Advertisement
Journal of Clinical Oncology  
Search for:
Limit by:
  Browse by Subject or Issue
Home Search or Browse JCO My JCO Subscriptions Customer Service Site Map

Journal of Clinical Oncology, Vol 26, No 8 (March 10), 2008: pp. 1253-1259
© 2008 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2007.13.3744
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dirix, L. Y.
Right arrow Articles by Lobelle, J.-P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dirix, L. Y.
Right arrow Articles by Lobelle, J.-P.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

Treatment of Advanced Hormone-Sensitive Breast Cancer in Postmenopausal Women With Exemestane Alone or in Combination With Celecoxib

Luc Yves Dirix, Jorge Ignacio, Shona Nag, Poonamally Bapsy, Henry Gomez, Digumarti Raghunadharao, Robert Paridaens, Stephen Jones, Silvia Falcon, Marina Carpentieri, Antonello Abbattista, Jean-Pierre Lobelle

From the Medical Oncology Unit, Oncologisch Centrum Sint-Augustinus, Wilrijk, Belgium; Philippine General Hospital, Manilla, Philippines; Jehangi Hospital, Pune, India; Kidwa Memorial Institute of Oncology, Bangalore, India; Instituto Nacional de Enfermedades Neoplasicas, Lima, Peru; Department of Medical Oncology, Nizam's Institute of Medical Sciences, Hyderabad, India; University Hospital Gasthuisberg, Leuven, Belgium; US Oncology, Dallas, TX; Es Salud, Lima, Peru; Pfizer Oncology, New York, NY

Corresponding author: Luc Y. Dirix, MD, Oncologisch Centrum Sint-Augustinus, Oosterveldlaan 24, 2610 Wilrijk, Belgium; e-mail: luc.dirix{at}gvagroup.be


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Purpose Preclinical data showed that the combination of exemestane and celecoxib has synergistic effects. Therefore, a study was undertaken to explore the efficacy and tolerability of this combination in postmenopausal patients with advanced, hormone-sensitive breast cancer.

Patients and Methods A randomized phase II study was conducted in postmenopausal patients with hormone-sensitive breast cancer and measurable disease who had progressive disease after treatment with tamoxifen. Patients were randomly assigned to either exemestane 25 mg daily or the combination of exemestane 25 mg daily with celecoxib 400 mg twice daily. Response Evaluation Criteria in Solid Tumors Group criteria were used to determine antitumor efficacy. Primary end point was the rate of clinical benefit. Secondary end points were tolerability, objective response rate, time to progression (TTP), and duration of clinical benefit. A pharmacodynamic and a pharmacokinetic study were conducted in parallel.

Results One hundred eleven patients (exemestane, n = 55; combination, n = 56) were enrolled in 2002. The demographic characteristics and prognostic factors were similar in both arms. In the assessable population, 24 of 51 patients in the combination arm and 24 of 49 patients in the exemestane arm achieved clinical benefit. TTP was similar in both groups. Duration of clinical benefit was longer in the combination group (median, 96.6 v 49.1 weeks). The addition of celecoxib did not change the tolerability profile of exemestane alone.

Conclusion Similar rates of clinical benefit were achieved in both groups.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Treatment of early breast cancer with surgery, irradiation, and systemic adjuvant therapy has substantially improved long-term survival.1-3 Recurrent or metastatic disease remains largely incurable, with a median survival of only up to 3 years,4 highlighting the need for new agents or combinations active in this disease. Tamoxifen has been the cornerstone of endocrine therapy for treating both early and advanced hormone-sensitive breast cancer.5 Aromatase inhibitors inhibit growth of breast tumors in postmenopausal women by blocking estrogen synthesis.6 Exemestane is a selective orally available steroidal aromatase inactivator, structurally related to the natural substrate androstenedione.7-9 In a randomized comparison versus megestrol acetate in patients whose disease had progressed with tamoxifen, exemestane resulted in equivalent tumor palliation and was associated with significantly prolonged time to progression (TTP), time to treatment failure (TTF), and overall survival.10 The adverse effects of exemestane are usually mild to moderate, and most can be attributed to the pharmacologic consequences of estrogen deprivation.

Experimental studies have shown that cyclooxygenase-2 (COX-2) is involved in tumor development and progression.11 COX-2 is frequently overexpressed in breast cancer, and elevated expression is associated with human epidermal growth factor receptor 2 positivity and unfavorable outcomes.12,13 Celecoxib is a COX-2 inhibitor with antiangiogenic and proapoptotic activity.14-16 The rationale for combining exemestane with celecoxib is based on in vitro and in vivo data.17-20

The combination of celecoxib and exemestane has been tested in the 7,12 dimethylbenzanthracene–induced breast cancer model in female rats, and a synergistic effect of the combination was observed compared with each agent alone.21 On the basis of these preclinical results and the known safety profiles of both drugs, a study was undertaken to explore the synergistic effect of celecoxib on the efficacy and tolerability of exemestane in postmenopausal women with advanced breast cancer that progressed with tamoxifen. At the same time, a pharmacodynamic and an exploratory pharmacokinetic study were conducted on this drug combination.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Study Design
After approval by Independent Ethics Committees, an open-label, multicenter, randomized phase II study was conducted in postmenopausal women with hormone-sensitive breast cancer that progressed with tamoxifen. In addition to the combination group, a control group (exemestane alone) was also included, and patients were also randomly assigned to allow, in case of expansion to a phase III study, the inclusion of the phase II patients in a possible overall analysis.

Eligible patients had an Eastern Cooperative Oncology Group performance status ≤ 2; adequate hematopoietic, kidney, and liver function; and one or more measurable lesions according to the Response Evaluation Criteria in Solid Tumors.22

Patients were excluded if they had received more than one chemotherapy regimen and/or more than one hormonotherapy regimen for advanced disease. Prior treatment with any type of aromatase inhibitor was not allowed. A previous history of hypersensitivity to COX-2 inhibitors, nonsteroidal anti-inflammatory drugs, salicylates, or sulfonamide represented exclusion criteria. Patients who currently or recently used a long-term full dose of aspirin, other nonsteroidal anti-inflammatory drugs, or other COX-2 inhibitors for a chronic nononcologic condition were also excluded. Low-dose cardioprotective aspirin was permitted.

After written informed consent and baseline assessments, patients were randomly assigned to treatment with either exemestane 25 mg daily or the combination of exemestane 25 mg daily with celecoxib 400 mg twice daily. During treatment, tumor assessments were to be repeated on weeks 8, 16, and 24; then every 12 weeks to week 108; and then every 24 weeks. The same methods and techniques of assessment were to be used consistently. The determination of response was based on the Response Evaluation Criteria in Solid Tumors system.22 Clinical benefit was defined as the sum of complete responses, partial responses, and stable disease lasting ≥ 24 weeks.

End Points
The primary study end point was the rate of clinical benefit in the assessable patient population. Patients were considered assessable for efficacy if they received at least 4 weeks of treatment and did not withdraw for reasons other than progressive disease before the first tumor assessment. The secondary end points were objective response rate; duration of response, clinical benefit, and long-term stable disease; TTP, defined as the time from the date of randomization to first objective documentation of tumor recurrence or progression or death from tumor progression in the absence of previous documentation of tumor progression; TTF, defined as the time from the date of randomization to the date of first objective documentation of tumor recurrence or progression or death from any cause or withdrawal from study treatment for any reason, whichever is the earliest event; survival; safety; and tolerability. Duration of clinical benefit was defined as the time from randomization until the first objective documentation of tumor progression or death from tumor progression in the absence of previous documentation of tumor progression. The clinical benefit rate and secondary end points were calculated for both the assessable and the intent-to-treat (ITT) populations.

Statistical Considerations
The sample size for the combination arm was determined according to one-stage Fleming design.23 No statistical comparison between the two regimens was planned at this stage. In the combination arm, the hypotheses to be tested for the primary end point (P = clinical benefit rate) were H0: P ≤ .35 versus HA: P ≥ .55, where .35 was considered a clinically uninteresting level of activity and .55 was a target level for the true clinical benefit rate. A total of 43 patients assessable for clinical benefit were needed, assuming a significance level = .05 (one-sided) and power 1-β = 0.85. At least 21 patients showing clinical benefit were needed in the combination treatment arm to conclude that a further extension of the study in phase III was warranted. To account for an approximately 10% nonassessability rate, 50 patients per arm needed to participate. Stratification factors at randomization were previous response to tamoxifen, previous chemotherapy, and site of metastasis.

Duration of clinical benefit, duration of objective response, duration of long-term stable disease, TTP, TTF, and survival were analyzed using the Kaplan-Meier method.

Pharmacodynamics
To investigate the influence of celecoxib on exemestane pharmacodynamics, plasma levels of estradiol, estrone, estrone sulfate, and sex-hormone–binding globulin were evaluated on two occasions before randomization and on days 29 and 57 of treatment. E2, E1, and E1S were determined using a validated high-performance liquid chromatography with radioimmunoassay method.

Pharmacokinetics
A limited pharmacokinetic study was conducted to investigate the effect of celecoxib treatment on exemestane plasma levels. Blood samples for plasma concentration of exemestane and its main metabolite, 17-hydroexemestane, were collected before dosing on day 1 and before dosing and at 1, 2, 4, 6, and 12 hours postdose on day 29.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
Patient enrollment began in January 2002 and was completed in October 2002, with 111 patients enrolled in the ITT population at 20 sites in nine countries (exemestane, n = 55; combination, n = 56; Fig 1). Six exemestane patients were not assessable for efficacy (two patients did not start treatment and four patients were treated for < 4 weeks). Five patients in the combination group were not assessable for efficacy (three patients were treated for a period < 4 weeks and two patients withdrew early). One hundred six patients were assessable for safety. Reasons for exclusion were as follows: two patients in the exemestane group did not start treatment and three patients in the combination group were treated but were never assessed for safety.


Figure 1
View larger version (18K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 1. CONSORT diagram. BID, twice daily.

 
Patient Characteristics
Patient characteristics for the ITT analysis are shown in Table 1. The two treatment groups were well balanced for age and race/ethnicity. Imbalances were noted in type of menopause, with more natural than surgical menopause in the exemestane arm, slightly more patients with an Eastern Cooperative Oncology Group performance status of 0 in the combination arm, and more visceral metastases and a larger number of metastatic sites in the exemestane arm. More patients experienced disease progression while being treated with adjuvant tamoxifen in the exemestane treated arm, and more women experienced disease progression after initial response to tamoxifen in the combination arm.


View this table:
[in this window]
[in a new window]

  		Table 1. Patient and Tumor Characteristics

 
Despite efforts to recover the histologic tumor blocks and determine estrogen receptor status, 21 of 55 patients in the exemestane arm and 17 of 56 patients in the combination arm were reported as having an unknown hormonal receptor status. Of the patients with the unknown status, two of 21 patients in the exemestane arm and three of 17 patients in the combination arm had previously responded to prior tamoxifen therapy.

Activity
In the group of assessable patients, 24 (47.06%) of 51 patients in the combination arm and 24 (48.98%) of 49 patients in the exemestane arm obtained clinical benefit (Table 2). Similar results were seen in the ITT population (24 [42.86%] of 56 patients and 24 [43.64%] of 55 patients achieved clinical benefit in the combination and the exemestane arm, respectively). In the assessable patients, median TTP was 23.4 weeks in the combination arm and 20.0 weeks in the exemestane arm (Fig 2, top panel). Median survival time was also similar for the two treatment arms: 73.9 weeks for the combination arm and 74.1 weeks for the exemestane arm. However, a trend toward a longer duration of clinical benefit in the combination arm than in the exemestane arm was suggested, with a median duration of 96.6 weeks versus 49.1 weeks (Fig 2, lower panel). Similar analyses were performed on an ITT population and provided similar results.


View this table:
[in this window]
[in a new window]

  		Table 2. Clinical Benefit and Objective Response Rate

 

Figure 2
View larger version (13K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 2. (A) Time to progression and (B) duration of clinical benefit in assessable patients treated with exemestane (Exe) or exemestane plus celecoxib (Cox2).

 
Safety
The duration of treatment exposure was similar in the two treatment groups, with a median duration of treatment of 16.1 weeks (range, 3.1 to 153.4 weeks) in the exemestane arm and 18.3 weeks (range, 0.1 to 157.1 weeks) in the combination arm. Thirteen and five patients in the exemestane arm and 15 and 11 in the combination arm received more than 48 and 96 weeks of therapy, respectively.

Both treatments were generally well tolerated. The majority of all grade 3 events reported were not considered to be related to treatment; no grade 4 adverse events were considered treatment-related. Treatment-related adverse events are reported in Table 3. There were few treatment-related adverse events reported by one patient or more. Hot flushes were reported in 9.4% and 11.3% of the exemestane and combination patients, respectively. One patient in the exemestane arm had a grade 3 deep venous thrombosis (DVT), which was considered possibly related to treatment. In the combination arm, two patients had grade 3 events (one patient with congestive heart failure; one patient with hypersensitivity) that were considered treatment-related.


View this table:
[in this window]
[in a new window]

  		Table 3. Adverse Events Related to Study Medication by Patient

 
Adverse events leading to treatment discontinuation occurred in four patients in the exemestane arm and four patients in the combination arm. Reasons for withdrawal in the exemestane arm were pain and jaundice concurrent with skin recurrence in one patient; ascites, jaundice, nausea, vomiting, and tremor, all considered disease-related, in a second patient; a third patient withdrew after 5 weeks of treatment because of skeletal pain, weakness, disorientation, and difficulty walking, all considered disease-related; and the fourth patient withdrew after 8 weeks because of vomiting, weakness, nausea, and fatigue, all considered disease-related. Reasons for withdrawal in the combination arm were skin recurrence and chest pain owing to disease progression in one patient; death from acute respiratory failure in one patient, who also had disease progression; DVT with disease progression in a third patient; and congestive heart failure considered to be study-related in a patient pretreated with doxorubicin.

Thirty-one patients treated in the exemestane arm died: five patients died during treatment or within 30 days after treatment discontinuation and 26 patients died during the follow-up period. In all but one case, the most probable cause of death was progressive disease. In the combination arm, 38 patients died: four patients died during the study and 34 patients died during the follow-up period. The most probable cause of death was progressive disease in 33 cases. In two of the deaths in the combination arm, the most probable cause of death was pulmonary embolism secondary to DVT (after a paresis in one patient and an acute respiratory failure in the other).

Pharmacodynamics
Results of the pharmacodynamic study are shown in Table 4. In both treatment arms, there was a profound and persistent suppression of circulating estrogens, ranging on average over time from 80.8% to 88.5% in the exemestane arm and from 72.1% to 85.1% in the combination arm. Plasma sex-hormone–binding globulin levels were reduced over time on average up to 41.2% and 39.9% in the exemestane arm and the combination arm, respectively. The addition of celecoxib to exemestane did not seem to influence the inhibitory effects of exemestane on estrogen synthesis. The slightly lower percentage of estradiol and estrone inhibition in the combination arm is likely due to the lower baseline levels in this group compared with the exemestane group.


View this table:
[in this window]
[in a new window]

  		Table 4. Pharmacodynamic Results

 
Pharmacokinetics
The pharmacokinetics study has been performed in five patients treated with exemestane and in 12 patients treated with exemestane and celecoxib. The pharmacokinetic profile over time is shown in Fig 3. In both arms, the time to maximum plasma concentration (Cmax) was approximately 2 hours for either unchanged exemestane or 17-hydroexemestane. Mean ± standard deviation Cmax was 36.4 ± 10.2 ng/mL for exemestane and 4.3 ± 2.1 ng/mL for 17-hydroexemestane in the exemestane arm, whereas Cmax was 27.7 ± 19.1 ng/mL for exemestane and 3.1 ± 1.8 ng/mL for 17-hydroexemestane in the combination arm. The area under the concentration-time curve from 0 to 24 hours (AUC0-24) for unchanged exemestane was 121 ng·h/mL (95%CI, 41.6 to 201 ng·h/mL) in the exemestane arm and 98 ng·h/mL (95% CI, 56.8 to 139 ng·h/mL) in the combination arm. The AUC0-24 for 17-hydroexemestane was 25.8 ng·h/mL in the exemestane arm and 17.6 ng·h/mL in the combination arm.


Figure 3
View larger version (17K):
[in this window]
[in a new window]
[PowerPoint Slide for Teaching]
  		Fig 3. Mean ± standard deviation exemestane and 17-hydroexemestane plasma levels (ng/mL) after combination therapy and exemestane given as single agent to advanced breast cancer patients. Conc, concentration.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
The purpose of this open-label, multicenter, randomized phase II study was to determine the clinical benefit rate (objective tumor response and stable disease for at least 24 weeks) in a cohort of patients treated with the combination of exemestane (25 mg once daily) plus celecoxib (400 mg twice daily). A treatment arm receiving exemestane alone (25 mg once daily) was included in the study as a control. The study was conducted in postmenopausal women with advanced breast cancer that had progressed with tamoxifen, consistent with the indicated use of exemestane. The demographic characteristics were similar in both arms, and no major differences in performance status at admission were observed. The two groups seemed to be reasonably balanced with respect to the prognostic factors, with slightly more patients with visceral disease and more than two sites of disease in the exemestane arm and slightly worse performance status and lower ER expression in the combination arm. The majority of patients in both groups were affected by visceral metastases, a factor that is known to be associated with worse prognoses and poorer outcomes. Clinical benefit was observed in 24 patients in each arm (combination, 47.1%; exemestane, 49.0%), disproving the null hypothesis and exceeding the level of interest that had been specified to proceed with a larger phase III trial. This extension trial was not pursued because of subsequent concerns raised in the community about the safety of the COX-2 inhibitor class,24,25 although a later meeting of an United States Food and Drug Administration Advisory Committee did recommend continuing use of COX-2 inhibitors, albeit with intensified safety warnings.26

Median duration of clinical benefit was two-fold longer in patients in the combination arm. The present trial is a randomized phase II study with a limited sample size, and the combination arm had a slightly better prognosis. The observed clinical benefit rate of nearly 50% in a patient population treated after exposure to tamoxifen and suffering from measurable and frequent (80%) visceral disease suggests that the overriding majority of patients in both arms had hormone-sensitive disease, despite the unknown receptor status in many patients. These clinical results showing similar response rates and clinical benefit rates with or without celecoxib contrast with the hypothesis generated by preclinical data, which had suggested a synergistic effect of the combination of exemestane with celecoxib.

The tolerability of exemestane was comparable to that seen in previous trials. The addition of celecoxib at the daily dose of 800 mg did not remarkably change the tolerability profile of exemestane alone; this observation was despite the fact that some frail older adult patients in the combination arm were treated for periods up to 3 years at the daily dose of 800 mg. This contrasts with one of the much larger polyp prevention trials, in which significantly more cardiac events were seen in the celecoxib group than in the placebo group.27This tolerability profile of this combination is in accordance with the feasibility study of Canney et al.28

In terms of pharmacodynamics, no clinically relevant difference was found between the two treatment arms. Because of the limited blood sampling, the pharmacokinetic results of this study should be interpreted with caution. Ninety-five percent CIs suggested no difference in terms of exemestane Cmax and AUC0-24 parameters between the two treatment arms. This study demonstrates the absence of any relevant clinical or pharmacologic interaction between celecoxib and exemestane.


   AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
AUTHOR CONTRIBUTIONS
 REFERENCES
 
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: Marina Carpentieri, Pfizer Inc (C); Antonello Abbattista, Pfizer Inc (C); Jean-Pierre Lobelle, Pfizer Inc (C) Consultant or Advisory Role: Stephen Jones, Pfizer Inc (C); Jean-Pierre Lobelle, Pfizer Inc (C) Stock Ownership: Antonello Abbattista, Pfizer Inc Honoraria: Stephen Jones, Pfizer Speakers Bureau Research Funding: Shona Nag, Pfizer Inc Expert Testimony: Jorge Ignacio, n/a (U) Other Remuneration: None


   AUTHOR CONTRIBUTIONS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
REFERENCES
 
Conception and design: Luc Yves Dirix, Robert Paridaens, Stephen Jones, Marina Carpentieri

Provision of study materials or patients: Luc Yves Dirix, Jorge Ignacio, Shona Nag, Henry Gomez, Digumarti Raghunadharao, Robert Paridaens, Stephen Jones, Silvia Falcon

Collection and assembly of data: Luc Yves Dirix, Jorge Ignacio, Poonamally Bapsy, Robert Paridaens

Data analysis and interpretation: Luc Yves Dirix, Jorge Ignacio, Robert Paridaens, Stephen Jones, Marina Carpentieri, Antonello Abbattista, Jean-Pierre Lobelle

Manuscript writing: Luc Yves Dirix, Robert Paridaens, Stephen Jones, Jean-Pierre Lobelle

Final approval of manuscript: Luc Yves Dirix, Jorge Ignacio, Shona Nag, Poonamally Bapsy, Henry Gomez, Digumarti Raghunadharao, Robert Paridaens, Stephen Jones, Silvia Falcon, Marina Carpentieri, Antonello Abbattista, Jean-Pierre Lobelle


   ACKNOWLEDGMENTS
 
We thank Vicki M. Houle, PhD, of Complete Healthcare Communications, Inc, for editorial support.


   NOTES
 
Supported by Pfizer Inc.

Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, May 31-June 3, 2003, Chicago, IL (abstr 77).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 AUTHORS' DISCLOSURES OF...
 AUTHOR CONTRIBUTIONS
 REFERENCES
 
1. Veronesi U, Boyle P, Goldhirsch A, et al: Breast cancer. Lancet 365:1727-1741, 2005[CrossRef][Medline]

2. Clarke M, Collins R, Darby S, et al: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005[Medline]

3. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: An overview of the randomised trials. Lancet 365:1687-1717, 2005[CrossRef][Medline]

4. Hamilton A, Hortobagyi G: Chemotherapy: What progress in the last 5 years? J Clin Oncol 23:1760-1775, 2005[Free Full Text]

5. Clemons M, Danson S, Howell A: Tamoxifen ("Nolvadex"): A review. Cancer Treat Rev 28:165-180, 2002[CrossRef][Medline]

6. Smith IE, Dowsett M: Aromatase inhibitors in breast cancer. N Engl J Med 348:2431-2442, 2003[Free Full Text]

7. Johannessen DC, Engan T, Di Salle E, et al: Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: A phase I study. Clin Cancer Res 3:1101-1108, 1997[Abstract]

8. Dixon JM, Grattage L, Renshaw L, et al: Exemestane as neoadjuvant treatment for locally advanced breast cancer: Endocrinologic and clinical endpoints. Breast Cancer Res Treat 64:53, 2000 (abstr 170)

9. Geisler J, King N, Anker G, et al: In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clin Cancer Res 4:2089-2093, 1998[Abstract]

10. Kaufmann M, Bajetta E, Dirix LY, et al: Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: Results of a phase III randomized double-blind trial. The Exemestane Study Group. J Clin Oncol 18:1399-1411, 2000[Abstract/Free Full Text]

11. Gasparini G, Longo R, Sarmiento R, et al: Inhibitors of cyclo-oxygenase 2: A new class of anticancer agents? Lancet Oncol 4:605-615, 2003[CrossRef][Medline]

12. Ristimäki A, Sivula A, Lundin J, et al: Prognostic significance of elevated cyclooxygenase-2 expression in breast cancer. Cancer Res 62:632-635, 2002[Abstract/Free Full Text]

13. Subbaramaiah K, Norton L, Gerald W, et al: Cyclooxygenase-2 is overexpressed in HER-2/neu-positive breast cancer: Evidence for involvement of AP-1 and PEA3. J Biol Chem 277:18649-18657, 2002[Abstract/Free Full Text]

14. Leahy KM, Ornberg RL, Wang Y, et al: Cyclooxygenase-2 inhibition by celecoxib reduces proliferation and induces apoptosis in angiogenic endothelial cells in vivo. Cancer Res 62:625-631, 2002[Abstract/Free Full Text]

15. Oshima M, Dinchuk JE, Kargman SL, et al: Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell 87:803-809, 1996[CrossRef][Medline]

16. Steinbach G, Lynch PM, Phillips RKS, et al: The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342:1946-1952, 2000[Abstract/Free Full Text]

17. Brueggemeier RW, Quinn AL, Parrett ML, et al: Correlation of aromatase and cyclooxygenase gene expression in human breast cancer specimens. Cancer Lett 140:27-35, 1999[CrossRef][Medline]

18. Díaz-Cruz ES, Shapiro CL, Brueggemeier RW: Cyclooxygenase inhibitors suppress aromatase expression and activity in breast cancer cells. J Clin Endocrinol Metab 90:2563-2570, 2005[Abstract/Free Full Text]

19. Harris RE, Alshafie GA, Abou-Issa H, et al: Chemoprevention of breast cancer in rats by celecoxib, a cyclooxygenase 2 inhibitor. Cancer Res 60:2101-2103, 2000[Abstract/Free Full Text]

20. Basu GD, Pathangey LB, Tinder TL, et al: Cyclooxygenase-2 inhibitor induces apoptosis in breast cancer cells in an in vivo model of spontaneous metastatic breast cancer. Mol Cancer Res 2:632-642, 2004[Abstract/Free Full Text]

21. Pesenti E, Masferrer J, di Salle E: Effect of exemestane and celecoxib alone or in combination on DBMA-induced mammary carcinoma in rats. Breast Cancer Res 69:288, 2001 (abstr 445)

22. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000[Abstract/Free Full Text]

23. Fleming TR: One-sample multiple testing procedure for phase II clinical trials. Biometrics 38:143-151, 1982[CrossRef][Medline]

24. FDA statement on the halting of a clinical trial of the Cox-2 inhibitor celebrex. US Food and Drug Administration. Accessed April 16, 2007. Http://www.fda.gov/bbs/topics/news/2004/NEW01144.html

25. Public Health Advisory: Non-steroidal anti-inflammatory drug products (NSAIDS). US Food and Drug Administration. Accessed April 16, 2007. Http://www.fda.gov/cder/drug/advisory/nsaids.htm

26. United States Food and Drug Administration: Analysis and recommendations for Agency action regarding non-steroidal anti-inflammatory drugs and cardiovascular risk. Accessed April 16, 2007. Http://www.fda.gov/cder/drug/infopage/COX2/NSAIDdecisionMemo.pdf

27. Solomon SD, McMurray JJ, Pfeffer MA, et al: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 352:1071-1080, 2005[Abstract/Free Full Text]

28. Canney PA, Machin MA, Curto J: A feasibility study of the efficacy and tolerability of the combination of Exemestane with the COX-2 inhibitor Celecoxib in post-menopausal patients with advanced breast cancer. Eur J Cancer 42:2751-2756, 2006[CrossRef][Medline]

Submitted July 12, 2007; accepted November 27, 2007.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Facebook Facebook   Add to Reddit Reddit   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 Anticancer ResHome page
M. THILL, D. FISCHER, S. BECKER, T. CORDES, C. DITTMER, K. DIEDRICH, D. SALEHIN, and M. FRIEDRICH
Prostaglandin Metabolizing Enzymes in Correlation with Vitamin D Receptor in Benign and Malignant Breast Cell Lines
Anticancer Res, September 1, 2009; 29(9): 3619 - 3625.
[Abstract] [Full Text] [PDF]

Home page
 Ann OncolHome page
C. Falandry, P. A. Canney, G. Freyer, and L. Y. Dirix
Role of combination therapy with aromatase and cyclooxygenase-2 inhibitors in patients with metastatic breast cancer
Ann. Onc., April 1, 2009; 20(4): 615 - 620.
[Abstract] [Full Text] [PDF]

Home page
 JNCI J Natl Cancer InstHome page
E.-M. Boneberg, D. F. Legler, H.-J. Senn, and G. Furstenberger
Reduced Expression of Cyclooxygenase-2 in Primary Breast Cancer
J Natl Cancer Inst, July 16, 2008; 100(14): 1042 - 1043.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Save to my personal folders
Right arrow Download to citation manager
Right arrowRights & Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Dirix, L. Y.
Right arrow Articles by Lobelle, J.-P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Dirix, L. Y.
Right arrow Articles by Lobelle, J.-P.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Facebook   Add to Reddit   Add to Technorati   Add to Twitter  
What's this?

About
JCO		 Editorial
Roster		 Advertising
Information		 Librarians &
Institutions		 Rights &
Permissions		 PDA Services

Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
Terms and Conditions of Use
  HighWire Press HighWire Press™ assists in the publication of JCO Online