BIG 1-98/IBCSG Henning Mouridsen for the BIG 1-98 Collaborative Group Authors: Sunil Verma Date posted: December 22, 2008

Background Previous reported data –Primary Core Analysis (PCA) median follow up of 26 months Letrozole superior to Tamoxifen –Statistically significant DFS and TTDR –Monotherapy Arm Analysis Median follow up 51 months Letrozole superior to Tamoxifen –Statistically significant improvement in DFS and TTDR

R Arm A: Tamoxifen x 5 years Arm D: Letrozole x 2 years followed by Tamoxifen Stratify -Institution -CT (Adj/NA) prior None Concurrent Arm B: Letrozole x 5 years Arm C: Tamoxifen x 2 years followed by Letrozole 5 years of endocrine therapy

BIG 1-98 Key Analysis Monotherapy update –Median follow up 76 months –Cross over effect 25.2% of patients randomized to Tam crossed over to Letrozole once L>T results available in 2005 Majority in year 3-5 with a median time on L of 18 months Sequential therapy vs. Letrozole –Final efficacy analysis – October 2008 with a median follow up of 71 months –The trial was designed to show superiority of sequential therapy over Letrozole

BIG 1.98 Monotherapy Analysis n = 4,922 patients Two Analysis –ITT –Censoring at crossover

BIG 1.98 Sequential vs. Letrozole 5 year DFS L87.9% L->T87.6% T->L86.2 %

STUDY COMMENTARY This study results were much awaited to help determine the ideal treatment strategy for HR positive post-menopausal women The results of the monotherapy arm are confounded by significant cross over 25% of patients randomized to T crossed over to L No information was presented on which subjects crossed over One may hypothesize that those at higher risk or those experiencing more toxicity on T were more likely to cross over The sequential arms were powered to look for superiority over L monotherapy arm This is the final efficacy analysis

BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS Aromatase Inhibitors are superior to Tamoxifen This is the second key trial showing upfront AI use is superior to Tamoxifen There is a trend towards improved survival seen with Letrozole over Tamoxifen This may be confounded by significant cross over, however the exact bias or effect may be difficult to elucidate The first two and half years are critical for disease recurrence An upfront therapy choice with an Aromatase Inhibitor may therefore be optimal especially for those at high risk of recurrence

BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS There is a suggestion that Aromatase Inhibitor therapy may be superior to the sequence of Tamoxifen to Aromatase Inhibitors This is the first trial to report a direct comparison between the two strategies It is important to note that the trial was designed to show superiority of sequence arm over Letrozole monotherapy, so all we can conclude is to say that the sequence strategy is not superior to Letrozole monotherapy

BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS There is also a suggestion that patients receiving Letrozole for two years and then switched over to Tamoxifen (reverse sequence arm) did just as well as those receiving Letrozole monotherapy alone - Again as this analysis was designed to show superiority, a lack of significant result just means that the reverse sequence arm was not superior to Letrozole monotherapy - Oncologists should be cautious to over interpret this result as there may be a natural tendency to switch patients from an Aromatase Inhibitor to Tamoxifen after two years or if they develop toxicity - We don’t have long term data on this single arm of an underpowered study - Furthermore, we know that 5 years of an AI is associated with significant carry over effect (ATAC 100), there is no such data for just two years of an Aromatase inhibitor

BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS Some important questions still remain to be answered Which is the most efficacious Aromatase Inhibitor? FACE and MA.27 trials should help address this What should be duration of endocrine therapy when using an AI? What role does Tamoxifen play in the treatment of postmenopausal HR positive breast cancer? Tamoxifen remains an effective drug but we need more information on what population derives a benefit from this drug Role of risk stratification Patient selection – prospective studies with CYP2D6