Influence of Breast Cancer Tumor Stage on Survival
Influence of Breast Cancer Tumor Stage on Survival
Objectives To assess the influence of stage at breast cancer diagnosis, tumour biology, and treatment on survival in contemporary times of better (neo-)adjuvant systemic therapy.
Design Prospective nationwide population based study.
Setting Nationwide Netherlands Cancer Registry.
Participants Female patients with primary breast cancer diagnosed between 1999 and 2012 (n=173 797), subdivided into two time cohorts on the basis of breast cancer diagnosis: 1999–2005 (n=80 228) and 2006–12 (n=93 569).
Main outcome measures Relative survival was compared between the two cohorts. Influence of traditional prognostic factors on overall mortality was analysed with Cox regression for each cohort separately.
Results Compared with 1999–2005, patients from 2006–12 had smaller (≤T1 65% (n=60 570) v 60% (n=48 031); P<0.001), more often lymph node negative (N0 68% (n=63 544) v 65% (n=52 238); P<0.001) tumours, but they received more chemotherapy, hormonal therapy, and targeted therapy (neo-adjuvant/adjuvant systemic therapy 60% (n=56 402) v 53% (n=42 185); P<0.001). Median follow-up was 9.8 years for 1999–2005 and 3.9 years for 2006–12. The relative five year survival rate in 2006–12 was 96%, improved in all tumour and nodal stages compared with 1999–2005, and 100% in tumours ≤1 cm. In multivariable analyses adjusted for age and tumour type, overall mortality was decreased by surgery (especially breast conserving), radiotherapy, and systemic therapies. Mortality increased with progressing tumour size in both cohorts (2006–12 T1c v T1a: hazard ratio 1.54, 95% confidence interval 1.33 to 1.78), but without a significant difference in invasive breast cancers until 1 cm (2006–12 T1b v T1a: hazard ratio 1.04, 0.88 to 1.22), and independently with progressing number of positive lymph nodes (2006–12 N1 v N0: 1.25, 1.17 to 1.32).
Conclusions Tumour stage at diagnosis of breast cancer still influences overall survival significantly in the current era of effective systemic therapy. Diagnosis of breast cancer at an early tumour stage remains vital.
Rates of survival with breast cancer have increased significantly all over the world in the past decades. In the United States, the five year relative survival rates for women with breast cancer have improved from approximately 75% in 1975–77 to 90% in 2003–09. This improvement in survival can mainly be explained by an effect both of earlier diagnosis as a result of breast cancer screening and awareness and of better treatment options.
The risk of metastases and death increases with both breast cancer size at detection and number of axillary lymph nodes involved. Screening aims to improve survival by decreasing the risk of metastases through early detection of breast cancer. In the Netherlands, the national breast screening programme with biennial mammography was implemented for all women aged 50–69 years in 1989, and in 1998 the programme was extended to age 71–75 years.
Next to tumour size and lymph node involvement, cancer related factors that influence survival are tumour grade, hormone receptor status, and human epidermal growth factor receptor 2 (HER2). Surgery, the cornerstone of breast cancer treatment, changed in the study period: to assess lymph node positivity, sentinel lymph node biopsy was first described in Dutch guidelines in 1999, although regional implementation had already started. The proportion of patients with early stage breast cancer who had sentinel lymph node biopsy increased from approximately 9% in 1998 to more than 70% in 2003. Recently, Mittendorf et al published data indicating that in patients with small breast cancers lymph node micro-metastases are not of any prognostic value. An explanation might be the increasing effectiveness of systemic therapy.
In more recent years, (neo-)adjuvant systemic treatment for breast cancer has improved considerably and is applied more often. Improvements include the use of trastuzumab, which significantly increases both short term and long term prognosis in HER2 positive breast cancer patients. Trastuzumab treatment was implemented in the Netherlands between 2005 and 2006. Moreover, a switch to more effective chemotherapy regimens has occurred. CMF (cyclophosphamide, methotrexate, 5-fluorouracil) was prescribed to 90% of breast cancer patients receiving chemotherapy in 2000 and to almost none in 2005. It was gradually replaced by the more effective anthracyclines (4% use in 2000 to 96% in 2005), which in turn were partly replaced by regimens containing taxane.
Data published on the effect of screening and better treatment options on survival were based on cohorts of patients with breast cancer diagnosed in 2004 at the latest, and changes to more recent systemic therapy had not yet occurred. Traditional prognostic factors, such as tumour size and number of positive lymph nodes, may no longer predict survival in the current era of new systemic therapy; and if these factors do affect survival, the size of this effect is unknown. To quantify the effect of traditional prognostic factors, both long term and in the current era, we describe overall survival of female patients with breast cancer from two time cohorts (1999–2005 and 2006–12) in a nationwide population based study using data from the Netherlands Cancer Registry.
Abstract and Introduction
Abstract
Objectives To assess the influence of stage at breast cancer diagnosis, tumour biology, and treatment on survival in contemporary times of better (neo-)adjuvant systemic therapy.
Design Prospective nationwide population based study.
Setting Nationwide Netherlands Cancer Registry.
Participants Female patients with primary breast cancer diagnosed between 1999 and 2012 (n=173 797), subdivided into two time cohorts on the basis of breast cancer diagnosis: 1999–2005 (n=80 228) and 2006–12 (n=93 569).
Main outcome measures Relative survival was compared between the two cohorts. Influence of traditional prognostic factors on overall mortality was analysed with Cox regression for each cohort separately.
Results Compared with 1999–2005, patients from 2006–12 had smaller (≤T1 65% (n=60 570) v 60% (n=48 031); P<0.001), more often lymph node negative (N0 68% (n=63 544) v 65% (n=52 238); P<0.001) tumours, but they received more chemotherapy, hormonal therapy, and targeted therapy (neo-adjuvant/adjuvant systemic therapy 60% (n=56 402) v 53% (n=42 185); P<0.001). Median follow-up was 9.8 years for 1999–2005 and 3.9 years for 2006–12. The relative five year survival rate in 2006–12 was 96%, improved in all tumour and nodal stages compared with 1999–2005, and 100% in tumours ≤1 cm. In multivariable analyses adjusted for age and tumour type, overall mortality was decreased by surgery (especially breast conserving), radiotherapy, and systemic therapies. Mortality increased with progressing tumour size in both cohorts (2006–12 T1c v T1a: hazard ratio 1.54, 95% confidence interval 1.33 to 1.78), but without a significant difference in invasive breast cancers until 1 cm (2006–12 T1b v T1a: hazard ratio 1.04, 0.88 to 1.22), and independently with progressing number of positive lymph nodes (2006–12 N1 v N0: 1.25, 1.17 to 1.32).
Conclusions Tumour stage at diagnosis of breast cancer still influences overall survival significantly in the current era of effective systemic therapy. Diagnosis of breast cancer at an early tumour stage remains vital.
Introduction
Rates of survival with breast cancer have increased significantly all over the world in the past decades. In the United States, the five year relative survival rates for women with breast cancer have improved from approximately 75% in 1975–77 to 90% in 2003–09. This improvement in survival can mainly be explained by an effect both of earlier diagnosis as a result of breast cancer screening and awareness and of better treatment options.
The risk of metastases and death increases with both breast cancer size at detection and number of axillary lymph nodes involved. Screening aims to improve survival by decreasing the risk of metastases through early detection of breast cancer. In the Netherlands, the national breast screening programme with biennial mammography was implemented for all women aged 50–69 years in 1989, and in 1998 the programme was extended to age 71–75 years.
Next to tumour size and lymph node involvement, cancer related factors that influence survival are tumour grade, hormone receptor status, and human epidermal growth factor receptor 2 (HER2). Surgery, the cornerstone of breast cancer treatment, changed in the study period: to assess lymph node positivity, sentinel lymph node biopsy was first described in Dutch guidelines in 1999, although regional implementation had already started. The proportion of patients with early stage breast cancer who had sentinel lymph node biopsy increased from approximately 9% in 1998 to more than 70% in 2003. Recently, Mittendorf et al published data indicating that in patients with small breast cancers lymph node micro-metastases are not of any prognostic value. An explanation might be the increasing effectiveness of systemic therapy.
In more recent years, (neo-)adjuvant systemic treatment for breast cancer has improved considerably and is applied more often. Improvements include the use of trastuzumab, which significantly increases both short term and long term prognosis in HER2 positive breast cancer patients. Trastuzumab treatment was implemented in the Netherlands between 2005 and 2006. Moreover, a switch to more effective chemotherapy regimens has occurred. CMF (cyclophosphamide, methotrexate, 5-fluorouracil) was prescribed to 90% of breast cancer patients receiving chemotherapy in 2000 and to almost none in 2005. It was gradually replaced by the more effective anthracyclines (4% use in 2000 to 96% in 2005), which in turn were partly replaced by regimens containing taxane.
Data published on the effect of screening and better treatment options on survival were based on cohorts of patients with breast cancer diagnosed in 2004 at the latest, and changes to more recent systemic therapy had not yet occurred. Traditional prognostic factors, such as tumour size and number of positive lymph nodes, may no longer predict survival in the current era of new systemic therapy; and if these factors do affect survival, the size of this effect is unknown. To quantify the effect of traditional prognostic factors, both long term and in the current era, we describe overall survival of female patients with breast cancer from two time cohorts (1999–2005 and 2006–12) in a nationwide population based study using data from the Netherlands Cancer Registry.
