Breast Density and Response to Adjuvant Endocrine Therapy
Breast Density and Response to Adjuvant Endocrine Therapy
Using our institution's prospectively maintained web-based database, we identified a total of 1,542 ER-positive breast cancer patients who underwent curative surgery at Seoul National University Hospital between October 2003 and December 2006. Patients were excluded if: 1) they did not receive adjuvant endocrine treatment, such as tamoxifen or an aromatase inhibitor, or were treated for less than 2 years; 2) their digital mammogram images were not available; 3) they had bilateral breast cancer, or 4) distant metastasis was observed before the start of endocrine therapy. Clinical and pathologic information on the 1,065 subjects was obtained from the database and used for further analysis. Treatment with adjuvant chemotherapy and/or radiotherapy was generally decided according to the institution's guidelines. The standard duration of treatment with tamoxifen is 5 years. Postmenopausal women were treated with the aromatase inhibitors anastrozole and letrozole for up to 5 years after surgery or after 2 to 3 years of tamoxifen.
MD was quantitatively measured on cranio-caudal (CC) images of the unaffected breast using Cumulus software 4.0 (University of Toronto, Toronto, Canada) by a single investigator (JK) blinded to treatment outcome. All evaluated images were digital mammograms performed at our institution, so film scanning was unnecessary. Mammographic density reduction (MDR) was based on two digital mammograms; the first was taken within 2 weeks pre-surgery (preMD), and the second 8 to 20 months after the start of adjuvant endocrine treatment (postMD), and defined as the absolute difference between the MD of these two images (% MDR = % preMD - % postMD). The MD reduction ratio (MDRR) was also calculated (% MDRR = (preMD -postMD) × 100/preMD). Intraobserver reproducibility, tested for 10% of randomly selected images (213/2,130), was 0.93 (Pearson correlation coefficient).
Change in MD was categorized into four levels, an increase (MDR < 0), 0 ≤ MDR < 5%, 5 ≤ MDR < 10%, and MDR ≥ 10%, and into a binary variable (MDR ≥ 5% and < 5%), with the 5% and 10% absolute reduction cut-offs based on previous findings. We also analyzed absolute MDR as a continuous variable. The chi-square test and t-test were used to compare factors that could affect change in MD.
All loco-regional or distant disease recurrences were regarded as recurrence events in recurrence-free survival analysis. Survival curves were estimated by the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses were conducted using Cox's proportional hazard regression model. All statistical analyses were performed using SPSS (version 17.0) software package (Chicago, IL, USA) and factors with P < 0.05 were considered statistically significant. Written informed consent was taken prior to surgery in all patients and the study protocol including the use of the database was approved by the Institutional Review Board of Seoul National University Hospital and met the guidelines of the responsible governmental agencies.
Materials and Methods
Study Population
Using our institution's prospectively maintained web-based database, we identified a total of 1,542 ER-positive breast cancer patients who underwent curative surgery at Seoul National University Hospital between October 2003 and December 2006. Patients were excluded if: 1) they did not receive adjuvant endocrine treatment, such as tamoxifen or an aromatase inhibitor, or were treated for less than 2 years; 2) their digital mammogram images were not available; 3) they had bilateral breast cancer, or 4) distant metastasis was observed before the start of endocrine therapy. Clinical and pathologic information on the 1,065 subjects was obtained from the database and used for further analysis. Treatment with adjuvant chemotherapy and/or radiotherapy was generally decided according to the institution's guidelines. The standard duration of treatment with tamoxifen is 5 years. Postmenopausal women were treated with the aromatase inhibitors anastrozole and letrozole for up to 5 years after surgery or after 2 to 3 years of tamoxifen.
Mammographic Density Measurement
MD was quantitatively measured on cranio-caudal (CC) images of the unaffected breast using Cumulus software 4.0 (University of Toronto, Toronto, Canada) by a single investigator (JK) blinded to treatment outcome. All evaluated images were digital mammograms performed at our institution, so film scanning was unnecessary. Mammographic density reduction (MDR) was based on two digital mammograms; the first was taken within 2 weeks pre-surgery (preMD), and the second 8 to 20 months after the start of adjuvant endocrine treatment (postMD), and defined as the absolute difference between the MD of these two images (% MDR = % preMD - % postMD). The MD reduction ratio (MDRR) was also calculated (% MDRR = (preMD -postMD) × 100/preMD). Intraobserver reproducibility, tested for 10% of randomly selected images (213/2,130), was 0.93 (Pearson correlation coefficient).
Statistical Analysis
Change in MD was categorized into four levels, an increase (MDR < 0), 0 ≤ MDR < 5%, 5 ≤ MDR < 10%, and MDR ≥ 10%, and into a binary variable (MDR ≥ 5% and < 5%), with the 5% and 10% absolute reduction cut-offs based on previous findings. We also analyzed absolute MDR as a continuous variable. The chi-square test and t-test were used to compare factors that could affect change in MD.
All loco-regional or distant disease recurrences were regarded as recurrence events in recurrence-free survival analysis. Survival curves were estimated by the Kaplan-Meier method and compared using the log-rank test. Multivariate analyses were conducted using Cox's proportional hazard regression model. All statistical analyses were performed using SPSS (version 17.0) software package (Chicago, IL, USA) and factors with P < 0.05 were considered statistically significant. Written informed consent was taken prior to surgery in all patients and the study protocol including the use of the database was approved by the Institutional Review Board of Seoul National University Hospital and met the guidelines of the responsible governmental agencies.