Etoricoxib and anastrozole in adjuvant early breast cancer : ETAN trial (phase III) #533# M.S. Rosati , M. Di Seri, G. Baciarello, V. Lo Russo, P. Grassi, L. Marchetti, S. Giovannoni, M. L. Basile, L. Frati Dpt Oncology A, Policlinico “Umberto I” Rome, Italy 1
Abstract ID (Temp. Abst. ID): 533(82701) Title: Etoricoxib and anastrozole in adjuvant early breast cancer: ETAN trial (phase III). Poster Board #: 22 Author(s): M. S. Rosati, M. Di Seri, G. Baciarello, V. LO Russo, P. Grassi, L. Marchetti, S. Giovannoni, M. Basile, L. Frati Abstract: Background: Preclinical data clearly demonstrated that cyclooxigenase activates growth-promoting and anti-apoptotic pathways as well as aromatase. However, data from clinical trial are poor, mainly due to the severe restrictions that the FDA has imposed to the COX-2 inhibitors in 2004 because of their serious adverse events. Methods: We designed a phase III, placebo-controlled prospective trial in which postmenopausal hormone-receptor positive early breast cancer (EBC) women were randomized 1:1 to receive anastrozole (1 mg/die) upfront in combination with placebo or etoricoxib (60 mg/die). Combined treatment was planned for 24 months. Patients were allowed to discontinue the etoricoxib or placebo for toxicity (censored). Anastrozole was continued for 5 years. The primary end-point was the 5-years event free survival (EFS). The secondary end-point was to compare the risk of fracture and the muscle-skeletal events in the two groups. Chi-Square tests for categorical data and time to event provided two-sided p values. Results: Since 2003 to 2006 we enrolled 182 patients. A number of 93 patients was enrolled in the treatment arm and N=89 in the control. The median treatment duration was 14 months in ETAN group and 12 in PAN group. A number of 37 patients in the treatment arm and 33 in the control discontinued etoricoxib after the FDA alert on COX-2 inhibitors. To a 5 years follow-up, the EFS rate was 83% versus 71%* (median DFS: 56.9 versus 53.14 months) [HR: 1.9; 95%CI (1.03 – 3.59), p= .03] in the treatment arm versus control, respectively. There were no significative differences in terms of fractures [RR: 0.58, 95%CI (0.14-2.38), p= .45]. Muscle-skeletal pain was significative lower in the treatment arm (50/73) than the control (16/67) [RR: 2.1, 95%CI (1.29-3.43), p= .002]. None of the patients in the treatment arm developed serious adverse event. Conclusions: Our data demonstrated a small but significative advantage in terms of EFS and muscle-skeletal events when etoricoxib is added to anastrozole in adjuvant setting. Data are strongly limited from the study drop-out, but the very long follow-up and the absence of major toxicity encourage larger phase III confirmatory trials. * Data missing in the original version 2
Conflict of interest • None declared 3
Study rationale (1) Preclinical evidence: Breast epithelial cancer cell GF Breast stromal cell modified by Brueggemeier RW, J Steroid Biochem Mol Biol. 2007 Aug-Sep;106(1-5):16-23. 4
Study rationale (2) Clinical evidence: • In the prospective Women’s Health Initiative Observational Study, regular use of NSAIDS was significantly correlated with a reduction in the incidence of breast cancer [1] • A meta-analysis of six cohort studies and eight controlled trials showed that the routinely use of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the relative risk of developing breast cancer [2] • The CAAN trial suggested that the addition of a COX-2 inhibitor may provide an additional benefit when using in association with AI in the neoadjuvant setting [3] • COX-2 inhibitors seems to be useful in preventing angiogenesis and lymphovascular spread at around the time of surgery [4] [1] Harris RE et al. Cancer Res 2003;63(18):6096 – 101. [2] Khuder SA et al. Br J Cancer 84:1188 – 1192 [3] Chow LW, et al. Biomed Pharmacother 2005; 59: S302 – S305. 5 • [4] O-Donoghue GT et al. Br J Surg 91(Suppl 1): 43
Study design (phase III, 2003-2006 y s ) ETAN (n=93) ET ORICOXIB (60 mg/die) ANASTROZOLE (1 mg/die) R AN ASTROZOLE (1 mg/die) A N postmenopausal 2 YEARS 3 YEARS D hormone-receptor 1:1 O (ER) positive M PAN (n=89) FDA alert ! early breast cancer I (EBC) Z N=182 P LACEBO ANASTROZOLE (1 mg/die) E AN ASTROZOLE (1 mg/die) Study follow-up was performed every 3 months with physical exam, blood and liver function tests and tumor markers (CEA, Ca 15-3, Ca 125); breast and liver ultrasound, echocardiography and ECG were performed every 6 months; chest imaging, bone scan, CT or MRI (when signs of recurrence where present), were performed every year. 6
Inclusion criteria • Postmenopausal women (defined as age 50 y and/or no periods for >6 months or in hysterectomized patients) • Confirmed ER positive (> 10%) invasive breast cancer after definitive surgical excision candidate to receive adjuvant aromatase inhibitors (alone or after chemotherapy) 7
Exclusion criteria • Woman who had used nonsteroidal antiinflammatory continuosly. • Use of COX inhibitors prescribed for rheumatoid arthritis and osteoarthritis. • DCIS, LCIS, controlateral breast cancer • Pre-existing severe cardiac disfunction or uncontrolled high blood pressure. 8
End points • The primary end-point was the 5-years event free survival (EFS). • The secondary end-point was to compare the risk of fracture and the muscle-skeletal events in the two groups. 9
Methods • EFS was calculated from the date of surgery up to the first date of locoregional or distant recurrence, contralateral breast cancer or death, whichever came first. • Muscle skeletal events, fracture, and cardiac toxicity were recorded according to NCI CTC 3.0. • Chi-Square tests for categorical data and time to event provided two-sided p values. • EFS distribution were plotted using Kaplan-Meier method. 10
Patients demographics (1) Patients profile ETAN arm PAN arm ETAN arm PAN arm (N) (N) (N) (N) Total assessable patients 93 89 Chemotherapy 73 62 Demographics CMF 35 25 Median age 58 (51-70) 61 (53-69) Anthracycline (FAC,FEC) 20 22 Clinicopathological c. Type of cancer Anthracycline and 18 15 Ductal 78 72 taxane (concomitant or Lobular 10 15 sequential) Mixed 5 2 Trastuzumab 12 9 Her2 status ECOG PS 0/1+ 60 64 0 85 87 2+ (FISH amplified) 4 8 1 5 2 // 2+ (FISH non amplified) 18 11 2 3 0 3+ 11 6 Pre-existing Grade Comorbidities 1 18 7 Osteoarthritis 23 19 2 46 48 3 29 39 Pherypheral neuropathy 9 5 Ki 67 High (>14%) 31 40 Diabetes 15 18 Low (< 14%) 62 49 Hypertension 6 9 Stage NYHA heart failure IA 5 8 1 2 1 IB 9 9 2 1 2 IIA 13 8 3A 1 0 IIB 31 34 11 3B 1 1 IIIA 35 30 Hyperlipemia 16 21
Results ETAN PAN HR Median (combined) 14 (5-24) 12 (4-24) treatment duration Drop-out (etoricoxib 37/93 33/89 discontinuation) after FDA alert 1.9 95%CI (1.03 – 3.59) 5y EFS rate 83% 71% p= .03 0.51 95%CI (0.27 – 0.97) 56.9 53.14 5y EFS months months p= .03 12
EFS 100 90 80 70 60 GROUP 50 ETAN PAN 40 30 EFS (ETAN vs PAN) 20 HR: 0.51; 95%CI (0.27 – 0.97), p= .03 10 0 0 12 24 36 48 60 Months Number at risk Group: ETAN 93 92 90 88 85 82 Group: PAN 89 89 85 73 67 65 13
EFS (< 12 months ET treatment) EFS in < 12 months treated patients 100 90 80 70 60 GROUP 50 ETAN PAN 40 30 EFS in < 12 months treated patients 20 ETAN vs PAN 10 HR: 1.29; 95%CI (0.47 – 3.53), p= .60 0 0 10 20 30 40 50 60 Months Number at risk Group: ETAN 25 24 24 23 23 21 20 14 Group: PAN 47 47 45 41 39 38 38
EFS (> 12 months ET treatment) EFS in >12 months treated patients 100 90 80 70 60 GROUP 50 ETAN PAN 40 30 EFS rate in > 12 months treated patients 20 ETAN vs PAN (14.7 % vs 32.7 %) 10 HR: 0.39; 95%CI (0.19 – 0.81), p= .01 0 10 20 30 40 50 60 Months Number at risk Group: ETAN 68 66 65 63 61 61 15 Group: PAN 61 58 53 46 42 41
0,80 Muscle-skeletal pain ETAN 0,75 0,70 (MSKe) 0,65 0,60 0,55 0,50 0,45 0,40 0,35 0,30 0,25 0,20 *31 % (ETAN) vs **76 % (PAN) with MSKe no MSKe experimented muscle skeletal pain 0,90 0,85 [RR: 2.1, 95%CI (1.29-3.43), p= .002] PAN 0,80 0,75 0,70 There were no significative differences in terms of 0,65 0,60 fractures [RR: 0.58, 95%CI (0.14-2.38), p= .45]. 0,55 0,50 0,45 0,40 0,35 0,30 *(50/73 evaluable in ETAN group) 0,25 **(16/67 evaluable in PAN group) 0,20 0,15 16 0,10 with MSKe no MSKe
Adverse Events • None of the patients in the treatment arm developed serious adverse event. • No thrombotic events were recorded. • Univariate and multivariate analysis (Cox model) is ongoing and data will be available in the next months for publication. 17
Conclusions • Our data demonstrated a small but significative advantage in terms of EFS and muscle-skeletal events when etoricoxib is added to anastrozole in adjuvant setting. • Treatment duration (< 12 or > 12 months) is significantly related to improved EFS and reduced recurrence risk. • Notwithstanding the study limitation, the very long follow- up and the absence of major toxicity encourage larger phase III confirmatory trials in this setting to further clarify the COX-2 inhibitors “Neverending Story” . 18
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