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Originally published as JCO Early Release 10.1200/JCO.2007.12.9437 on January 28 2008 © 2008 American Society of Clinical Oncology. Relationship Between Quantitative Estrogen and Progesterone Receptor Expression and Human Epidermal Growth Factor Receptor 2 (HER-2) Status With Recurrence in the Arimidex, Tamoxifen, Alone or in Combination Trial
From the Academic Department of Biochemistry, Royal Marsden Hospital; Departments of Epidemiology and Mathematics & Statistics, Cancer Research UK, Wolfson Institute of Preventive Medicine; Clinical Trials Group, Department of Surgery, University College London, London; Department of Pathology, The Western Infirmary, Glasgow; Department of Surgery, The Royal Bolton Hospital, Bolton; Department of Histopathology, Nottingham University, Nottingham City Hospital, Nottingham; Bradford Teaching Hospitals NHS Foundation Trust, Bradford Royal Infirmary, Bradford; Wythenshawe Hospital, Wythenshawe, Manchester; Leeds Institute of Molecular Medicine, St James's University Hospital, Leeds, United Kingdom; Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO; Department of Pathology, Translational Research Unit, Institut Jules Bordet, Brussels, Belgium; Department of Pathology, Tohoku University School of Medicine, Sendai, Japan; Medical Oncology Service, Hospital Universitario Arnau Vilanova, Lleida, Spain; Department of Surgical Oncology, University of Newcastle, Newcastle Mater Hospital, New South Wales, Australia; and the Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX Corresponding author: Mitch Dowsett, MD, Academic Department of Biochemistry, Royal Marsden Hospital, Fulham Road, London SW3 6JJ, United Kingdom; e-mail: mitch.dowsett{at}icr.ac.uk
Purpose To determine the relationship between quantitative estrogen-receptor (ER) and progesterone-receptor (PgR) expression and human epidermal growth factor 2 (HER-2) status with time to recurrence (TTR) in postmenopausal women with hormone receptor–positive primary breast cancer treated with anastrozole or tamoxifen as adjuvant therapy. Patients and Methods Formalin-fixed, paraffin-embedded tumor blocks were retrospectively collected from patients in the monotherapy arms of the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial and centrally tested for ER, PgR and HER-2. ER and PgR were scored using continuous scales and HER-2 was scored as 0 to 3+ with 2+ cases being analyzed by fluorescence in situ hybridization. Results Blocks were collected from 2,006 of 5,880 eligible patients. Tissue was assessable and ER and/or PgR positivity confirmed centrally in 1,782 cases. In these, TTR was longer for anastrozole than for tamoxifen by a similar extent to that in the overall trial. None of the three biomarkers identified a set of patients with differential benefit from anastrozole over tamoxifen. Patients with low ER, low PgR, and high HER-2 expression had a poorer prognosis with either drug. Only 2.6% of patients in the highest quartile of PgR experienced recurrence after 5 years, compared with 13.2% in the lowest quartile. Conclusion Quantitative expression of ER and PgR and HER-2 status did not identify patients with differential relative benefit from anastrozole over tamoxifen: TTR was longer for anastrozole than for tamoxifen in all molecular subgroups. Low ER or PgR or high HER-2 expression are associated with a high risk of recurrence with either anastrozole or tamoxifen.
The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared adjuvant treatment with anastrozole (Arimidex, AstraZeneca, Wilmington, DE) alone versus tamoxifen alone versus the combination for 5 years in postmenopausal women with early-stage, operable breast cancer. The trial reported a significant improvement in time to recurrence (TTR) for anastrozole versus tamoxifen in the hormone receptor–positive trial population, with a hazard ratio of 0.74 (95% CI, 0.64 to 0.87; P = .0002) after 68 months of median follow-up.1 This improved efficacy of anastrozole and other aromatase inhibitors over tamoxifen seems, at least in part, to result from the partial agonist activity of tamoxifen, which limits its antitumor efficacy.2,3 Laboratory studies have suggested that the degree to which tamoxifen acts as an agonist may be determined by molecular characteristics that vary between breast carcinomas, such as progesterone receptor (PgR) and human epidermal growth factor 2 (HER-2) expression.4,5 In addition, neoadjuvant studies have reported that, in contrast to tamoxifen, aromatase inhibitors have similar efficacy in HER-2–positive and HER-2–negative tumors6-9: One trial reported clinical activity of letrozole in patients with very low estrogen-receptor (ER)–positive tumors but no activity of tamoxifen.7 Consistent with these observations of differential activity, we published a hypothesis-generating report from ATAC, indicating that, although TTR was longer for anastrozole- than tamoxifen-treated patients in both ER-positive/PgR-positive and ER-positive/PgR-negative subgroups, the relative benefit from anastrozole was substantially greater in the PgR-negative subgroup.10 This analysis was based on data derived from case record forms (CRFs), which recorded receptor status as measured by local laboratories, involving varying methodologies and differing positive/negative thresholds. In an effort to identify molecular characteristics of tumors that indicate differential benefit from anastrozole versus tamoxifen, we initiated the TransATAC project to collect tumor blocks from patients participating in ATAC. Initially, the effect of quantitative expression of ER, PgR, and HER-2 positivity has been investigated.
Patients The ATAC trial was a randomized (1:1:1), double-blind trial of the adjuvant use of anastrozole 1 mg versus tamoxifen 20 mg versus the combination for 5 years. Eligible patients were postmenopausal women with histologically proven, operable, invasive breast cancer who had completed primary surgery ± radiotherapy and/or chemotherapy. Detailed aspects of the study at a median follow-up of 68 months (the 5-year completion analysis) have been published previously.1,11 After the first analysis, at a median 33 months follow-up, the combination arm was discontinued because of no greater efficacy than tamoxifen alone. The ATAC trial was initiated in 1996 and included 9,366 patients from 381 centers in 21 countries. The primary trial end points were disease-free survival, safety, and tolerability. Secondary trial end points included TTR, overall survival, and incidence of contralateral breast cancer. The TransATAC project was initiated in 2002 under the TA/01 protocol to establish a tissue bank from archival histopathology blocks from ATAC patients retrospectively. The TA/01 protocol describing the proposed work was approved by the ethics committees within the participating centers, and the relevant patient consents were obtained. Archival tumor blocks were requested for patients except those known to be ER and PgR negative according to local tests, and those randomly assigned to the combination arm. Tissue blocks were sent by courier to one of two centers: North American centers to Baylor Medical College, Houston, TX, and all other centers to the Royal Marsden Hospital, London, United Kingdom. In each of these centers, tissue microarrays (TMAs) were constructed using core diameters of 600 µm with three identical TMAs of 200 samples each being produced. Tissue sections of 3 to 4 µm were taken in the London laboratory. Block collection continued until September 30, 2006.
Methodology ER was quantitated using the H-score, which is defined as the percentage of cell staining weakly plus 2x the percentage of cell staining moderately, plus 3x the percentage of cell staining strongly.12 ER was considered positive if the H-score was more than 1, being similar to an Allred Score cutoff of more than 2.13 PgR was scored as the percentage of cells staining. Tumors with more than 10% of cell staining were regarded positive.
Statistical Analysis
Of the 9,366 patients in ATAC, 3,486 were excluded from TransATAC as ER and PgR negative or in the combination arm, leaving a total of 5,880 eligible monotherapy patients. Blocks were received for 2,006 of these, and results obtained from 1,856; the absence of a result in almost all cases was caused by a lack of sufficient malignant tissue in the block. Tissue was received and results obtained from 79% of 1,918 eligible patients from the United Kingdom, from 9% of 1,908 North American patients, and from 8% of 2054 patients from the rest of the world (RoW). The demographics of the TransATAC population and the ATAC hormone receptor–positive group are compared in Table 1. The proportion of node-negative patients was slightly higher in TransATAC (66%) compared with ATAC (60%). Only 9% of patients in TransATAC received adjuvant chemotherapy compared with 21% in ATAC. Otherwise, the populations were similar.
In the central analysis, 1,782 patients were ER and/or PgR positive; this constitutes the group we describe as the TransATAC Tissue Resource Group (TRG). In this group, 78.5% of the patients were PgR positive and 10.5% HER-2 positive. In the PgR-positive and -negative groups, 8.1% and 21.7% of patients were HER-2 positive, respectively—a similar distribution to that reported previously by us14 and others.15,16 Figure 1 compares the TTR for anastrozole and tamoxifen in the ATAC hormone receptor–positive group for the ATAC study and for the TransATAC population. The latter includes all 1,856 TransATAC patients to be equivalent to the ATAC population where central confirmation of hormone-receptor positivity was not performed. The hazard ratio for anastrozole versus tamoxifen was 0.74 (95% CI, 0.64 to 0.87; P = .0002) for the ATAC hormone receptor–positive population, and 0.69 (95% CI, 0.53 to 0.91; P = .008) for TransATAC. For both arms, recurrence was slightly lower in the TransATAC group than in the ATAC group.
ER in TransATAC There was a marginally statistically significant relationship between ER level (as a continuous variable) and TTR, with lower levels being associated with a shorter TTR. For tamoxifen-treated patients, the effect was less strong (P = .078) than for anastrozole-treated patients (P = .0009). Figure 2 illustrates the relationships between ER H-score and TTR for patients grouped according to quartile of ER H-score. For anastrozole, recurrence for the lowest ER quartile was more common than for the other quartiles, which were not distinct from one another. There was no significant interaction between ER level and treatment for TTR.
PgR in TransATAC PgR levels were strongly correlated with TTR for tamoxifen-treated patients (P = .0012) and more strongly for anastrozole-treated patients (P < .0001). For example, after 5 years' anastrozole treatment 2.6%, 5.1%, 8.3%, and 13.2% of patients recurred in the highest, second-highest, third-highest, and lowest PgR quartiles, respectively. Hazard ratios for the third, second and lowest quartile compared with the highest quartile were 1.99, 3.83, and 4.58, respectively (Fig 2B). No significant interaction between PgR (as a continuous variable) and treatment for TTR was seen. We have reported a major difference in the TTR hazard ratio between anastrozole and tamoxifen for the ER-/PgR-positive (0.84; 95% CI, 0.69 to 1.02) versus the ER-positive/PgR-negative (0.43; 95% CI, 0.31 to 0.61) subgroups, using locally derived results from the CRFs for the ATAC hormone receptor–positive population (Fig 3).10 The data from CRFs for the TransATAC TRG did not show this same difference between the two PgR subgroups: For PgR-positive patients, the hazard ratio was 0.67 (95% CI, 0.47 to 0.95); for PgR-negative patients, it was 0.57 (95% CI, 0.31 to 1.04). This point estimate of slightly greater relative benefit in the PgR-negative group was also found in the TransATAC central analysis with hazard ratios of 0.72 (95% CI, 0.52 to 1.01) and 0.68 (95% CI, 0.40 to 1.17), respectively. Thus, neither the CRF data nor the central analysis for TransATAC gave any indication of an important difference between relative benefit from the two drugs in PgR-negative and -positive patients in this subgroup of patients.
HER-2 Status in TransATAC HER-2–positive patients showed a shorter TTR for both tamoxifen- and anastrozole-treated patients (P = .0018 and < .0001, respectively) at 5 years (Fig 4). For tamoxifen, the recurrence rate at 5 years was 9.0% for HER-2–negative patients and 18.8% for HER-2–positive patients; for anastrozole, it was 5.9% for HER-2–negative and 19.8% for HER-2–positive patients. Thus, there was no indication of a greater differential benefit of anastrozole over tamoxifen in the HER-2–positive patients. However, there were only 44 events in the HER-2–positive group, so the CIs are wide.
Multivariate Model Using TransATAC Data
Aromatase inhibitors have been found consistently to be more effective agents than tamoxifen in delaying recurrence when administered as adjuvant treatment to patients with hormone receptor–positive early breast cancer, whether immediately after surgery or in a switching strategy after 2 to 3 years of tamoxifen. There is considerable interest in determining whether this greater efficacy is uniform across all subgroups, particularly those defined by molecular characteristics for which there is evidence from laboratory or other clinical settings for a differential response to tamoxifen or aromatase inhibitors. If confirmed, such differences could influence the choice of agent for treatment. This analysis of a subset of the ATAC trial depended on retrospective collection of archival tumor blocks. Overall blocks were obtained from 34% of eligible patients, but there was much greater completeness from the United Kingdom that constituted approximately one third of the ATAC population but approximately four fifths of the TransATAC TRG. Despite this, the demographics of the TransATAC and ATAC populations were similar, other than a small difference in the nodal status of the population and less use of adjuvant chemotherapy in TransATAC, both of which may be related to the slightly better outcome seen for both drugs in TransATAC. Importantly, a significantly better TTR was found for anastrozole over tamoxifen in TransATAC that was similar in magnitude to that in the whole ATAC hormone receptor–positive group. Additionally, the distribution of PgR and HER-2 positivity in the TransATAC TRG was similar to that reported previously.14-16 It would therefore seem that this group of patients is likely to yield a valid evaluation of the effect of these markers on TTR in ATAC. In this analysis, quantitative expression of ER and PgR and HER-2 status did not identify patients with differential relative benefit from anastrozole over tamoxifen: TTR was longer for anastrozole than for tamoxifen in all molecular subgroups. However, although the test set of 1,782 tumors seems large, some subgroups are small, and the power to detect moderate differences is limited. It is therefore possible that moderate differences exist between anastrozole and tamoxifen for some subgroups, but TransATAC would seem to exclude major differences. Similar data for PgR and HER-2 status have been reported in relation to early relapse for letrozole versus tamoxifen.17 The data derived on PgR status seem at first sight to conflict with our previously published hypothesis-generating data, which revealed a greater relative benefit of anastrozole over tamoxifen in patients with ER-positive/PgR-negative tumors than in those with ER-/PgR-positive tumors. This conflict might indicate that the earlier result was an artifact of unplanned subgroup analysis, but it should be noted that the TransATAC population may not be a fair test of the hypothesis because no significant difference was seen for this subgroup when the CRF receptor data were used. Thus, this nonrepresentative set of data from the CRFs did not allow us to determine whether central analysis supported or refuted the earlier results. There were major differences in geographic distribution of ATAC and TransATAC patients. Although there is no obvious reason why these or any other factors should lead to this disparity we conducted separate analyses for the ATAC data for the United Kingdom, North America, and RoW. In the ER-positive/PgR-known (CRF) population analyzed in the hypothesis generating publication, 85%, 82% and 78% were PgR+ in the United Kingdom, United States, and RoW, respectively. The hazard ratios for recurrence for anastrozole versus tamoxifen in these populations were 0.73, 0.61, and 0.78, respectively. There was no statistical evidence of an interaction between region and outcome in the PgR subgroups. PgR, HER-2, and (to a lesser extent) ER were significant predictors of outcome on both anastrozole and tamoxifen. The extent to which this reflects benefit from treatment as opposed to intrinsic prognosis is not possible to estimate in the absence of a no-treatment arm. However, we reported recently from a central analysis of blocks from two randomized trials of tamoxifen versus no treatment, that the poorer outcome of tamoxifen-treated, PgR-negative patients compared with PgR-positive patients was largely a result of poorer prognosis, and that PgR-positive and PgR-negative patients gained significant benefit from tamoxifen.14 This outcome is consistent with data from the Oxford overview analysis.18 Indirect comparison therefore suggests that the major reason for the strong influence of PgR status on outcome for both anastrozole and tamoxifen is an intrinsic prognostic effect. In contrast, the relationship between ER levels (in an ER-positive population) with outcome on tamoxifen seems to be related to treatment benefit, both in the overview18 and in analyses based on RNA.19 The effect of ER on TTR for tamoxifen-treated patients in this study was less than might have been expected from earlier studies. It is possible that, despite our prior validation studies of TMAs versus sections for ER quantitation, a single core in a TMA may not provide the best quantitative measure. Thus, ER might be retained in the multivariate analysis if this analysis had also been based on sections or multiple cores. Only approximately 10% of hormone receptor–positive tumors are also HER-2 positive. This has meant that the effect of HER-2 status on benefit from tamoxifen over no treatment in adjuvant therapy trials has been difficult to assess. In our own study14 and the Gruppo Universitario Napoletano (GUN) trial20 no benefit was seen in the ER-positive/HER-2–positive group, but in both cases, the CIs were wide. However, overall clinical data indicate that the effectiveness of tamoxifen may be impeded by HER-2 positivity, although this does not render tumors refractory to tamoxifen.21 The data generated in the TransATAC analysis indicated no difference between tamoxifen and anastrozole in this regard. Neoadjuvant studies suggested that response to tamoxifen but not aromatase inhibitors was adversely affected by HER-2–positive status7,8 but reanalysis of the letrozole/tamoxifen study9 revealed that HER-2 FISH+/ER-positive tumors were associated with higher levels of post-treatment proliferation when compared with HER-2–tumors, which is consistent with the data in TransATAC that tumors with this profile exhibit poorer outcome on endocrine therapy. There is substantial interest in determining the likelihood of recurrence, particularly in node-negative patients treated with endocrine therapy, to identify patients with a sufficiently small chance of recurrence that they do not require chemotherapy. Data enabling this for tamoxifen have emerged from panels of biomarkers measured either by IHC or by reverse transcription polymerase chain reaction for RNA transcripts. Our data revealed strong prognostic importance for the three markers measured, particularly with anastrozole, and suggest that such assessment may be possible using just these three markers, possibly plus markers evaluating proliferation, for example. The formal comparison of such an approach with RNA evaluation in the TransATAC TRG will be important for clinical practice.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Mitch Dowsett, AstraZeneca (C); John Forbes, AstraZeneca (C); Aman Buzdar, AstraZeneca (C) Stock Ownership: None Honoraria: Mitch Dowsett, AstraZeneca; Jack Cuzick, AstraZeneca; Joan Houghton, AstraZeneca; John Forbes, AstraZeneca; Aman Buzdar, AstraZeneca Research Funding: Mitch Dowsett, AstraZeneca; Craig Allred, AstraZeneca; Jack Cuzick, AstraZeneca; Joan Houghton, AstraZeneca; John Forbes, AstraZeneca Expert Testimony: None Other Remuneration: None
Conception and design: Mitch Dowsett, Craig Allred, Jack Cuzick Administrative support: Jill Knox, Joan Houghton, Norman Williams Provision of study materials or patients: Hugh Bishop, Ian Ellis, Denis Larsimont, Pauline Carder, Antonio Llombart Cussac, Fiona Knox, Valerie Speirs, John Forbes, Aman Buzdar Collection and assembly of data: Mitch Dowsett, Craig Allred, Jill Knox, Emma Quinn, Janine Salter, Chris Wale, Joan Houghton, Norman Williams, Elizabeth Mallon Data analysis and interpretation: Mitch Dowsett, Craig Allred, Emma Quinn, Janine Salter, Chris Wale, Jack Cuzick, Joan Houghton, Elizabeth Mallon, Hugh Bishop, Ian Ellis, Denis Larsimont, Hironobu Sasano, John Forbes, Aman Buzdar Manuscript writing: Mitch Dowsett, Craig Allred, Jack Cuzick, Hironobu Sasano, Valerie Speirs Final approval of manuscript: Mitch Dowsett, Craig Allred, Jill Knox, Emma Quinn, Janine Salter, Chris Wale, Jack Cuzick, Joan Houghton, Norman Williams, Elizabeth Mallon, Hugh Bishop, Ian Ellis, Denis Larsimont, Hironobu Sasano, Pauline Carder, Antonio Llombart Cussac, Fiona Knox, Valerie Speirs, John Forbes, Aman Buzdar
The ATAC Trialists' Group ATAC Steering Committee. Judith Adams: University of Manchester, Manchester, United Kingdom; M. Baum: University College London, London, United Kingdom; A.R. Bianco: Universita Degli Studi Di Napoli Federico II, Napoli, Italy; A. Buzdar: The University of Texas M.D. Anderson Cancer Center, Houston, TX; D. Cella: Northwestern University, Evanston, IL; M. Coibion: Institut Bordet, Brussels, Belgium; R. Coleman: Cancer Research Centre, Weston Park Hospital, Sheffield, United Kingdom; M. Constenla: Hospital Montecelo, Pontevedra, Spain; J. Cuzick: Cancer Research UK, London, United Kingdom; W. Distler: Universitätsklinikum Dresden, Dresden, Germany; M. Dowsett: The Royal Marsden Hospital, London, United Kingdom; S. Duffy: St James's University Hospital, Leeds, United Kingdom; R. Eastell: University of Sheffield, Sheffield, United Kingdom; L.J. Fallowfield, University of Sussex, Brighton, United Kingdom; J.F. Forbes (chairman): Calvary Mater Newcastle Hospital, WARATAH (Newcastle), Australia; W.D. George: Beatson Oncology Centre, Western Infirmary, Glasgow, United Kingdom; J. Gray: Belfast City Hospital, Belfast, United Kingdom; J.-P. Guastalla: Centre Léon Bérard, Lyon, France; J. Houghton, N. Williams: Clinical Trials Group of the Department of Surgery, UCL, London, United Kingdom; A. Howell: Christie Hospital, Manchester, United Kingdom; J.G.M. Klijn: Daniel den Hoed Kliniek and University Hospital, Rotterdam, the Netherlands; J. Mackey: Cross Cancer Institute, Edmonton, Alberta, Canada; R.E. Mansel: University of Wales College of Medicine, Cardiff, United Kingdom; J.M. Nabholtz: Hartman Oncology Institute, Levallois-Perret, France; T. Nagykalnai: Uzsoki U. Hospital, Budapest, Hungary; U. Nylen: Radiumhemmet, Karolinska Sjukhuset, Stockholm, Sweden; R. Sainsbury: University College London, London, United Kingdom; V.J. Suarez-Mendez, J. Diver, K. Pemberton: AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom; J.S. Tobias: The Meyerstein Institute of Clinical Oncology, Middlesex Hospital, London, United Kingdom. ATAC Pathology Subcommittee. Mitch Dowsett (chairman): Royal Marsden Hospital, London, United Kingdom; Craig Allred: Washington University School of Medicine, St. Louis, MO; Hugh Bishop: The Royal Bolton Hospital, Bolton, United Kingdom; Jo Diver: AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom; Ian Ellis: Nottingham City Hospital, Nottingham, United Kingdom; Joan Houghton, Norman Williams: University College London, London, United Kingdom; Denis Larsimont: Institut Jules Bordet, Brussels, Belgium; Elizabeth Mallon: The Western Infirmary, Glasgow, United Kingdom; Soonmyung Paik: National Surgical Breast and Bowel Project, Pittsburgh, PA; Hironobu Sasano: Tohoku University School of Medicine, Sendai, Japan. International Project Team. V.J. Suarez-Mendez: AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom; E. Foster: ISD Cancer Clinical Trials Team, Edinburgh, United Kingdom; J. Houghton, N. Williams: Clinical Trials Group of the Department of Surgery, UCL, London, United Kingdom; J. Gray: Clinical Trials Research Unit, Leeds, United Kingdom. Data Monitoring Committee. M. Buyse: International Institute for Drug Development (ID squared), Brussels, Belgium; J. Cuzick (Independent statistician), Cancer Research UK, London, United Kingdom; R. Margolese: McGill University, The Sir Mortimer B. Davis Jewish General Hospital, Montreal, Québec, Canada; J.J. Body: Institute J. Bordet, Brussels, Belgium. Collaborative/Operational Groups. J.F. Forbes (group coordinator), J.K. Wakeham (study coordinator): Australian New Zealand Breast Cancer Trials Group Operations Office; S. de Placido (study coordinator), C. Carlomagno (study coordinator): Universita Degli Studi Di Napoli Federico II, Italy; A. Nicolucci (group coordinator), M. Belfiglio (study coordinator), M. Valentini (study coordinator): GIVIO Group, Consorzio Mario Negri Sud, Italy; E. Foster (principal trial coordinator and CCTT contact): ISD Cancer Clinical Trials Team, Edinburgh, United Kingdom, Liz.Foster{at}isd.csa.scot.nhs.uk; C. Lacey (trial monitor): North West Breast Group, Burnley, Lancashire, United Kingdom; J. Gray (head of pharmaceutical collaboration): Clinical Trials Research Unit, University of Leeds, Leeds, United Kingdom; J. Houghton (senior lecturer in clinical trials and CTG contact), N. Williams (trial coordinator): Clinical Trials Group of the Department of Surgery, UCL, London, United Kingdom, j.houghton{at}ctg.ucl.ac.uk.
Participating Pathologists
We thank collaborating investigators and pathologists; ATAC Steering and Pathology committees for guidance; and Mark Walker for editorial assistance.
Supported by Breakthrough Breast Cancer, AstraZeneca, and the Royal Marsden Hospital. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article. published online ahead of print at www.jco.org on January 28, 2008.
1. Howell A, Cuzick J, Baum M: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365:60-62, 2005[CrossRef][Medline] 2. Osborne CK, Coronado-Heinsohn EB, Hilsenbeck SG, et al: Comparison of the effects of a pure steroidal antiestrogen with those of tamoxifen in a model of human breast cancer. J Natl Cancer Inst 87:746-750, 1995 3. Dowsett M, Howell A: Breast cancer: Aromatase inhibitors take on tamoxifen. Nat Med 8:1341-1344, 2002[CrossRef][Medline] 4. Kurokawa H, Arteaga CL: ErbB (HER) receptors can abrogate antiestrogen action in human breast cancer by multiple signaling mechanisms. Clin Cancer Res 9:511S-515S, 2003 5. Shou J, Massarweh S, Osborne CK, et al: Mechanisms of tamoxifen resistance: Increased estrogen receptor-HER2/neu cross-talk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96:926-935, 2004 6. Dixon JM, Jackson J, Hills M, et al: Anastrozole demonstrates clinical and biological effectiveness in oestrogen receptor-positive breast cancers, irrespective of the erbB2 status. Eur J Cancer 40:2742-2747, 2004[CrossRef][Medline] 7. Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 19:3808-3816, 2001 8. Smith IE, Dowsett M, Ebbs SR, et al: Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) multicenter double-blind randomized trial. J Clin Oncol 23:5108-5116, 2005 9. Ellis MJ, Tao Y, Young O, et al: Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole. J Clin Oncol 24:3019-3025, 2006 10. Dowsett M, Cuzick J, Wale C, et al: Retrospective analysis of time to recurrence in the ATAC trial according to hormone receptor status: An hypothesis-generating study. J Clin Oncol 23:7512-7517, 2005 11. Baum M, Budzar AU, Cuzick J: Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002[CrossRef][Medline] 12. Budwit-Novotny DA, McCarty KS, Cox EB, et al: Immunohistochemical analyses of estrogen receptor in endometrial adenocarcinoma using a monoclonal antibody. Cancer Res 46:5419-5425, 1986 13. Harvey JM, Clark GM, Osborne CK, et al: Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474-1481, 1999 14. Dowsett M, Houghton J, Iden C, et al: Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according to oestrogen receptor, progesterone receptor, EGF receptor and HER2 status. Ann Oncol 17:818-826, 2006 15. Tovey S, Dunne B, Witton CJ, et al: Can molecular markers predict when to implement treatment with aromatase inhibitors in invasive breast cancer? Clin Cancer Res 11:4835-4842, 2005 16. Arpino G, Weiss H, Lee AV, et al: Estrogen receptor-positive, progesterone receptor-negative breast cancer: Association with growth factor receptor expression and tamoxifen resistance. J Natl Cancer Inst 97:1254-1261, 2005 17. Mauriac L, Keshaviah A, Debled M, et al: Predictors of early relapse in postmenopausal women with hormone receptor-positive breast cancer in the BIG 1-98 trial. Ann Oncol 18:859-867, 2007 18. Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomized trials. Lancet 365:1687-1717, 2005[CrossRef][Medline] 19. Baehner FL, Habel LA, Quesenberry CP, et al: Quantitative RT-PCR analysis of ER and PR by oncotype DX indicates distinct and different associations with prognosis and prediction of tamoxifen benefit. Br Cancer Res Treat 100:S20, 2006 (abstr 45) 20. De Placido S, De Laurentiis M, Carlomagno C, et al: Twenty-year results of the Naples GUN randomized trial: Predictive factors of adjuvant tamoxifen efficacy in early breast cancer. Clin Cancer Res 9:1039-1046, 2003 21. Ring A, Dowsett M: Human epidermal growth factor receptor-2 and hormonal therapies: Clinical implications. Clin Breast Cancer 4:S34-S41, 2003 (suppl)[Medline] Submitted June 7, 2007; accepted November 14, 2007.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
