Time to Surgery and Breast
Cancer Survival in the United
States
INTRODUCTIO
N
OBJECTIVE:
To investigate the relationship between
the time from diagnosis to breast cancer
surgery and survival, using separate
analyses of 2 of the largest cancer
databases in the United States.
METHOD
S
● Permission to use the SEER-Medicare and NCDB datasets
were obtained from the National Cancer Institute (NCI) and
American College of Surgeons, respectively.
● The SEER-Medicare and NCDB analyses were each approved
by, and the need for informed consent waived by, the Fox
Chase Cancer Center institutional review board.
● No statistical analyses between cohorts has been
attempted, nor was one warranted because of the
differences in populations, variable definitions, and ranges.
● Time intervals between diagnosis and surgery for overall
survival (OS) were set at 30-day increments, with the last 2
intervals combined owing to small numbers in each.
● Disease-specific survival (DSS) intervals were set at 60-days
increments because of the lower rate of cancer specific
events and to minimize estimator variance.
● Time from diagnosis was used for OS and DSS so that
patients would have a uniform starting time.
● Propensity score–based weighting, to adjust for
confounding, was used to adjust for covariate differences in
the time-interval groups.
● Multinomial logistic regression was used to estimate the
propensity scores and stabilize them to improve covariate
balance.
● Inverse probability weight method was used to create
adjusted OS curves and cause-specific cumulative incidence
functions.
● Cox proportional hazards regression with propensity
score–based weights were used to estimate the hazard
ratios (HRs) associated with the time interval groupings and
OS.
● Fine and Gray proportional hazards regression with
propensity score-based weights was used to estimate
the subdistribution hazard ratios (HR) associated with the
interval length and breast cancer-specific mortality
● Bootstrap standard errors were used for hypothesis
testing and accounted for propensity score estimation
● Differences in the effect of preoperative time interval by
American Joint Committee on Cancer (AJCC) stage were
examined via propensity score-based weighted regressions
which included main effect terms for stage, preoperative
time interval variable and interactions of AJCC stage
indicators with that interval length.
SEER-Medicare Database
●Inclusion criteria:
○ SEER- Medicare patients diagnosed from 1992-2009 with
invasive noninflammatory, nonmetastatic breast cancer
○ Surgery was done as first therapy and a definitive
surgery date in Medicare claims of 180 days or less after
diagnosis.
SEER-Medicare Database
●Exclusion criteria:
○ Those with missing covariate data
○ Younger than 66 years old
○ Patients with no discernable biopsy date
○ Patients receiving neoadjuvant chemotherapy were
excluded
Table 1. Missing covariate Data for the SEER Medicare and NCDB
cohorts
SEER-Medicare Database
● The diagnosis date used as the preoperative interval start
date, was determined by using SEER clinical diagnosis date
(consisted of only a month and a year) and searching for the
first biopsy date during that month or subsequent month.
● A patient’s definitive surgery is defined as the first date on
which claims for both 1 or more breast excisions or
mastectomy and a lymph node procedure were performed
SEER-Medicare Database
Propensity score-based weighing was used to make
adjustments for age, sex, race, marital status, income,
education, size of metropolitan area, geographical region, year
of diagnosis, sequence of breast cancer (within a his- tory of
other cancers), Charlson and Elixhauser comorbidity scores,
histologic findings, grade, tumor size, number of lymph nodes
examined, number of positive lymph nodes, AJCC stage,
surgery type, chemotherapy use, and radiotherapy use.
National Cancer Database
● Inclusion criteria:
○ Patients diagnosed with noninflammatory, invasive,
nonmetastatic breast cancer
○ Having surgery as their first treatment 6 months or less
after their diagnosis date
○ Patients had breast cancer as their first and only
malignant neoplasm and if diagnosis and treatment (all or
part) was at the reporting facility
National Cancer Database
● Exclusion criteria:
○ Patients without lymph node surgery or whose staging,
diagnosis method, or treatment order was unknown
○ Patients with more than 1 breast procedure
○ Patients receiving neoadjuvant chemotherapy
The NCDB requires follow-up of greater than 5 years, so the
cohort only included cases from 2003 to 2005 with follow-up
through 2010.
National Cancer Database
● Propensity score-based weighting was used to make
adjustments for age, sex, race, income, edu- cation, size of
metropolitan area, geographical region, year of diagnosis,
Charlson-Deyo comorbidity score, histologic find- ings, grade,
tumor size, surgical margins, number of nodes ex- amined,
number of positive nodes, AJCC stage, surgery type,
chemotherapy, radiotherapy, endocrine therapy, facility
type, distance to facility, class of case, and insurance type.
RESULTS
SEER- MEDICARE DATABASE
Figure 1. Flow Diagram of exclusions for the SEER- Medicare Database cohort
SEER- MEDICARE DATABASE
SEER- MEDICARE
DATABASE
SEER- MEDICARE DATABASE
SEER- MEDICARE DATABASE
SEER- MEDICARE DATABASE
Figure 2. Adjusted Overall Survival for SEER- Medicare database patients for preoperative
delay intervals of 30, 31-60, 61-90, 91-120, and 121-180 days.
SEER- MEDICARE DATABASE
SEER- MEDICARE DATABASE
Figure 3. Adjusted overall survival for SEER-Medicare Database patients with Stage I
breast cancer for preoperative delay intervals of ≤30, 31-60, 61-90, 91-120, and 121-180
SEER- MEDICARE DATABASE
Figure 4. Adjusted overall survival for SEER-Medicare Database patients with Stage II
breast cancer for preoperative delay intervals of ≤30, 31-60, 61-90, 91-120, and 121-180
SEER- MEDICARE DATABASE
Figure 5. Adjusted overall survival for SEER-Medicare Database patients with Stage III
breast cancer for preoperative delay intervals of ≤30, 31-60, 61-90, 91-120, and 121-180
SEER- MEDICARE DATABASE
Figure 6. Adjusted breast cancer-specific mortality rate for SEER-Medicare Database patients
for preoperative delay intervals of <60, 61-120, and 121-180 days for all breast cancer stages
SEER- MEDICARE DATABASE
Figure 7. Adjusted breast cancer-specific mortality rate for SEER-Medicare Database
patients for preoperative delay intervals of <60, 61-120, and 121-180 days for stage I
SEER- MEDICARE DATABASE
Figure 8. Adjusted breast cancer-specific mortality rate for SEER-Medicare Database
patients for preoperative delay intervals of <60, 61-120, and 121-180 days for stage II
SEER- MEDICARE DATABASE
Figure 9. Adjusted breast cancer-specific mortality rate for SEER-Medicare Database
patients for preoperative delay intervals of <60, 61-120, and 121-180 days for stage III
SEER- MEDICARE DATABASE
Table 3. Hazard and SubHazard ratios for Cox and Fine and Gray models
SEER- MEDICARE DATABASE
Table 4. Top 10 causes of death for SEER-Medicare Database patients in descending order of frequency
NATIONAL CANCER DATABASE
Figure 10. Flow Diagram of exclusions
for the National Cancer Database cohort
NATIONAL CANCER DATABASE
Table 5. Adjusted/Weighted and Unadjusted/Unweighted Patient and Tumor
Characteristics from the NCDB Study by Surgery Delay Interval
NATIONAL CANCER DATABASE
NATIONAL CANCER DATABASE
NATIONAL CANCER DATABASE
NATIONAL CANCER DATABASE
Figure 11. Adjusted Overall Survival for NCDB database patients for preoperative delay intervals
of 30, 31-60, 61-90, 91-120, and 121-180 days.
NATIONAL CANCER DATABASE
Figure 12. Adjusted overall survival for National Cancer Database patients with Stage I breast
cancer for preoperative delay intervals of ≤30, 31-60, 61-90, 91-120, and 121-180 days
NATIONAL CANCER DATABASE
Figure 13. Adjusted overall survival for National Cancer Database patients with Stage II breast
cancer for preoperative delay intervals of ≤30, 31-60, 61-90, 91-120, and 121-180 days
NATIONAL CANCER DATABASE
Figure 14. Adjusted overall survival for National Cancer Database patients with Stage III breast
cancer for preoperative delay intervals of ≤30, 31-60, 61-90, 91-120, and 121-180 days
NATIONAL CANCER DATABASE
Table 6. Hazard and SubHazard ratios for Cox and Fine and Gray models
DISCUSSION
● Delays in surgery still independently correlated with a
slightly lower survival rate in both the SEER- Medicare and
NCDB cohorts.
● Overall Survival (OS) declines when the Time To Surgery
(TTS) increases (Stage I and Stage II).
● With cancer-specific mortality data (SEER- Medicare dataset),
patients with stage I cancer exhibited lower survival as TTS
increased.
○ There are lower numbers of patients with higher-stage
disease
○ Baseline mortality is smaller relative to the effect
imposed by a delay in treatment
● In both cohorts, OS and Disease-Specific Survival (DSS) for
stage III disease were not influenced by TTS which may be
attributed to:
○ Partial biologic predestination of outcome
○ Mortality risk that overshadows any small effect of
reducing delay by a matter of months
○ Patient age (owing to competing mortality risks)
● Efforts to minimize preoperative delay for all patients is
advisable.
● Unmeasured confounders could still exist affecting survival
negatively or positively.
● Patients having neoadjuvant chemotherapy were excluded in
the study because:
○ Cohort homogeneity will be maintained
○ These patients had a markedly longer TTS because of the
lengthy time imposed by the treatment itself
Differences in the magnitude of effect of delay for the SEER-
Medicare vs NCDB cohort may be due to:
● Complexities in the relationship between age and tumor
biology, or age and treatment
● Delay to surgery
● Delay to postoperative therapy
The benefit of minimizing time to
surgery is comparable to the addition of
some standard therapies while not
having the adverse effects or costs
found with most interventions.
Whether TTS should be revisited as a quality measure could be
debated in light of practical matters that contribute to delay
which may either be:
● Patient driven (desire for multiple opinions, limitations in the
patient’s schedule, or not seeking care as instructed)
● System driven (lack of available operating room time,
appointment times, insurance issues, and barriers to care)
● Physician related (schedule limitations or excessive use of
imaging or other testing)
The similar results between separate
analyses of these 2 large national data
sets suggests that the effect of delay
on survival is a true phenomenon and
not one specific to a particular cohort.
CONCLUSIO
N
IN CONCLUSION,
● Greater TTS is associated with lower overall and
disease-specific survival.
● A shortened delay is associated with benefits
comparable to some standard therapies.
● Although time is required for preoperative evaluation and
consideration of options such as reconstruction, efforts to
reduce TTS should be pursued when possible to
enhance survival.
IN ADDITION,
● Survival outcomes in early-stage breast cancer are affected
by the length of the interval between diagnosis and surgery.
● Efforts to minimize that interval are appropriate.
● Although the effect on both overall and disease-specific
survival remains small, consideration should be given to
establishing reasonable and attainable goals for the timing of
surgical interventions to afford this population a finite, but
clinically relevant, survival benefit.
