Abstract PD03-04: Effects of Diabetes (DM), Hypertension (HTN) and Coronary Artery Disease (CAD) on Prognosis after 5 Years of Adjuvant Tamoxifen (TAM) and on Treatment Outcomes with the Use of Extended Letrozole (LET): NCIC CTG MA.17
Authors: Goodwin RA , Jamal R , Booth CM , Goss PE , Eisenhauer EA , Tu D , Shepherd LE. 
Published: April 2011

Abstract
Background: Women with early stage breast cancer and DM have poorer survival compared to non-DM women (Lipscombe 2008). Mechanisms include insulin dysregulation and/or DM related comorbidities such as HTN and CAD. MA.17 showed that adjuvant LET after five yrs of TAM reduced the risk of recurrence in women with ER+ early stage breast cancer and improved survival in node +ve disease. We evaluated the impact of DM, HTN, or CAD on prognosis after 5 yrs of TAM and the efficacy of LET in MA.17.
Methods: All 5170 women randomized to MA.17 were included. Four year disease free survival (DFS), distant disease free survival (DDFS) and overall survival (OS) were compared using Cox regression model adjusting for other prognostic factors: a) in women treated with placebo (PLAC) based on the presence or absence of baseline DM (n=462), HTN (n=1627), CAD (n=604) or any one of these comorbidities (n=2049), and b) between LET and PLAC groups in each comorbidity. Analyses based on nodal status were also performed. Test for interaction assessed for differential treatment effects in comorbidity groups. Results: Women with DM on PLAC had non-significant lower DFS (89.7 vs. 89.9%, p=0.68), DDFS (92.1 vs 93.9%, p=0.85), and OS (92.1 vs 95.2, p=0.37) than those without DM on PLAC. Treatment effect outcomes were similar between those with and without DM. Women with HTN on PLAC trended toward lower DDFS (92.2 vs 94.4%, HR=1.50, 95%CI: 0.98-2.3, p=0.06) and OS (93.7 vs. 95.5%, HR=1.61, 95%CI: 0.95-2.72, p=0.08) than non-HTN women on PLAC. The interaction between treatment and HTN status was significant for DDFS (p=0.004) with HTN women having significantly better outcome on LET vs PLAC (HR=0.27, 95%CI: 0.13 to 0.54; p=0.0002) compared to non-HTN women on LET vs PLAC (HR=0.82, 95%CI: 0.56-1.20; p=0.31). Women with CAD on PLAC did not have worse outcome, nor did CAD status have a treatment related effect. Women with at least one co-morbidity on PLAC had significantly lower OS (93.6 vs. 95.8%, HR=2.10, 95%CI:1.26-3.51, p=0.004) than those free of comorbidity. For node +ve women, the difference between LET and PLAC in DDFS was greater among women with at least one co-morbidity (HR=0.30, 95%CI:0.15-0.60, p=0.001) compared to those without any co-morbidity (HR=0.72, 95%CI:0.45-1.16, p=0.17) with interaction p=0.04.
Conclusions: Having at least one comorbidity was a negative prognostic indicator for OS after 5 yrs of TAM and led to improved DDFS for node +ve women taking LET. DM was not prognostic nor did it predict treatment outcomes. Explanations include not controlling for DM medications; as well, MA.17 enrolled women 5 yrs after TAM with evidence suggesting hyperinsulinemia being a risk for early rather than late recurrence. HTN was a potential risk factor with a trend for worse DDFS and OS. HTN also predicted for treatment benefit: HTN women on LET had improved DDFS compared to non-HTN women on LET. Hypothesis include antihypertensive agents slowing the metabolism of LET; alternatively there may be variations in VEGF levels between groups. HTN predictive effects will be further explored in MA.27 with potential to correlate with VEGF levels.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-04.