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ORIGINAL ARTICLE – BREAST ONCOLOGY
Outcomes of Delays in Time to Treatment in Triple NegativeBreast Cancer
Amy Eastman, MD, Yolanda Tammaro, MD, Amy Moldrem, MD, Valerie Andrews, MD, James Huth, MD,
David Euhus, MD, Marilyn Leitch, MD, and Roshni Rao, MD
Department of Surgery, Division of Surgical Oncology, University of Texas Southwestern Medical Center, Dallas, TX
ABSTRACT
Background. Compared with other breast cancer sub-
types, triple negative breast cancers (TNBC) are associated
with higher recurrence rates and worse survival. Because of
the aggressive nature of TNBC, outcomes may be more
sensitive to delays in time to treatment. This study evalu-
ates whether delays from diagnosis to initial treatment in
TNBC impacts survival or locoregional recurrence (LRR).
Methods. Retrospective review of TNBC patients treated
between January 2004 and January 2011 at an academic
center was performed. Data collected included demo-
graphics, pathology, treatment, recurrence, and survival.
Interval to treatment was defined as days from pathologic
diagnosis to first local or systemic treatment. The t test,
Cox regression, and Kaplan–Meier analyses were used to
evaluate impact of time to treatment on overall survival
and LRR.
Results. Median follow-up was 40 months for 301 TNBC
patients. Mean interval to treatment was 46 ± 2 days.
Higher initial stage yielded worse survival (p \ .0001).
Interval to treatment did not impact overall survival
(p = .24), although there was a trend toward worse sur-
vival with delays of[90 days (p = .06). LRR was seen in
20 patients (7 %). Median time to recurrence was
15 months. Time to treatment was 38 ± 6 days for patients
with LRR versus 44 ± 2 days without a recurrence
(p = .37). Short delay in time to treatment did not impact
LRR (p = .54).
Conclusions. In TNBC, a short delay from pathologic
diagnosis to initial treatment does not appear to adversely
affect survival or LRR. Appropriate time to perform
evaluations such as genetic testing, imaging, or additional
consultation can be taken to guide optimal treatment
options.
In a recent review using the National Cancer Data Base
to evaluate wait times for cancer treatment in the United
States, time to treatment for all cancers, including breast,
was shown to have increased over the last decade.1 The
acceptable time interval from diagnosis of breast cancer to
initiation of treatment remains an area of controversy.2–6
While is it agreed upon that therapy should be started as
promptly as possible, the current multidisciplinary
approach to breast cancer treatment can sometimes require
additional workup, including imaging, genetic testing, and
additional consultations, which may delay treatment. In
general, delays of less than 90 days have not been found to
negatively impact survival.7
Triple negative breast cancer is defined by a lack of
expression of estrogen receptor (ER), progesterone recep-
tor (PR), and human epidermal growth factor receptor 2
(HER2).8,9 Pathologically, these tumors are most often
characterized by invasive ductal histology, high grade, and
high proliferation rates (Ki67).10–12 This subtype of breast
cancer makes up approximately 15 % of invasive breast
cancers in the United States and is most prevalent among
African Americans.13–15 Unlike hormone receptor positive
or Her2 positive tumors, there are no targeted therapies for
triple negative breast cancers (TNBC). Compared with
other breast cancer subtypes, TNBC have high recurrence
rates and worse overall survival.16–18 Because of their
aggressive phenotype, it has been proposed that triple
negative tumors may be more sensitive to delays in time to
treatment. In addition, African American and Hispanic
patients are more likely to experience a delay in time to
treatment, irrespective of insurance status.19 A delay in
time to treatment along with a higher rate of TNBC may
� Society of Surgical Oncology 2013
First Received: 21 May 2012;
Published Online: 5 January 2013
R. Rao, MD
e-mail: [email protected]
Ann Surg Oncol (2013) 20:1880–1885
DOI 10.1245/s10434-012-2835-z
contribute to worse overall outcomes and could potentially
be an opportunity for process improvements.
Studies have shown that gaps in health care quality exist
for all medical and surgical specialties, including breast
surgery.20,21 Timeliness of care, defined as time between
diagnosis and initial definitive treatment, has been pro-
posed as a quality measure for cancer care. Numerous
groups, including the National Quality Measures for Breast
Centers (NQMBC) program, the National Accreditation
Program for Breast Centers (NAPBC), the National Quality
Forum, and the American Society of Breast Surgeons
(ASBS), have become interested in developing quality
measurement programs that may include time to treatment
benchmarks.22–24 Whether or not short delays to initial
treatment affect outcomes is still in question, indicating
that time to treatment may not be a meaningful indicator of
breast surgical care.
The purpose of this study was to evaluate whether
delays from diagnosis to initial treatment in patients with
TNBC impact survival or locoregional recurrence (LRR).
METHODS
We included two hospital systems in our study. Parkland
Memorial Hospital (PMH) is a county hospital affiliated
with the University of Texas Southwestern Medical Center
(UTSW). It serves a primarily minority, indigent popula-
tion. PMH has been approved as a Commission on Cancer
program since 1979. The Simmons Cancer Center (SCC) is
owned by the University of Texas Southwestern and serves
a primarily white, insured population. Both PMH and SCC
are part of the UTSW National Cancer Institute’s desig-
nated cancer center and staffed by the same clinical faculty,
residents, and medical students. Both centers follow iden-
tical clinical protocols; however, because of limited
resources at PMH (operative time, clinical space, etc.),
there is typically a longer delay in time to treatment at
PMH when compared with SCC.7
After obtaining institutional review board approval, the
tumor registries for both hospital systems were queried to
identify patients diagnosed with TNBC between January
2004 and January 2011. Patients who received treatment
elsewhere or for whom no vital status information was
available were excluded. A retrospective chart review was
performed to obtain information regarding patient demo-
graphics, pathology, stage, initial treatment, recurrence,
and survival. Interval to treatment was calculated as the
number of days from pathologic diagnosis (typically via
core needle biopsy) to first treatment, whether local or
systemic. Several health care quality organizations rec-
ommend time to treatment be no more than 4–6 weeks;
given this, a short delay in time to treatment for this study
was defined as \45 days.25 Graphpad prism was used to
create Kaplan–Meier survival curves, and statistical anal-
ysis between groups was performed using chi-square
analysis, as well as Cox regression.
RESULTS
Study Cohort
A total of 301 patients were included in the study pop-
ulation. Of these, 220 patients were treated in the county
hospital, and 81 patients were treated at SCC. Median
follow-up was 40 months. For all patients undergoing
surgery, 139 patients (50.2 %) had partial mastectomy and
138 patients (49.8 %) had total mastectomy. The charac-
teristics of the study population are listed in Table 1.
Interval to Treatment
The mean interval to treatment for all patients treated
during the study period was 46 days. When comparing the
interval to treatment based on treatment hospital, there was
a significant difference. The interval to treatment was
longer for those patients treated at the county hospital
compared with those treated at the university hospital
[54 ± 3 vs 24 ± 2 days; mean ± standard error of the
mean (SEM), p \ .0001].
Overall Survival Based on Stage and Treatment
Hospital
Survival was initially evaluated based on stage of pre-
sentation for all patients. Worse survival was demonstrated
in patients with higher stage at presentation, as would be
TABLE 1 Demographic and stage information for study population
County
N = 220
University
N = 81
Total
N = 301
Ethnicity
White 28 (13 %) 45 (56 %) 73 (24 %)
African American 125 (57 %) 24 (30 %) 149 (50 %)
Hispanic 60 (27 %) 12 (15 %) 72 (24 %)
Asian 5 (2 %) 0 5 (2 %)
Other 2 (1 %) 0 2 (1 %)
Stage
0 3 (1 %) 10 (12 %) 13 (4 %)
I 29 (13 %) 30 (37 %) 59 (20 %)
II 101 (46 %) 29 (36 %) 130 (43 %)
III 62 (28 %) 8 (10 %) 70 (23 %)
IV 25 (11 %) 4 (5 %) 29 (10 %)
Triple Negative Breast Cancer Treatment Delay 1881
expected (p \ .001). Analysis of survival was then per-
formed based on treatment hospital. Patients treated at the
county hospital had worse overall survival compared with
those treated at the university hospital (Fig. 1a). However,
when comparing survival between the two hospital groups
with patients matched for stage, similar outcomes were
seen (Fig. 1b).
Overall Survival Based on Interval to Treatment
Time to treatment was then evaluated as a potential
independent factor influencing survival. Initially, the
patients were divided into three groups based on interval to
treatment: 0–45, 46–90, and [90 days (Fig. 2a). No asso-
ciation between the interval to treatment and survival was
seen. Since previous studies had revealed decreased sur-
vival with delays C90 days, patients were then divided into
the groups of\90 and C90 days (Fig. 2b). Once again, no
significant difference in survival was seen between these
two groups (p = .06).
Locoregional Recurrence Based on Interval
to Treatment
When the impact of delay on LRR was evaluated,
patients with stage IV disease at presentation, distant
recurrence as first event, and other causes of death were
excluded. A total of 218 patients were included in this
analysis. LRR was seen in 20 (9 %) patients. Median time
to recurrence was 15 months. Overall survival was worse
in patients with LRR versus those with no evidence of
recurrence (p \ .0001). Median survival in patients with
LRR was 32 months. There was no significant difference in
time to treatment for those patients with a LRR compared
with those without a recurrence (38 ± 6 vs 44 ± 2 days;
mean ± SEM, p = .37). In addition, LRR and time to
treatment were evaluated in a Cox regression model, and
there was no increased risk of recurrence in patients with
increased interval to treatment (p = .5). There was also no
significant difference in LRR free survival for patients
comparing time to treatment of \45 versus C45 days
(p = .46) (Fig. 3).
a b
FIG. 1 a Evaluation of survival according to treatment hospital. b Evaluation of survival for all patients controlling for stage at presentation
1882 A. Eastman et al.
Overall Survival Based on Surgical Treatment
Analysis of survival was also performed based on surgical
treatment for patients presenting with DCIS and stage 1, 2,
and 3 disease. Four patients did not undergo surgical inter-
vention and were excluded. A total of 135 patients (50.4 %)
had a partial mastectomy and 133 patients (49.6 %) had
a total mastectomy as their definitive surgical treatment.
Survival was significantly better in patients undergoing
partial mastectomy (p = .004) (Fig. 4). A total of 81 patients
(61 %) undergoing TM had adjuvant radiation therapy.
DISCUSSION
To our knowledge, this is the first study to evaluate the
impact of interval to treatment on outcomes for patients
with TNBC. Previous data from our institution has shown
no association between interval to treatment for breast
cancer and survival, but did not include specific analysis of
survival based on more aggressive subtypes, such as
TNBC.7 When comparing TNBCs to other breast cancer
subtypes, these tumors have been shown to exhibit higher
nuclear grade and high proliferation rate—both of which
contribute to their biologic aggressiveness.12 In our study
population, 79 % of the tumors were high grade, and 96 %
exhibited high proliferation rates, with a mean ki67 of
69 %. Despite the aggressive nature associated with
TNBCs, short delay to treatment, defined as 45 days based
on national organizations standards, did not impact LRR or
survival in our study population.
Worse survival was demonstrated in the county hospital
when compared with the university hospital. Although the
interval to treatment was significantly longer at the county
hospital, worse survival in this population is best explained
by the characteristics of the patients in this group, not the
a bFIG. 2 a Evaluation of survival
according to interval of treatment
(45 days). b Evaluation of survival
according to interval of treatment
(90 days)
FIG. 3 Evaluation of LRR-free survival according to interval to
treatmentFIG. 4 Evaluation of survival according to surgical treatment
Triple Negative Breast Cancer Treatment Delay 1883
interval to treatment. The county hospital patients had
more advanced disease at presentation. Of the patients in
the county hospital group, 39 % presented with stage III or
IV disease compared with only 15 % of the patients in the
university hospital group. Furthermore, increased breast
cancer mortality is seen in African Americans because of
the increased prevalence of TNBCs in this ethnic group.26
Of the women in our study population, 50 % were African
American, and survival was noted to be worse in these
women compared with other ethnicities, likely due to a
significant proportion of these patients (36 %) presenting at
advanced stages.
Patients with TNBC are known to be at increased risk of
developing LRR compared with other breast cancer subtypes.
LRR was seen in 20 of our TNBC patients (7 %). Of our
patients, 50 % were treated with partial mastectomy, and
50 % were treated with total mastectomy. All but one patient
received chemotherapy, and 14 (70 %) received radiation.
LRR in TNBC occurs early, and the median time to recur-
rence was 15 months in our study population, with an
expected plateau in recurrence-free survival after 3 years.
Those patients with LRR have been shown to have a high risk
of subsequent events and death.27 A total of 18 patients with
LRR developed distant metastasis and 16 died. Interval to
treatment did not impact risk of LRR or time to recurrence.
With the known aggressive nature of TNBCs, it has
been questioned whether surgical treatment in these
patients should also be more aggressive. The data evalu-
ating effect of surgical treatment, partial mastectomy
versus total mastectomy, on outcomes in TNBC has thus
far has varied. Zaky et al. cautioned against the use of
breast conserving therapy (BCT) in patients with TNBC
because of increased rates of local and distant recurrence in
patients with TNBC after BCT.28 In contrast, Abdulkarim
et al.29 described an increased risk of LRR after modified
radical mastectomy in those patients not undergoing
radiotherapy compared with those patients undergoing
BCT, implying that radiation may be protective. Parker
et al.30 reported that BCT does not increase LRR rates in
TNBC patients and also saw an improved overall survival
in patients undergoing BCT. These results were echoed by
Adkins et al.31 from MD Anderson, who in addition found
no impact of radiation therapy on LRR in the mastectomy
group. Our data is consistent with these findings as the
incidence of LRR in our study population was not different
between the BCT and mastectomy groups, and overall
survival was significantly better in the BCT group
(p = .004), likely because 86 % of the tumors were T2 or
less in size.
Outcomes in cancer treatment, such as survival and
LRR, are important quality measures; however, because of
the long follow-up required to attain these outcomes, pro-
grams such as the American College of Surgeons
Commission on Cancer, the Mastery program of the ASBS,
NQMBC, and NAPBC evaluate process of care measures as
surrogates for outcomes.20 Time to treatment is one such
surrogate measure.32 It attempts to evaluate how centers
handle case volume, efficiency of the system, and the avail-
ability of resources. While each of these can contribute to a
delay in treatment, there is no definitive data to support that
this delay actually translates into worse outcome. While
Richards et al.3,7 reported a negative effect on overall survival
with delays of[12 weeks to treatment, a retrospective review
performed in 2010 at our institution showed that prolonged
interval to treatment did not translate into worse survival.
There are a number of limitations to this study. First and
foremost, it is a retrospective review and subject to the
inherent limitations of this type of study. A prospective study
evaluating effect of delay to treatment for breast cancer would
be unethical, especially in a patient population with a more
aggressive tumor type such as TNBC. Additionally, our
sample size may not be large enough to draw definitive con-
clusions regarding the impact of delays to treatment on
survival, especially for longer intervals to treatment. In the
group of patients with a delay of C90 days, there were only 24
patients, with 10 deaths. In the patients with a time to treat-
ment of\90 days, the death rate was 25 %, which means we
would need 91 patients with a delay of[90 days to detect a
20 % survival difference and 348 patients to detect a 10 %
survival difference (95 % CI). Furthermore, our median fol-
low-up was relatively short. While longer follow-up may
allow for demonstration in differences in overall survival, the
follow-up of our study was likely adequate to assess LRR- and
LRR-free survival as these tend to occur earlier in triple
negative breast cancer. Lastly, the tumor registry data
regarding survival is not disease specific, although most
deaths in this series were known to be due to disease.
In conclusion, a short (\45-day) delay from diagnosis to
treatment for triple negative breast cancer does not impact
overall survival or risk of LRR. While centers should strive
to initiate therapy as promptly as possible, it is safe to take
appropriate time to perform necessary evaluations such as
genetic testing, imaging, or additional consultation in order
to guide optimal treatment in patients with this more
aggressive subtype of breast cancer.
ACKNOWLEDGMENT The authors wish to thank the David M.
Crowley Foundation for their support of this research.
DISCLOSURES No financial disclosures.
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