European Celecoxib Trial in Primary Breast Cancer

It has long been recognised that there is an association between chronic immune activation and cancer but the mechanisms behind this observation are not fully understood. The inflammatory process may provide an environment for development of malignant disease, with mediators of inflammatory response such as the cyclo-oxygenases playing an important role and providing a target for therapeutic intervention. Prostaglandins (PGs) are synthesised from phospholipids by the action of phospholipase A2 and cyclo-oxygenases. Cyclo-oxygenase (COX) -1 differs from COX-2 in that the latter is inducible and its expression is induced by a large range of oncogenes and growth factors. Celecoxib is a selective COX-2 inhibitor that does not cause the effects of COX-1 inhibition, namely gastrointestinal ulceration. The key regulatory step in this process is the enzymatic conversion of fatty acids to PGG2 and PGH2 by COX. PGH2 is subsequently converted to one of several structurally related PGs including PGE2, PGD2, PGF2, and thromboxane A2 (TxA2), by the activity of specific PG synthases. PGs have important functions in every organ system and regulate a variety of physiological functions such as immunity, maintenance of vascular integrity and bone metabolism. COX-2 is not normally expressed in most tissues, but is induced by a wide spectrum of growth factors and pro-inflammatory cytokines in specific pathophysiological conditions. The expression of COX-2 is highly induced in cells transformed with the oncogene v-src or treated with phorbol esters. Several studies have suggested an association between non-steroidal anti-inflammatory drug (NSAID) consumption and decreased breast cancer risk. Elevated COX expression in breast cancer was suggested some time ago by the finding of elevated PG production in breast tumours. There is pharmacological and genetic evidence to indicate that a significant component of the anticancer property of NSAIDs is due to their ability to inhibit the COX-2 enzyme. This phase III randomised study assesses the impact on disease free survival and overall survival of the Cox-2 inhibitor Celecoxib as maintenance therapy following surgery and chemotherapy in the treatment of primary breast cancer. 2590 women with primary breast cancer will be recruited in this study from several locations in the United Kingdom and Germany. Prior to randomization all patients should have completed at least 4 cycles of (neo) adjuvant chemotherapy. Patients who satisfy all the eligibility criteria for the study will be informed and consented to join the study. The Local Investigator will then contact the ICCG randomization centre to randomize the patient by fax or by telephone. 1. Assessments required pre-randomisation * Complete history and physical examination (within 4 weeks before randomisation) * Haematology (Hb, WBC or ANC, platelets) \& Biochemistry \[serum bilirubin, creatinine, alkaline phosphatase\] (within 4 weeks before randomisation) * Mammogram, Chest X-ray, liver ultrasound, bone scan (at a maximum 00 months prior to diagnosis of breast cancer). In case of clinical symptoms metastatic disease has to be excluded before randomisation by the appropriate investigations * Collection of tissue blocks for the central tumour banks at Glasgow Royal Infirmary (for sites managed by ICCG) land Studienzentrale in Frankfurt (for sites managed by GBG) 2. Treatment Treatment must begin within 14 working days after randomisation and within 12 weeks of day 1 of the last cycle of adjuvant chemotherapy. Radiotherapy should be given according to local policy (concomitant trial treatment and radiotherapy is permitted). Patients will be randomised 2: 1 (in favour of celecoxib) to receive: Two Placebo capsules twice daily with food or Two Celecoxib 200mg capsules twice daily (800mg per day) with food The duration of celecoxib/placebo treatment is 2 years. In addition all postmenopausal ER + and/or PgR+ postmenopausal patients will receive exemestane (25mg daily) for 5 years. The start of the treatment will be at same time as starting celecoxib or placebo. 3. Routine Follow up Visits During the course of the trial all patients will be followed up every 3 months in the first year, every 6 months in !years 2 and 3 and annually from year 4 onwards. Follow up Assessments * Clinical examination and history * Haematology \& biochemistry * Metastatic screen -additional tests/investigations (eg. Bone/liver scan etc) are at the investigators discretion if clinically indicated. * Serious Adverse Events 4. Follow up upon relapse Any relapse requires treatment to be stopped and patients should have the minimum tests carried out as described in section (c) above. Relapse is categorized as ipsilateral breast or axillary nodal relapse \[loco regional\] distant relapse (including supraclavicular nodes) \[distant\] and contralateral breast disease (malignant) \[2nd primary\]. In the event of tumor recurrence the relevant recurrence form should be completed and the trials office notified within 4 weeks. All patients will be followed up long term irrespective o whether they have been withdrawn from treatment prematurely.