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Objectives To determine the predictive effect of molecular subtyping using the six biomarker immunohistochemical panel in predicting ipsilateral breast relapse (IBR) in women age 50 and older with T1 and T2 node negative breast cancer in a randomized trial of tamoxifen (Tam) +/−whole breast radiation (WBRT). Methods Between December 1992 and June 2000, 769 women were randomized to WBRT and Tamoxifen (Tam, n=386) 20 mg daily for 5 years or Tam alone (n=383). Median age was 68 years, 639 (83%) had pT1 tumors. Intrinsic molecular subtype was determined using semi-quantitative analysis of ER, PR, Ki-67, HER2, EGFR and cytokeratin (CK) 5/6 on tissue microarrays constructed from tumor blocks from 172 of 345 available tumors. Patients were classified into the following categories: luminal A, luminal B, luminal-HER2, HER2 enriched, basal-like, or triple-negative phenotype-nonbasal. Median follow-up was 10 years. Results IBR at 10 years was 13.8% with Tam compared to 5.0% with Tam/WBRT (p<0.0001). Tumour size (HR 1.54, p=0.001), ER positive (HR 0.35, p=0.006), age (HR 0.96, p=0.014), and treatment with Tam/WBRT (HR 0.28, p<0.0001) were significant factors for IBR. Luminal A tumors (ER or PR positive, HER2 negative, Ki-67<14%, n=95) had the lowest rate of IBR, 6.9% at 10 years with Tam alone and 4.5% with Tam/WBRT, p=0.4). In women aged 60 and over with Luminal A subtype IBR was 5.4% with Tam alone and 6% with Tam/WBRT (n=74, p=0.8). Luminal B (ER or PR positive, HER2 negative, Ki67>14%, n=53) had an IBR of 23.8% with Tam alone and 0% with Tam/WBRT, p=0.012). Luminal HER2 (ER or PR positive, HER2 positive, n=10) and HER2−enriched (ER and PR negative, HER2 positive, n=14) demonstrated the highest risk of IBR. Conclusions: Six marker IHC subtype appears to be predictive for radiation response in women over 50 with T1/2 node-negative breast cancer. Luminal A subtype demonstrated a low risk of breast relapse with Tam alone, particularly in women age 60 and older. These results require validation in additional specimens and clinical trials, but this subgroup represents a significant proportion of women (74/172 or 43%), who may be spared the inconvenience and side effects of breast radiation. In contrast, breast RT is beneficial in women with higher risk subtypes (Luminal B, HER2 enriched, basal). Limitations of this analysis include the relatively small numbers of patients and the low event rate in smaller subgroups. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S2-2.