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Originally published as JCO Early Release 10.1200/JCO.2006.09.6578 on August 6 2007 © 2007 American Society of Clinical Oncology. A Phase II Placebo-Controlled Trial of Neoadjuvant Anastrozole Alone or With Gefitinib in Early Breast Cancer
From the Royal Marsden Hospital and Institute of Cancer Research; Royal Marsden Hospital, London; Royal Bournemouth Hospital, Bournemouth; AstraZeneca, Macclesfield, United Kingdom; Hospital Arnau I Vilanova, Lleida; and Hospital Lozano Blesa, Zaragoza, Spain. Address reprint requests to Ian E. Smith, MD, Breast Unit, The Royal Marsden Hospital, Fulham Rd, London, SW3 6JJ United Kingdom; e-mail: ian.smith{at}rmh.nhs.uk
Purpose: Increased epidermal growth factor receptor (EGFR) expression may promote breast cancer resistance to endocrine therapy. We have therefore investigated whether neoadjuvant gefitinib, an EGFR inhibitor, might overcome biologic and clinical resistance to neoadjuvant anastrozole in a phase II placebo-controlled trial. Patients and Methods: Postmenopausal women with stage I to IIIB hormone receptor–positive early breast cancer received anastrozole 1 mg daily for 16 weeks and were randomly assigned at a ratio of 2:5:5 to receive, in addition, gefitinib 250 mg/d orally for 16 weeks: placebo 1 tablet/d orally for 2 weeks and then gefitinib for 14 weeks or placebo for 16 weeks. The primary end point was biologic change in proliferation as measured by Ki67 at 2 and 16 weeks; the main secondary end point was overall objective response (OR). Results: Two hundred six women were randomly assigned. Mean changes in Ki67 with anastrozole and gefitinib versus anastrozole alone were –77.4% and –83.6%, respectively, between baseline and 16 weeks (geometric mean ratio = 1.37; 95% CI, 0.79 to 2.39; P = .26), –80.1% and –71.3% between baseline and 2 weeks (geometric mean ratio = 0.70; 95% CI, 0.39 to 1.25; P = .22) and –19.3% and –43% (geometric mean ratio = 1.42; 95% CI, 0.86 to 2.35; P = .16) between 2 and 16 weeks. ORs in the combination and anastrozole alone groups were 48% and 61% (estimated difference = –13.1%; 95% CI, –27.3% to 1.2%), respectively, with a nonsignificant trend against the combination (P = .08) and 48% versus 72% (estimated difference = –24.1%; 95% CI, –45.3% to –2.9%) in the progesterone-receptor–positive subgroup, which was significant (P = .03) and consistent with Ki67 changes. Common treatment-related adverse events included diarrhea, rash, alopecia, dry skin, and nausea. There was no evidence of a pharmacokinetic interaction. Conclusion: Addition of gefitinib to neoadjuvant anastrozole had no additional clinical or biologic effect, failing to support our original hypothesis.
Endocrine therapy is often ineffective in women with hormone receptor–positive breast cancer, and this is an important challenge for translational and clinical research. There are now compelling preclinical data to suggest that crosstalk occurs between growth factor receptor pathways and estrogen receptors (ERs).1 For example, increased expression of type 1 growth factor receptors, including epidermal growth factor receptor (EGFR), activate the ER through downstream effectors and may account at least in part for the endocrine-resistant phenotype.1 This activation can result in hypersensitivity to estrogen, and resistance of MCF-7 breast cancer cells in vitro to estrogen deprivation appears at least in some cases to result from acquired hypersensitivity, which may be explained by increased levels of phosphorylated ER receptor.2 Concurrent blockade of both the ER and EGFR signaling pathways might therefore enhance response to endocrine therapy. Gefitinib (Iressa; AstraZeneca, Wilmington, DE) is an orally active EGFR tyrosine kinase inhibitor (EGFR-TKI).3 It has been shown to overcome tamoxifen resistance in HER-2 transfected MCF-7 xenografts4 and it suppresses the growth of MCF-7 cells otherwise resistant to estrogen withdrawal.5 In our previous IMPACT (Immediate Preoperative Anastrozole Combined with Tamoxifen) trial, neoadjuvant anastrozole in the treatment of postmenopausal women with ER-positive breast cancer achieved significantly greater suppression of tumor cell proliferation, as measured by change in Ki67, than either tamoxifen or a combination of tamoxifen and anastrozole.6 These findings reflected clinical long-term outcome results in the adjuvant ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial.7 Analysis of changes in Ki67 2 weeks and 12 weeks after starting anastrozole in individual patients showed that some tumors have a persistently poor antiproliferative response to anastrozole, or show evidence of "escape" after initial suppression (Fig A1, online only). We postulated that breast cancers less sensitive to anastrozole might be particularly sensitive to added gefitinib, and describe here the results of a placebo controlled neoadjuvant trial (study IL1839/223) designed to test this hypothesis. EGFR positivity was not required for entry into the trial because of low rates of overexpression particularly in ER-positive tumors.8-10
Patient Eligibility Postmenopausal women with measurable (stage I to IIIB) nonmetastatic, noninflammatory, histologically confirmed ER- and/or progesterone receptor (PgR)-positive adenocarcinoma of the breast (  2 cm) with a WHO performance status of 0 to 2 were eligible for inclusion in the study. The details of the main exclusion criteria are given in the Appendix (online only). This study received approval from an institutional review board at each site and was conducted in accordance with the 1964 Declaration of Helsinki11 and International Conference on Harmonization/Good Clinical Practice guidelines. Written informed consent was obtained from each patient before participation.
Treatment Patients continued to receive study medication throughout the 16-week study period. Specific reasons for discontinuation before 16 weeks included objective disease progression, withdrawal of consent, patient lost to follow-up, withdrawal for safety reasons or severe noncompliance, or if patients were found by retrospective analysis to have an ER- and/or PgR-negative tumor or were incorrectly enrolled. Gefitinib or anastrozole dose reductions were not permitted, but dose interruptions were allowed for the management of toxicity. Repeat dose interruptions (a maximum of two interruptions) were allowed as required, for a maximum of 14 days.
Ki67 Analyses
Efficacy Assessments Secondary end points. Objective tumor response rates (complete response plus partial response) were determined using the modified International Union Against Cancer (UICC)/WHO assessment criteria.13 Objective tumor response was compared between anastrozole and placebo (arm C) versus anastrozole and gefitinib (combination of arms A and B) overall and according to initial sensitivity to anastrozole (arm C v arm B). The mastectomy rate was compared between arms A and B versus arm C overall and among patients for whom mastectomy was the planned operative procedure at baseline. Estradiol levels were assessed at baseline, 2 weeks after starting treatment, and the day before surgery at week 16 using an assay sensitive to 3 pmol/L,14 to assess whether gefitinib affects the suppression of the mean plasma level of estradiol compared with that obtained with anastrozole alone. Steady-state plasma concentrations of gefitinib and anastrozole were measured during treatment to assess whether the steady-state exposure of gefitinib was altered by anastrozole and vice versa, by comparison with historical data. Plasma levels of anastrozole were determined by MDS Pharma Services (Montreal, Canada) using a high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method (sensitivity limit, 1.0 ng/mL). Plasma levels of gefitinib were determined by Analytico Medinet BV (Breda, the Netherlands), using a validated HPLC-MS/MS method (sensitivity limit, 0.5 ng/mL).15 The relationship between gefitinib minimum serum trough concentration (Cmin) and changes in the expression of Ki67 and other exploratory biomarkers from baseline was also assessed.
Safety Assessments
Exploratory Assessments
Statistical Considerations
Two hundred six women were randomly assigned into the three arms of the trial (Table 1). More patients discontinued treatment in the two gefitinib arms A (26%) and B (20%) than in the anastrozole alone arm C (13%) and this was largely because of an increased incidence of adverse effects with gefitinib (discussed later herein). Only 16 of 31 patients in arm A were available for full biomarker studies, 43 of 90 patients in arm B and 50 of 85 patients in arm C, because of incomplete sets of three serial biopsies for Ki67. Patient demographic details are presented in Table 2, and a patient disposition flow chart is given in Figure 1.
Change in Ki67 There was no significant difference in the mean change in Ki67 for anastrozole with gefitinib compared with anastrozole alone between baseline and 16 weeks, the primary comparison (–77.4% v –83.6% respectively; geometric mean ratio = 1.37; 95% CI, 0.79 to 2.39; Fig 2A). Likewise, there was no significant difference in the mean change in Ki67 for the two treatment groups between baseline and 2 weeks of treatment (–80.1% v –71.3%, respectively; geometric mean ratio = 0.70; 95% CI, 0.39 to 1.25; Fig 2B); between 2 and 16 weeks, mean changes of –19.3% and –43% (Fig 2C), respectively, suggested a trend against the combination (geometric mean ratio = 1.42; 95% CI, 0.86 to 2.35; P = .16) although the changes occurred from low values at 2 weeks (3.6% and 4.3%, respectively). When the data were subdivided into those patients deemed to be (a) less sensitive to anastrozole and (b) sensitive to anastrozole according to the change in Ki67 over the first 2 weeks, no significant difference was seen in either subgroup (Fig 3A and B); mean changes of –10.5% and –40.9% in the combination and in the anastrozole alone arms suggested a trend against the combination for the anastrozole-sensitive patients (geometric mean ratio = 1.51; 95% CI, 0.77 to 2.97; P = .22), but the changes occurred from low Ki67 values at 2 weeks (1.5% and 2.1% respectively) and were quantitatively small.
Clinical and Pathologic Response The overall objective response (OR) for anastrozole with gefitinib was 48% compared with 61% for anastrozole alone (estimated difference = –13.1%; 95% CI, –27.3% to 1.2%; P = .077). No complete pathologic responses were seen in either arm (Table 3). There was no significant difference in OR rates in patients deemed initially sensitive to anastrozole by 2-week Ki67 suppression, although there was a trend against the combination (46% v 66% for anastrozole alone; estimated difference = –19.6%; 95% CI, –41.4% to 2.1%; P = .08), or in those deemed initially less sensitive (38% for the combination v 48% for anastrozole alone; estimated difference = –9.9%; 95% CI, –38.5% to 18.6%; P = .50).
The OR for women with PgR-positive cancers was significantly worse for the combination than for anastrozole alone (21 of 44 [48%] v 28 of 39 [72%], respectively; estimated difference = –24.1%; 95% CI, –45.3% to –2.9%; P = .03), but there was no significant difference for those with PgR-negative cancers (six of 15 [40%] v four of 11 [36%] respectively; estimated difference = 3.6%; 95% CI, –34.3% to 41.5%).
Mastectomy Rates
EGFR and HER-2
Plasma Estradiol Levels and Pharmacokinetic Interaction Simultaneous analysis of gefitinib plasma concentrations and Ki67 levels showed no detectable effect of gefitinib on Ki67 against the background of the anastrozole effect.
Treatment-Related Adverse Events and Discontinuations
This is the first neoadjuvant breast cancer trial of which we are aware where a biologic end point, Ki67, took precedence over clinical response or pathologic complete remission as the primary efficacy end point. The basis for this was our previous IMPACT neoadjuvant endocrine therapy trial, in which we found that short-term changes in Ki676 predicted for the long-term disease-free survival benefit found with anastrozole over tamoxifen or the combination in the equivalent adjuvant ATAC trial,7 whereas clinical response did not.17 This raises the important possibility that short-term molecular markers such as Ki67 in relatively small neoadjuvant studies could be used as surrogates to predict long-term outcome in large scale adjuvant trials. Trial 223 has failed to support the hypothesis that the EGFR-TKI gefitinib might help overcome de novo resistance of hormone receptor–positive breast cancers to standard endocrine therapy with anastrozole. We found no evidence of additional biologic or clinical efficacy overall or in any subgroup of patients. There was no significant effect of gefitinib on the level of Ki67 suppression by anastrozole, although there was a trend against gefitinib for clinical response, both overall (48% v 61% for anastrozole alone) and in the "sensitive to anastrozole" group (46% v 66%). Although these differences were not significant, they were nevertheless consistent with the biologic findings. More patients discontinued treatment early because of adverse effects in the gefitinib group, and there were more T4 tumors in this group; both these observations might have adversely influenced response, but this could not explain the consistent Ki67 results. Furthermore, our results showed no evidence of a pharmacokinetic interaction between gefitinib and anastrozole that could explain this. The only significant negative interaction between gefitinib and anastrozole in our trial was in clinical response for patients with PgR-positive cancers (48% v 72%; P = .03). This was a subgroup analysis that must be interpreted with caution. A recent study showed that ER-positive, PgR-negative, HER-2–amplified tumors in women with operable breast cancer treated with at least 2 weeks of preoperative gefitinib were more likely to show a molecular growth inhibition as defined by changes in Ki67 mRNA and cell cycle gene expression; conversely, PgR-positive tumors were more likely to show molecular growth proliferation,18 a finding compatible with our own clinical response results. These data were interpreted as supporting the hypothesis that ER+, PgR–breast cancer is growth factor dependent and constitutes a subgroup of ER+ patients who may be more likely to benefit from EGFR inhibition. In the largest study comparing PgR-positive and -negative breast cancers involving 47,000 patients, a worse outcome was found for tamoxifen in PgR-negative cancers that also overexpressed EGFR or HER-2, and the authors concluded that PgR negativity was a surrogate measure of aberrant growth factor signaling.19 On this premise, it might be predicted that an EGFR-TKI such as gefitinib would be most likely to have activity in PgR negative cancers, but we were unable to show this. Previous data on gefitinib in breast cancer have given conflicting results. In a phase II and tumor pharmacodynamic study, Baselga et al20 found that single-agent gefitinib achieved no clinical responses despite immunohistochemical evidence of complete inhibition of EGFR phosphorylation in both tumor and healthy skin. Likewise, in a phase II study, single-agent gefitinib in taxane- and anthracycline- pretreated patients with advanced breast cancer achieved only one partial response in 58 patients.21 In contrast, a double-blind placebo controlled randomized trial of 56 postmenopausal patients with EGFR-positive primary breast cancer using two antibodies validated in the authors' laboratory found ultrasound partial responses in 12 of 22 patients assigned to gefitinib alone compared with 14 of 28 patients assigned to the combination. The combination of gefitinib and anastrozole had a greater reduction in Ki67 than gefitinib alone (98% v 92.4% mean reduction).22 In a further study presented only in abstract, single-agent gefitinib achieved clinical benefit in 56% of 27 patients with ER-positive tumors and 21% of 27 patients with ER-negative tumors, with a mean duration of response of 9.3 and 3.6 months, respectively.23 Gefitinib has also been assessed in nonrandomized phase II combination chemotherapy studies involving docetaxel,24 epirubicin,25 and a combination of paclitaxel and carboplatin.26 Our results with gefitinib do not imply that other signal transduction inhibitors would also prove ineffective in enhancing the clinical or biologic response of breast cancer to endocrine therapy. It may be that another agent would have given a different result. It may also be that we failed to identify prospectively an appropriate subgroup of tumors, such as those overexpressing EGFR, where gefitinib might be of benefit, as suggested in another similar study.22 Finally, it is of interest that the response rate to anastrozole alone administered for 16 weeks in this study was 61% compared with the 37% found in our IMPACT trial, where treatment was administered for only 12 weeks.17 The response rate for neoadjuvant letrozole also administered for 16 weeks was 56%.27 Although these trials cannot be directly compared, they reinforce the clinical impression that clinical response to neoadjuvant endocrine therapy takes time, and suggest that at least 16 weeks of treatment may be required for optimal effect.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. 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: Emma Clark, AstraZeneca UK Ltd; Patrick Magill, AstraZeneca Leadership: N/A Consultant: Ian E. Smith, AstraZeneca; Mitch Dowsett, AstraZeneca Stock: N/A Honoraria: Ian E. Smith, AstraZeneca; Anthony Skene, AstraZeneca; Mitch Dowsett, AstraZeneca Research Funds: Anthony Skene, Funds, AstraZeneca; Janine Salter, Funds, AstraZeneca; Mitch Dowsett, Funds, AstraZeneca Testimony: N/A Other: Anthony Skene, AstraZeneca
Conception and design: Ian E. Smith, Anthony Skene, Mitch Dowsett Administrative support: Geraldine Walsh, Janine Salter Provision of study materials or patients: Ian E. Smith, Anthony Skene, Antonio Llombart, José Ignacio Mayordomo, Janine Salter Collection and assembly of data: Antonio Llombart, Simone Detre, Janine Salter Data analysis and interpretation: Ian E. Smith, Anthony Skene, Emma Clark, Patrick Magill, Mitch Dowsett Manuscript writing: Ian E. Smith, Patrick Magill, Mitch Dowsett Final approval of manuscript: Ian E. Smith, Anthony Skene, Antonio Llombart, José Ignacio Mayordomo, Simone Detre, Patrick Magill, Mitch Dowsett
Patient Exclusion Criteria Patient exclusion criteria included any evidence of clinically active interstitial lung disease (except patients with chronic stable, radiographic changes who were symptomatic); coexistent malignancies or malignancies diagnosed in the previous 5 years; any previous endocrine treatment within 2 weeks of starting the study; metastatic disease; prior treatment with a tyrosine kinase inhibitor; prior treatment with any investigational drug within 30 days of study treatment; any previous chemotherapy or hormonal therapy (including tamoxifen and aromatase inhibitors) for invasive cancer; and radiation treatment at the tumor site. Patients found to have a serum estradiol of more than 100 pmol/L were also excluded retrospectively. Patients who were prospectively unwilling to undergo a core biopsy after the initial 2-week treatment of anastrozole or to undergo breast surgery at the end of the neoadjuvant treatment period were also excluded from the study.
Primary End Points
Statistical Considerations
published online ahead of print at www.jco.org on August 6, 2007. Supported by a research grant from AstraZeneca. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Johnston SR, Head J, Pancholi S, et al: Integration of signal transduction inhibitors with endocrine therapy: An approach to overcoming hormone resistance in breast cancer. Clin Cancer Res 9:524S-532S, 2003 2. Chan CM, Martin LA, Johnston SR, et al: Molecular changes associated with the acquisition of oestrogen hypersensitivity in MCF-7 breast cancer cells on long-term oestrogen deprivation. J Steroid Biochem Mol Biol 81:333-341, 2002[CrossRef][Medline] 3. Wakeling AE, Guy SP, Woodburn JR, et al: ZD1839 (Iressa): An orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy. Cancer Res 62:5749-5754, 2002 4. 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 5. Martin LA, Farmer I, Johnston SR, et al: Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation. J Biol Chem 287:30458-30468, 2003 6. Dowsett M, Ebbs SR, Dixon JM, et al: Biomarker changed during neoadjuvant anastrozole, tamoxifen, or the combination: Influence of hormonal status and HER-2 in breast cancer- a study from the IMPACT trialists. J Clin Oncol 23:2477-2492, 2005 7. Baum M, Buzdar AU, Cuzick J, et al: 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] 8. Horne GM, Angus B, Wright C, et al: Relationships between oestrogen receptor, epidermal growth factor receptor, ER-D5, and P24 oestrogen regulated protein in human breast cancer J Pathol 155:143-150, 1988[CrossRef][Medline] 9. Tsutsui S, Ohno S, Murakami S, et al: Prognostic value of epidermal growth factor receptor (EGFR) and its relationship to the estrogen receptor status in 1029 patients with breast cancer. Breast Cancer Res Treat 71:67-75, 2002[CrossRef][Medline] 10. Newby JC, A'Hern RP, Leek RD, et al: Immunohistochemical assay for epidermal growth factor receptor on paraffin-embedded sections: Validation against ligand-binding assay and clinical relevance in breast cancer. Br J Cancer 71:1237-1242, 1995[Medline] 11. The World Medical Association: The Declaration of Helsinki. http://www.wma.net/e/policy/b3htm 12. Ellis PA, Smith IE, Detre S, et al: Reduced apoptosis and proliferation and increased Bcl-2 in residual breast cancer following preoperative chemotherapy. Breast Cancer Res Treat 48:107-116, 1998[CrossRef][Medline] 13. Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10:239-253, 1992[CrossRef][Medline] 14. Dowsett M, Goss PE, Powles TJ, et al: Use of the aromatase inhibitor 4-hydroxyandrostenedione in postmenopausal breast cancer: Optimisation of therapeutic dose and route. Cancer Res 47:1957-1961, 1987 15. Jones HK, Stafford LE, Swaisland HC, et al: A sensitive assay for ZD1839 ('Iressa') in human plasma by liquid-liquid extraction and high performance liquid chromatography with mass spectrometric detection: Validation and use in phase I clinical trials. J Pharm Biomed Anal 29:221-228, 2002[CrossRef][Medline] 16. Chan KC, Knox WF, Gee JM, et al: Effect of epidermal growth factor receptor tyrosine kinase inhibition on epithelial proliferation in normal and premalignant breast. Cancer Res 62:122-128, 2002 17. 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 18. Finn RS, Dering C, Ginther M, et al: ER+ PR- breast cancer defines a unique subtype of breast cancer that is driven by growth factor signaling and may be more likely to respond to EGFR targeted therapies. J Clin Oncol 24:6s, 2006 (abstr 514) 19. 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 20. Baselga J, Albanell J, Amparo R, et al: Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol 23:5323-5333, 2005 21. von Minckwitz G, Jonat W, Fasching P, et al: A multicentre phase II study on gefitinib in taxane- and anthracycline-pretreated metastatic breast cancer. Breast Cancer Res Treat 89:165-172, 2005[CrossRef][Medline] 22. Polychronis A, Sinnett HD, Hadjiminis D, et al: Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: A double-blind placebo-controlled phase II randomised trial. Lancet Oncology 6:383-391, 2005[CrossRef][Medline] 23. Agrawal A, Gutteridge E, Cheung KL, et al: Efficacy and tolerability of gefitinib in oestrogen receptor negative and tamoxifen resistant oestrogen receptor positive locally advanced or metastatic breast cancer. Proc San Antonio Breast Cancer Symp, 2005 (abstr 1065) 24. Ciardiello F, Troiani T, Caputo F, et al: Phase II study of gefitinib in combination with docetaxel as first-line therapy in metastatic breast cancer. Br J Cancer 94:1604-1609, 2006[Medline] 25. Gasparini G, Sarmiento R, Amici S, et al: Gefitnib (ZD1839) combined with weekly epirubicin in patients with metastatic breast cancer: A phase I study with biological correlate. Ann Oncol 16:1867-1873, 2005 26. Fountzilas G, Pectasides D, Kalogera-Fountzila A, et al: Paclitaxel and carboplatin as first-line chemotherapy combined with gefitinib (IRESSA) in patients with advanced breast cancer: A phase I/II study conducted by the Hellenic Cooperative Oncology Group. Breast Cancer Res Treat 92:1-9, 2005[CrossRef][Medline] 27. Eiermann W, Paepke S, Appfelstaedt J, et al: Preoperative treatment of postmenopausal breast cancer patients with letrozole: A randomized double-blind multicenter study. Ann Oncol 12:1527-1532, 2001 Submitted October 30, 2006; accepted June 4, 2007. 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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Mastectomy rate was compared by a descriptive summary, together with the treatment difference and 95% CI. The estradiol levels at 2 and 16 weeks were log-transformed before analysis and compared between treatments by ANCOVA, with baseline estradiol as a covariate. Data are summarized by geometric means (data log-transformed before analysis) or the number and percentage of patients (categoric variables). 
) arm C; (
) arm A; (
) arms B and C.
