Gelmon, KA

Abstract Background: Based on recent breast cancer literature, we hypothesized that there could be substantive differences in apparent efficacy estimates using a log-normal (LN) survival model rather than with standard Kaplan-Meier (K-M) or Cox model methods. While both Cox and LN survival analyses offer greater specification by individual patient characteristics, the LN model may more robustly estimate survival under model misspecification. Methods: We recently pooled data for 5 NCIC CTG primary breast cancer trials: MA.5, MA.12, MA.14, MA.21, and MA.27. The total patient count for patients who received at least 1 dose of trial therapy is 11,253. Compilation included definition of STEEP endpoints (C Hudis, JCO, 2008) and standardized factor categorizations. The primary endpoint is Breast Cancer Free Interval (BCFI) defined as the time from randomization until recurrence: first local invasive or DCIS; regional, or distant; contralateral invasive or DCIS; or death from breast cancer. We found substantive evidence of non-proportionality for 7 factors compiled for the meta-analyses. In this work, we fit multivariate Cox and LN models with these 7 factors, lymph node status and pathologic T status. We then compare BCFI efficacy estimates for patient and tumour characteristics at 1-, 3-, and 5-years obtained with K-M, Cox, and LN models. Results: There was evidence that the Cox assumption of proportional hazards was violated for 7 factors: age, menopausal status, hormone receptor status, anthracycline use, chemotherapy use, race, and ECOG performance status. Differences between models were intrinsically affected by timing and extent of non-proportionality; there was no consistent pattern. In particular, investigations to date indicate efficacy estimates with absolute differences between K-M, Cox and LN estimates which varied by time of assessment: at 1-year 0.0 to 6.7%, at 3-years 0.4 to 18.6%, and at 5-years 0.2 to 17.0%. BCFI estimates with the K-M were inconsistently closer to those with the LN or Cox model: for K-M to Cox at 1-year 0.4 to 5.2%, at 3-years 0.4 to 15%, at 5-years 0.4 to 14.3%; for K-M to LN at 1-year 0.0 to 6.7%, at 3-years 0.5 to 18.6%, at 5-years 0.2 to 17.0%; for Cox to LN at 1-year 0.8 to 1.8%, at 3-years 1.9 to 6.0%, at 5-years 0.6 to 5.7%. K-M and Cox models have step-wise adjustments at events for K-M and Cox, rather than smooth modeling with the LN. Discussion: Even with reasonably large population subgroups, there were substantive differences in apparent survival (0.0 to 18.6%) between K-M, Cox and LN model types. The magnitude of differences in survival estimates was large enough to be clinically relevant and warrant further consideration as we evaluate new therapies and prognostic/predictive factors. We will be statistically investigating framework robustness under differing levels of model misspecification. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-01.

Abstract Background Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. We previously reported that racial/ethnic minority women receiving an AI in NCIC CTG MA.17 experienced fewer hot flashes, fatigue, and arthralgias than Caucasians (Moy B et al. Ann Oncol 2006;17:1637). Here we examined whether race affected clinical outcomes in the MA.27 AI trial comparing exemestane (E) with anastrozole (A). Methods: Fisher's exact test was used to compare observed side effects (0 vs grades 1–5) between minority and Caucasian women. Adverse events (AE), including menopausal symptoms, were assessed according to the Common Terminology Criteria of the National Cancer Institute (version 3.0). ITT univariate test of race effects on overall survival (OS) was determined with a stratified log-rank test, while multivariate testing was with stratified Cox regression. Results: Among 7312 for whom race was known, distribution was: Caucasian (n=6939; 95%); black (n=235; 3%); Asian/Native Hawaiian/Pacific Islander (n=93); 1%; American Indian (n=39; 1%); and mixed race (n=6). Among women treated with E, minorities reported a significantly lower incidence of hot flashes (45% vs. 56%; p=0.003) and fatigue (34% vs. 46%; p=0.001) compared to Caucasians. Similarly with A, minority women reported significantly fewer hot flashes (47% vs. 58%; p=0.002) and lower cholesterol (12% vs. 18%; p=0.01); however, they reported more headaches than Caucasians (16% vs. 10%; p=0.01). Caucasian women were more likely to discontinue therapy due to AE or side effects (32% vs. 24%). There was a significant OS interaction (p=0.02) between race and treatment with minority women on E having fewer deaths than those on A. Caucasian women had HR of E to A of 0.98 (95% CI 0.81−1.20), p=0.85, while minorities had HR of E to A of 0.72 (95% CI 0.33−1.58), p=0.41. Conclusions: Minority women tolerated AIs better and were also more compliant than Caucasians, supporting our previous findings. A significant interaction between race and type of AI therapy for OS was seen, favoring exemestane in minority women. Replication of these findings in larger cohorts is necessary. Since race/ethnicity may serve as a surrogate for genetic differences, our findings suggest pharmacogenomic differences which require further research. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-14-02.