Influence of Breast Cancer Tumor Stage on Survival
Influence of Breast Cancer Tumor Stage on Survival
We selected women diagnosed as having primary breast cancer between 1 January 1999 and 31 December 2012 from the Netherlands Cancer Registry. We excluded patients with a previous history of invasive cancer or lack of information on both clinical and pathological tumour size.
The Netherlands Cancer Registry is a nationwide prospective population based cancer registry in which all newly pathologically confirmed malignancies in the Netherlands are recorded. New malignancies are detected through the national pathology archive (PALGA), in which all pathological reports from Dutch hospitals are collected. Trained registrars from the cancer registry collect characteristics of patients and tumours and details of primary treatment directly from the patients' medical records. Vital status and date of death, if applicable, are verified by linkage to the municipal administration. Last date of linkage was 31 December 2013. Follow-up was complete for all women, except those who emigrated out of the Netherlands before that time.
Regular contact of SSiesling and MMAT-L with members and representatives of the breast cancer patients' organisations the Netherlands Breast Cancer Association (NBCA), Pink Ribbon, and A Sister's Hope made the relevance of the outcome measures of this study clear for patients in making informed decisions about treatment and screening. Patients were not further involved in the design of the study. Patients will be informed of the results of this study through the websites of the NBCA, Netherlands Cancer Registry, and Dutch Cancer Society and information evenings of Pink Ribbon and a Sister's Hope.
We subdivided patients into two time cohorts—1999–2005 and 2006–12—on the basis of their breast cancer diagnosis. We chose these cohorts because from 2005 onwards chemotherapy schemes used were changed, trastuzumab was implemented, and Dutch guidelines were more liberal on who should receive adjuvant treatment. We did analyses of the 1999–2005 cohort to confirm long term effects of traditional prognostic factors on survival in earlier times in our Dutch population-wide cohort.
The following data were registered: date and age at breast cancer diagnosis, tumour characteristics, local and systemic therapy, vital status, second primary breast cancer, date of follow-up, and date of death. Local recurrence and occurrence of distant metastases were not registered by the cancer registry. Second primary breast cancer was defined as contralateral ductal carcinoma in situ or invasive epithelial breast cancer. For local breast therapy, we used the most extensive surgery performed within one year of diagnosis. Data on whether patients had axillary lymph node dissection was registered all years, but data on sentinel lymph node biopsy procedure was registered only from 2011. Staging of primary tumours was based on the American Joint Committee on Cancer pathological cancer staging classification, seventh edition. If pathological tumour size was missing, we used clinical stage based on imaging studies and clinical examination. Tumour stage was defined according to the greatest dimension of the largest tumour size (Tis=ductal carcinoma in situ, T1a=≤0.5 cm (including micro-invasion), T1b=>0.5 cm and ≤1 cm, T1c=>1 cm and ≤2 cm, T2=>2 cm and ≤5 cm, T3=>5 cm, T4=any size with direct extension to chest wall and/or skin). Lymph node status was described according to the number of regional lymph nodes with pathologically proven metastasis. Determination of lymph node positivity included results of sentinel lymph node biopsy. Lymph nodes with only isolated tumour cells were defined lymph node negative (N0=no pathologically proven positive lymph nodes, N1=1–3 positive, N2=4–9 positive, N3= ≥10 positive). Grading of tumours was based on the modified Bloom and Richardson grading system. Patients were considered oestrogen positive and progesterone positive in case of more than 10% nuclear staining. Hormone receptor status was registered from 2005 and onward, and HER2 status was registered in the Netherlands Cancer Registry from 2006 onward.
We used Pearson's χ tests to calculate differences in stage distributions, lymph node status, and tumour characteristics between the two time cohorts. We assessed differences in age distribution at breast cancer diagnosis as a continuous variable with the Mann-Whitney U test and also assessed them with a χ test after categorical subdivision.
We defined overall survival as time from diagnosis of breast cancer to death from any cause. We defined relative survival as the relative excess risk of death or the observed survival of our study population divided by the expected survival of the corresponding general population by sex, age, and year of diagnosis. We calculated relative survival by using the Ederer II method. We used Dutch national life tables from the Central Bureau of Statistics (CBS) to estimate expected survival in the general population. We estimated relative five year survival rates and plotted relative survival curves stratified for tumour stage and nodal stage. Women were censored at date of last follow-up. As the follow-up of women in the two time cohorts differed considerably, all analyses were stratified for time period of breast cancer detection.
We developed Cox univariable and multivariable proportional hazard models for overall mortality for invasive breast cancers to estimate hazard ratios with 95% confidence intervals. We used Cox regression univariable and multivariable analyses only for invasive breast cancers, because hormone receptor and HER2 status are not routinely determined for ductal carcinoma in situ tumours in the Netherlands and including them in analyses would make inclusion of these factors into multivariable analyses impossible. To compare differences in hazard rates between the two time cohorts, we did additional analyses and limited maximum follow-up time for both cohorts to five years. We did not include hormone receptor and HER2 status, as these were unavailable in the oldest cohort; to compare hazard rates between the two time cohorts, we built a similar model but ductal carcinoma in situ was included. In multivariable analyses, we included all relevant clinicopathological variables and variables with a P value below 0.05 in univariable analyses. We found the assumption of proportional hazards to be valid by graphically plotting the log-log survival curves. We considered a two sided P value of 0.05 or less to be statistically significant. We analysed missing values as a separate unknown group within the same variable. We present hazard ratios with corresponding 95% confidence intervals and used the rule of four to ensure that the rounding error was less than 1.3% for all ratios. We used SPSS Statistics for Windows (version 20.0) for statistical analyses and SAS (version 9.4) for relative survival.
Methods
Patient Population
We selected women diagnosed as having primary breast cancer between 1 January 1999 and 31 December 2012 from the Netherlands Cancer Registry. We excluded patients with a previous history of invasive cancer or lack of information on both clinical and pathological tumour size.
The Netherlands Cancer Registry is a nationwide prospective population based cancer registry in which all newly pathologically confirmed malignancies in the Netherlands are recorded. New malignancies are detected through the national pathology archive (PALGA), in which all pathological reports from Dutch hospitals are collected. Trained registrars from the cancer registry collect characteristics of patients and tumours and details of primary treatment directly from the patients' medical records. Vital status and date of death, if applicable, are verified by linkage to the municipal administration. Last date of linkage was 31 December 2013. Follow-up was complete for all women, except those who emigrated out of the Netherlands before that time.
Patient Involvement
Regular contact of SSiesling and MMAT-L with members and representatives of the breast cancer patients' organisations the Netherlands Breast Cancer Association (NBCA), Pink Ribbon, and A Sister's Hope made the relevance of the outcome measures of this study clear for patients in making informed decisions about treatment and screening. Patients were not further involved in the design of the study. Patients will be informed of the results of this study through the websites of the NBCA, Netherlands Cancer Registry, and Dutch Cancer Society and information evenings of Pink Ribbon and a Sister's Hope.
Procedures
We subdivided patients into two time cohorts—1999–2005 and 2006–12—on the basis of their breast cancer diagnosis. We chose these cohorts because from 2005 onwards chemotherapy schemes used were changed, trastuzumab was implemented, and Dutch guidelines were more liberal on who should receive adjuvant treatment. We did analyses of the 1999–2005 cohort to confirm long term effects of traditional prognostic factors on survival in earlier times in our Dutch population-wide cohort.
The following data were registered: date and age at breast cancer diagnosis, tumour characteristics, local and systemic therapy, vital status, second primary breast cancer, date of follow-up, and date of death. Local recurrence and occurrence of distant metastases were not registered by the cancer registry. Second primary breast cancer was defined as contralateral ductal carcinoma in situ or invasive epithelial breast cancer. For local breast therapy, we used the most extensive surgery performed within one year of diagnosis. Data on whether patients had axillary lymph node dissection was registered all years, but data on sentinel lymph node biopsy procedure was registered only from 2011. Staging of primary tumours was based on the American Joint Committee on Cancer pathological cancer staging classification, seventh edition. If pathological tumour size was missing, we used clinical stage based on imaging studies and clinical examination. Tumour stage was defined according to the greatest dimension of the largest tumour size (Tis=ductal carcinoma in situ, T1a=≤0.5 cm (including micro-invasion), T1b=>0.5 cm and ≤1 cm, T1c=>1 cm and ≤2 cm, T2=>2 cm and ≤5 cm, T3=>5 cm, T4=any size with direct extension to chest wall and/or skin). Lymph node status was described according to the number of regional lymph nodes with pathologically proven metastasis. Determination of lymph node positivity included results of sentinel lymph node biopsy. Lymph nodes with only isolated tumour cells were defined lymph node negative (N0=no pathologically proven positive lymph nodes, N1=1–3 positive, N2=4–9 positive, N3= ≥10 positive). Grading of tumours was based on the modified Bloom and Richardson grading system. Patients were considered oestrogen positive and progesterone positive in case of more than 10% nuclear staining. Hormone receptor status was registered from 2005 and onward, and HER2 status was registered in the Netherlands Cancer Registry from 2006 onward.
Statistical Analysis
We used Pearson's χ tests to calculate differences in stage distributions, lymph node status, and tumour characteristics between the two time cohorts. We assessed differences in age distribution at breast cancer diagnosis as a continuous variable with the Mann-Whitney U test and also assessed them with a χ test after categorical subdivision.
We defined overall survival as time from diagnosis of breast cancer to death from any cause. We defined relative survival as the relative excess risk of death or the observed survival of our study population divided by the expected survival of the corresponding general population by sex, age, and year of diagnosis. We calculated relative survival by using the Ederer II method. We used Dutch national life tables from the Central Bureau of Statistics (CBS) to estimate expected survival in the general population. We estimated relative five year survival rates and plotted relative survival curves stratified for tumour stage and nodal stage. Women were censored at date of last follow-up. As the follow-up of women in the two time cohorts differed considerably, all analyses were stratified for time period of breast cancer detection.
We developed Cox univariable and multivariable proportional hazard models for overall mortality for invasive breast cancers to estimate hazard ratios with 95% confidence intervals. We used Cox regression univariable and multivariable analyses only for invasive breast cancers, because hormone receptor and HER2 status are not routinely determined for ductal carcinoma in situ tumours in the Netherlands and including them in analyses would make inclusion of these factors into multivariable analyses impossible. To compare differences in hazard rates between the two time cohorts, we did additional analyses and limited maximum follow-up time for both cohorts to five years. We did not include hormone receptor and HER2 status, as these were unavailable in the oldest cohort; to compare hazard rates between the two time cohorts, we built a similar model but ductal carcinoma in situ was included. In multivariable analyses, we included all relevant clinicopathological variables and variables with a P value below 0.05 in univariable analyses. We found the assumption of proportional hazards to be valid by graphically plotting the log-log survival curves. We considered a two sided P value of 0.05 or less to be statistically significant. We analysed missing values as a separate unknown group within the same variable. We present hazard ratios with corresponding 95% confidence intervals and used the rule of four to ensure that the rounding error was less than 1.3% for all ratios. We used SPSS Statistics for Windows (version 20.0) for statistical analyses and SAS (version 9.4) for relative survival.
