Etoricoxib and anastrozole in adjuvant early breast cancer : ETAN - - PowerPoint PPT Presentation

Etoricoxib and anastrozole in adjuvant early breast cancer : ETAN trial (phase III) #533#

Dpt Oncology A, Policlinico “Umberto I” Rome, Italy

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M.S. Rosati, M. Di Seri, G. Baciarello, V. Lo Russo, P. Grassi, L. Marchetti,

• S. Giovannoni, M. L. Basile, L. Frati

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.

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* Data missing in the original version

Conflict of interest

• None declared

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Study rationale (1)

Preclinical evidence:

4 modified by Brueggemeier RW, J Steroid Biochem Mol Biol. 2007 Aug-Sep;106(1-5):16-23.

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Breast epithelial cancer cell Breast stromal cell

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.

• [4] O-Donoghue GT et al. Br J Surg 91(Suppl 1): 43

Study rationale (2)

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Study design (phase III, 2003-2006 ys)

postmenopausal hormone-receptor (ER) positive early breast cancer (EBC) N=182 R A N D O M I Z E

ETORICOXIB (60 mg/die) ANASTROZOLE (1 mg/die) PLACEBO ANASTROZOLE (1 mg/die)

1:1

ANASTROZOLE (1 mg/die) ANASTROZOLE (1 mg/die) 2 YEARS 3 YEARS

ETAN (n=93) PAN (n=89) FDA alert !

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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.

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)

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• 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.

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Exclusion criteria

End points

• The primary end-point was the 5-years event free

survival (EFS).

• The secondary end-point was to compare the risk
• f fracture and the muscle-skeletal events in the

two groups.

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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.

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Patients demographics (1)

Patients profile ETAN arm (N) PAN arm (N) Total assessable patients 93 89 Demographics Median age 58 (51-70) 61 (53-69) Clinicopathological c. Type of cancer Ductal 78 72 Lobular 10 15 Mixed 5 2 Her2 status 0/1+ 60 64 2+ (FISH amplified) 4 8 2+ (FISH non amplified) 18 11 3+ 11 6 Grade 1 18 7 2 46 48 3 29 39 Ki 67 High (>14%) 31 40 Low (< 14%) 62 49 Stage IA 5 8 IB 9 9 IIA 13 8 IIB 31 34 IIIA 35 30 ETAN arm (N) PAN arm (N) Chemotherapy 73 62 CMF 35 25 Anthracycline (FAC,FEC) 20 22 Anthracycline and taxane (concomitant or sequential) 18 15 Trastuzumab 12 9 ECOG PS 85 87 1 5 2 2 3 Pre-existing Comorbidities Osteoarthritis 23 19 Pherypheral neuropathy 9 5 Diabetes 15 18 Hypertension 6 9 NYHA heart failure 1 2 1 2 1 2 3A 1 3B 1 1 Hyperlipemia 16 21 11

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Results

ETAN PAN HR Median (combined) treatment duration 14 (5-24) 12 (4-24) Drop-out (etoricoxib discontinuation) after FDA alert 37/93 33/89 5y EFS rate 83% 71% 1.9 95%CI (1.03 – 3.59) p= .03 5y EFS 56.9 months 53.14 months 0.51 95%CI (0.27 – 0.97) p= .03

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EFS

12 24 36 48 60 100 90 80 70 60 50 40 30 20 10 Months Number at risk Group: ETAN 93 92 90 88 85 82 Group: PAN 89 89 85 73 67 65 GROUP ETAN PAN

EFS (ETAN vs PAN) HR: 0.51; 95%CI (0.27 – 0.97), p= .03

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EFS (< 12 months ET treatment)

EFS in < 12 months treated patients 10 20 30 40 50 60 100 90 80 70 60 50 40 30 20 10 Months Number at risk Group: ETAN 25 24 24 23 23 21 20 Group: PAN 47 47 45 41 39 38 38 GROUP ETAN PAN

EFS in < 12 months treated patients ETAN vs PAN HR: 1.29; 95%CI (0.47 – 3.53), p= .60

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EFS in >12 months treated patients 10 20 30 40 50 60 100 90 80 70 60 50 40 30 20 10 Months Number at risk Group: ETAN 68 66 65 63 61 61 Group: PAN 61 58 53 46 42 41 GROUP ETAN PAN

EFS rate in > 12 months treated patients ETAN vs PAN (14.7 % vs 32.7 %) HR: 0.39; 95%CI (0.19 – 0.81), p= .01

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EFS (> 12 months ET treatment)

Muscle-skeletal pain (MSKe)

0,80 0,75 0,70 0,65 0,60 0,55 0,50 0,45 0,40 0,35 0,30 0,25 0,20 with MSKe no MSKe 0,90 0,85 0,80 0,75 0,70 0,65 0,60 0,55 0,50 0,45 0,40 0,35 0,30 0,25 0,20 0,15 0,10 with MSKe no MSKe

ETAN PAN *31 % (ETAN) vs **76 % (PAN) experimented muscle skeletal pain [RR: 2.1, 95%CI (1.29-3.43), p= .002]

There were no significative differences in terms of fractures [RR: 0.58, 95%CI (0.14-2.38), p= .45].

*(50/73 evaluable in ETAN group) **(16/67 evaluable in PAN group) 16

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
• ngoing and data will be available in the next months for

publication.

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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”.

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Study limitation

• Since high COX-2 expression has been demonstrated a

negative prognostic factor, a study population’s stratification according to COX-2 tumor expression could help to address the eligible patients. (retrospective data analysis is ongoing)

• Data are strongly limited from the study drop-out due to

FDA alert.

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References

1. "World Cancer Report". International Agency for Research on Cancer. 2008. Retrieved 2011-02-26. 2. Simpson ER, Mahendroo MS, Means GD, Kilgore MW, Hinselwood MM, Graham-Lorence S, Amarneh B, Ito Y, Fisher CR, Michael MD, Mendelson CR, Bulun SE 1994 Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis. Endocr Rev 15:342–355 3.

• Y. Zhao, V.R. Agarwal, C.R. Mendelson, E.R. Simpson, Estrogen biosynthesis proximal to a breast tumor is

stimulated by PGE2 via cyclic AMP, leading to activation of promoter II of the CYP19 (aromatase) gene, Endocrinology 137 (1996) 5739–5742 4. O’Neill GP, Ford-Hutchinson AW. Expression of mRNA for cyclooxygenase-1 and cyclooxygenase-2 in human tissues. FEBS Lett 1993; 330: 156–160. 5. Parrett ML, Harris RE, Joarder FS, Ross MS, Clausen KP, Robertson FM. Cyclooxygenase-2 gene expression in human breast cancer. Int J 6. Oncol 1997;10:503–7. 7. Brueggemeier RW, Quinn AL, Parrett ML, Joarder FS, Harris RE, Robertson FM. Correlation of aromatase and cyclooxygenase gene expression in human breast cancer specimens. Cancer Lett 1999;140(1–2):27– 35. 8. Diaz-Cruz ES, Shapiro CL, Brueggemeier RW. Cyclooxygenase inhibitors suppress aromatase expression and activity in breast cancer cells. J Clin Endocrinol Metab 2005; 90: 2563–2570. 9. Harris RE, Chlebowski RT, Jackson RD, et al.Women’s Health Initiative. Breast cancer and nonsteroidal anti-inflammatory drugs: prospective

• 10. results from the Women’s Health Initiative. Cancer Res 2003;63(18):6096–101.
• 11. Chow LW, Cheng CW, Wong JL, Toi M. Serum lipid profiles in patients receiving endocrine treatment for

breast cancer—the results from the Celecoxib Antiaromatase Neoadjuvant (CAAN) Trial. Biomed Pharmacother 2005; 59: S302–S305.

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Acknowledgements

Thanks to all the patients who partecipated in this trial

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