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Outcome Prediction for Estrogen Receptor–Positive Breast Cancer Based on Postneoadjuvant Endocrine Therapy Tumor Characteristics

Outcome Prediction for Estrogen Receptor–Positive Breast Cancer Based on Postneoadjuvant... ARTICLE Outcome Prediction for Estrogen Receptor – Positive Breast Cancer Based on Postneoadjuvant Endocrine Therapy Tumor Characteristics Matthew J. Ellis , Yu Tao , Jingqin Luo , Roger A’Hern , Dean B. Evans , Ajay S. Bhatnagar , Hilary A. Chaudri Ross , Alexander von Kameke , William R. Miller , Ian Smith , Wolfgang Eiermann , Mitch Dowsett Background Understanding how tumor response is related to relapse risk would help clinicians make decisions about additional treatment options for patients who have received neoadjuvant endocrine treatment for estro- gen receptor – positive (ER+) breast cancer. Methods Tumors from 228 postmenopausal women with confirmed ER+ stage 2 and 3 breast cancers in the P024 neoadjuvant endocrine therapy trial, which compared letrozole and tamoxifen for 4 months before sur- gery, were analyzed for posttreatment ER status, Ki67 proliferation index, histological grade, pathological tumor size, node status, and treatment response. Cox proportional hazards were used to identify factors associated with relapse-free survival (RFS) and breast cancer – specific survival (BCSS) in 158 women. A preoperative endocrine prognostic index (PEPI) for RFS was developed from these data and validated in an independent study of 203 postmenopausal women in the IMPACT trial, which compared treatment with anastrozole, tamoxifen, or the combination 3 months before surgery. Statistical tests were two-sided. Results Median follow-up in P024 was 61.2 months. Patients with confirmed baseline ER+ clinical stage 2 and 3 tumors that were downstaged to stage 1 or 0 at surgery had 100% RFS (compared with higher stages, P < .001). Multivariable testing of posttreatment tumor characteristics revealed that pathological tumor size, node status, Ki67 level, and ER status were independently associated with both RFS and BCSS. The PEPI model based on these factors predicted RFS in the IMPACT trial ( P = .002). Conclusions Breast cancer patients with pathological stage 1 or 0 disease after neoadjuvant endocrine therapy and a low-risk biomarker profile in the surgical specimen (PEPI score 0) have an extremely low risk of relapse and are therefore unlikely to benefit from adjuvant chemotherapy. J Natl Cancer Inst 2008;100: 1380 – 1388 An accurate test to predict the effectiveness of adjuvant endocrine model that incorporates standard pathological staging variables therapy for hormone receptor – positive breast cancer on an indi- and “on-treatment” biomarker values. We validated the model vidual basis would be an important advance ( 1 ). Current approaches internally though bootstrap analysis and subsequently validated it focus on biomarker analysis of the diagnostic specimen. An alter- externally using data from an independent neoadjuvant native is to treat patients with an endocrine agent for several months before surgery to identify tumors that are responsive to Affiliations of authors : Siteman Cancer Center, Washington University, treatment, with the assumption that responsiveness indicates a St Louis, MO (MJE, YT, JL); Clinical Trials and Statistics Unit, Institute of lower risk of relapse. However, compared with neoadjuvant che- Cancer Research, Sutton, UK (RAH); Novartis Pharma AG, Basel, Switzerland motherapy studies ( 2 ), fewer neoadjuvant endocrine therapy trials (DBE, ASB, HACR, AvK); Edinburgh Breast Unit, Edinburgh University, Edinburgh, UK (WRM ); Royal Marsden Hospital, London, UK (IS, MD); Red have been conducted; thus, fewer data are available to link post- Cross Women ’ s Hospital, Munich, Germany (WE) . neoadjuvant therapy tumor characteristics and survival. Correspondence to: Matthew J. Ellis, MB, BChir, PhD, Siteman Cancer The P024 neoadjuvant endocrine therapy trial, which com- Center, Washington University School of Medicine, 660 South Euclid Ave, pared 4 months of letrozole and tamoxifen before surgery ( 3 , 4 ), St Louis, MO 63119 (e-mail: mellis@wustl.edu ). now has suffi cient follow-up (median >60 months) to address the See “Notes” following “References.” relationships between postneoadjuvant endocrine therapy tumor DOI: 10.1093/jnci/djn309 characteristics and risk of early relapse. In this study, we used © 2008 The Author(s). This is an Open Access article distributed under the terms of the Creative Com- data from P024 to examine pathological stage posttreatment, mons Attribution Non-Commercial License (http://creativecommons.org/licenses/ histological grade posttreatment, response to treatment, and the by-nc/2.0/uk/), which permits unrestricted non-commercial use, distribution, and biomarker status of the surgical specimen to develop a prognostic reproduction in any medium, provided the original work is properly cited. 1380 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008 endocrine therapy study that compared anastrozole, tamoxifen, CONTEXT AND CAVEATS or the combination for 3 months before surgery (the IMPACT Prior knowledge trial) ( 5 , 6 ). Endocrine therapy before surgery increases the rate of breast con- servation surgery for patients with hormone receptor – positive Subjects and Methods breast cancer, but factors to predict risk of relapse after treatment have not been identified. Study Population and Tumor Bank Both clinical trials described in this manuscript were approved Study design Posttreatment prognostic factors from patients enrolled in clinical by the local institutional review boards that enrolled patients into trials of neoadjuvant endocrine therapy were used to develop and the studies ( 3 , 5 ). The P024 protocol compared 4 months of validate a model to predict risk of relapse. neoadju vant letrozole therapy with 4 months of neoadjuvant tamoxifen therapy in postmenopa usal women with clinical stage Contribution 2 and 3 hormone receptor – positive breast cancers (classified as at A model that includes information on standard surgical staging least 10% nuclear staining for estrogen receptor [ER] and/or pro- parameters after neoadjuvant endocrine treatment, estrogen recep- tor status, and levels of Ki67 proliferation antigen can define broad gesterone receptor [PgR]) who were ineligible for breast conserva- relapse risk groups. tive surgery ( 3 ). The clinical findings, tumor bank characteristics, and biomarker measurements have been described previously Implications ( 3 , 4 , 7 ). The cut point for ER positivity for central laboratory Data from this model may prove useful with respect to other deci- analysis was an Allred score of 3 ( 8 ). Information on tumor grade, sions that must be made after a patient is treated with neoadjuvant clinical response by caliper measurements, definitive pathological endocrine therapy, such as the use of adjuvant chemotherapy. staging at surgery , and chemotherapy administration was collected Limitations prospectively. Patients in P024 were recommended to receive The studies used for developing and validating the model were adjuvant tamoxifen for 5 years. The IMPACT study design, short- small, used different treatments, and had relatively short median and long-term outcomes, and biomarker methodology have also follow-up data available (just more than 5 years). been described previously ( 5 , 6 , 9 ). For the validation analysis, we From the Editors compiled information on surgical stage, surgical specimen Ki67 proliferation antigen levels, ER data, duration of follow-up, and relapse dates. The IMPACT study used the H-score ( 10 ) to assess ER status. We converted the H-score ER cutoff to an Allred score the statistical significance of a factor after adjusting for the other ER cutoff for the analyses. An Allred score of 2 can be derived in factors. The proportionality assumption was checked by testing only one way, ie, less than 1% of cells staining weakly, which time-dependent covariates in the model and graphically examining equates to an H-score of less than 1. Thus, it is valid to use an scaled Schoenfeld residuals. Hazard ratio (HR) estimates of each H-score of at least 1 as the equivalent of an Allred score of at least factor in the final multivariable model were used to construct a 3 as the threshold for ER positivity. score, the preoperative endocrine prognostic index (PEPI), for risk of relapse and breast cancer – specific death for each sample in the Statistical Analysis test cohort. The PEPI score was derived as an arithmetic sum of Relapse-free survival (RFS) was defined as the interval between risk points weighted by the size of the HR assigned to each statisti- random assignment to treatment and the earliest subsequent breast cally significant factor ( 11 ). The overall discriminatory capacity of cancer event. No new breast primary tumors were documented in the Cox model on the P024 data was assessed using Harrell’s C either dataset, effectively excluding this class of event from the risk index, which was then adjusted after a 1000 bootstrap assessment model that was developed. Breast cancer – specific survival (BCSS) of the overfitting (optimism) portion. The 95% confidence inter- was defined as the interval between random assignment and the val (CI) for the adjusted C index was also reported ( 12 ). For the date of death after breast cancer relapse. When we included all IMPACT trial validation analysis, we calculated the PEPI score for deaths, irrespective of cause, as RFS and overall survival events, all patients who had data for the four factors and examined the there were no major changes in the P024 results (data not shown). association of PEPI score with RFS. SAS version 9.02 (SAS Survival curves were estimated by the Kaplan – Meier method, and Institute, Cary, NC) and R 2.6 software (R Foundation for a two-sided P value of .05 from a log-rank test was considered a Statistical Computing) were used for all analyses. statistically significant difference. A multivariable Cox propor- tional hazard regression model was used to evaluate the indepen- Results dent prognostic relevance of each factor, namely, pathological tumor size (T1/2 vs T3/4 or T1 vs T2 – 4), pathological node status Definition of the Patient Populations for Analysis (negative vs positive), clinical response (complete plus partial clini- Detailed information on the P024 population used in each of the cal response vs stable disease plus progressive disease), surgical analyses was compiled and is summarized in Figure 1 . The median specimen ER status (Allred score ≥ 3 vs 0 or 2), histological grade follow-up was 61.2 months for the patients who underwent sur- (grade 1 vs grade 2/3), and the Ki67 level, as natural log-trans- gery at the end of 4 months of endocrine treatment (n = 290) and formed intervals ( 9 ), in both the pretreatment specimen and the 62.0 months for the patients with a complete dataset for the mul- surgical specimen. P values from Wald chi-square tests indicated tivariable analysis (n = 158). Assignment to neoadjuvant letrozole jnci.oxfordjournals.org JNCI | Articles 1381 Figure 1 . Patient populations for univari- ate and multivariable analysis. The patient populations are described in this diagram to illustrate how the univariable analysis sought to include the largest population possible. The multivariable analysis was performed on a subset of patients among whom all factors in the model were available for comparison. ER = estrogen receptor. or tamoxifen had no impact on RFS or BCSS, but because all response — stage 0) were compared with patients with p-stage 2 patients received adjuvant tamoxifen a difference was not antici- or 3 disease at surgery. No relapses and only one death without pated. Thus, for the purposes of these analyses, the results from known relapse (which was censored) were recorded in the group both arms were pooled together. As described in the original of 29 patients with p-stage 1 disease plus one patient with p-stage report on central laboratory ER testing ( 4 ), 12% of patients had 0 disease vs 53 of the 175 patients (30% relapse incidence) with ER  tumors at baseline, and of the 28 ER  and PgR  tumors, p-stage 2 and 3 disease ( Figure 2, A , P < .001). The p-stage 1 or 0 only one was reported to respond to treatment. Long-term status appeared to reflect downstaging of a group of endocrine follow-up confirmed that these tumors were likely to have been therapy – responsive tumors because the clinical response rate was correctly assigned by the central laboratory because baseline ER  79% in the p-stage 1 or 0 group vs 52% in the p-stage 2 or 3 status was associated with poor overall survival ( P = .004, data not group (response rate difference = 27%, 95% CI = 10.5% to shown). Subsequent analysis therefore focused on patients with 42.5%; P = .006). Furthermore, tumors in the p-stage 1 or 0 group ER+ tumors as assigned by the central laboratory (n = 228). had lower posttreatment geometric mean Ki67 levels than higher p-stage tumors (0.39 vs 0.98, ratio of geometric means = 0.40, Pathological Stage, Tumor Grade, and Response 95% CI = 0.18 to 0.89; P = .03). The average baseline tumor size on Outcome for the pT1 or pT0N0 tumors was predictably smaller than that All patients had clinical stage 2 or 3 tumor at diagnosis. To exam- of tumors with a higher pT stage at surgery; 3.9 vs 5.2 cm (longest ine the impact of pathological (p) stage on outcome, patients diameter) by clinical caliper measurement ( P < .001), 2.8 vs 4.0 by whose tumors were downstaged at surgery to pT1N0 (node mammogram ( P < .001), and 2.6 vs 3.4 cm by ultrasound ( P = negative with a tumor size of ≤ 2 cm diameter with negative .003). However, given that these average measurements are all ax illary lymph nodes — stage 1) or pT0N0 (pathological complete larger than 2 cm, it is unlikely that many tumors in the P024 study 1382 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008 Figure 2 . Kaplan – Meier analysis of relapse- free survival (RFS) and breast cancer – specifi c survival (BCSS) among women whose tumors were established to be estrogen receptor positive (ER+) at baseline by central laboratory analysis. A ) RFS for posttreatment pathological stage 1 or 0 (T1N0 or T0N0, green ) vs higher stages ( red ), P < .001; B ) RFS for posttreatment pathological node negative ( green ) vs node positive ( red ), P < .001; C ) RFS for posttreatment clinical responders ( green ) vs no clinical response ( red ), P = .002; D ) RFS for posttreatment histological grade (Grade I, green, vs Grade II/III, red ), P < .001. E ) RFS for patients with ER+ tumors post- treatment ( green ) vs ER negative (  ) tumors posttreatment ( red ), P = .03; F ) BCSS for patients with ER+ tumors posttreatment ( green ) vs ER  tumors posttreatment ( red ), P = .002; censorship marks are provided as open circles . All P values (two-sided) were calculated using the log-rank test. were p-stage 1 at diagnosis and therefore likely that p-stage 1 .002; Figure 2, C ), pretreatment grade ( P = .002) (data not shown), status usually reflects the effects of tumor regression induced by and posttreatment grade (grade I vs grade II or III, P < .001; Figure treatment. The excellent outcome in the p-stage 1 or 0 group was 2, D ). The alternative grade dichotomy of grade I or II vs III did not strongly influenced by chemotherapy because only 2 of the 30 not have better prognostic characteristics (data not shown). (7%) patients with p-stage 1 or 0 disease underwent adjuvant chemotherapy vs 61 of 175 (35%) patients with p-stage 2 or 3 The Association of Posttreatment ER Status with Outcome disease ( P = .001). Other factors that were associated with RFS We had previously noted that a number of tumor samples that were in univariate analysis included posttreatment pathological node ER+ before treatment had lost ER expression in the posttreatment status ( P < .001; Figure 2, B ), clinical response to treatment ( P = sample [ie, converted to an Allred score of 0 or 2, or unequivocally jnci.oxfordjournals.org JNCI | Articles 1383 Table 1 . Univariate and multivariable analysis of relapse-free survival according to posttreatment pathological tumor size, post treatment node status, posttreatment Ki67 level, posttreatment ER status, and posttreatment tumor grade in the P024 trial * Relapse-free survival Univariate analysis Multivariable analysis No. of patients No. of events/no. Factor definitions in each group of patients HR (95% CI) P HR (95% CI) P Pathological tumor size † T1/2 vs T3/4 138/33 47/171 2.7 (1.4 to 5.0) .002 3.0 (1.54 to 5.91) .001 T1 vs T2–4 53/118 47/171 2.01 (1.0 to 4.1) .05 — Node status (positive vs negative) 90/69 44/159 3.9 (1.8 to 8.4) <.001 2.8 (1.31 to 6.19) .009 Ki67 level, per 2.7-fold increase ‡ NA 48/174 1.4 (1.2 to 1.6) <.001 1.3 (1.05 to 1.50) .01 ER, Allred score (0 or 2 vs 3 – 8) § 16/157 48/173 2.4 (1.0 to 5.3) .04 2.6 (1.1 to 6.0) .03 Clinical response (yes vs no) 70/104 49/174 2.8 (1.6 to 4.9) <.001 1.72 (0.96 to 3.09) .07 Grade (I vs II/III) 33/126 46/159 3.8 (1.4 to 10.8) .011 2.72 (0.95 to 7.8) .06 * The total number in each univariate analysis varied depending on the number of cases in which information on the individual factor was available. Cox proportional hazards models were used to calculate hazard ratios (HRs) and their 95% confidence intervals (CIs) of relapse, comparing tumors with the adverse factor relative to tumors without the adverse factor. Two-sided P values are provided throughout. † Tumor size was examined with two cutoff points, pT1/2 vs pT3/4 and pT1 vs pT2 – 4. A cutoff point of pT1/2 provided the smallest univariate P value and was used in the multivariable analysis (which excluded factors with a univariate P value of >.05). ‡ Ki67 was analyzed as the natural logarithm values, or per 2.7-fold increase according to the original scale of percentage values. § The estrogen receptor (ER) analysis refers to the posttreatment values; before treatment all tumors in this dataset were ER+. NA (not applicable) because K167 divided into five risk groups (see Table 4). ER  ( 4 )]. We therefore compared RFS and BCSS between patients as a continuous variable after natural log transformation, as recom- with tumors that converted from ER+ to ER  and patients with mended by Dowsett et al. ( 9 ). This analysis approach examines the tumors that were persistently ER+ at surgery. The 16 patients with HR per 2.7-fold increase in the Ki67 value (referred to as “natural posttreatment ER  tumors had worse RFS (HR of relapse = 2.4, log intervals”). Pretreatment Ki67 natural log intervals were not 95% CI = 1.0 to 5.3; P = .03) and BCSS (HR of breast cancer death = associated with relapse, whereas there was a highly statistically 4.3, 95% CI = 1.6 to 11.7; P = .002) ( Figure 2, E and F ) than patients significant association between RFS and posttreatment Ki67 natu- with tumors that retained ER+ after treatment. The pretreatment ral log intervals (HR = 1.4, 95% CI = 1.2 to 1.6 per log unit Allred scores of tumors that were ER  after treatment was similar increase; P < .001; Table 1 ), which also held for BCSS (HR = 1.4, to that of tumors that retained ER expression ( P = .2). CI = 1.1 to 1.7; P = .009; Table 2 ). The Association of Pre- and Posttreatment Ki67 Development of a Multivariable Cox Model Proliferation Index with Outcome Pathological tumor size (T1/2 vs T3/4 or T1 vs T2 – 4), patho- Ki67 is a commonly used proliferation antigen that identifies cells logical node status (negative vs positive), clinical response (com- in the G1/S and M phases of the cell cycle ( 13 ). Ki67 was examined plete plus partial clinical response vs stable disease plus Table 2 . Univariate and multivariable analysis of breast cancer – specific survival according to pathological tumor size, node status, posttreatment Ki67, posttreatment ER status, and posttreatment tumor grade in the P024 trial * Breast cancer – specific mortality Univariate analysis Multivariable analysis No. of patients No. of events/no. Factor definition in each group of patients HR (95% CI) P HR (95% CI) P Pathological tumor size † T1/2 vs T3/4 138/33 24/171 3.5 (1.5 to 8.3) .004 4.4 (1.7 to 11.3) .002 T1 vs T2–4 53/118 24/171 4.1 (1.2 to 13.8) .025 — Node status (positive vs negative) 90/69 22/159 4.6 (1.4 to 15.8) .01 3.2 (0.9 to 11.2) .07 Ki67 level, per 2.7-fold increase ‡ NA 25/174 1.4 (1.1 to 1.7) .009 1.4 (1.1 to 1.8) .02 ER, Allred score (0 or 2 vs 3 – 8) § 16/157 25/173 4.3 (1.6 to 11.7) .005 6.3 (2.1 to 18.7) <.001 Clinical response (yes vs no) 70/104 25/174 2.2 (0.97 to 4.9) .06 1.1 (0.5 to 2.5) .78 Grade (I vs II/III) 33/126 24/159 7.1 (0.96 to 53) .05 4.62 (0.6 to 35.0) .1 * The total number in each univariate analysis varied depending on the number of tumors in which information on the individual factor was available. Cox proportional hazards model was used to calculate hazard ratios (HRs) and their confidence intervals (CIs) of relapse, comparing tumors with the adverse factor relative to those without the adverse factor. Two-sided P values are provided throughout. † Tumor size was examined by two cutoffs, pT1/2 vs pT3/4 and pT1 vs pT2 – 4. A cutoff of pT1/2 provided the smallest univariate P value and was used in the multivariable analysis (which excluded factors with a univariate P value of >.05). ‡ Ki67 analyzed as the natural-logarithm values, or per 2.7-fold increase according to the original scale of percentage values. § The estrogen receptor (ER) analysis refers to the posttreatment values; before treatment all the tumors in this dataset were ER+. 1384 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008 Table 3 . Multivariable Cox proportional hazards analysis of progressive disease), surgical specimen ER status (Allred score relapse-free survival (RFS) and breast cancer – specific survival ≥ 3 vs 0 or 2), histological grade (grade I vs grade II/III), and (BCSS) from the P024 trial * Ki67 natural log intervals were used in a multivariable Cox pro- Pathology portional hazard model to determine their association with RFS RFS BCSS biomarker and ( Table 1 ) and BCSS ( Table 2 ). For Ki67, the posttreatment response factors HR (95% CI) P HR (95% CI) P natural log intervals were statistically significantly associated Pathological tumor 2.8 (1.4 to 5.4) .003 4.4 (1.7 to 11.2) .002 with both RFS (per log unit increase, HR of relapse = 1.3, 95% size (T1/2 vs T3/4) CI = 1.05 to 1.50; P = .01) and BCSS (per log unit increase, HR Node status 3.2 (1.5 to 6.9) .004 3.9 (1.1 to 13.7) .04 of breast cancer death = 1.4, 95% CI = 1.1 to 1.8; P = .02). (positive vs Pathological tumor size (pT1/2 vs pT3/4) was strongly associ- negative) ated with RFS (HR = 3.0, 95% CI = 1.54 to 5.91; P = .001) and Ki67 level per 1.3 (1.1 to 1.6) .003 1.4 (1.07 to 1.9) .01 2.7-fold increase BCSS (HR = 4.4, 95% CI = 1.7 to 11.3; P = .002). Pathological ER, Allred score 2.8 (1.2 to 6.4) .02 7.0 (2.4 to 20.9) <.001 node status was also associated with RFS (positive vs negative, (0 or 2 vs 3 – 8) HR = 2.8, 95% CI = 1.31 to 6.19; P = .009). ER status posttreat- ment (Allred score 0 or 2 vs 3 – 8) was also independently associ- * The four factors associated with a P value of .05 or less for RFS in Table 1 were reanalyzed in a Cox model to assign final hazard ratios for risk of ated with RFS (HR = 2.6, 95% CI = 1.1 to 6.0; P = .03). For relapse (RFS) and breast cancer mortality (BCSS). ER = estrogen receptor; BCSS, ER loss stands out as being particularly strongly associ- HR = hazards ratio; CI = confidence interval. ated with poor outcome (HR = 6.3, 95% CI = 2.1 to 18.7; P < .001). Clinical response and grade were not independently associated ( P = .03; Figure 3, D ). Of particular note, there were no recorded with RFS or BCSS. relapses in either study for the p-stage 1 or 0 group with a PEPI risk score of 0, with a combined median follow-up of 60.3 months An Integrated Biomarker Model to Predict Long-term (range = 4.5 – 86.5 months). Outcome for Patients Treated with Neoadjuvant To determine the potential infl uence of adjuvant chemo- Endocrine Therapy therapy on the RFS estimates in the PEPI score, the use of The four factors that were associated with P values of less than .05 in the multivariable analysis (pathological tumor size, patho- logical node status, ER status, and Ki67 natural log intervals — all Table 4 . The preoperative endocrine prognostic index * derived from the surgical specimen analysis) were promoted to RFS BCSS the next analysis phase, which focused on developing a prognos- Pathology, biomarker tic classification schema. For the first step in model building, the status HR Points HR Points four statistically significant risk factors were reanalyzed by Cox Pathological tumor size proportional hazards to derive a “final” HR associated with each T1/2 — 0 — 0 factor ( Table 3 ). Risk points were then applied using an approach T3/4 2.8 3 4.4 3 Node status used for the development of prognostic models in cardiovascular Negative — 0 — 0 disease to weight the different prognostic strengths associated Positive 3.2 3 3.9 3 with the final HRs assigned to each factor ( Table 4 ) ( 11 ). The Ki67 level scoring process outlined in Table 4 produced three groups (risk 0% – 2.7% (0 – 1 † ) — 0 — 0 score 0, 1 – 3, and ≥ 4) that were associated with relapse risks of >2.7% – 7.3% (1 – 2 † ) 1.3 1 1.4 1 >7.3% – 19.7% (2 – 3 † ) 1.7 1 2.0 2 10%, 23%, and 48% ( P < .001; Figure 3, A ). For breast cancer >19.7% – 53.1% (3 – 4 † ) 2.2 2 2.7 3 death, the risk was 2%, 11%, and 17% ( P < .001; Figure 3, B ). >53.1% (>4 † ) 2.9 3 3.8 3 For RFS, the C index for the four-component model after ER status, Allred score adjustment for overfitting was 0.723 (95% CI = 0.67 to 0.82). For 0 – 2 2.8 3 7.0 3 BCSS, the adjusted C index was 0.78 (95% CI = 0.71 to 0.91). 3 – 8 — 0 — 0 These C indices are within the range that defines a clinically * To obtain the preoperative endocrine prognostic index (PEPI) score, risk valuable prognostic model, which we termed “PEPI” for preop- points for relapse-free survival (RFS) and breast cancer – specific survival erative endocrine prognostic index. (BCSS) were assigned depending on the hazard ratio (HR) given in Table 3 . The points scale was adapted from the cardiovascular literature on predict- ing outcomes for myocardial infarction ( 11 ). The total PEPI score assigned to Independent Validation of the PEPI Model each patient is the sum of the risk points derived from the pT stage, We sought to validate the PEPI model in the IMPACT study, a pN stage, Ki67 level, and estrogen receptor (ER) status of the surgical speci - men. An HR in the range of 1 – 2 receives one risk point; a HR in the 2 – 2.5 neoadjuvant endocrine therapy trial with short-term endpoints range, two risk points; a HR greater than 2.5, three risk points. The total risk similar to those of the P024 trial ( 6 ). Data on pathological stage, point score for each patient is the sum of all the risk points accumulated ER status, and Ki67 intervals were available from 203 surgical from the four factors in the model. For example, a patient with a T1N0 tumor, a Ki67 staining percentage of 1 and an ER Allred score of 6 will have no risk specimens. The model produced a statistically significant separa- points assigned. In contrast, a patient with a T3N1 tumor, a Ki67 tion of the three PEPI risk groups (risk score 0, 1 – 3, and ≥ 4), staining percentage of 25, and an ER Allred score of 2 will have a total indicating that the model is valid ( Figure 3, C ) ( P = .002). As with relapse score of 3 + 3 + 2 + 3 = 11. the P024 study, IMPACT patients with p-stage 1 or 0 disease had † The natural logarithm interval corresponding to the percent Ki67 values on the original percentage scale. a more favorable outcome than patients with p-stage 2 or 3 disease jnci.oxfordjournals.org JNCI | Articles 1385 Figure 3 . Development and validation of the Preoperative Endocrine Prognostic Index (PEPI). A ) Relapse-free survival (RFS) for the three PEPI risk groups identifi ed in the P024 model with a log-rank statistic to test the overall trend ( P < .001). The green line represents group 1, patients with a PEPI risk score of 0; the red line group 2, a PEPI risk score of 1 – 3; and the purple line group 3, a PEPI risk score of 4 or more. The three groups have distinct risks of relapse. B ) PEPI groups 1, 2, and 3 also have distinct risks of breast cancer death, with similar statistical sig- nifi cance as the RFS data ( P < .001). C ) The PEPI model was validated in the IMPACT trial for RFS, with a statistically signifi cant association between relapse risk and risk score ( P = .002). D ) Pathological stage (stage 1 or 0 [ green line ] vs stage 2 or 3 [ red line ]) has a distinctly favor- able outcome in the IMPACT trial ( P = .03). Of 43 patients in the stage 1 or 0 group, only one experienced relapse. This patient’s tumor had the highest Ki67 level in the stage 1 or 0 group, and had therefore been correctly assigned to PEPI group 2. E ) Top, relationships among risk score, relapse events, and adjuvant chemother- apy administration (Chemo) in patients in the P024 trial. Bottom, heat map summarizing the distribution of the individual components of the risk score. F ) Top, relationships among risk score, relapse events, and adjuvant chemother- apy administration (Chemo) in patients in the IMPACT trial. Bottom, heat map summarizing the distribution of the individual components of the risk score. The heat maps indicate the pres- ence of a favorable factor ( green ) or an adverse factor ( red ) for large tumor size, node-positive status, or estrogen receptor (ER) negativity. The color coding in the Ki67 line of the heat map indicates Ki67 with a risk point of 0 as green , a risk point of 1 as dark red , and risk point of 2 as red . The bar over the heat map indicates the three risk groups generated by the risk point assignments ( green , group 1; red, group 2; and purple, group 3). adjuvant chemotherapy was tabulated by PEPI risk group for relapse risk assigned to PEPI group 2 will require studies with both studies ( Figure 3, E [P024] and F [IMPACT]). The per- larger sample sizes and longer follow-up. Finally, because of the centages of patients who were treated with chemotherapy in shorter follow-up, there were too few deaths in the IMPACT PEPI group 1 (no risk points) were 12% (P024) and 3% trial to validate the PEPI model for the prediction of BCSS. (IMPACT ), too low for chemotherapy to have had a major role in producing the favorable outcomes observed in this group. Discussion The heat maps in Figure 3 , E and F, serve to display the distri- bution of adverse factors in the two studies. These data illustrate Neoadjuvant endocrine therapy has been widely adopted as a prac- the mixed nature of the intermediate group of tumors (PEPI tical means to improve surgical outcomes for postmenopausal score 1 – 3), which consisted of either low-stage tumors with women with ER+ stage 2 and 3 breast cancer ( 14 ), but little was adverse biomarkers or higher-stage tumors with favorable bio- known about how the post–neoadjuvant endocrine therapy patho- markers. Ultimately, the clinical signifi cance of the PEPI model logical stage and biomarker status could be used to make decisions lies in its ability to identify patients at low risk of relapse in the regarding other adjuvant treatments. To address this question, we absence of adjuvant chemotherapy (group 1) and patients at very integrated information on standard pathological staging parame- high relapse risk that should mandate all appropriate adjuvant ters after neoadjuvant endocrine therapy with measurements of ER treatments (group 3). More confi dence around the estimates of status and levels of the Ki67 proliferation antigen in the surgical 1386 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008 specimen to create the PEPI score that weights these factors would be expected to have a worse prognosis because these tumors according the magnitude of the HR. Of particular note, patients have not maintained the pathway required to respond to endocrine with low pathological stage (stage 1 or 0) and a favorable biomarker therapy after treatment had been initiated ( 18 ). profile (PEPI score 0) at surgery had such a low rate of relapse that In addition to consideration of the PEPI approach as a tool for further adjuvant systemic therapy beyond continuation of an endo- treatment individualization, the data presented also strongly sup- crine agent appears unnecessary. In striking contrast, patients with port clinical trials in the neoadjuvant setting that study the effects high pathological stage disease at surgery and a poor biomarker of novel endocrine therapy agents and combinations on short-term profile (PEPI group 3) had a statistically significant higher risk of endpoints, such as Ki67 and pathological downstaging, as a prelude early relapse, more typical of ER  disease, and therefore should be to large adjuvant trials ( 19 ). offered all appropriate adjuvant treatments available. The biomarker analysis we have presented here would clearly References benefi t from additional retrospective studies of tumor samples from 1. Bast RC Jr , Hortobagyi GN . Individualized care for patients with cancer — a work in progress . N Engl J Med . 2004 ; 351 ( 27 ): 2865 – 2867 . other patients who were treated in a similar fashion, with longer 2. Mazouni C , Peintinger F , Wan-Kau S , et al . Residual ductal carcinoma follow-up. Prospective validation studies are also warranted to con- in situ in patients with complete eradication of invasive breast cancer after fi rm the PEPI as a tool for individualization of adjuvant chemo- neoadjuvant chemotherapy does not adversely affect patient outcome . therapy treatment. As part of these investigations, further study of J Clin Oncol . 2007 ; 25 ( 19 ): 2650 – 2655 . the PEPI group 2 to more clearly defi ne relapse risk categories 3. Eiermann W , Paepke S , Appfelstaedt J , et al . Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized would greatly improve the model. For example, a larger sample size double-blind multicenter study . Ann Oncol . 2001 ; 12 ( 11 ): 1527 – 1532 . could further defi ne the risk of relapse associated with modest eleva- 4. Ellis MJ , Coop A , Singh B , et al . Letrozole is more effective neoadjuvant tions of Ki67 above 2.7% in pathological stage 1 and 2A disease. An endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, ideal prospective validation study would include an immediate-sur- estrogen receptor-positive primary breast cancer: evidence from a phase gery control arm to directly compare a standard adjuvant chemo- III randomized trial . J Clin Oncol . 2001 ; 19 ( 18 ): 3808 – 3816 . 5. Smith IE , Dowsett M , Ebbs SR , et al . Neoadjuvant treatment of post- therapy decision-making approach vs pathological staging and tumor menopausal breast cancer with anastrozole, tamoxifen, or both in combi- biomarker profi ling after neoadjuvant endocrine therapy. Pending nation: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined the results from such a trial, we can state with confi dence that analy- with Tamoxifen (IMPACT) multicenter double-blind randomized trial . sis of post–neoadjuvant endocrine therapy surgical samples with J Clin Oncol . 2005 ; 23 ( 22 ): 5108 – 5116 . Ki67 and ER provides additional useful prognostic information that 6. Dowsett M , Ebbs SR , Dixon JM , et al . Biomarker changes during neoad- juvant anastrozole, tamoxifen, or the combination: infl uence of hormonal is not provided by an analysis of the baseline sample alone. Repeat status and HER-2 in breast cancer — a study from the IMPACT trialists . ER analysis reveals the presence of a subset of tumors with unstable J Clin Oncol . 2005 ; 23 ( 11 ): 2477 – 2492 . ER expression and very aggressive clinical course. “On-treatment” 7. Ellis MJ , Coop A , Singh B , et al . Letrozole inhibits tumor proliferation Ki67 levels more accurately predict relapse risk than baseline values, more effectively than tamoxifen independent of HER1/2 expression sta- whether measured at 3 – 4 months, as discussed in this study, or as tus . Cancer Res. 2003 ; 63 ( 19 ): 6523 – 6531 . 8. Allred DC , Harvey JM , Berardo M , Clark GM . Prognostic and predictive early as 2 weeks after initiaton of endocrine treatment, as shown factors in breast cancer by immunohistochemical analysis . Mod Pathol . earlier by the IMPACT investigators ( 9 ). A standardized ER and 1998 ; 11 ( 2 ): 155 – 168 . Ki67 analysis approach should be adopted as part of any prospective 9. Dowsett M , Smith IE , Ebbs SR , et al . Prognostic value of Ki67 expression plan to validate the PEPI model as a clinical decision tool. after short-term presurgical endocrine therapy for primary breast cancer . The data presented may prove useful with respect to other deci- J Natl Cancer Inst . 2007 ; 99 ( 2 ): 167 – 170 . 10. Katz RL , Patel S , Sneige N , et al . Comparison of immunocytochemical sions that must be made when a patient is treated with neoadjuvant and biochemical assays for estrogen receptor in fi ne needle aspirates and endocrine therapy. For example, nodal stage after neoadjuvant histologic sections from breast carcinomas . Breast Cancer Res Treat . 1990 ; endocrine therapy was powerfully predictive, suggesting that 15 ( 3 ): 191 – 203 . upfront staging of the axillary nodes may not be necessary before 11. Morrow DA , Antman EM , Charlesworth A , et al . TIMI risk score for initiation of neoadjuvant endocrine treatment because the prog- ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an intravenous nPA for treatment of nostic impact of this factor is preserved after therapy. In addition, infarcting myocardium early II trial substudy . Circulation . 2000 ; 102 ( 17 ): the PEPI score might be used to tailor radiotherapy decisions. 2031 – 2037 . That is, in the setting of a favorable PEPI score and low pathologi- 12. Harrell FE Jr , Lee KL , Mark DB . Multivariable prognostic models: issues cal stage, it might be appropriate to consider partial breast irradia- in developing models, evaluating assumptions and adequacy, and measur- tion, or even no radiation, as part of a prospective study ( 15 ). The ing and reducing errors . Stat Med . 1996 ; 15 ( 4 ): 361 – 387 . 13. Urruticoechea A , Smith IE , Dowsett M . Proliferation marker Ki-67 in ER and Ki67 data in the present study suggests that prognostic early breast cancer . J Clin Oncol . 2005 ; 23 ( 28 ): 7212 – 7220 . tests that contain signatures for proliferation, ER and ER regulated 14. Ma CX , Ellis MJ . Neoadjuvant endocrine therapy for locally advanced genes, such as the 21 gene recurrence score (16) or the distinction breast cancer . Semin Oncol . 2006 ; 33 ( 6 ): 650 – 656 . between Luminal A and luminal B tumors ( 17 ) may have additional 15. Hughes KS , Schnaper LA , Berry D , et al . Lumpectomy plus tamoxifen valuable qualities when applied to samples that have been exposed with or without irradiation in women 70 years of age or older with early breast cancer . N Engl J Med . 2004 ; 351 ( 10 ): 971 – 977 . to endocrine treatment. Specifi cally, tumors that lose the prolifera- 16. Paik S , Shak S , Tang G , et al . A multigene assay to predict recurrence of tion gene expression signature in response to endocrine therapy tamoxifen-treated, node-negative breast cancer . N Engl J Med . 2004 ; would be expected to have a better prognosis than tumors in which 351 ( 27 ): 2817 – 2826 . the proliferation signature persisted despite treatment. In contrast, 17. Hu Z , Fan C , Oh DS , et al . The molecular portraits of breast tumors are tumors that lose aspects of the luminal signature, particularly ER, conserved across microarray platforms . BMC Genomics . 2006 ; 7 : 96 – 108 . jnci.oxfordjournals.org JNCI | Articles 1387 18. Ellis MJ , Tao Y , Luo J , et al . A poor prognosis ER and HER2-negative, Pharmaceuticals Corp and hold stock in the company. A. S. Bhatnagar is on nonbasal, breast cancer subtype identifi ed through postneoadjuvant the speaker’s bureau for Novartis Pharmaceuticals Corp. Ian Smith received endocrine therapy tumor profi ling . J Clin Oncol . 2008 ; 26 : Abstract honoraria for lecturing at and attending advisory board meetings for Novartis 502 . Pharmaceuticals Corp, Pfi zer, Inc, and AstraZeneca. M. Dowsett receives 19. Ellis MJ . Neoadjuvant endocrine therapy as a drug development strategy . research grant funds and has received honoraria for consulting and advi- Clin Cancer Res. 2004 ; 10 ( 1 pt 2 ): 391S – 395S . sory board work from AstraZeneca and Novartis Pharmaceuticals Corp. Representatives from Novartis Pharmaceuticals Corp have coauthored, edited, reviewed, and approved parts of this manuscript. Notes Present address: World Wide Services Group Ltd, Geispelgasse 13, M. J. Ellis is a consultant for, on the speaker’s bureau of, and currently doing CH-4132 Muttenz, Switzerland (A. S. Bhatnagar). research sponsored by, Novartis Pharmaceuticals Corp and AstraZeneca. D. Manuscript received March 10 , 2008 ; revised July 14 , 2008 ; accepted July B. Evans, H. A. Chaudri Ross, and A. von Kameke are employees of Novartis 29 , 2008 . 1388 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Journal of the National Cancer Institute Pubmed Central

Outcome Prediction for Estrogen Receptor–Positive Breast Cancer Based on Postneoadjuvant Endocrine Therapy Tumor Characteristics

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Pubmed Central
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© 2008 The Author(s).
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0027-8874
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1460-2105
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10.1093/jnci/djn309
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Abstract

ARTICLE Outcome Prediction for Estrogen Receptor – Positive Breast Cancer Based on Postneoadjuvant Endocrine Therapy Tumor Characteristics Matthew J. Ellis , Yu Tao , Jingqin Luo , Roger A’Hern , Dean B. Evans , Ajay S. Bhatnagar , Hilary A. Chaudri Ross , Alexander von Kameke , William R. Miller , Ian Smith , Wolfgang Eiermann , Mitch Dowsett Background Understanding how tumor response is related to relapse risk would help clinicians make decisions about additional treatment options for patients who have received neoadjuvant endocrine treatment for estro- gen receptor – positive (ER+) breast cancer. Methods Tumors from 228 postmenopausal women with confirmed ER+ stage 2 and 3 breast cancers in the P024 neoadjuvant endocrine therapy trial, which compared letrozole and tamoxifen for 4 months before sur- gery, were analyzed for posttreatment ER status, Ki67 proliferation index, histological grade, pathological tumor size, node status, and treatment response. Cox proportional hazards were used to identify factors associated with relapse-free survival (RFS) and breast cancer – specific survival (BCSS) in 158 women. A preoperative endocrine prognostic index (PEPI) for RFS was developed from these data and validated in an independent study of 203 postmenopausal women in the IMPACT trial, which compared treatment with anastrozole, tamoxifen, or the combination 3 months before surgery. Statistical tests were two-sided. Results Median follow-up in P024 was 61.2 months. Patients with confirmed baseline ER+ clinical stage 2 and 3 tumors that were downstaged to stage 1 or 0 at surgery had 100% RFS (compared with higher stages, P < .001). Multivariable testing of posttreatment tumor characteristics revealed that pathological tumor size, node status, Ki67 level, and ER status were independently associated with both RFS and BCSS. The PEPI model based on these factors predicted RFS in the IMPACT trial ( P = .002). Conclusions Breast cancer patients with pathological stage 1 or 0 disease after neoadjuvant endocrine therapy and a low-risk biomarker profile in the surgical specimen (PEPI score 0) have an extremely low risk of relapse and are therefore unlikely to benefit from adjuvant chemotherapy. J Natl Cancer Inst 2008;100: 1380 – 1388 An accurate test to predict the effectiveness of adjuvant endocrine model that incorporates standard pathological staging variables therapy for hormone receptor – positive breast cancer on an indi- and “on-treatment” biomarker values. We validated the model vidual basis would be an important advance ( 1 ). Current approaches internally though bootstrap analysis and subsequently validated it focus on biomarker analysis of the diagnostic specimen. An alter- externally using data from an independent neoadjuvant native is to treat patients with an endocrine agent for several months before surgery to identify tumors that are responsive to Affiliations of authors : Siteman Cancer Center, Washington University, treatment, with the assumption that responsiveness indicates a St Louis, MO (MJE, YT, JL); Clinical Trials and Statistics Unit, Institute of lower risk of relapse. However, compared with neoadjuvant che- Cancer Research, Sutton, UK (RAH); Novartis Pharma AG, Basel, Switzerland motherapy studies ( 2 ), fewer neoadjuvant endocrine therapy trials (DBE, ASB, HACR, AvK); Edinburgh Breast Unit, Edinburgh University, Edinburgh, UK (WRM ); Royal Marsden Hospital, London, UK (IS, MD); Red have been conducted; thus, fewer data are available to link post- Cross Women ’ s Hospital, Munich, Germany (WE) . neoadjuvant therapy tumor characteristics and survival. Correspondence to: Matthew J. Ellis, MB, BChir, PhD, Siteman Cancer The P024 neoadjuvant endocrine therapy trial, which com- Center, Washington University School of Medicine, 660 South Euclid Ave, pared 4 months of letrozole and tamoxifen before surgery ( 3 , 4 ), St Louis, MO 63119 (e-mail: mellis@wustl.edu ). now has suffi cient follow-up (median >60 months) to address the See “Notes” following “References.” relationships between postneoadjuvant endocrine therapy tumor DOI: 10.1093/jnci/djn309 characteristics and risk of early relapse. In this study, we used © 2008 The Author(s). This is an Open Access article distributed under the terms of the Creative Com- data from P024 to examine pathological stage posttreatment, mons Attribution Non-Commercial License (http://creativecommons.org/licenses/ histological grade posttreatment, response to treatment, and the by-nc/2.0/uk/), which permits unrestricted non-commercial use, distribution, and biomarker status of the surgical specimen to develop a prognostic reproduction in any medium, provided the original work is properly cited. 1380 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008 endocrine therapy study that compared anastrozole, tamoxifen, CONTEXT AND CAVEATS or the combination for 3 months before surgery (the IMPACT Prior knowledge trial) ( 5 , 6 ). Endocrine therapy before surgery increases the rate of breast con- servation surgery for patients with hormone receptor – positive Subjects and Methods breast cancer, but factors to predict risk of relapse after treatment have not been identified. Study Population and Tumor Bank Both clinical trials described in this manuscript were approved Study design Posttreatment prognostic factors from patients enrolled in clinical by the local institutional review boards that enrolled patients into trials of neoadjuvant endocrine therapy were used to develop and the studies ( 3 , 5 ). The P024 protocol compared 4 months of validate a model to predict risk of relapse. neoadju vant letrozole therapy with 4 months of neoadjuvant tamoxifen therapy in postmenopa usal women with clinical stage Contribution 2 and 3 hormone receptor – positive breast cancers (classified as at A model that includes information on standard surgical staging least 10% nuclear staining for estrogen receptor [ER] and/or pro- parameters after neoadjuvant endocrine treatment, estrogen recep- tor status, and levels of Ki67 proliferation antigen can define broad gesterone receptor [PgR]) who were ineligible for breast conserva- relapse risk groups. tive surgery ( 3 ). The clinical findings, tumor bank characteristics, and biomarker measurements have been described previously Implications ( 3 , 4 , 7 ). The cut point for ER positivity for central laboratory Data from this model may prove useful with respect to other deci- analysis was an Allred score of 3 ( 8 ). Information on tumor grade, sions that must be made after a patient is treated with neoadjuvant clinical response by caliper measurements, definitive pathological endocrine therapy, such as the use of adjuvant chemotherapy. staging at surgery , and chemotherapy administration was collected Limitations prospectively. Patients in P024 were recommended to receive The studies used for developing and validating the model were adjuvant tamoxifen for 5 years. The IMPACT study design, short- small, used different treatments, and had relatively short median and long-term outcomes, and biomarker methodology have also follow-up data available (just more than 5 years). been described previously ( 5 , 6 , 9 ). For the validation analysis, we From the Editors compiled information on surgical stage, surgical specimen Ki67 proliferation antigen levels, ER data, duration of follow-up, and relapse dates. The IMPACT study used the H-score ( 10 ) to assess ER status. We converted the H-score ER cutoff to an Allred score the statistical significance of a factor after adjusting for the other ER cutoff for the analyses. An Allred score of 2 can be derived in factors. The proportionality assumption was checked by testing only one way, ie, less than 1% of cells staining weakly, which time-dependent covariates in the model and graphically examining equates to an H-score of less than 1. Thus, it is valid to use an scaled Schoenfeld residuals. Hazard ratio (HR) estimates of each H-score of at least 1 as the equivalent of an Allred score of at least factor in the final multivariable model were used to construct a 3 as the threshold for ER positivity. score, the preoperative endocrine prognostic index (PEPI), for risk of relapse and breast cancer – specific death for each sample in the Statistical Analysis test cohort. The PEPI score was derived as an arithmetic sum of Relapse-free survival (RFS) was defined as the interval between risk points weighted by the size of the HR assigned to each statisti- random assignment to treatment and the earliest subsequent breast cally significant factor ( 11 ). The overall discriminatory capacity of cancer event. No new breast primary tumors were documented in the Cox model on the P024 data was assessed using Harrell’s C either dataset, effectively excluding this class of event from the risk index, which was then adjusted after a 1000 bootstrap assessment model that was developed. Breast cancer – specific survival (BCSS) of the overfitting (optimism) portion. The 95% confidence inter- was defined as the interval between random assignment and the val (CI) for the adjusted C index was also reported ( 12 ). For the date of death after breast cancer relapse. When we included all IMPACT trial validation analysis, we calculated the PEPI score for deaths, irrespective of cause, as RFS and overall survival events, all patients who had data for the four factors and examined the there were no major changes in the P024 results (data not shown). association of PEPI score with RFS. SAS version 9.02 (SAS Survival curves were estimated by the Kaplan – Meier method, and Institute, Cary, NC) and R 2.6 software (R Foundation for a two-sided P value of .05 from a log-rank test was considered a Statistical Computing) were used for all analyses. statistically significant difference. A multivariable Cox propor- tional hazard regression model was used to evaluate the indepen- Results dent prognostic relevance of each factor, namely, pathological tumor size (T1/2 vs T3/4 or T1 vs T2 – 4), pathological node status Definition of the Patient Populations for Analysis (negative vs positive), clinical response (complete plus partial clini- Detailed information on the P024 population used in each of the cal response vs stable disease plus progressive disease), surgical analyses was compiled and is summarized in Figure 1 . The median specimen ER status (Allred score ≥ 3 vs 0 or 2), histological grade follow-up was 61.2 months for the patients who underwent sur- (grade 1 vs grade 2/3), and the Ki67 level, as natural log-trans- gery at the end of 4 months of endocrine treatment (n = 290) and formed intervals ( 9 ), in both the pretreatment specimen and the 62.0 months for the patients with a complete dataset for the mul- surgical specimen. P values from Wald chi-square tests indicated tivariable analysis (n = 158). Assignment to neoadjuvant letrozole jnci.oxfordjournals.org JNCI | Articles 1381 Figure 1 . Patient populations for univari- ate and multivariable analysis. The patient populations are described in this diagram to illustrate how the univariable analysis sought to include the largest population possible. The multivariable analysis was performed on a subset of patients among whom all factors in the model were available for comparison. ER = estrogen receptor. or tamoxifen had no impact on RFS or BCSS, but because all response — stage 0) were compared with patients with p-stage 2 patients received adjuvant tamoxifen a difference was not antici- or 3 disease at surgery. No relapses and only one death without pated. Thus, for the purposes of these analyses, the results from known relapse (which was censored) were recorded in the group both arms were pooled together. As described in the original of 29 patients with p-stage 1 disease plus one patient with p-stage report on central laboratory ER testing ( 4 ), 12% of patients had 0 disease vs 53 of the 175 patients (30% relapse incidence) with ER  tumors at baseline, and of the 28 ER  and PgR  tumors, p-stage 2 and 3 disease ( Figure 2, A , P < .001). The p-stage 1 or 0 only one was reported to respond to treatment. Long-term status appeared to reflect downstaging of a group of endocrine follow-up confirmed that these tumors were likely to have been therapy – responsive tumors because the clinical response rate was correctly assigned by the central laboratory because baseline ER  79% in the p-stage 1 or 0 group vs 52% in the p-stage 2 or 3 status was associated with poor overall survival ( P = .004, data not group (response rate difference = 27%, 95% CI = 10.5% to shown). Subsequent analysis therefore focused on patients with 42.5%; P = .006). Furthermore, tumors in the p-stage 1 or 0 group ER+ tumors as assigned by the central laboratory (n = 228). had lower posttreatment geometric mean Ki67 levels than higher p-stage tumors (0.39 vs 0.98, ratio of geometric means = 0.40, Pathological Stage, Tumor Grade, and Response 95% CI = 0.18 to 0.89; P = .03). The average baseline tumor size on Outcome for the pT1 or pT0N0 tumors was predictably smaller than that All patients had clinical stage 2 or 3 tumor at diagnosis. To exam- of tumors with a higher pT stage at surgery; 3.9 vs 5.2 cm (longest ine the impact of pathological (p) stage on outcome, patients diameter) by clinical caliper measurement ( P < .001), 2.8 vs 4.0 by whose tumors were downstaged at surgery to pT1N0 (node mammogram ( P < .001), and 2.6 vs 3.4 cm by ultrasound ( P = negative with a tumor size of ≤ 2 cm diameter with negative .003). However, given that these average measurements are all ax illary lymph nodes — stage 1) or pT0N0 (pathological complete larger than 2 cm, it is unlikely that many tumors in the P024 study 1382 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008 Figure 2 . Kaplan – Meier analysis of relapse- free survival (RFS) and breast cancer – specifi c survival (BCSS) among women whose tumors were established to be estrogen receptor positive (ER+) at baseline by central laboratory analysis. A ) RFS for posttreatment pathological stage 1 or 0 (T1N0 or T0N0, green ) vs higher stages ( red ), P < .001; B ) RFS for posttreatment pathological node negative ( green ) vs node positive ( red ), P < .001; C ) RFS for posttreatment clinical responders ( green ) vs no clinical response ( red ), P = .002; D ) RFS for posttreatment histological grade (Grade I, green, vs Grade II/III, red ), P < .001. E ) RFS for patients with ER+ tumors post- treatment ( green ) vs ER negative (  ) tumors posttreatment ( red ), P = .03; F ) BCSS for patients with ER+ tumors posttreatment ( green ) vs ER  tumors posttreatment ( red ), P = .002; censorship marks are provided as open circles . All P values (two-sided) were calculated using the log-rank test. were p-stage 1 at diagnosis and therefore likely that p-stage 1 .002; Figure 2, C ), pretreatment grade ( P = .002) (data not shown), status usually reflects the effects of tumor regression induced by and posttreatment grade (grade I vs grade II or III, P < .001; Figure treatment. The excellent outcome in the p-stage 1 or 0 group was 2, D ). The alternative grade dichotomy of grade I or II vs III did not strongly influenced by chemotherapy because only 2 of the 30 not have better prognostic characteristics (data not shown). (7%) patients with p-stage 1 or 0 disease underwent adjuvant chemotherapy vs 61 of 175 (35%) patients with p-stage 2 or 3 The Association of Posttreatment ER Status with Outcome disease ( P = .001). Other factors that were associated with RFS We had previously noted that a number of tumor samples that were in univariate analysis included posttreatment pathological node ER+ before treatment had lost ER expression in the posttreatment status ( P < .001; Figure 2, B ), clinical response to treatment ( P = sample [ie, converted to an Allred score of 0 or 2, or unequivocally jnci.oxfordjournals.org JNCI | Articles 1383 Table 1 . Univariate and multivariable analysis of relapse-free survival according to posttreatment pathological tumor size, post treatment node status, posttreatment Ki67 level, posttreatment ER status, and posttreatment tumor grade in the P024 trial * Relapse-free survival Univariate analysis Multivariable analysis No. of patients No. of events/no. Factor definitions in each group of patients HR (95% CI) P HR (95% CI) P Pathological tumor size † T1/2 vs T3/4 138/33 47/171 2.7 (1.4 to 5.0) .002 3.0 (1.54 to 5.91) .001 T1 vs T2–4 53/118 47/171 2.01 (1.0 to 4.1) .05 — Node status (positive vs negative) 90/69 44/159 3.9 (1.8 to 8.4) <.001 2.8 (1.31 to 6.19) .009 Ki67 level, per 2.7-fold increase ‡ NA 48/174 1.4 (1.2 to 1.6) <.001 1.3 (1.05 to 1.50) .01 ER, Allred score (0 or 2 vs 3 – 8) § 16/157 48/173 2.4 (1.0 to 5.3) .04 2.6 (1.1 to 6.0) .03 Clinical response (yes vs no) 70/104 49/174 2.8 (1.6 to 4.9) <.001 1.72 (0.96 to 3.09) .07 Grade (I vs II/III) 33/126 46/159 3.8 (1.4 to 10.8) .011 2.72 (0.95 to 7.8) .06 * The total number in each univariate analysis varied depending on the number of cases in which information on the individual factor was available. Cox proportional hazards models were used to calculate hazard ratios (HRs) and their 95% confidence intervals (CIs) of relapse, comparing tumors with the adverse factor relative to tumors without the adverse factor. Two-sided P values are provided throughout. † Tumor size was examined with two cutoff points, pT1/2 vs pT3/4 and pT1 vs pT2 – 4. A cutoff point of pT1/2 provided the smallest univariate P value and was used in the multivariable analysis (which excluded factors with a univariate P value of >.05). ‡ Ki67 was analyzed as the natural logarithm values, or per 2.7-fold increase according to the original scale of percentage values. § The estrogen receptor (ER) analysis refers to the posttreatment values; before treatment all tumors in this dataset were ER+. NA (not applicable) because K167 divided into five risk groups (see Table 4). ER  ( 4 )]. We therefore compared RFS and BCSS between patients as a continuous variable after natural log transformation, as recom- with tumors that converted from ER+ to ER  and patients with mended by Dowsett et al. ( 9 ). This analysis approach examines the tumors that were persistently ER+ at surgery. The 16 patients with HR per 2.7-fold increase in the Ki67 value (referred to as “natural posttreatment ER  tumors had worse RFS (HR of relapse = 2.4, log intervals”). Pretreatment Ki67 natural log intervals were not 95% CI = 1.0 to 5.3; P = .03) and BCSS (HR of breast cancer death = associated with relapse, whereas there was a highly statistically 4.3, 95% CI = 1.6 to 11.7; P = .002) ( Figure 2, E and F ) than patients significant association between RFS and posttreatment Ki67 natu- with tumors that retained ER+ after treatment. The pretreatment ral log intervals (HR = 1.4, 95% CI = 1.2 to 1.6 per log unit Allred scores of tumors that were ER  after treatment was similar increase; P < .001; Table 1 ), which also held for BCSS (HR = 1.4, to that of tumors that retained ER expression ( P = .2). CI = 1.1 to 1.7; P = .009; Table 2 ). The Association of Pre- and Posttreatment Ki67 Development of a Multivariable Cox Model Proliferation Index with Outcome Pathological tumor size (T1/2 vs T3/4 or T1 vs T2 – 4), patho- Ki67 is a commonly used proliferation antigen that identifies cells logical node status (negative vs positive), clinical response (com- in the G1/S and M phases of the cell cycle ( 13 ). Ki67 was examined plete plus partial clinical response vs stable disease plus Table 2 . Univariate and multivariable analysis of breast cancer – specific survival according to pathological tumor size, node status, posttreatment Ki67, posttreatment ER status, and posttreatment tumor grade in the P024 trial * Breast cancer – specific mortality Univariate analysis Multivariable analysis No. of patients No. of events/no. Factor definition in each group of patients HR (95% CI) P HR (95% CI) P Pathological tumor size † T1/2 vs T3/4 138/33 24/171 3.5 (1.5 to 8.3) .004 4.4 (1.7 to 11.3) .002 T1 vs T2–4 53/118 24/171 4.1 (1.2 to 13.8) .025 — Node status (positive vs negative) 90/69 22/159 4.6 (1.4 to 15.8) .01 3.2 (0.9 to 11.2) .07 Ki67 level, per 2.7-fold increase ‡ NA 25/174 1.4 (1.1 to 1.7) .009 1.4 (1.1 to 1.8) .02 ER, Allred score (0 or 2 vs 3 – 8) § 16/157 25/173 4.3 (1.6 to 11.7) .005 6.3 (2.1 to 18.7) <.001 Clinical response (yes vs no) 70/104 25/174 2.2 (0.97 to 4.9) .06 1.1 (0.5 to 2.5) .78 Grade (I vs II/III) 33/126 24/159 7.1 (0.96 to 53) .05 4.62 (0.6 to 35.0) .1 * The total number in each univariate analysis varied depending on the number of tumors in which information on the individual factor was available. Cox proportional hazards model was used to calculate hazard ratios (HRs) and their confidence intervals (CIs) of relapse, comparing tumors with the adverse factor relative to those without the adverse factor. Two-sided P values are provided throughout. † Tumor size was examined by two cutoffs, pT1/2 vs pT3/4 and pT1 vs pT2 – 4. A cutoff of pT1/2 provided the smallest univariate P value and was used in the multivariable analysis (which excluded factors with a univariate P value of >.05). ‡ Ki67 analyzed as the natural-logarithm values, or per 2.7-fold increase according to the original scale of percentage values. § The estrogen receptor (ER) analysis refers to the posttreatment values; before treatment all the tumors in this dataset were ER+. 1384 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008 Table 3 . Multivariable Cox proportional hazards analysis of progressive disease), surgical specimen ER status (Allred score relapse-free survival (RFS) and breast cancer – specific survival ≥ 3 vs 0 or 2), histological grade (grade I vs grade II/III), and (BCSS) from the P024 trial * Ki67 natural log intervals were used in a multivariable Cox pro- Pathology portional hazard model to determine their association with RFS RFS BCSS biomarker and ( Table 1 ) and BCSS ( Table 2 ). For Ki67, the posttreatment response factors HR (95% CI) P HR (95% CI) P natural log intervals were statistically significantly associated Pathological tumor 2.8 (1.4 to 5.4) .003 4.4 (1.7 to 11.2) .002 with both RFS (per log unit increase, HR of relapse = 1.3, 95% size (T1/2 vs T3/4) CI = 1.05 to 1.50; P = .01) and BCSS (per log unit increase, HR Node status 3.2 (1.5 to 6.9) .004 3.9 (1.1 to 13.7) .04 of breast cancer death = 1.4, 95% CI = 1.1 to 1.8; P = .02). (positive vs Pathological tumor size (pT1/2 vs pT3/4) was strongly associ- negative) ated with RFS (HR = 3.0, 95% CI = 1.54 to 5.91; P = .001) and Ki67 level per 1.3 (1.1 to 1.6) .003 1.4 (1.07 to 1.9) .01 2.7-fold increase BCSS (HR = 4.4, 95% CI = 1.7 to 11.3; P = .002). Pathological ER, Allred score 2.8 (1.2 to 6.4) .02 7.0 (2.4 to 20.9) <.001 node status was also associated with RFS (positive vs negative, (0 or 2 vs 3 – 8) HR = 2.8, 95% CI = 1.31 to 6.19; P = .009). ER status posttreat- ment (Allred score 0 or 2 vs 3 – 8) was also independently associ- * The four factors associated with a P value of .05 or less for RFS in Table 1 were reanalyzed in a Cox model to assign final hazard ratios for risk of ated with RFS (HR = 2.6, 95% CI = 1.1 to 6.0; P = .03). For relapse (RFS) and breast cancer mortality (BCSS). ER = estrogen receptor; BCSS, ER loss stands out as being particularly strongly associ- HR = hazards ratio; CI = confidence interval. ated with poor outcome (HR = 6.3, 95% CI = 2.1 to 18.7; P < .001). Clinical response and grade were not independently associated ( P = .03; Figure 3, D ). Of particular note, there were no recorded with RFS or BCSS. relapses in either study for the p-stage 1 or 0 group with a PEPI risk score of 0, with a combined median follow-up of 60.3 months An Integrated Biomarker Model to Predict Long-term (range = 4.5 – 86.5 months). Outcome for Patients Treated with Neoadjuvant To determine the potential infl uence of adjuvant chemo- Endocrine Therapy therapy on the RFS estimates in the PEPI score, the use of The four factors that were associated with P values of less than .05 in the multivariable analysis (pathological tumor size, patho- logical node status, ER status, and Ki67 natural log intervals — all Table 4 . The preoperative endocrine prognostic index * derived from the surgical specimen analysis) were promoted to RFS BCSS the next analysis phase, which focused on developing a prognos- Pathology, biomarker tic classification schema. For the first step in model building, the status HR Points HR Points four statistically significant risk factors were reanalyzed by Cox Pathological tumor size proportional hazards to derive a “final” HR associated with each T1/2 — 0 — 0 factor ( Table 3 ). Risk points were then applied using an approach T3/4 2.8 3 4.4 3 Node status used for the development of prognostic models in cardiovascular Negative — 0 — 0 disease to weight the different prognostic strengths associated Positive 3.2 3 3.9 3 with the final HRs assigned to each factor ( Table 4 ) ( 11 ). The Ki67 level scoring process outlined in Table 4 produced three groups (risk 0% – 2.7% (0 – 1 † ) — 0 — 0 score 0, 1 – 3, and ≥ 4) that were associated with relapse risks of >2.7% – 7.3% (1 – 2 † ) 1.3 1 1.4 1 >7.3% – 19.7% (2 – 3 † ) 1.7 1 2.0 2 10%, 23%, and 48% ( P < .001; Figure 3, A ). For breast cancer >19.7% – 53.1% (3 – 4 † ) 2.2 2 2.7 3 death, the risk was 2%, 11%, and 17% ( P < .001; Figure 3, B ). >53.1% (>4 † ) 2.9 3 3.8 3 For RFS, the C index for the four-component model after ER status, Allred score adjustment for overfitting was 0.723 (95% CI = 0.67 to 0.82). For 0 – 2 2.8 3 7.0 3 BCSS, the adjusted C index was 0.78 (95% CI = 0.71 to 0.91). 3 – 8 — 0 — 0 These C indices are within the range that defines a clinically * To obtain the preoperative endocrine prognostic index (PEPI) score, risk valuable prognostic model, which we termed “PEPI” for preop- points for relapse-free survival (RFS) and breast cancer – specific survival erative endocrine prognostic index. (BCSS) were assigned depending on the hazard ratio (HR) given in Table 3 . The points scale was adapted from the cardiovascular literature on predict- ing outcomes for myocardial infarction ( 11 ). The total PEPI score assigned to Independent Validation of the PEPI Model each patient is the sum of the risk points derived from the pT stage, We sought to validate the PEPI model in the IMPACT study, a pN stage, Ki67 level, and estrogen receptor (ER) status of the surgical speci - men. An HR in the range of 1 – 2 receives one risk point; a HR in the 2 – 2.5 neoadjuvant endocrine therapy trial with short-term endpoints range, two risk points; a HR greater than 2.5, three risk points. The total risk similar to those of the P024 trial ( 6 ). Data on pathological stage, point score for each patient is the sum of all the risk points accumulated ER status, and Ki67 intervals were available from 203 surgical from the four factors in the model. For example, a patient with a T1N0 tumor, a Ki67 staining percentage of 1 and an ER Allred score of 6 will have no risk specimens. The model produced a statistically significant separa- points assigned. In contrast, a patient with a T3N1 tumor, a Ki67 tion of the three PEPI risk groups (risk score 0, 1 – 3, and ≥ 4), staining percentage of 25, and an ER Allred score of 2 will have a total indicating that the model is valid ( Figure 3, C ) ( P = .002). As with relapse score of 3 + 3 + 2 + 3 = 11. the P024 study, IMPACT patients with p-stage 1 or 0 disease had † The natural logarithm interval corresponding to the percent Ki67 values on the original percentage scale. a more favorable outcome than patients with p-stage 2 or 3 disease jnci.oxfordjournals.org JNCI | Articles 1385 Figure 3 . Development and validation of the Preoperative Endocrine Prognostic Index (PEPI). A ) Relapse-free survival (RFS) for the three PEPI risk groups identifi ed in the P024 model with a log-rank statistic to test the overall trend ( P < .001). The green line represents group 1, patients with a PEPI risk score of 0; the red line group 2, a PEPI risk score of 1 – 3; and the purple line group 3, a PEPI risk score of 4 or more. The three groups have distinct risks of relapse. B ) PEPI groups 1, 2, and 3 also have distinct risks of breast cancer death, with similar statistical sig- nifi cance as the RFS data ( P < .001). C ) The PEPI model was validated in the IMPACT trial for RFS, with a statistically signifi cant association between relapse risk and risk score ( P = .002). D ) Pathological stage (stage 1 or 0 [ green line ] vs stage 2 or 3 [ red line ]) has a distinctly favor- able outcome in the IMPACT trial ( P = .03). Of 43 patients in the stage 1 or 0 group, only one experienced relapse. This patient’s tumor had the highest Ki67 level in the stage 1 or 0 group, and had therefore been correctly assigned to PEPI group 2. E ) Top, relationships among risk score, relapse events, and adjuvant chemother- apy administration (Chemo) in patients in the P024 trial. Bottom, heat map summarizing the distribution of the individual components of the risk score. F ) Top, relationships among risk score, relapse events, and adjuvant chemother- apy administration (Chemo) in patients in the IMPACT trial. Bottom, heat map summarizing the distribution of the individual components of the risk score. The heat maps indicate the pres- ence of a favorable factor ( green ) or an adverse factor ( red ) for large tumor size, node-positive status, or estrogen receptor (ER) negativity. The color coding in the Ki67 line of the heat map indicates Ki67 with a risk point of 0 as green , a risk point of 1 as dark red , and risk point of 2 as red . The bar over the heat map indicates the three risk groups generated by the risk point assignments ( green , group 1; red, group 2; and purple, group 3). adjuvant chemotherapy was tabulated by PEPI risk group for relapse risk assigned to PEPI group 2 will require studies with both studies ( Figure 3, E [P024] and F [IMPACT]). The per- larger sample sizes and longer follow-up. Finally, because of the centages of patients who were treated with chemotherapy in shorter follow-up, there were too few deaths in the IMPACT PEPI group 1 (no risk points) were 12% (P024) and 3% trial to validate the PEPI model for the prediction of BCSS. (IMPACT ), too low for chemotherapy to have had a major role in producing the favorable outcomes observed in this group. Discussion The heat maps in Figure 3 , E and F, serve to display the distri- bution of adverse factors in the two studies. These data illustrate Neoadjuvant endocrine therapy has been widely adopted as a prac- the mixed nature of the intermediate group of tumors (PEPI tical means to improve surgical outcomes for postmenopausal score 1 – 3), which consisted of either low-stage tumors with women with ER+ stage 2 and 3 breast cancer ( 14 ), but little was adverse biomarkers or higher-stage tumors with favorable bio- known about how the post–neoadjuvant endocrine therapy patho- markers. Ultimately, the clinical signifi cance of the PEPI model logical stage and biomarker status could be used to make decisions lies in its ability to identify patients at low risk of relapse in the regarding other adjuvant treatments. To address this question, we absence of adjuvant chemotherapy (group 1) and patients at very integrated information on standard pathological staging parame- high relapse risk that should mandate all appropriate adjuvant ters after neoadjuvant endocrine therapy with measurements of ER treatments (group 3). More confi dence around the estimates of status and levels of the Ki67 proliferation antigen in the surgical 1386 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008 specimen to create the PEPI score that weights these factors would be expected to have a worse prognosis because these tumors according the magnitude of the HR. Of particular note, patients have not maintained the pathway required to respond to endocrine with low pathological stage (stage 1 or 0) and a favorable biomarker therapy after treatment had been initiated ( 18 ). profile (PEPI score 0) at surgery had such a low rate of relapse that In addition to consideration of the PEPI approach as a tool for further adjuvant systemic therapy beyond continuation of an endo- treatment individualization, the data presented also strongly sup- crine agent appears unnecessary. In striking contrast, patients with port clinical trials in the neoadjuvant setting that study the effects high pathological stage disease at surgery and a poor biomarker of novel endocrine therapy agents and combinations on short-term profile (PEPI group 3) had a statistically significant higher risk of endpoints, such as Ki67 and pathological downstaging, as a prelude early relapse, more typical of ER  disease, and therefore should be to large adjuvant trials ( 19 ). offered all appropriate adjuvant treatments available. The biomarker analysis we have presented here would clearly References benefi t from additional retrospective studies of tumor samples from 1. Bast RC Jr , Hortobagyi GN . Individualized care for patients with cancer — a work in progress . N Engl J Med . 2004 ; 351 ( 27 ): 2865 – 2867 . other patients who were treated in a similar fashion, with longer 2. Mazouni C , Peintinger F , Wan-Kau S , et al . Residual ductal carcinoma follow-up. Prospective validation studies are also warranted to con- in situ in patients with complete eradication of invasive breast cancer after fi rm the PEPI as a tool for individualization of adjuvant chemo- neoadjuvant chemotherapy does not adversely affect patient outcome . therapy treatment. As part of these investigations, further study of J Clin Oncol . 2007 ; 25 ( 19 ): 2650 – 2655 . the PEPI group 2 to more clearly defi ne relapse risk categories 3. Eiermann W , Paepke S , Appfelstaedt J , et al . Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized would greatly improve the model. For example, a larger sample size double-blind multicenter study . Ann Oncol . 2001 ; 12 ( 11 ): 1527 – 1532 . could further defi ne the risk of relapse associated with modest eleva- 4. Ellis MJ , Coop A , Singh B , et al . Letrozole is more effective neoadjuvant tions of Ki67 above 2.7% in pathological stage 1 and 2A disease. An endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, ideal prospective validation study would include an immediate-sur- estrogen receptor-positive primary breast cancer: evidence from a phase gery control arm to directly compare a standard adjuvant chemo- III randomized trial . J Clin Oncol . 2001 ; 19 ( 18 ): 3808 – 3816 . 5. Smith IE , Dowsett M , Ebbs SR , et al . Neoadjuvant treatment of post- therapy decision-making approach vs pathological staging and tumor menopausal breast cancer with anastrozole, tamoxifen, or both in combi- biomarker profi ling after neoadjuvant endocrine therapy. Pending nation: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined the results from such a trial, we can state with confi dence that analy- with Tamoxifen (IMPACT) multicenter double-blind randomized trial . sis of post–neoadjuvant endocrine therapy surgical samples with J Clin Oncol . 2005 ; 23 ( 22 ): 5108 – 5116 . Ki67 and ER provides additional useful prognostic information that 6. Dowsett M , Ebbs SR , Dixon JM , et al . Biomarker changes during neoad- juvant anastrozole, tamoxifen, or the combination: infl uence of hormonal is not provided by an analysis of the baseline sample alone. Repeat status and HER-2 in breast cancer — a study from the IMPACT trialists . ER analysis reveals the presence of a subset of tumors with unstable J Clin Oncol . 2005 ; 23 ( 11 ): 2477 – 2492 . ER expression and very aggressive clinical course. “On-treatment” 7. Ellis MJ , Coop A , Singh B , et al . Letrozole inhibits tumor proliferation Ki67 levels more accurately predict relapse risk than baseline values, more effectively than tamoxifen independent of HER1/2 expression sta- whether measured at 3 – 4 months, as discussed in this study, or as tus . Cancer Res. 2003 ; 63 ( 19 ): 6523 – 6531 . 8. Allred DC , Harvey JM , Berardo M , Clark GM . Prognostic and predictive early as 2 weeks after initiaton of endocrine treatment, as shown factors in breast cancer by immunohistochemical analysis . Mod Pathol . earlier by the IMPACT investigators ( 9 ). A standardized ER and 1998 ; 11 ( 2 ): 155 – 168 . Ki67 analysis approach should be adopted as part of any prospective 9. Dowsett M , Smith IE , Ebbs SR , et al . Prognostic value of Ki67 expression plan to validate the PEPI model as a clinical decision tool. after short-term presurgical endocrine therapy for primary breast cancer . The data presented may prove useful with respect to other deci- J Natl Cancer Inst . 2007 ; 99 ( 2 ): 167 – 170 . 10. Katz RL , Patel S , Sneige N , et al . Comparison of immunocytochemical sions that must be made when a patient is treated with neoadjuvant and biochemical assays for estrogen receptor in fi ne needle aspirates and endocrine therapy. For example, nodal stage after neoadjuvant histologic sections from breast carcinomas . Breast Cancer Res Treat . 1990 ; endocrine therapy was powerfully predictive, suggesting that 15 ( 3 ): 191 – 203 . upfront staging of the axillary nodes may not be necessary before 11. Morrow DA , Antman EM , Charlesworth A , et al . TIMI risk score for initiation of neoadjuvant endocrine treatment because the prog- ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an intravenous nPA for treatment of nostic impact of this factor is preserved after therapy. In addition, infarcting myocardium early II trial substudy . Circulation . 2000 ; 102 ( 17 ): the PEPI score might be used to tailor radiotherapy decisions. 2031 – 2037 . That is, in the setting of a favorable PEPI score and low pathologi- 12. Harrell FE Jr , Lee KL , Mark DB . Multivariable prognostic models: issues cal stage, it might be appropriate to consider partial breast irradia- in developing models, evaluating assumptions and adequacy, and measur- tion, or even no radiation, as part of a prospective study ( 15 ). The ing and reducing errors . Stat Med . 1996 ; 15 ( 4 ): 361 – 387 . 13. Urruticoechea A , Smith IE , Dowsett M . Proliferation marker Ki-67 in ER and Ki67 data in the present study suggests that prognostic early breast cancer . J Clin Oncol . 2005 ; 23 ( 28 ): 7212 – 7220 . tests that contain signatures for proliferation, ER and ER regulated 14. Ma CX , Ellis MJ . Neoadjuvant endocrine therapy for locally advanced genes, such as the 21 gene recurrence score (16) or the distinction breast cancer . Semin Oncol . 2006 ; 33 ( 6 ): 650 – 656 . between Luminal A and luminal B tumors ( 17 ) may have additional 15. Hughes KS , Schnaper LA , Berry D , et al . Lumpectomy plus tamoxifen valuable qualities when applied to samples that have been exposed with or without irradiation in women 70 years of age or older with early breast cancer . N Engl J Med . 2004 ; 351 ( 10 ): 971 – 977 . to endocrine treatment. Specifi cally, tumors that lose the prolifera- 16. Paik S , Shak S , Tang G , et al . A multigene assay to predict recurrence of tion gene expression signature in response to endocrine therapy tamoxifen-treated, node-negative breast cancer . N Engl J Med . 2004 ; would be expected to have a better prognosis than tumors in which 351 ( 27 ): 2817 – 2826 . the proliferation signature persisted despite treatment. In contrast, 17. Hu Z , Fan C , Oh DS , et al . The molecular portraits of breast tumors are tumors that lose aspects of the luminal signature, particularly ER, conserved across microarray platforms . BMC Genomics . 2006 ; 7 : 96 – 108 . jnci.oxfordjournals.org JNCI | Articles 1387 18. Ellis MJ , Tao Y , Luo J , et al . A poor prognosis ER and HER2-negative, Pharmaceuticals Corp and hold stock in the company. A. S. Bhatnagar is on nonbasal, breast cancer subtype identifi ed through postneoadjuvant the speaker’s bureau for Novartis Pharmaceuticals Corp. Ian Smith received endocrine therapy tumor profi ling . J Clin Oncol . 2008 ; 26 : Abstract honoraria for lecturing at and attending advisory board meetings for Novartis 502 . Pharmaceuticals Corp, Pfi zer, Inc, and AstraZeneca. M. Dowsett receives 19. Ellis MJ . Neoadjuvant endocrine therapy as a drug development strategy . research grant funds and has received honoraria for consulting and advi- Clin Cancer Res. 2004 ; 10 ( 1 pt 2 ): 391S – 395S . sory board work from AstraZeneca and Novartis Pharmaceuticals Corp. Representatives from Novartis Pharmaceuticals Corp have coauthored, edited, reviewed, and approved parts of this manuscript. Notes Present address: World Wide Services Group Ltd, Geispelgasse 13, M. J. Ellis is a consultant for, on the speaker’s bureau of, and currently doing CH-4132 Muttenz, Switzerland (A. S. Bhatnagar). research sponsored by, Novartis Pharmaceuticals Corp and AstraZeneca. D. Manuscript received March 10 , 2008 ; revised July 14 , 2008 ; accepted July B. Evans, H. A. Chaudri Ross, and A. von Kameke are employees of Novartis 29 , 2008 . 1388 Articles | JNCI Vol. 100, Issue 19 | October 1, 2008

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