CEF Other Hormonl tretment No <0.001 Yes Tmoxifen <0.001 Tmoxifen + medicl OA Aromtse inhibitor Aromtse inhibitor plus medicl OA OA lone (RT or surgery) Genomic Helth, Redwood City, CA, U.S.A. b Medin ge: 52 yers (rnge: yers); medin nodes removed: 3; medin tumour size: 17 mm. NG = Nottinghm grde; LVI = lymphovsculr invsion; SNLB = sentinel lymph node biopsy; AC = cyclophosphmide doxorubicin; CMF = cyclophosphmide methotrexte fluorourcil; FEC100 = fluorourcil epirubicin cyclophosphmide; CEF = cyclophosphmide epirubicin fluorourcil; OA = ovrin bltion; RT = rdiotherpy. Current Oncology, Vol. 22, No. 3, June Multimed Inc. 195

5 Modertely significnt positive correltions between rs risk group nd overll grde (Spermn coefficient: 0.45; 95% ci: 0.34 to 0.55) nd between rs nd mc (Spermn coefficient: 0.43; 95% ci: 0.32 to 0.53; Tble iv) were observed 11. Wekly significnt positive correltions between rs nd tf (Spermn coefficient: 0.24; 95% ci: 0.11 to 0.36) nd between rs nd np (Spermn coefficient: 0.34; 95% ci: 0.22 to 0.45) were observed. The Ki-67 index ws vilble for only 24 ptients, of whom only 20 hd n evluble score, with 8 being below the cut-point, nd 12 being bove it. A detiled nlysis nd determintion of correltions with mc nd rs ws therefore not possible. Of the 8 cses with Ki-67 index below the cut-point, none hd high mc, nd none underwent Oncotype dx testing. Published retrospective reports suggest tht chemotherpy hs vlue predominntly in cncers with high rs 1, nd so second nlysis of correltion tht grouped the women hving low nd intermedite rs scores nd compred them with the women hving high rs scores ws performed. When the ng, tf, np, nd mc scores nd the rs risk group scores were converted into binry vribles, the strength of the correltions incresed (Tble iv). A strongly significnt positive correltion between the mc nd rs (Spermn correltion: 0.61; 95% ci: 0.52 to 0.69) ws observed. None of the cncers with low ng overll or low tf or np hd n Oncotype dx rs tht ws clssified s high risk; 4 cncers with mc of 1 (1.8%) hd high Oncotype dx rs. Becuse the presence of lvi is risk fctor used by some clinicins in determining the risk:benefit rtio for chemotherpy, secondry nlysis considered just the lvi-negtive cses. Spermn correltion coefficients of the ng overll nd the tf, np, nd mc with the Oncotype dx rs were stronger for the lvi-negtive cncers (n = 190) thn for the lvi-positive (n = 35) cncers (Tble v). The lvi-negtive cses showed modertely significnt positive correltions between rs risk group nd ng overll (Spermn coefficient: 0.46; 95% ci: 0.34 to 0.56) nd between rs nd mc (Spermn coefficient: 0.44; 95% ci: 0.32 to 0.55). When the nlysis in lvi-negtive cses ws repeted using the binry ng nd mc scores compred with the rs, modertely significnt positive correltions between ng overll nd rs (Spermn coefficient: 0.56; 95% ci: 0.45 to 0.65) nd between mc nd rs (Spermn coefficient: 0.59; 95% ci: 0.49 to 0.68) were observed. Most of the 226 er-positive, her2-negtive, T1 2, N0 brest cncers for which n Oncotype dx ws performed (n = 136, 60%) lso underwent n internl bcc pthology review bsed on the specimen used for the Oncotype dx test. Applying weighted kpp test to ssess interobserver TABLE IV Correltion nlysis of grde scores in 226 ptients with estrogen receptor positive, HER2-negtive, T1 2, N0 brest cncer Nottinghm fctor nd score Recurrence score risk group Spermn correltion coefficient Low Intermedite High Strength of correltion p Vlue Overll grde Moderte <0.001 (n = 226) Tubule formtion Wek <0.001 (n = 222) Nucler polymorphism Wek <0.001 (n = 222) Mitotic count Moderte <0.001 (n = 221) Low + intermedite High Overll grde Moderte <0.001 (n = 226) Tubule formtion Wek (n = 222) Nucler polymorphism Moderte <0.001 (n = 222) Mitotic count Strong <0.001 (n = 221) By Oncotype DX (Genomic Helth, Redwood City, CA, U.S.A.). HER2 = humn epiderml growth fctor receptor Current Oncology, Vol. 22, No. 3, June Multimed Inc.

6 vrition (Tble vi), we observed very good significnt correltion for ng overll between the review nd nonreview pthology reports (κ = 0.84, p < 0.001) nd tf (κ = 0.84, p < 0.001). The pthology reports lso showed good significnt correltion for np (κ = 0.66, p < 0.001) nd mc (κ = 0.69, p < 0.001) 12. Becuse discordnce in mc nd ng between the initil nd the review pthology ws observed in only 10 cses, nlyses tht excluded the review pthology showed no significnt differences in the correltion of mc nd ng with rs. DISCUSSION Ptients with er-positive, her2-negtive, T1 2, N0 brest cncers represent group for whom decision-mking bout djuvnt chemotherpy cn be difficult. Prognostic estimtes nd mrkers of prolifertion embedded within the ng nd the Oncotype dx rs cn help group ptients into risk ctegories, which might enhnce confidence bout tretment recommendtions. The Oncotype dx ssy ppers to be informtive for scores clssified s low- nd high-risk, s demonstrted by severl retrospective studies 1,8. For exmple, retrospective nlysis of the Ntionl Surgicl Adjuvnt Brest nd Bowel Project B20 tril showed significnt benefit from djuvnt chemotherpy only in the high-risk group, nd little-to-no benefit in the low-risk group 1. The benefit in the intermedite risk ctegory is less cler. Argubly, the Oncotype dx test is not yet informtive for those cses; results of the tilorx study re wited 9. Our findings re consistent with severl retrospective studies lso investigting the correltions between rs nd routine pthology prmeters 2, In study of 138 invsive brest cncer cses, Auerbch et l. 13 showed tht combintion of negtivity for the progesterone receptor nd mc greter thn 1 correlted with n intermedite or high Oncotype dx rs. However, those results were bsed only on subset of 12 cses. In test dtset of 104 cses, Allison et l. 14 found tht combintion of ng 1, strong positivity for the progesterone receptor (Allred score 5), nd Ki-67 below 10% predicted low Oncotype dx rs. In study of 42 cses, Flngn et l. 15 lso demonstrted tht the Oncotype dx rs correlted with ng nd mc. The study by Zybtek et l. 2 of 137 er-positive invsive brest cncers lso found high correltion with Nottinghm mc nd Oncotype dx rs. Our study, which encompsses one of the lrgest cohorts used in n exmintion of this topic, dds to the literture nd focuses on her2-negtive ptient popultion. The dt from both the prctitioner survey nd the 5% retrospective review indicte tht, of most such ptients in British Columbi whose ng nd mc were determined during the period of interest, reltively few underwent Ki-67 or Oncotype dx testing. The survey suggests tht oncologists fvour Nottinghm mc nd Oncotype dx rs to inform chemotherpy decisions. The Ki-67 ssy is considered less vluble (in prt for the resons outlined in the Introduction). Oncotype dx is the lest ccessible nd most expensive, but lso the most desired prolifertive index for er-positive, her2-negtive, T1 2, N0 ptients. In the present study, we observed modertely significnt positive correltions of ng nd mc with Oncotype dx rs nd wekly positive correltions of tf nd np. Mirroring the findings of the Ntionl Surgicl Adjuvnt Brest nd Bowel Project B20 tril, we observed tht when the rw scores for ng overll, tf, np, mc, nd rs re converted to binry vribles, the strength of correltions increses. The very good strength of interobserver correltion between the non- TABLE V Correltion nlysis of Nottinghm histology with Oncotype DX recurrence score risk group, by lymphovsculr invsion sttus Correltion Lymphovsculr invsion Negtive (n=190) Positive (n=35) Spermn coefficient p Vlue Spermn coefficient p Vlue Overll grde vs. risk group 0.46 < Tubulr formtion vs. risk group Nucler polymorphism vs. risk group 0.35 < Mitotic count vs. risk group 0.45 < Genomic Helth, Redwood City, CA, U.S.A. TABLE VI Inter-observer vrition in Nottinghm grde subscores Nottinghm grde fctor Medin score Kpp Strength of greement p Vlue Outside report Review report Overll grde Very good <0.001 Tubule formtion Very good <0.001 Nucler polymorphism Good <0.001 Mitotic count Good <0.001 Current Oncology, Vol. 22, No. 3, June Multimed Inc. 197

7 review nd centrl review pthology reports is ressuring for the scoring consistency of the ng nd its subcomponents in the pthology community in British Columbi. It suggests tht cncers with low or intermedite score for tf, np, nd mc re unlikely to return tretment-chnging rs (tht is, be reclssified s high-risk). In the current helth cre climte influenced by limited resources, clinicins cn use those dt to guide their determintion of when n Oncotype dx rs will dd the most vlue. Tht finding is importnt given tht most clinicins responding to survey preferred the rs bove other mesures of prolifertion, presumbly on the bsis tht it provided more or better informtion, which it does not pper to do for cncers with low mc nd ng vlues. If n Oncotype dx test cnnot be offered to ll such ptients, our dt show tht testing will be most useful nd cliniclly ctionble in ptients with high histologic scores. Our nlysis hs severl limittions. Reltively few ptients in British Columbi underwent Ki-67 testing during the er of interest, limiting our bility to clculte correltions with tht index. No provincil policy on centrlized testing for Ki-67 or the consistency of its cut-point hs been rticulted, rendering its interprettion t popultion level difficult, nd belief bout the utility of the Ki-67 index (compred with ng nd rs) is less consistent. Also, not ll cses underwent centrl review of their ng. Use of Oncotype dx testing ws reltively low. Our nlysis in some wys simplifies the complex decisions mde by medicl oncologists in individul cses, nd s lwys, there will be exceptions for whom n Oncotype dx rs might hve dditionl vlue. For exmple, fctors tht require dditionl considertion re tumour size, ptient ge, nd comorbidities. Within T stge, tumour size (much like er sttus, grde, nd lvi) is fctor tht informs the decision bout chemotherpy. Specificlly when considering chemotherpy, oncologists might be more inclined to wnt dditionl guidnce from rs for lrge low-grde tumour. Similrly, when the potentil benefit of chemotherpy is diminished becuse of ptient s dvnced ge or significnt comorbidity, the rs might help to justify disinclintion towrd chemotherpy in tumours with high ng or mc score. Despite the foregoing limittions, our series ddressing vrious prolifertive scoring methods is one of the lrgest nd is specificlly focused on er-positive, her2-negtive, T1 2, N0 disese. CONCLUSIONS The Oncotype dx rs very rrely provides informtion tht will chnge tretment recommendtions for cncers with low ng or mc scores. Although oncologists responding to survey identified rs s their preferred method of ssessing prolifertion nd the vlue of chemotherpy in er-positive, her2-negtive, T1 2, N0 disese, our dt suggest tht rs is no better thn mc nd ng when those prmeters score low. In helth cre system with limited resources, such dt should inform clinicins nd dministrtors with respect to how the cost of rs cn be blnced ginst dditionl ctionble informtion to id in chemotherpy recommendtions. CONFLICT OF INTEREST DISCLOSURES We hve red nd understood Current Oncology s policy on disclosing conflicts of interest, nd we declre tht we hve none. AUTHOR AFFILIATIONS * Deprtment of Rdition Oncology, BC Cncer Agency, Vncouver Centre, BC; Deprtment of Cncer Surveillnce nd Outcomes, BC Cncer Agency, Vncouver Centre, BC; Deprtment of Medicl Oncology, BC Cncer Agency, Vncouver Centre, BC; Deprtment of Pthology, BC Cncer Agency, Vncouver Centre, BC. REFERENCES 1. Pik S, Tng G, Shk S, et l. Gene expression nd benefit of chemotherpy in women with node-negtive, estrogen receptor-positive brest cncer. J Clin Oncol 2006;24: Zybtek B, Cohen C, Wng J, Pge A, Willims DJ, Adms AL. Nottinghm-defined mitotic score: comprison with visul nd imge cytometric phosphohistone H3 lbeling indices nd correltion with Oncotype dx Recurrence Score. Appl Immunohistochem Mol Morphol 2013;21: Dowsett M, Nielsen TO, A Hern R, et l. Assessment of Ki67 in brest cncer: recommendtions from the Interntionl Ki67 in Brest Cncer Working Group. J Ntl Cncer Inst 2011;103: Inwld EC, Klinkhmmer-Schlke M, Hofstädter F, et l. Ki-67 is prognostic prmeter in brest cncer ptients: results of lrge popultion-bsed cohort of cncer registry. Brest Cncer Res Tret 2013;139: Goldhirsch A, Ingle JN, Gelber RD, Cotes AS, Thürlimnn B, Senn HJ. Thresholds for therpies: highlights of the St Gllen Interntionl Expert Consensus on the primry therpy of erly brest cncer Ann Oncol 2009;20: Cheng MC, Chi SK, Voduc D, et l. Ki67 index, her2 sttus, nd prognosis of ptients with luminl B brest cncer. J Ntl Cncer Inst 2009;101: de Azmbuj E, Crdoso F, de Cstro G Jr, et l. Ki-67 s prognostic mrker in erly brest cncer: met-nlysis of published studies involving 12,155 ptients. Br J Cncer 2007;96: Pik S, Shk S, Tng G, et l. A multigene ssy to predict recurrence of tmoxifen-treted, node-negtive brest cncer. N Engl J Med 2004;351: Zujewski JA, Kmin L. Tril ssessing individulized options for tretment for brest cncer. The tilorx tril. Future Oncol 2008;4: Dvidson JA, Cromwell I, Ellrd SL, et l. A prospective clinicl utility nd phrmcoeconomic study of the impct of the 21- gene Recurrence Score ssy in oestrogen receptor positive node negtive brest cncer. Eur J Cncer 2013;49: Dncey CP, Reidy J. Sttistics Without Mths for Psychology. 5th ed. Hrlow, UK: Person Eduction; Cohen J. A coefficient of greement for nominl scles. Educ Psychol Mes 1960;20: Auerbch J, Kim M, Fineberg S. Cn fetures evluted in the routine pthologic ssessment of lymph node-negtive estrogen receptor-positive stge i or ii invsive brest cncer be used to predict the Oncotype dx Recurrence Score? Arch Pthol Lb Med 2010;134: Allison KH, Kndlft PL, Sitlni CM, Dintzis SM, Gown AM. Routine pthologic prmeters cn predict Oncotype dx recurrence scores in subsets of er positive ptients: who does not lwys need testing? Brest Cncer Res Tret 2012;131: Flngn MB, Dbbs DJ, Brufsky AM, Beriwl S, Bhrgv R. Histopthologic vribles predict Oncotype dx Recurrence Score. Mod Pthol 2008;21: Current Oncology, Vol. 22, No. 3, June Multimed Inc.