The Need for New and Uniformly Defined Clinical Trial Endpoints

2. Objectives of AdjuvantEndocrine Therapy of Breast Cancer What is the primary objective of adjuvant endocrine therapy? To reduce risk of recurrence? To reduce risk of developing distant metastases? To reduce the risk of dying? To improve QOL?

3. Multitude of Endpoints in Adjuvant Endocrine Trials OS, DFS, DDFS, TTP, time to distant metastases Regulatory bodies do not necessarily agree on common definition for end points DFS has generally been the primary end point for adjuvant endocrine therapy trials There is no standard definition of DFS Differences in events included Nonrecurrence cancer events included (eg, new contralateral breast primary cancer; second nonbreast cancer; death from any cause) Challenge for cross-trial comparisons 

4. Definition of DFS or Event-Free Survival in Adjuvant AI Trials

5. BIG 1-98: Secondary Efficacy End Points Protocol-defined1 Overall survival (OS) Time from randomisation to death from any cause Systemic disease-free survival (SDFS) Time from randomisation to systemic recurrence (excluding local and contralateral breast events), a second nonbreast cancer, or death from any cause Prospectively defined in statistical analysis plan Time to recurrence Time to distant recurrence Time from randomisation to first recurrence at a distant sitea

6. ATAC: Protocol-DefinedSecondary Efficacy End Points Time to recurrence (TTR) Including new contralateral breast cancer (invasive and DCIS) Time to distant recurrence (TTDR) Contralateral breast cancer Time to breast cancer death (death after recurrence) OS

7. Impact of Distant Metastases in Breast Cancer More than two thirds of all breast cancer recurrences are distant metastases1,2 Based on data for the tamoxifen arms in the ATAC and BIG 1-98 trials Distant recurrences are strongly associated with the highest risk of death3 3-4 times higher risk than locoregional recurrences or contralateral occurrences

8. QOL Considerations in Adjuvant Endocrine Therapy Trials Long-term side effects of therapy vs efficacy benefits Distant metastases worsen QOL more than locoregional recurrences or occurrences of new contralateral breast cancers1,2

9. Distant Metastases: Different Definitions Used Across Trials SDFS Time from randomisation to systemic recurrence (excluding local and contralateral breast events), a second nonbreast cancer, or death from any cause TTDR Time from randomisation to a recurrence at a distant sitea Distant disease–free survival (DDFS) Time from randomisation to first recurrence at a distant site or death from any cause

10. Proposal for Standardised Definitions of Efficacy End Points

11. Proposed Standardised Definition of End Points in Adjuvant Breast Cancer Trials Events that have been inconsistently included, as well as inconsistently defined, within the definition of breast cancer DFS Contralateral breast cancer: only invasive lobular (LCIS) or invasive ductal cancer (DCIS), or both In situ carcinomas: DCIS only, or both DCIS and LCIS Second primary cancers: including or excluding contralateral breast cancer, including or excluding nonbreast cancers or unknown cancers at nonbreast sites Death from other causes: known to be other than breast cancer

12. Proposed Standardised Definition of End Points in Adjuvant Breast Cancer Trials (cont’d) “Invasive disease–free survival” (IDFS) includes Ipsilateral invasive breast tumour recurrence (IBTR) Locoregional invasive breast cancer recurrence (invasive breast cancer in the breast, axilla, regional lymph nodes, chest wall) Distant recurrence (biopsy-confirmed or clinically diagnosed) Death attributable to any cause, including breast cancer, nonbreast cancer, or unknown cause Contralateral invasive breast cancer Second primary nonbreast invasive cancer

13. Proposed Standardised Definition of End Points in Adjuvant Breast Cancer Trials (cont’d) DDFS includes Distant recurrence Death attributable to any cause including breast cancer, nonbreast cancer, or unknown cause OS includes Death attributable to any cause including breast cancer, nonbreast cancer, or unknown cause

14. DDFS as Surrogate for OS(or “Breast Cancer Death”)

15. Meta-Analysis: DFS Not Strongly Correlated With OS Meta-analysis of 118 adjuvant breast cancer trials explored correlation between 2-y DFS and 5-y OS DFS predictor of OS (P<0.001) However, for a hypothetical trial of N=1000, the 95% prediction interval of 5-y OS ranges from -0.2% to 11.3% even if 2-y DFS difference is 10% in favor of the experimental arm Therefore, despite a moderately strong correlation, 2-y DFS is not strong enough to be used as a surrogate for 5-y OS

16. DDFS as a Surrogate for OS in Adjuvant AI Breast Cancer Trials? MA.17 (node+, 30-mo FU): letrozole vs placebo DDFS (HR 0.53, P=0.001) and OS (HR 0.61, P=0.04) MA.17 (late extended adjuvant, 5.3-y FU): placebo-to-letrozole vs placebo DDFS (HR 0.39, P=0.004) and OS (HR 0.30, P<0.0001) IES: tamoxifen ? exemestane vs tamoxifen DDFS (HR 0.66, P=0.0004) at 30.6-mo FU Trend for OS (HR 0.83, P=0.08) at 37.4-mo FU ABCSG-8/ARNO 95 and ITA meta-analysis: tamoxifen ? anastrozole vs tamoxifen DDFS (HR 0.61, P=0.002); OS (HR 0.71, P=0.04)

17. What Should Be the Primary End Point for Adjuvant Cancer Trials in Good-Prognosis Patients?

18. DFS and OS as End Points Traditionally, DFS (however defined) and OS have been the key end points Used by medical journals and regulatory bodies Adapted when most patients died of their treated cancer (now only 30% die of breast cancer) Provided reliable and rapid results DFS and OS include all deaths, even those unrelated to treated cancer DFS may also include occurrence of any new unrelated cancer Major drawback with DFS and OS is lack of disease-specific outcome

19. Problems With OS in Adjuvant Studies in Early Breast Cancer Only 30% of women with breast cancer die of their disease In current adjuvant trials half of the deaths are in women without recurrence Situation is particularly important for stage I patients1 Addition of deaths without recurrence dilutes ability to detect effect of treatment on breast cancer control

20. Proposed Primary End Points for Trials of Good-Prognosis Breast Cancer Patients TTR Very sensitive to early treatment effects Includes all breast cancer-related outcomes (ie, local, regional, and distant recurrence, and any contralateral breast cancers) TTDR Only includes distant recurrences for which the likelihood of death within the next 5 years is high Other cancer occurrences and deaths from other causes properly belong in a safety analysis Combining them with breast cancer-specific events and deaths will only confuse interpretation of treatment efficacy