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⅐ N U M B E R 2 ⅐ J A N U A R Y 1 0 2 0 1 3 Prognostic Significance of Progesterone Receptor–PositiveTumor Cells Within Immunohistochemically DefinedLuminal A Breast Cancer Aleix Prat, Maggie Chon U. Cheang, Miguel Martín, Joel S. Parker, Eva Carrasco, Rosalía Caballero,Scott Tyldesley, Karen Gelmon, Philip S. Bernard, Torsten O. Nielsen, and Charles M. Perou Purpose
Current immunohistochemical (IHC)-based definitions of luminal A and B breast cancers are
imperfect when compared with multigene expression-based assays. In this study, we sought to improve the IHC subtyping by examining the pathologic and gene expression characteristics of sitario Gregorio Maran˜o´n, Facultad de genomically defined luminal A and B subtypes.
Patients and Methods
lía Caballero, Grupo Espan˜ol de Investi- Gene expression and pathologic features were collected from primary tumors across five independent cohorts: British Columbia Cancer Agency (BCCA) tamoxifen-treated only, Grupo Espan˜ol de Investi- gacio´n en Ca´ncer de Mama 9906 trial, BCCA no systemic treatment cohort, PAM50 microarray training data set, and a combined publicly available microarray data set. Optimal cutoffs of percentage of progesterone receptor (PR) –positive tumor cells to predict survival were derived and independently tested. Multivariable Cox models were used to test the prognostic significance.
Clinicopathologic comparisons among luminal A and B subtypes consistently identified higher rates of PR positivity, human epidermal growth factor receptor 2 (HER2) negativity, and histologic grade 1 in luminal A tumors. Quantitative PR gene and protein expression were alsofound to be significantly higher in luminal A tumors. An empiric cutoff of more than 20% of PR-positive tumor cells was statistically chosen and proved significant for predicting survivaldifferences within IHC-defined luminal A tumors independently of endocrine therapy admin- istration. Finally, no additional prognostic value within hormonal receptor (HR) –positive/HER2- negative disease was observed with the use of the IHC4 score when intrinsic IHC-based subtypes were used that included the more than 20% PR-positive tumor cells and vice versa.
Conclusion
Me´dica. A.P. is affiliated with the Medi- Semiquantitative IHC expression of PR adds prognostic value within the current IHC-based luminal A definition by improving the identification of good outcome breast cancers. The new proposed IHC-based definition of luminal A tumors is HR positive/HER2 negative/Ki-67 less J Clin Oncol 31:203-209. 2012 by American Society of Clinical Oncology Authors’ disclosures of potential conflicts the intrinsic molecular subtypes of breast cancer and INTRODUCTION
provides a risk of relapse (ROR) score in a fashion Hormonal receptor (HR) –positive breast cancer similar to the Oncotype DX (Genomic Health, Red- is a clinically and biologically heterogeneous wood City, CA) recurrence score (RS).4-6 These two entity.1-3 Studies based on gene expression profil- assays provide valuable and independent prognostic ing have identified at least two major groups of information beyond standard clinicopathologic HR-positive tumors, known as the luminal A and variables. However, standardized gene expression– B intrinsic subtypes of breast cancer. These two based tests are not readily available in most of the molecular entities have shown significant differ- world as a result of cost, assay turnaround times, and ences in baseline prognosis and sensitivity to cy- other logistic issues. Thus surrogate definitions of the intrinsic subtypes and/or risk of relapse groups Currently, a gene expression– based assay developed using routine pathology and clinical pa- known as the PAM50 subtype predictor identifies rameters could be of great practical value.7,8 2012 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org by TORU WATANABE on March 13, 2013 from 212.243.104.170 Copyright 2013 American Society of Clinical Oncology. All rights reserved.
Prat et al
We have previously reported an immunohistochemical (IHC)- line only). All IHC-based tissue microarray images of both BCCA cohorts can based surrogate definition of the luminal A (IHC-luminal A) and be obtained via the Genetic Pathology Evaluation Centre TMA Viewer.13 luminal B/human epidermal growth factor receptor 2 (HER2) IHC4 Score
-negative (IHC-luminal B/HER2-negative) subtypes based on the A version of the IHC4 score was evaluated in HER2-negative disease quantitative expression of the proliferation-related marker Ki-67 using the reported formula.8 However, instead of using the H-score reported within HR-positive/HER2-negative disease.9 This definition has now in Cuzick et al8 for estimating the semiquantitative expression of ER, we been adopted by the 2011 St Gallen Expert Consensus Panel Recom- determined a general intensity score value of 0 to 3 and multiplied this value bythe percentage of ER-positive tumor cells for a final ER score of 0 to 300.
mendation Guidelines for the systemic treatment of early breast can-cer,10 which recommend adjuvant endocrine therapy alone for Statistical Analysis
patients with IHC-luminal A tumors and the addition of chemother- Significant differences in clinicopathologic features between groups were apy for patients with IHC-luminal B/HER2-negative tumors. Here we evaluated using either the ␹2 test or the t test. Estimates of survival were from further refine the IHC-based definition of luminal A and B through the Kaplan-Meier curves and tests of differences by the log-rank test. Univar-iate and multivariate Cox models were used to test the independent prognostic the use of quantitative progesterone receptor (PR) expression.
significance of each variable. Over-represented biologic processes were identi-fied with Expression Analysis Systematic Explorer (EASE). 14 To identify an optimal cutoff of percentage of PR-positive tumor cells PATIENTS AND METHODS
within IHC-luminal A tumors, we applied the penalized spline method onmultivariable Cox regression analysis in the BCCA-tamoxifen cohort6 (train-ing data set), and the optimal cutoff to predict distant relapse–free survival Patients, Samples, and Clinical Data
(DRFS) was independently tested in the GEICAM 990611 and BCCA-no Multiple different and independent data sets were used to assess the significance of PR IHC results. Gene expression and/or clinicopathologic To test the contribution of the IHC4 score, IHC-based subtyping and the features were evaluated across five different data sets: (1) a combined genomic PAM50 ROR-P score, all of these variables were tested in a prognostic model data set of nine publicly available microarray cohorts (GSE18229, GSE18864, within HR-positive/HER2-negative disease. Here we estimated the log likeli- GSE22219, GSE25066, GSE2990, GSE4922, GSE7390, GSE7849, and hood ratio statistic of each variable as an addition to a model containing the NKI295), (2) the PAM50 microarray-based subtype predictor training data set following clinical variables in the GEICAM 9906 cohort11: treatment arm, (PAM50-training, GSE10886),5 (3) a British Columbia Cancer Agency histologic grade, tumor stage, nodal status, and age. Finally, we estimated the (BCCA) tamoxifen-treated cohort (BCCA-tamoxifen),6 (4) the Grupo Espa- log likelihood ratio statistic of each variable as an addition to a model contain- ˜ol de Investigacio´n en Ca´ncer de Mama (GEICAM) 9906 trial,11 and (5) the ing clinical variables and one or two of the three variables being evaluated BCCA no adjuvant systemic therapy (AST) cohort (BCCA-no AST).9 A de- (IHC4 score, intrinsic IHC-based subtyping, and PAM50 ROR-P).
tailed CONSORT diagram can be found in Appendix Table A1 (online only).
All patients from the BCCA-tamoxifen cohort6 had early-stage HR- positive disease and received adjuvant treatment with tamoxifen only. In the GEICAM 9906 phase III trial cohort,11 patients with node-positive diseasewere randomly assigned to adjuvant fluorouracil, epirubicin, and cyclophos-phamide versus fluorouracil, epirubicin, and cyclophosphamide followed by Gene and Protein Expression Differences Between
weekly paclitaxel, and patients with HR-positive disease subsequently received Luminal A and B Tumors
adjuvant endocrine therapy. The BCCA-no AST cohort9 includes “clinically To identify global and single gene expression differences, we low risk” patients with primary breast cancer diagnosed between 1986 and performed a two-class significance analysis of microarrays between 1992 who did not receive adjuvant systemic therapy. Characteristics of both prototypical luminal A and B tumors from the PAM50-training co- BCCA cohorts and the GEICAM 9906 cohort have been previously de- hort.5 A total of 1,539 genes (348 upregulated and 1,191 downregu- scribed.6,9,11 From the PAM50-training cohort, we performed global andsingle gene expression analyses using only the prototypical samples of the lated) were found differentially expressed (false discovery rate Ͻ 1%) luminal A and B subtype. Finally, the combined microarray data set included between both subtypes (Appendix Fig A1, online only; Data Supple- nine publicly available data sets of primary breast cancers with annotated ment). The upregulated gene list in luminal A tumors was found enriched for genes involved in cell differentiation (eg, Kruppel-likefactor 4 and jun proto-oncogene) and cell adhesion (eg, vinculin and PAM50 Intrinsic Subtyping
All tumors were assigned an intrinsic molecular subtypes of breast cancer collagen, type XVI, ␣1) biologic processes. Conversely, the downregu- (luminal A, luminal B, HER2-enriched, and basal-like) and the normal-like lated gene list in luminal A tumors (ie, genes highly expressed in group using the PAM50 subtype predictor.5,6 In the BCCA-tamoxifen and luminal B tumors) was found enriched for genes involved in immune GEICAM 9906 cohorts,11 PAM50 was determined using a quantitative response (eg, interleukin 2 receptor ␣ and CD86) and cell-cycle (eg, reverse-transcriptase polymerase chain reaction– based assay.5,6 In the cyclin B1 and RAD51) biologic processes, which is indicative of the GEICAM 9906 cohort, we evaluated the PAM50 ROR score based on subtype faster proliferation rates known to be part of luminal B tumors.
and proliferation (ROR-P) as previously described for the BCCA-tamoxifencohort.6 In each individual publicly available microarray cohort, we applied Among the relatively upregulated genes in luminal A tumors was the PAM50 microarray-based algorithm5 after data set to data set normaliza- the progesterone receptor gene (PGR), but not the estrogen receptor tion based on median gene centering within each data set.
gene (ESR1). To further explore these findings, we evaluated the IHC-based subtyping was determined using the following definitions mRNA expression of PGR and ESR1 in two independent studies in adopted by the 2011 St Gallen Consensus Panel10: IHC-luminal A (HR posi- which PAM50 was performed using the quantitative reverse- tive/HER2 negative/Ki-67 Ͻ 14%), IHC-luminal B/HER2-negative (HR pos- transcriptase polymerase chain reaction platform (GEICAM 990611 itive/HER2 negative/Ki-67 Ͼ 14%), IHC-luminal B/HER2-positive (HR and BCCA-tamoxifen6) and confirmed that PGR, but not ESR1, was positive/HER2 positive), IHC-HER2ϩ (HR negative/HER2 positive), andtriple-negative (HR negative/HER2 negative). Detailed IHC-based protocols found significantly upregulated in luminal A tumors compared with for estrogen receptor (ER), PR, HER2, and Ki-67 determinations have been luminal B tumors (Figs 1A and 1B; P Ͻ .001, t test). Interestingly, PGR previously described6,9,11,12 and are summarized in Appendix Table A2 (on- was found only weakly correlated (Pearson correlation coefficient ϭ 2012 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org by TORU WATANABE on March 13, 2013 from 212.243.104.170 Copyright 2013 American Society of Clinical Oncology. All rights reserved.
Prognostic Significance of PR-Positive Breast Tumor Cells
Fig 1. Expression of the hormonal receptors in the Grupo Espan˜ol de Investigacio´n en Ca´ncer de Mama 9906 data set. (A) Estrogen receptor (ER) gene (ESR1) and
(B) progesterone receptor (PR) gene (PGR) as assayed using quantitative reverse-transcriptase polymerase chain reaction expression in luminal A and B tumors. Densityplots based on the percentage of (C) ER-positive and (D) PR-positive tumor cells as assessed by immunohistochemistry.
Ϫ0.19) with the expression of the Ki-67 gene MKI67, indicating that pathologic features of 2,257 patients with luminal A or B primary these two genes may provide different biologic information.
breast cancer. Across three independent cohorts (Table 1), luminal The mRNA expression-based data suggested that semiquan- A tumors showed significantly higher rates of PR positivity, HER2 titative scoring of the PR protein, but not ER protein, might help negativity, histologic grade 1, and tumor stage T0-T1 compared discriminate the genomically defined luminal A from B tumors. To with luminal B tumors. No significant differences in ER status were further explore this hypothesis, we compared the percentage of observed, with the vast majority (92% to 96%) of luminal A and B PR-positive and ER-positive tumor cells as assessed by IHC, among luminal A and B tumors in the GEICAM 9906 cohort,11 andobserved that only the percentage of PR-positive cells can discrim- IHC-Based Versus PAM50 Subtype Definitions
inate luminal A from B tumors (Figs 1C and 1D). However, it is Current IHC-based definitions of luminal A and B subtypes are important to note that considerable overlap was observed. Finally,PR protein expression was also weakly anticorrelated with Ki-67 imperfect when compared with multigene expression-based assays.5 protein expression (r ϭ Ϫ0.20).
To further illustrate this, we evaluated the distribution of theIHC-based definitions within luminal A and B tumors in the BCCA- Clinicopathologic Features of Luminal
tamoxifen6 and the GEICAM 9906 cohorts.11 As expected, whereas a A and B Tumors
large majority (81% to 85%) of luminal A tumors were identified as To identify clinicopathologic differences among the genomi- IHC-luminal A, 35% to 52% of luminal B tumors were also identified cally defined luminal A and B tumors, we evaluated the clinico- 2012 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org by TORU WATANABE on March 13, 2013 from 212.243.104.170 Copyright 2013 American Society of Clinical Oncology. All rights reserved.
Prat et al
Table 1. Clinicopathologic Characteristics of Luminal A and B Tumors
Abbreviations: BCCA, British Columbia Cancer Agency; ER, estrogen receptor; GEICAM, Grupo Español de Investigación en Cáncer de Mama; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; PR, progesterone receptor.
Finally, we explored the survival of the luminal A and B subtypes percentage of PR-positive and ER-positive invasive breast carcinoma within the IHC-based luminal A and IHC-luminal B/HER2-negative cells with survival outcomes within IHC-luminal A tumors of the BCCA- tumors in the BCCA-tamoxifen cohort6 (Appendix Table A3, online tamoxifen cohort.6 As expected, the percentage of PR-positive cancer only). In both cases, luminal A tumors showed a significantly better cells, but not the percentage of ER-positive cancer cells (data not shown), DRFS outcome than non–luminal A tumors. In multivariable Cox was associated with DRFS after adjusting for standard clinicopathologic model survival analyses adjusted for histologic grade, age at diagnosis, variables, with the optimal PR percentage cutoff to predict outcome being nodal positivity, and tumor size, the hazard ratio for DRFS in PAM50 found to be 20% (Appendix Fig A2-A3, online only). In contrast, within luminal A tumors compared with PAM50 non–luminal A was 0.642 IHC-luminal B/HER2-negative tumors (ie, HR-positive/Ki-67 Ͼ 14%), within IHC-luminal A tumors (95% CI, 0.422 to 0.975, P ϭ .038) and semiquantitative expression of either PR or ER was not found to be 0.582 within IHC-luminal B/HER2-negative tumors (95% CI, 0.323 associated with outcome differences (data not shown).
We then tested the prognostic value of the PR cutoff of more than Survival Outcomes Based on the Percentage of
20% within IHC-luminal A tumors in two independent cohorts of PR-Positive Cells
patients with primary breast cancer (GEICAM 990611 and the These data suggested that (1) further improvements in the IHC- BCCA-no AST cohorts9). In both data sets, patients with IHC-luminal luminal A definition is needed because many PAM50-defined luminal A tumors having low positive PR-positive tumor cells (Յ 20%) B tumors are erroneously identified as IHC-luminal A and (2) quan- showed significantly poorer survival compared with tumors with titative scoring of PR-positive tumor cells, but not ER-positive tumor more than 20% of PR-positive tumor cells (Figs 2A and 2B).
cells, might help identify good-outcome breast cancers. To test this Multivariable analyses confirmed the independent association hypothesis, we evaluated the association of the visually determined between PR expression and survival (Appendix Table A4-A5, online Table 2. Distribution of the IHC-Based Subtypes Across the Luminal A and B Intrinsic Subtypes
NOTE. Within hormone receptor–positive/HER2-negative disease, the concordance ␬ value score between the PAM50 luminal A and B definition with the IHC-luminal A and IHC-luminal B/HER2-negative definitions was 0.196 and 0.407 (slight to fair agreement) in the GEICAM 9906 cohorts11 andBCCA-tamoxifen,6 respectively.
Abbreviations: BCCA, British Columbia Cancer Agency; GEICAM, Grupo Español de Investigación en Cáncer de Mama; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry.
2012 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org by TORU WATANABE on March 13, 2013 from 212.243.104.170 Copyright 2013 American Society of Clinical Oncology. All rights reserved.
Prognostic Significance of PR-Positive Breast Tumor Cells
Fig 2. Kaplan-Meier survival analysis within immunohistochemical-based luminal A tumors (hormone receptor positive/HER2 negative/Ki-67 Ͻ 14%) based on the
percentage of progesterone receptor (PR) –positive tumor cells. (A) Grupo Espan˜ol de Investigacio´n en Ca´ncer de Mama 9906 cohort. (B) British Columbia CancerAgency–no adjuvant systemic therapy cohort.
only). In the BCCA-no AST cohort, the breast cancer–specific survival negative/Ki-67 Ͼ 14%]) with a version of the IHC4 score8 and with at 15 years of patients with IHC-luminal A tumors with more than PAM50 ROR-P score6 in the subset of patients with HR-positive/ 20% PR-positive tumor cells was 94.0% (95% CI, 91.6% to 98.2%).
HER2-negative tumors from the GEICAM 9906 cohort11 (n ϭ 580).
We next evaluated the distribution of the gene-expression based All three classifications added significant prognostic information be- intrinsic subtypes (gold standard) within IHC-luminal A tumors in the yond clinical variables (Figs 3A, 3B, and 3C), with IHC-based subtypes GEICAM 9906 cohort based on this more than 20% PR cutoff (Table 3).
and IHC4 score providing similar amounts of prognostic information Consistent with the preceding findings, 63% of IHC-luminal A tumors and PAM50 ROR-P providing the largest amount.
with more than 20% of PR-positive cells were identified as luminal A, Finally, we evaluated the independent prognostic information whereas 24% of IHC-luminal A tumors with Յ 20% of PR-positive cells that each classification provided when considered in the presence of were identified as luminal A, thus confirming that this definition helps to one of the others. When the IHC4 score was included in the model, better discriminate true luminal A tumors from the rest. Finally, although adding intrinsic IHC-based subtype did not provide significant inde- the PR cutoff of 20% increased the percentage of luminal A tumors pendent information (Fig 3D). However, when the IHC-based sub- identified within what would otherwise have been considered IHC- type was included in the model, the IHC4 score did not provide luminal B/HER2-negative tumors from 5.9% to 30.9%, the majority of additional information (Fig 3E). On the other hand, inclusion of this group remained composed of luminal B (55.6%) tumors.
PAM50 ROR-P provided significant independent prognostic infor-mation beyond the information provided by either the IHC4 score or Comparison of Prognostic Values of IHC-Based
the IHC-based subtypes (Figs 3D and 3E).
Subtypes, IHC4 Score, and PAM50-ROR-P Score
We compared the contribution of the newly proposed IHC- DISCUSSION
based subtype definitions (IHC-luminal A [HR positive/HER2 nega-tive/Ki-67 Ͻ 14%/PR Ͼ 20%] and IHC-luminal B [HR positive/ Patients with early breast cancer with tumors that are ER positive HER2 negative/Ki-67 Ͻ 14%/PR Յ 20% or HR positive/HER2 and/or PR positive (ie, luminal) have lower risks of recurrence and Table 3. Distribution of the PAM50 Subtypes Across the Luminal A and B IHC-Based Subtypes in GEICAM 9906
Abbreviations: GEICAM, Grupo Español de Investigación en Cáncer de Mama; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; PR, 2012 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org by TORU WATANABE on March 13, 2013 from 212.243.104.170 Copyright 2013 American Society of Clinical Oncology. All rights reserved.
Prat et al
to cytotoxic drugs than HR-negative tumors. Moreover, in the neoad- juvant setting, luminal A tumors achieve lower rates of pathologic complete response with anthracycline/taxane-based chemotherapy compared with luminal B tumors.24 In addition, Oncotype DX has shown that within HR-positive disease, those tumors with high RS (ie, non–luminal A tumors) benefit the most from adjuvant chemother- apy.25,26 Interestingly, in a retrospective analysis from three adjuvant clinical trials, low expression of both ER and PR, and potentially low expression of PR within ER-positive patients, was found predictive of adding chemotherapy to endocrine therapy.27 Overall, these data sug- gest that luminal A tumors are less chemosensitive than luminal Bs.
A critical issue in HR-positive disease is the identification of Fig 3. Disease-free survival log likelihood ratio (LR) statistics of six different
patients who can be considered virtually cured with endocrine therapy predictive models (A–E) in patients of the Grupo Espan˜ol de Investigacio´n enCa´ncer de Mama 9906 cohort with hormone receptor (HR) –positive/human alone and so do not need adjuvant systemic chemotherapy.4,6 Gene epidermal growth factor receptor 2 (HER2) --negative breast cancer. The vari- expression– based assays such as the PAM50 ROR and Oncotype DX ables evaluated were the following: immunohistochemical (IHC)-based scoring ofestrogen receptor, progesterone receptor, HER2, and Ki-67 (IHC4 score; contin- RS can help identify these groups of patients, especially within node- uous variable), IHC-based subtypes (HR positive/HER2 negative/Ki-67 Ͻ 14% negative disease.28 Recently, a combined semiquantitative IHC-based Ͼ 20% [luminal A], HR positive/HER2 negative/Ki-67 Ͻ 14% Յ 20% and HR scoring of ER, PR, HER2, and Ki-67, known as IHC4 score, has shown positive/HER2 negative/Ki-67 Ͼ 14% [luminal B]), and PAM50 risk of recurrencescore based on subtype and proliferation (ROR-P; continuous variable). (*) P Ͻ .05.
to provide similar prognostic information as is provided by OncotypeDX RS.8 In this report, we have shown that a version of the IHC4 scoreis significantly associated with outcome, but did not add significant mortality compared with women with ER-negative and/or PR- prognostic information once our newly improved intrinsic IHC- negative disease.3,15 However, few studies have evaluated variations in based subtypes were known within HR-positive/HER2-negative dis- these risks across ER/PR status.15-18 In Dunnwald et al,16 women with ease. This is probably due to the fact that both pathology-based ER-positive/PR-negative, ER-negative/PR-positive, or ER-negative/ determinations are using the same four biomarkers to identify similar PR-negative tumors experienced higher risks of mortality compared with women with ER-positive/PR-positive tumors, independent of There are several issues that need to be considered in this study.
the various demographic and clinical tumor characteristics. These First, the information provided by IHC-based biomarkers cannot data are concordant with our centrally reviewed pathology data pre- simply be used to substitute the information coming from multigene- sented here, which show that PR positivity, and especially high expres- based assays, and even in the presence of IHC-based assays, the gene sion of PR protein, is more frequently observed in tumors with a better expression ROR assay was a strong prognostic feature. However, as baseline prognosis (ie, luminal A) than tumors with a poor baseline stated previously, multigene expression-based assays are not globally prognosis (ie, luminal B). It is important to note that a substantial available, and in their absence, well-designed IHC assays are valuable number of luminal B tumors (ϳ50% to 75%) are still PR positive, for baseline prognostic estimations. A second issue is that many genes although the expression of PR may be less than in luminal A tumors.
The ability of ER and/or PR expression to predict benefit to were found differentially expressed when luminal A tumors were endocrine and/or cytotoxic therapy has also been evaluated. In terms compared with luminal B tumors, and the quantitative IHC expres- of endocrine sensitivity, a recent patient-level meta-analysis of ran- sion of some of these biomarkers could have potentially performed domized trials from the Early Breast Cancer Trialists’ Collaborative better than PR. However, we decided to focus on the expression of PR Group that evaluated adjuvant tamoxifen versus no adjuvant tamox- because this biomarker is widely used in the community and is already ifen suggested that recurrence and death rate ratio is independent of part of the standard assessment at most institutions. Third, the IHC- PR status (or level) in ER-positive disease.19 Similar data have been based subtype definitions evaluated here were performed in a central- observed in another smaller randomized adjuvant study.20 In addi- ized laboratory under a single protocol, and one antibody per protein/ tion, PR expression levels have not shown to predict aromatase inhib- target, which may not reflect the everyday performance of these tests in itor efficacy over tamoxifen in ER-expressing tumors in two large the clinical setting, where multiple laboratories with different antibod- adjuvant clinical trials.21,22 This is concordant with a recent neoadju- ies is more likely to be the approach. Fourth, the IHC4 score evaluated vant trial in which luminal A and B tumors, as defined by the PAM50 in our study is slightly different from that of Cuzik et al8 as a result of assay, did not show significant differences in terms of response to the use of different antibodies for ER and PR and the use of a general aromatase inhibitors, although luminal A tumors achieved higher intensity score of ER-positive tumor cells. Nonetheless, the association rates of Preoperative Endocrine Prognostic Index score of 0, which is a of the IHC4 score with survival was found to be strong, as previ- validated biomarker of outstanding outcome after adjuvant endocrine therapy alone.23 Overall, these data suggest that luminal A and B To conclude, IHC subtype– based definitions of genomically de- tumors benefit similarly from endocrine therapies, but that patients fined luminal A and B tumors are imperfect because of the nature and with luminal A tumors have a better baseline prognosis than those limitations of pathology-based tests. However, semiquantitative mea- surement of the percentage of PR-positive cells within HR-positive/ In terms of chemotherapy benefit, the majority of adjuvant and HER2-negative/Ki-67 less than 14% tumors helps to identify patients neoadjuvant data suggest that HR status is a strong predictor of gen- who may be considered most effectively treated with endocrine eral chemosensitivity, with HR-positive tumors showing less benefit therapy alone. Therefore, the new proposed IHC-based definition of 2012 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org by TORU WATANABE on March 13, 2013 from 212.243.104.170 Copyright 2013 American Society of Clinical Oncology. All rights reserved.
Prognostic Significance of PR-Positive Breast Tumor Cells
luminal A tumors is HR-positive/HER2-negative/Ki-67 less than 14% University Genomics, BioClassifier Honoraria: None Research Funding:
None Expert Testimony: None Other Remuneration: None
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
AUTHOR CONTRIBUTIONS
OF INTEREST
Conception and design: Aleix Prat, Charles M. Perou
Although all authors completed the disclosure declaration, the following Administrative support: Rosalía Caballero
author(s) and/or an author’s immediate family member(s) indicated a Provision of study materials or patients: Maggie Chon U. Cheang,
financial or other interest that is relevant to the subject matter under Miguel Martín, Eva Carrasco, Rosalía Caballero, Philip S. Bernard, consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked Collection and assembly of data: Aleix Prat, Maggie Chon U. Cheang,
with a “C” were compensated. For a detailed description of the disclosure Miguel Martín, Eva Carrasco, Rosalía Caballero, Philip S. Bernard, categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Data analysis and interpretation: Aleix Prat, Maggie Chon U. Cheang,
Potential Conflicts of Interest section in Information for Contributors. Miguel Martín, Joel S. Parker, Scott Tyldesley, Karen Gelmon, Philip S.
Employment or Leadership Position: None Consultant or Advisory
Bernard, Torsten O. Nielsen, Charles M. Perou Role: Torsten O. Nielsen, BioClassifier (C) Stock Ownership: Philip S.
Manuscript writing: All authors
Bernard, University Genomics, BioClassifier; Charles M. Perou, Final approval of manuscript: All authors
11. Martín M, Rodríguez-Lescure A, Ruiz A, et al:
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