Among the immunohistochemical biomarkers studied were ER, progesterone (PR), and ERBB2 receptor status and antigen Ki-67 expression. A threshold of >10% was used to define ER+ and PR+ status, whereas ERBB2 positivity was observed when an intensity of >3 was present. The Ki-67 threshold for medium to high expression was >15%.
Tumor grade classification was based on the Nottingham system and was graded from 1 to 3. Tumor size was broken into three groups: <10 mm (T1a and T1b), 11-20 mm (T1c), and >20 mm (T2).
Recursive partitioning analysis (RPA) was conducted to determine which clinical BC markers or patient characteristics were associated with long-term survival.
Using univariant Kaplan-Meier analysis, the investigators found that both tumor size and tumor grade were associated with long-term distant recurrence-free interval (DRFI). This was confirmed by multivariant Cox proportional-hazards survival analysis. Patients were more likely to have DRFI if they had smaller tumors (T1a/b and T1c vs. T2, hazard ratio [HR] = 0.31, CI: 0.17-0.55 for T1a/b and HR = 0.58, CI: 0.38-0.88 for T1c) and had a grade 1 tumor compared with a grade 3 tumor (HR = 0.48, CI: 0.24-0.95). Neither PR status nor Ki-67 expression was associated with DRFI in univariant or multivariant analyses.
The use of tamoxifen reduced the long-term risk of distant recurrences by 47% for T1c tumors (HR = 0.53, CI: 0.32-0.89) and by 66% for T2 tumors (HR = 0.34, CI: 0.16-0.73). There was no difference in survival benefit for T1a/b tumors between tamoxifen users and nonusers. Patients with grade 1 (76% reduction of risk; HR = 0.24, CI: 0.07-0.82) and grade 2 tumors (50%, HR = 0.5, CI: 0.31-0.80) experienced a significant benefit in the long-term risk reduction of distant recurrences from tamoxifen; however, those with grade 3 tumors did not. Tamoxifen reduced the long-term risk of distant recurrences by 62% (HR = 0.38, CI: 0.24-0.62) in PR+ patients but not in PR-negative patients. Tamoxifen therapy was found to be beneficial in reducing long-term risks for all degrees of Ki-67 expression (i.e., low, medium, and high).
RPA demonstrated long-term DRFI benefit from tamoxifen for smaller tumors compared with larger ones. Patients with T1c and T2 tumor size who did not receive tamoxifen had a worse outcome.
Limitations of this study included the administration of high doses of tamoxifen, which are not used clinically today, shorter tamoxifen administration periods, and lack of data on the effects of aromatase inhibitors on DRFI.
Pharmacists can use the information from this study to educate BC patients on the long-term benefits and importance of adherence to ET.
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