Abstract PD2-02: NEO-EXCEL phase III neoadjuvant trial of pre-operative exemestane or letrozole +/- celecoxib in the treatment of ER positive postmenopausal early breast cancer
Authors: Rea D , Francis A , Poole C , Brookes C , Stein R , Bartlett J , Dunn J , Canney P , Sutton R , Daoud R , Hallissey M , Achuthan R , Grant M , Babrah J , Smith S , Fraser J , Desai A , Al Dubaisi M , Patel A , Bristol J , Chandrasekharan S , Prest C , Jewkes A 
Published: May 2016

Abstract
COX2 has been implicated in breast tumorigenesis, tumour proliferation & invasion. The role of COX2 in carcinogenesis is thought to be related to its abilities to increase production of prostaglandins, convert pro-carcinogens to carcinogens, inhibit apoptosis, promote angiogenesis, modulate inflammation & immune function & increase tumour cell invasiveness. COX2 inhibition may synergise with aromatase inhibition in controlling endocrine responsive breast cancer. The COX2 product prostaglandin E2 (PGE2) & cytokines such as interleukin-6 (IL6) can up regulate aromatase expression suggesting that aromatase inhibition may be more effective in combination with a COX2 inhibitor. There may be additional COX2 mediated anticancer activity. The hypothesis addressed is that activity of aromatase inhibitors(AI) as neoadjuvant endocrine therapy for early breast cancer may be enhanced by the addition of a COX2 inhibitor.
TRIAL OBJECTIVES
To determine whether the activity of AIs as neo-adjuvant endocrine therapy for ER positive breast cancer in postmenopausal women may be enhanced by the addition of the selective COX2 inhibitor celecoxib.
TRIAL DESIGN
Prospective phase III multicentre randomised trial. Patients were randomised to receive 16 weeks of exemestane 25 mg daily or letrozole 2.5 mg daily (open label) and celecoxib 400 mg twice daily or matched placebo (double blinded). Translational research tumour samples were collected before, during & after therapy.
KEY ELIGIBILITY CRITERIA
Post menopausal, ER positive, invasive cancer, 2cms or greater with calipers & visible on USS.
PRIMARY OUTCOME MEASURE
Objective clinical response to neoadjuvant treatment by RECIST criteria.
RESULTS
Primary Outcome; Response to treatment has been calculated for 266 patients (Table 1). Response rate was 73% in the celecoxib arm & 55% in the placebo arm (p=0.0022). The response rates 4 arm comparison are shown in Table 2. After adjustment for AI effect the significant difference in response rates remained (p=0.0023); the difference in response rates was greater in the exemestane treated group (29%) compared to the letrozole group (7%) although heterogeneity between AI arms was statistically non-significant (p=0.06).
Table 1 Primary Outcome Results: response ratesOUTCOMEPLACEBO N (%)CELECOXIB N (%)TOTAL N (%)X2statisticP-valueRESPONSE73(55)97(73%)170 (64%)9.38820.0022NO RESPONSE60 (45%)36 (27%)96 (36%) TOTAL133133266
Table 2: Response Rates 4 Arm Comparison EXEMESTANELETROZOLERESPONSEPLACEBO n(%)CELECOXIB n(%)TOTAL n(%)PLACEBO n(%)CELECOXIB n(%)TOTAL n(%)RESPONSE33 (49)52(78)85(63)40(61)45(68)85(64)NO RESPONSE34(51)15(22)49(37)26(39)21(32)47(36)TOTAL67671346666132
Secondary outcome; There was an USS response rate of 42% v 37% for celecoxib & placebo arms respectively (p=0.2513)
CONCLUSION
The addition of the COX2 inhibitor celecoxib to an AI significantly & substantially increased the clinical response from 55% to 73%. Effect on tumour size assessed with USS is less marked with a non-significant increase in responses from 37% to 42%.
This work was supported by CRUK: CRUK/06/005 and Pfizer.
Citation Format: Rea D, Francis A, Poole C, Brookes C, Stein R, Bartlett J, Dunn J, Canney P, Sutton R, Daoud R, Hallissey M, Achuthan R, Grant M, Babrah J, Smith S, Fraser J, Desai A, Al Dubaisi M, Patel A, Bristol J, Chandrasekharan S, Prest C, Jewkes A. NEO-EXCEL phase III neoadjuvant trial of pre-operative exemestane or letrozole +/- celecoxib in the treatment of ER positive postmenopausal early breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD2-02.