A prospectively planned pathology study within the TEAM trial confirms that progesterone receptor expression is prognostic but is not predictive for differential response to exemestane versus tamoxifen.

Abstract #81

Background: The multinational TEAM trial evaluated the steroidal aromatase inactivator Exemestane (E) compared to Tamoxifen (T) as initial adjuvant endocrine therapy. The trial was initiated in 2001 with a primary endpoint of DFS between T and E. In 2004, based on results of the Intergroup Exemestane Study (IES) TEAM was modified so all patients on T were switched to E after 2.5-3 years. The modified design includes 2 co-primary endpoints: DFS of T vs E at 2.75 years, and DFS of E vs T followed by E at 5 years. A prospective pathology study was initiated in 2001 involving patients from 5/9 countries participating in the main trial.
 Methods: Pathology blocks were collected and centralized in the Edinburgh laboratory. The prospective hypotheses defined in 2001 were 1) PgR poor and 2) HER1-3+ve tumors derive additional benefit from EvsT. Sample size was increased to 5000 cases in 2004. TMAs were constructed in sextuplet.
 Results: 4805 tumor samples collected centrally and TMAs constructed from 4556 cases (UK/Ireland, Netherlands/Belgium, Germany and Greece contributed tumour samples). Quantititive ER & PgR data for 4300 cases were included in this analysis of ER/PgR status and treatment benefit, for ER 106 cases were excluded (<100 cells) and 40 cases were ER-ve (of which 30 were PgR positive) by central pathology review (1.0%), 85% of cases had ER Allred scores of 7-8, 3.6% were ER poor (Allred 2-4). Of 4052 ER+ve cases with quantitative PgR data, (excluding 95 cases with <100 cells) 912 were PgR poor (Allred 4 or below, 22.5%) and 3140 were PgR rich (Allred 5 or above, 77.5%) in line with our original power calculations for this interaction. In these 4052 cases there were 352 DFS events (April 2008, locoregional or distant recurrence, second breast cancers, or death without recurrence) were recorded in the TEAM trial within 2.75 years of randomization. There was a statistically significant benefit of exemestane versus tamoxifen in this sub-group (HR = 0.81, 95% CI 0.654-0.996, p =0.046) Using Cox regression analysis to test the interaction between PgR status and EvsT no evidence for a treatment by marker effect for PgR with Exemestane was observed (PgR Rich EvT HR 0.77, 95% CI 0.59-1.00, PgR poor HR 0.87, 95% CI 0.62-1.18, p value for interaction 0.58). However PgR was a significant prognostic factor in univariate (PgR rich vs poor HR = 0.49, 95% CI 0.39-0.61, p<0.0001) and multivariate (p<0.0001) regression analysis in this predominantly ER rich population.
 Conclusion: The TEAM pathology study is the only prospective analysis of the interaction between PgR and efficacy of an AI versus tam as initial endocrine therapy. This study supports the prognostic value of PgR in ER rich early breast cancer but does not provide evidence that PgR poor tumors respond preferentially to AIs vs Tam. This prospectively planned and powered study has 90% power to detect such an interaction with a HR of 1.9. We therefore conclude that PgR status is not a predictive marker for AIvT in line with previous retrospective pathology analyses in BIG-I-98 and Trans-ATAC but in contrast with the original report from ATAC. However the use of PgR as a marker of increased risk of early relapse has been further validated by this study.

Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 81.