S1-7: Molecular Tumor Characteristics Influence Adjuvant Endocrine Treatment Outcome.
Authors: Bianchini G , Pusztai L , Iwamoto T , Kelly CM , Zambetti M , Fasolo A , Del Conte G , Santarpia L , Symmans WF , Gianni L 
Published: June 2012

Abstract
Background
Used upfront or after 2 to 3 years (yrs) of tamoxifen (TAM) or as extended treatment after 5 yrs of TAM, aromatase inhibitors (AIs) are associated with less recurrences than with 5 yrs of TAM. However, up front AIs were not superior to TAM→AI sequence in node negative (N-) tumors (TEAM study, SABCS 2009; BIG1-98 trial, NEJM 2009). The observation is consistent with the hypothesis that early relapses may be more frequently due to intrinsic endocrine resistance irrespective of the use of TAM or AIs whereas late relapses depend on acquired resistance.
Methods
Affymetrix HGU133A-based gene expression profiles from two adjuvant datasets (n=556) of patients treated with 5 yrs TAM were evaluated and included 285 N-, 247 N+ and 24 Nx estrogen receptor-positive cases. A proliferation score based on the expression of 12 mitotic kinases (MKS) (Bianchini, Cancer Res 2010) and a 4-gene estrogen-related score (ERS) adopted from the Oncotype DX Recurrence Score were assessed. Median cut-off points were used for both biomarkers. Pattern of relapse according to marker status were evaluated in three distinct time cohorts (0–2.5 yrs, 2.5–5 yrs, 5–10 yrs). Outcome was assessed according to distant relapse rates.
Results
A violation of the proportional hazards assumption was found for both scores indicating time-dependent effects. The table shows distant relapse rates according to biomarker group within each time cohort.

Among low proliferation tumors (lowMKS), the highERS group had low and steadily increasing recurrence rates, while the lowERS group showed a higher risk of relapse that increased continuously over the time. Among the highly proliferative tumors (highMKS), the high endocrine-sensitive group (highERS) had a lower risk of relapse within the 0–2.5 yrs compared to lowERS cancers. The difference is not persisting at the longer follow up of 2.5–5 yrs, and at 5–10 yrs the highERS group has higher risk of relapse. The pattern of relapse was similar for N- and N+ cancers. However, in the 0–2.5 yrs interval all recurrences occurred in the highMKS/lowERS among N- cancers, while only 57% of recurrences did occur in N+ cases in the same biomarkers group (p=0.012).
Discussion
Highly proliferative, high endocrine-sensitive (highERS) cancers are at the greatest risk of late relapse and extended endocrine therapy beyond 5 yrs may be useful. Low proliferation, low ERS cancers also remain at substantial risk for late recurrences. Between 0 to 2.5 yrs all recurrences in N- tumors and close to 60% in N+ were in high proliferative/low endocrine-sensitive tumors. This difference could explain the beneficial trend for up-front AIs vs. sequential TAM→AIs in the N+, but not in N- subgroups of the TEAM and BIG1-98 trials. It also is consistent with the hypothesis that the highly proliferative low ERS group includes tumors intrinsically resistant to both AIs and TAM. Risk stratification by these two simple metrics may improve the readout of future adjuvant clinical trials with endocrine drugs, and may influence their design.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S1-7.