Hormone Receptor-positive Operable Breast Research Articles

BMI is an independent prognostic factor for late outcome in patients diagnosed with early breast cancer: A landmark survival analysis

BMI is an independent prognostic factor for late outcome in patients diagnosed with early breast cancer: A landmark survival analysis

Follow up after sample size re-estimation in a breast cancer trial for time to recurrence

In an international trial of premenopausal women with hormone receptor positive operable breast cancer that compares how the timing of surgical oophorectomy and mastectomy affects time to recurrence, we re-evaluated the required sample size near the end of the planned accrual period. We had anticipated that failure probabilities used at the design stage were too high resulting in a loss of power for the hazard ratio of interest. Extending follow up to obtain the number of events expected during the initial planning was not a viable option due to evidence in several previous trials of converging hazard functions. We proceeded to develop a method to re-estimate sample size in this time to event trial based on the blinded trial. Blinded re-estimation was our preference since we did not want to risk the perception that the sample size was manipulated because a smaller effect, than was anticipated, was found. Using data from a previous trial in a similar patient population receiving the same therapy (but who were not randomized to surgery timing) and the current blinded trial data, we re-estimated the required sample size. The distribution of bootstrap re-estimates of sample size indicated no increase in sample size was needed for the proposed HR. Follow-up for this trial is now complete. We will examine the final failure rates and hazard functions to see how well our re-estimation procedure performed. We will be able to explore if the hazard functions converged dramatically and what this impact would have been without this consideration.

Effects on survival of menstrual cycle phase of adjuvant surgical oophorectomy in premenopausal women with breast cancer

Adjuvant surgical oophorectomy is an effective and remarkably cost effective treatment for premenopausal women with hormone receptor positive operable breast cancer. Previously published secondary analyses indicated a survival benefit for patients whose surgery was performed in the luteal phase of the menstrual cycle as opposed to the follicular. This study utilizes additional follow-up and more fully examines this hypothesis and the general implications of long-term follow-up on trial design. Beginning in 1993 we recruited women to a multicenter randomized clinical trial of adjuvant surgical oophorectomy and tamoxifen for 5 years. We recorded the reported day 1 of the patients' last menstrual cycle on the day of their adjuvant surgery. We conducted secondary analyses of the association of history-estimated luteal or follicular phase oophorectomy surgery with disease-free and overall survival. In multivariable Cox analyses, disease-free survival (DFS) exhibited a positive trend and overall survival (OS) showed a significant improvement in patients whose surgery was estimated to have occurred in the luteal phase of the menstrual cycle compared to the follicular (HR for DFS: 0.66, 95% CI: 0.37-1.16; HR for OS: 0.49, 95% CI: 0.27-0.88). From the hazard function plots, it appears that the luteal phase surgery effect on DFS diminishes after 6 years of follow-up. In conclusion, adjuvant surgical oophorectomy during the luteal phase of the menstrual cycle resulted in a reduced hazard of recurrence as compared to oophorectomy in the follicular phase during the first 5.5 years of follow-up. The practical and biological implications of these findings deserve rigorous evaluation in clinical trials.

Abstract S2-1: Obesity at Diagnosis Is Associated with Inferior Outcomes in Hormone Receptor Positive Breast Cancer

Abstract Background: Obesity has been associated with worse outcomes in operable breast cancer. We evaluated the effect of obesity on outcomes in several adjuvant trials coordinated by the ECOG which included doxorubicin/cyclophosphamide plus other agents, including E1199 (NEJM 2008; 358: 1663), E5188 (JCO 2005; 23: 5973) and E3189 (JCO 10998; 16: 2382). Methods: The relationship between body mass index (BMI in kg/m2) and disease free survival (DFS) and overall survival (OS) was evaluated in multivariate models adjusted for covariates including age, tumor size, nodal status, race (black vs. other), surgery type, prior RT, menopausal status, treatment arm, and treatment adherence. Results are expressed as hazard ratios (HR) from Cox's proportional hazards models (HR > 1 indicates a worse outcome). All p-values are two sided. Results: The study characteristics and results are shown in the table below. We first evaluated results for the E1199 trial (for the 75% of those with BMI data available) and found a non-significant trend toward inferior DFS (HR 1.10, 95% CI 0.96, 1.26, p=0.18) and OS (HR 1.13, 95% CI 0.96, 1.33, p=0.15) for obese subjects compared with others. When evaluated by breast cancer subtype, however, obese subjects with ER and/or PR-positive/HER2-negative disease had significantly inferior DFS (HR 1.24, p=0.026) and OS (HR 1.42, p=0.003), an effect that was not seen for HER2-positive and triple negative disease. In a model including obesity, ER and/or PR-pos/HER2-neg disease, and their interaction, the interaction term was significant for OS (p=0.017) but not DFS (p=0.21). There was no evidence for differing chemotherapy delivery or endocrine therapy adherence, or differences in toxicity for obese subjects in the E1199 trial. We then evaluated the relationship between obesity and outcomes in two prior ECOG studies which included only premenopausal women with ER positive, node positive breast cancer (E5188) and women of any age with ER/PR negative, node positive disease (E3189), and confirmed a relationship between obesity and poor outcomes only in women with hormone receptor positive disease. HR-hazard ratio; ER/PR-estrogen/progesterone receptor Conclusions: Obesity was associated with significantly inferior DFS and OS in hormone receptor positive operable breast cancer treated with adjuvant chemotherapy. These findings suggest that hyperinsulinemia or other factors associated with obesity may predispose to recurrence specifically in hormone receptor positive disease, and requires further evaluation in prospective studies in order to identify modifiable factors contributing to this effect. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S2-1.