Abstract P2-09-16: Effect of Continuous Statistically Standardized qPCR and IHC ER and PR on Disease-Free Survival in NCIC CTG MA.12

Abstract Background: Inter-laboratory comparability of ER and PR assay results has been problematic for decades. Statistical standardization has been proposed as an adjunct following good laboratory quality control. We demonstrate this process for ER and PR centrally assessed by qPCR and IHC. Methods: NCIC CTG MA.12 is a placebo-controlled trial of tamoxifen therapy following adjuvant chemotherapy in premenopausal women with early breast cancer. 672 women were accrued, 505 of whom had locally determined ER and/or PR positive tumours. ER was centrally assessed by qPCR and IHC for respectively 385 and 392 patients, and by PR, for 389 and 376. The effects on DFS of continuous 1) log2 (qPCR) and 2) ln (IHC % positive stain) in statistically standardized units were investigated for all women with all lab results, and in the subgroup with IHC ER+ and/or PR+ tumours. DFS is defined as the time from randomization to recurrence or death. Multivariate examinations were with adjusted Cox regression, with adjustment by stratification factors nodal status and chemotherapy type; ER and PR had forced inclusion in models, while trial therapy and baseline patient characteristics were added in step-wise mode (p<=0.05). Unvariate tests were with adjusted log-rank statistic and Kaplan-Meier plots for ER and PR (ER and PR 0; standardized cut-points for ER and PR with positive stain of <= 1.0; > 1.0, <= 0.0; > 0.0, <= 1.0; >1.0). Results: Median follow-up for the MA.12 trial was 9.7 years. Univariately, qPCR ER was not associated with DFS (p=0.19), while both qPCR PR (p=0.09) and IHC ER (p=0.08) had weak evidence of association, and IHC PR had p=0.04. Multivariately, patients randomized to tamoxifen had significantly better DFS (p=0.002-0.005) in all patients assessed and in those with ER and/or PR > 0; ER and PR by qPCR and IHC were not associated multivariately with DFS (P>0.05). ER and PR were not associated with DFS (P>0.05) for those who received tamoxifen, while qPCR ER and/or PR, and IHC ER were inconsistently associated with DFS for those on the placebo arm. Conclusions: In this subgroup of centrally assessed MA.12 patients, trial therapy was significantly associated with DFS. Similar non-significant multivariate results were obtained multivariately with statistically standardized, continuous qPCR and IHC ER and PR. We plan to further investigate adjunctive statistical standardization in larger NCIC CTG trials. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-16.