ABSTRACT The SETER/PR index of sensitivity to endocrine therapy measures endocrine receptor-related transcription from formalin-fixed paraffin-embedded tumor sections and is highly reproducible within and between laboratories. SETER/PR values correlate with the ligand binding activity of estrogen receptors and progesterone receptors, predict early pharmocodynamic response to endocrine therapy and prognosis following endocrine therapy in palliative and adjuvant treatment settings. Secondly, SET2,3 index adjusts the measurements of SETER/PR index for baseline prognostic factors, enabling the assessment of endocrine-related transcriptional activity in the context of baseline prognostic risk. Both indices add independently prognostic information to contemporary genomic tests, likely due to stronger prediction of the cancer’s sensitivity to endocrine therapy. The NSABP B-42 trial compared extended duration of adjuvant endocrine therapy with letrozole for 5 additional years, versus placebo for 5 years, in patients who had completed 5 years of adjuvant endocrine therapy. Extended endocrine therapy demonstrated improved disease-free survival at 10 years from randomization, although there was no difference between treatments during the initial 4 years. To-date, correlative science studies from NSABP B-42 have evaluated the Breast Cancer Index 2-gene ratio of HOXB13/IL17BR expression, the 70-gene MammaPrint assay, and normalized ESR1 gene expression scores from the 21-gene Recurrence Score. All failed to demonstrate predictive interaction in their respective primary analyses, although exploratory analyses suggest that prediction will be possible with a more specific biomarker. We hypothesize that SETER/PR index will predict benefit from extended letrozole therapy (ELT) in hormone receptor-positive HER2-negative breast cancer. Specifically, that ELT offers most benefit to patients whose breast cancer has a moderate degree of endocrine sensitivity. Our primary analysis plan is to test whether SETER/PR index between 1.10 and 2.10 (inclusive) has significant interaction with lower rate of breast cancer- free interval (BCFI) from extended letrozole treatment. This represents an inter-quartile range from a similar population to NSABP B-42. Secondary analyses will evaluate other endpoints, subtypes defined by nodal status or prior tamoxifen treatment, and other cutpoints of SETER/PR index. Secondly, we will evaluate SET2,3 for long-term risk of late relapse in patients from each treatment arm. Clinically, a robust predictor of benefit from extended duration of endocrine therapy will be useful, as 10 years of treatment is too long for many patients to tolerate and the absolute rate of benefit is small in the overall population with hormone receptor-positive breast cancer. Current evidence shows SETER/PR index to be an independently strong predictor of tumoral sensitivity to endocrine therapy, and associated prognosis, with strong potential to predict who is likely...