Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
TITLE De-novo post-diagnosis aspirin use and mortality in women with stage I-III breast cancer
AUTHORS Thomas I. Barron1,2 Laura M. Murphy1 Chris Brown3 Kathleen Bennett1 Kala Visvanathan2,4 Linda Sharp3
INSTITUTIONS 1
Trinity Centre for Health Sciences, Trinity College, University of Dublin, Dublin, Ireland.
2
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
3
National Cancer Registry Ireland, Cork, Ireland.
4
Sidney Kimmel Comprehensive Cancer Centre, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
RUNNING TITLE Post-diagnosis aspirin use and breast cancer mortality
KEY WORDS Breast Cancer, Aspirin, Adjuvant Therapy, Survival, Epidemiology
FINANCIAL SUPPORT This work was supported by the Health Research Board Ireland [ICE20119 to K Bennett, L Sharp, HSR201230 to L Sharp, K Bennett, TI Barron]; and the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT [CCRC13GAL to K Bennett, T I Barron].
CONFLICT OF INTEREST L Sharp held an unrestricted project grant from Sanofi-Aventis in 2011-2012 for research on survival from breast cancer. All remaining authors have declared no conflicts of interest.
CORRESPONDING AUTHOR Dr Thomas I Barron Department of Pharmacology & Therapeutics,
1 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Trinity Centre for Health Sciences, St James’s Hospital, Dublin 8, Ireland. [email protected]
WORD COUNT 2,728 (Microsoft Word 2010)
TABLES 4
FIGURES 1
2 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
ABSTRACT Background: Aspirin use has been associated with significant reductions in breast cancer mortality in some observational studies. However, these studies included women who initiated aspirin use prior to breast cancer diagnosis. It is unclear whether initiating aspirin use after diagnosis is associated similar reductions in mortality. This study investigates associations between de-novo post-diagnostic aspirin use and all cause, breast cancer-specific mortality. Methods: Women, aged 50 to 80, with a diagnosis of stage I-III breast cancer were identified from Ireland’s National Cancer Registry (N=4,540). Initiation of de-novo post-diagnostic aspirin use was identified from linked national prescription refill data (N=764). Adjusted hazard ratios were estimated for associations between de-novo aspirin use and allcause, breast cancer-specific mortality. Results: The median time from diagnosis to aspirin initiation was 1.8 years. The mean number of days’ supply of aspirin received was 631, and 95% of users were taking less than 150mg/day. We found no association between de-novo aspirin use and breast cancerspecific mortality (HR=0.98, 95%CI 0.74-1.30). Similar null associations were found in women taking aspirin at high-intensity (HR=1.03, 95%CI 0.72-1.47) and women initiating use in the 1.5 years after diagnosis (HR=1.04, 95%CI 0.77-1.40). There was no effect modification by oestrogen (Pinteraction=0.81) or progesterone (P-interaction=0.41) receptor status. Conclusion: Initiating aspirin use after a breast cancer diagnosis was not associated with a reduction in breast cancer-specific mortality. Impact: Based on our findings we suggest that a clearer understanding of aspirin’s mechanism of action is needed to help inform the design of future studies in breast cancer.
3 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
INTRODUCTION The use of aspirin, a cyclooxygenase (COX) -1/-2 inhibitor, was associated with significant reductions in the risk of cancer mortality in recent meta-analyses of randomized trials for cardiovascular disease prevention.(1,2) Randomization to aspirin use was associated with a 40% reduction in the risk of developing distant metastasis after diagnosis and a 15% reduction in the risk of a cancer-related death, suggesting a potential therapeutic role for aspirin in some cancers.(1,2) In women with breast cancer, aspirin use was associated with non-significant reductions in the risk of developing metastasis and death.(2) Of note, aspirin use was initiated prior to cancer diagnosis in these studies and it is plausible that some of the observed benefit is attributable to pre-diagnostic use.(3,4) It is unclear whether mortality is reduced in patients starting aspirin de-novo after a cancer is diagnosed. In breast cancer, a number of observational studies have examined associations between aspirin use and disease recurrence or death,(4–12) with three reporting statistically-significant reductions in breast cancer mortality.(5–7) Most of these studies included women taking aspirin prior to their breast cancer diagnosis and did not distinguish between pre- and post-diagnostic initiation of exposure in their analyses.(5–9) Only two previous studies have examined associations between de-novo postdiagnostic aspirin use and breast cancer outcomes.(11,12) In these, no association was observed between aspirin use initiated after diagnosis and breast cancer outcomes. However, these analyses were limited by either small numbers of de-novo aspirin users (N=148),(11) or did not adjust for tumour stage.(12) In this study we aimed to investigate, in a large national cancer registry and prescribing database, associations between de-novo aspirin use, initiated after a breast cancer diagnosis, and both all-cause and breast cancer-specific mortality. We also evaluated effect modification by tumour characteristics at diagnosis. 4 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
MATERIALS AND METHODS SETTING & DATA SOURCES The study was conducted using individual-level patient records from the National Cancer Registry Ireland (NCRI), which were linked to prescription dispensing data from Ireland's Primary Care Reimbursement Services (PCRS) pharmacy claims database. These linked data have been described previously.(13) The NCRI database records information collected by trained hospital-based tumour registration officers on all incident cancers diagnosed in the population usually resident in Ireland. Completeness of registration is estimated to be at least 97% overall, and higher for breast cancer.(14) The use for research of anonymized data held by the NCRI is covered by the Health (Provision of Information) Act 1997. The PCRS database records claims from pharmacies for financial reimbursement of medications dispensed through the General Medical Services (GMS) scheme. The GMS scheme provides universal healthcare, including free medications, to approximately one third (1.4 million) of the Irish population. This includes most high-dose aspirin preparations and all low-dose aspirin preparations, which are prescription-only in Ireland as in some other European countries.(15) A small number of high-dose aspirin preparations are available to purchase without prescription, but only for specified short-term indications and in small pack sizes (≤24-50 doses). Women with GMS eligibility can obtain these – and all other – high-dose aspirin preparations on-prescription without charge or restriction. Eligibility for the GMS scheme is assessed by a combination of means-test and age. The GMS population is therefore older and more socioeconomically deprived than the full Irish population.
COHORT & EXPOSURE DEFINITIONS Women not receiving aspirin prior to their breast cancer diagnosis were identified within the linked NCRI-PCRS database. Specifically, the study population was defined as all women with a diagnosis of
5 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
stage I-III invasive breast cancer(16) (ICD-10 C50) between 1st January 2001 and 31st December 2011, aged 50 to 80 years at diagnosis and with GMS eligibility starting at least one year prior to diagnosis. The lower age limit was set at 50 years to exclude women unlikely to be prescribed aspirin. Women over the age of 80 years were excluded as they are less likely to receive definitive breast cancer staging or treatment.(17) Women were also excluded if they had a prior invasive cancer other than nonmelanoma skin cancer or if their cancer diagnosis was made at the time of death. We identified all prescriptions for aspirin (WHO-ATC drug classifications(18); Table S1) dispensed in the year prior to breast cancer diagnosis, and women with aspirin use during this time were excluded. Within the remaining women we identified de-novo post-diagnostic aspirin exposure from prescriptions dispensed between breast cancer diagnosis and the end of follow-up (date of death or 31st December 2012, whichever occurred first). The number of days’ supply on each prescription was used to calculate aspirin dosing intensity (in the previous six months), for each day of follow-up. These longitudinal aspirin exposure histories were used to define aspirin exposures as follows. Firstly women were identified as exposed (yes/no) from the date they received their first aspirin prescription. Secondly within this group of aspirin users women were identified as having high-intensity exposure (yes/no) from the first date they had taken aspirin at an intensity of ≥80% for longer than six consecutive months. In addition a landmark analysis was conducted in which women were identified as exposed (yes/no) if they started de-novo aspirin use in the 1.5 years after their breast cancer diagnosis. Once allocated to an exposure category, women remained in this category to the end of follow-up.
OUTCOMES & COVARIATES We identified the date and cause of death (all-cause or breast cancer-specific) from death certificate information. Breast cancer-specific deaths were categorised using previously published SEER definitions (Table S1).(19); women who died from other causes were censored at the date of death. 6 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
The following patient, tumour and treatment characteristics were abstracted from the NCRI database: age at diagnosis (years); smoking status at diagnosis (never, past, current, unspecified); tumour stage (I, IIa, IIb, IIIa, IIIb-c);(16) tumour grade (low, intermediate, high, unspecified); oestrogen (ER), progesterone (PR) and human epidermal growth factor-2 (HER2) receptor status (positive, negative, unspecified; Table S1); and receipt of chemotherapy (yes, no) in the year post-diagnosis. Antioestrogen therapy starting in the year post-diagnosis (yes, no; Table S1) was identified using PCRS prescription data. The PCRS database was also used to identify exposures to other potentially relevant medication in the year prior to diagnosis (exposed, unexposed; Table S1). These were, lipophilic statins, hydrophilic statins, bisphosphonates, anti-diabetics and other non-steroidal anti-inflammatory drugs (NSAIDs). The number of medication classes (WHO-ATC classification, 4th level, chemical subgroup) dispensed in the year prior to breast cancer diagnosis was used as a measure of comorbidity.(20)
STATISTICAL ANALYSIS All analyses were conducted using SAS® v9.3 (SAS® Institute Inc, Cary, NC) and results were considered statistically significant at a two-sided α-level of 0.05. We tabulated the proportion of de-novo postdiagnostic aspirin users, and compared differences in the rates of post-diagnostic aspirin initiation across baseline socio-demographic and clinical covariates by univariate Poisson regression. For women with de-novo post-diagnostic aspirin exposure we estimated the median duration of aspirin use from first to last exposure using Kaplan Meier analysis with censoring at death or end of follow-up (minus exposure lag time). We also calculated the number of day’s supply of aspirin received during follow-up and the exposure intensity while on treatment (number of day’s supply received divided by number of days from first to last exposure). Person time was calculated from the date of breast cancer diagnosis to the end of follow-up.
7 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Adjusted hazard ratios (HR) with 95% confidence intervals (CI) for associations between de-novo aspirin use and breast cancer-specific and all-cause mortality were estimated using multivariate Cox models. Aspirin exposure was included in survival analyses as a time-varying covariate. Patients were identified as exposed (yes/no) from the time they received their first aspirin prescription plus a lag time. Exposures were lagged to reduce the possibility that changing prognosis influenced the probability of receiving aspirin. There are no data to indicate what the appropriate lag time should be for post-diagnostic exposures in analyses of breast cancer-specific mortality. The exposure lag was therefore set at 2 years, the median survival time after a breast cancer recurrence,(21) and varied in sensitivity analyses (0, 1, 3, 4 years). We used prior knowledge of predictors of breast cancer-specific mortality to select covariates for inclusion in multivariate models. The variables included in the models were clinical and demographic characteristics (tumour stage; tumour grade; ER, PR, HER2 status; primary treatment with chemotherapy or hormonal therapy; comorbidity-score; age); co-prescribed medications (hydrophilic statins, lipophilic statins, bisphosphonates, other NSAIDS) and the presence of specific comorbidities (diabetes, defined by receipt of an anti-diabetic medication). Effect modification by baseline tumour characteristics was evaluated with the inclusion of an interaction term in the multivariate model. Tumour characteristics previously associated with COX-2 expression were considered as potential effect modifiers (tumour size, lymph node metastasis, and ER and PR status).(22) We also conducted analyses stratified by aspirin dosing intensity (high/low). De-novo aspirin users were identified as having high-intensity exposure if they had taken aspirin at an intensity of ≥80% for longer than six consecutive months (time varying, lagged by 2 years).(5) Finally we repeated analyses using a landmark approach(23) to simulate a clinically-relevant scenario of adjuvant aspirin use initiated shortly after diagnosis. In this analysis, patients were identified as exposed (yes/no) if they 8 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
started de-novo aspirin use in the 1.5 years after their breast cancer diagnosis and survival analyses were conducted with follow-up beginning at 2 years after diagnosis. Sensitivity analyses were also undertaken using a stricter definition of de-novo aspirin use, in which the study population was restricted to those without pre-diagnostic aspirin exposure for at least 3 years prior to diagnosis.(2) We conducted two post-hoc analyses to further explore the influence of longer-term, high intensity denovo aspirin use on breast cancer outcomes. In the first of these we defined de-novo aspirin users as having high-intensity exposure from the first date they had taken aspirin at an intensity of ≥80% for longer than two consecutive years. Secondly we conducted an analysis of cumulative average intensity of aspirin exposure since diagnosis (0,
TITLE De-novo post-diagnosis aspirin use and mortality in women with stage I-III breast cancer
AUTHORS Thomas I. Barron1,2 Laura M. Murphy1 Chris Brown3 Kathleen Bennett1 Kala Visvanathan2,4 Linda Sharp3
INSTITUTIONS 1
Trinity Centre for Health Sciences, Trinity College, University of Dublin, Dublin, Ireland.
2
Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
3
National Cancer Registry Ireland, Cork, Ireland.
4
Sidney Kimmel Comprehensive Cancer Centre, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.
RUNNING TITLE Post-diagnosis aspirin use and breast cancer mortality
KEY WORDS Breast Cancer, Aspirin, Adjuvant Therapy, Survival, Epidemiology
FINANCIAL SUPPORT This work was supported by the Health Research Board Ireland [ICE20119 to K Bennett, L Sharp, HSR201230 to L Sharp, K Bennett, TI Barron]; and the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT [CCRC13GAL to K Bennett, T I Barron].
CONFLICT OF INTEREST L Sharp held an unrestricted project grant from Sanofi-Aventis in 2011-2012 for research on survival from breast cancer. All remaining authors have declared no conflicts of interest.
CORRESPONDING AUTHOR Dr Thomas I Barron Department of Pharmacology & Therapeutics,
1 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Trinity Centre for Health Sciences, St James’s Hospital, Dublin 8, Ireland. [email protected]
WORD COUNT 2,728 (Microsoft Word 2010)
TABLES 4
FIGURES 1
2 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
ABSTRACT Background: Aspirin use has been associated with significant reductions in breast cancer mortality in some observational studies. However, these studies included women who initiated aspirin use prior to breast cancer diagnosis. It is unclear whether initiating aspirin use after diagnosis is associated similar reductions in mortality. This study investigates associations between de-novo post-diagnostic aspirin use and all cause, breast cancer-specific mortality. Methods: Women, aged 50 to 80, with a diagnosis of stage I-III breast cancer were identified from Ireland’s National Cancer Registry (N=4,540). Initiation of de-novo post-diagnostic aspirin use was identified from linked national prescription refill data (N=764). Adjusted hazard ratios were estimated for associations between de-novo aspirin use and allcause, breast cancer-specific mortality. Results: The median time from diagnosis to aspirin initiation was 1.8 years. The mean number of days’ supply of aspirin received was 631, and 95% of users were taking less than 150mg/day. We found no association between de-novo aspirin use and breast cancerspecific mortality (HR=0.98, 95%CI 0.74-1.30). Similar null associations were found in women taking aspirin at high-intensity (HR=1.03, 95%CI 0.72-1.47) and women initiating use in the 1.5 years after diagnosis (HR=1.04, 95%CI 0.77-1.40). There was no effect modification by oestrogen (Pinteraction=0.81) or progesterone (P-interaction=0.41) receptor status. Conclusion: Initiating aspirin use after a breast cancer diagnosis was not associated with a reduction in breast cancer-specific mortality. Impact: Based on our findings we suggest that a clearer understanding of aspirin’s mechanism of action is needed to help inform the design of future studies in breast cancer.
3 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
INTRODUCTION The use of aspirin, a cyclooxygenase (COX) -1/-2 inhibitor, was associated with significant reductions in the risk of cancer mortality in recent meta-analyses of randomized trials for cardiovascular disease prevention.(1,2) Randomization to aspirin use was associated with a 40% reduction in the risk of developing distant metastasis after diagnosis and a 15% reduction in the risk of a cancer-related death, suggesting a potential therapeutic role for aspirin in some cancers.(1,2) In women with breast cancer, aspirin use was associated with non-significant reductions in the risk of developing metastasis and death.(2) Of note, aspirin use was initiated prior to cancer diagnosis in these studies and it is plausible that some of the observed benefit is attributable to pre-diagnostic use.(3,4) It is unclear whether mortality is reduced in patients starting aspirin de-novo after a cancer is diagnosed. In breast cancer, a number of observational studies have examined associations between aspirin use and disease recurrence or death,(4–12) with three reporting statistically-significant reductions in breast cancer mortality.(5–7) Most of these studies included women taking aspirin prior to their breast cancer diagnosis and did not distinguish between pre- and post-diagnostic initiation of exposure in their analyses.(5–9) Only two previous studies have examined associations between de-novo postdiagnostic aspirin use and breast cancer outcomes.(11,12) In these, no association was observed between aspirin use initiated after diagnosis and breast cancer outcomes. However, these analyses were limited by either small numbers of de-novo aspirin users (N=148),(11) or did not adjust for tumour stage.(12) In this study we aimed to investigate, in a large national cancer registry and prescribing database, associations between de-novo aspirin use, initiated after a breast cancer diagnosis, and both all-cause and breast cancer-specific mortality. We also evaluated effect modification by tumour characteristics at diagnosis. 4 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
MATERIALS AND METHODS SETTING & DATA SOURCES The study was conducted using individual-level patient records from the National Cancer Registry Ireland (NCRI), which were linked to prescription dispensing data from Ireland's Primary Care Reimbursement Services (PCRS) pharmacy claims database. These linked data have been described previously.(13) The NCRI database records information collected by trained hospital-based tumour registration officers on all incident cancers diagnosed in the population usually resident in Ireland. Completeness of registration is estimated to be at least 97% overall, and higher for breast cancer.(14) The use for research of anonymized data held by the NCRI is covered by the Health (Provision of Information) Act 1997. The PCRS database records claims from pharmacies for financial reimbursement of medications dispensed through the General Medical Services (GMS) scheme. The GMS scheme provides universal healthcare, including free medications, to approximately one third (1.4 million) of the Irish population. This includes most high-dose aspirin preparations and all low-dose aspirin preparations, which are prescription-only in Ireland as in some other European countries.(15) A small number of high-dose aspirin preparations are available to purchase without prescription, but only for specified short-term indications and in small pack sizes (≤24-50 doses). Women with GMS eligibility can obtain these – and all other – high-dose aspirin preparations on-prescription without charge or restriction. Eligibility for the GMS scheme is assessed by a combination of means-test and age. The GMS population is therefore older and more socioeconomically deprived than the full Irish population.
COHORT & EXPOSURE DEFINITIONS Women not receiving aspirin prior to their breast cancer diagnosis were identified within the linked NCRI-PCRS database. Specifically, the study population was defined as all women with a diagnosis of
5 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
stage I-III invasive breast cancer(16) (ICD-10 C50) between 1st January 2001 and 31st December 2011, aged 50 to 80 years at diagnosis and with GMS eligibility starting at least one year prior to diagnosis. The lower age limit was set at 50 years to exclude women unlikely to be prescribed aspirin. Women over the age of 80 years were excluded as they are less likely to receive definitive breast cancer staging or treatment.(17) Women were also excluded if they had a prior invasive cancer other than nonmelanoma skin cancer or if their cancer diagnosis was made at the time of death. We identified all prescriptions for aspirin (WHO-ATC drug classifications(18); Table S1) dispensed in the year prior to breast cancer diagnosis, and women with aspirin use during this time were excluded. Within the remaining women we identified de-novo post-diagnostic aspirin exposure from prescriptions dispensed between breast cancer diagnosis and the end of follow-up (date of death or 31st December 2012, whichever occurred first). The number of days’ supply on each prescription was used to calculate aspirin dosing intensity (in the previous six months), for each day of follow-up. These longitudinal aspirin exposure histories were used to define aspirin exposures as follows. Firstly women were identified as exposed (yes/no) from the date they received their first aspirin prescription. Secondly within this group of aspirin users women were identified as having high-intensity exposure (yes/no) from the first date they had taken aspirin at an intensity of ≥80% for longer than six consecutive months. In addition a landmark analysis was conducted in which women were identified as exposed (yes/no) if they started de-novo aspirin use in the 1.5 years after their breast cancer diagnosis. Once allocated to an exposure category, women remained in this category to the end of follow-up.
OUTCOMES & COVARIATES We identified the date and cause of death (all-cause or breast cancer-specific) from death certificate information. Breast cancer-specific deaths were categorised using previously published SEER definitions (Table S1).(19); women who died from other causes were censored at the date of death. 6 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
The following patient, tumour and treatment characteristics were abstracted from the NCRI database: age at diagnosis (years); smoking status at diagnosis (never, past, current, unspecified); tumour stage (I, IIa, IIb, IIIa, IIIb-c);(16) tumour grade (low, intermediate, high, unspecified); oestrogen (ER), progesterone (PR) and human epidermal growth factor-2 (HER2) receptor status (positive, negative, unspecified; Table S1); and receipt of chemotherapy (yes, no) in the year post-diagnosis. Antioestrogen therapy starting in the year post-diagnosis (yes, no; Table S1) was identified using PCRS prescription data. The PCRS database was also used to identify exposures to other potentially relevant medication in the year prior to diagnosis (exposed, unexposed; Table S1). These were, lipophilic statins, hydrophilic statins, bisphosphonates, anti-diabetics and other non-steroidal anti-inflammatory drugs (NSAIDs). The number of medication classes (WHO-ATC classification, 4th level, chemical subgroup) dispensed in the year prior to breast cancer diagnosis was used as a measure of comorbidity.(20)
STATISTICAL ANALYSIS All analyses were conducted using SAS® v9.3 (SAS® Institute Inc, Cary, NC) and results were considered statistically significant at a two-sided α-level of 0.05. We tabulated the proportion of de-novo postdiagnostic aspirin users, and compared differences in the rates of post-diagnostic aspirin initiation across baseline socio-demographic and clinical covariates by univariate Poisson regression. For women with de-novo post-diagnostic aspirin exposure we estimated the median duration of aspirin use from first to last exposure using Kaplan Meier analysis with censoring at death or end of follow-up (minus exposure lag time). We also calculated the number of day’s supply of aspirin received during follow-up and the exposure intensity while on treatment (number of day’s supply received divided by number of days from first to last exposure). Person time was calculated from the date of breast cancer diagnosis to the end of follow-up.
7 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
Adjusted hazard ratios (HR) with 95% confidence intervals (CI) for associations between de-novo aspirin use and breast cancer-specific and all-cause mortality were estimated using multivariate Cox models. Aspirin exposure was included in survival analyses as a time-varying covariate. Patients were identified as exposed (yes/no) from the time they received their first aspirin prescription plus a lag time. Exposures were lagged to reduce the possibility that changing prognosis influenced the probability of receiving aspirin. There are no data to indicate what the appropriate lag time should be for post-diagnostic exposures in analyses of breast cancer-specific mortality. The exposure lag was therefore set at 2 years, the median survival time after a breast cancer recurrence,(21) and varied in sensitivity analyses (0, 1, 3, 4 years). We used prior knowledge of predictors of breast cancer-specific mortality to select covariates for inclusion in multivariate models. The variables included in the models were clinical and demographic characteristics (tumour stage; tumour grade; ER, PR, HER2 status; primary treatment with chemotherapy or hormonal therapy; comorbidity-score; age); co-prescribed medications (hydrophilic statins, lipophilic statins, bisphosphonates, other NSAIDS) and the presence of specific comorbidities (diabetes, defined by receipt of an anti-diabetic medication). Effect modification by baseline tumour characteristics was evaluated with the inclusion of an interaction term in the multivariate model. Tumour characteristics previously associated with COX-2 expression were considered as potential effect modifiers (tumour size, lymph node metastasis, and ER and PR status).(22) We also conducted analyses stratified by aspirin dosing intensity (high/low). De-novo aspirin users were identified as having high-intensity exposure if they had taken aspirin at an intensity of ≥80% for longer than six consecutive months (time varying, lagged by 2 years).(5) Finally we repeated analyses using a landmark approach(23) to simulate a clinically-relevant scenario of adjuvant aspirin use initiated shortly after diagnosis. In this analysis, patients were identified as exposed (yes/no) if they 8 Downloaded from cebp.aacrjournals.org on March 23, 2015. © 2015 American Association for Cancer Research.
Author Manuscript Published OnlineFirst on March 19, 2015; DOI: 10.1158/1055-9965.EPI-14-1415 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.
started de-novo aspirin use in the 1.5 years after their breast cancer diagnosis and survival analyses were conducted with follow-up beginning at 2 years after diagnosis. Sensitivity analyses were also undertaken using a stricter definition of de-novo aspirin use, in which the study population was restricted to those without pre-diagnostic aspirin exposure for at least 3 years prior to diagnosis.(2) We conducted two post-hoc analyses to further explore the influence of longer-term, high intensity denovo aspirin use on breast cancer outcomes. In the first of these we defined de-novo aspirin users as having high-intensity exposure from the first date they had taken aspirin at an intensity of ≥80% for longer than two consecutive years. Secondly we conducted an analysis of cumulative average intensity of aspirin exposure since diagnosis (0,
