Clinical Study
Oncology
DOI: 10.1159/000504964
Does the Timing of Surgery after
Neoadjuvant Therapy in Breast Cancer
Patients Affect the Outcome?
Kausar Suleman a Osama Almalik a Emaan Haque b Ali Mushtaq b
Ahmed Badran a, c Adher Alsayed a Dahish Ajarim a Taher Al-Tweigeri a
Noha Jastaniyah a Tusneem Elhassan a Wafa Alkhayal a
aOncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Kingdom of Saudi Arabia;
bAlfaisal
University, Riyadh, Kingdom of Saudi Arabia; cDepartment of Clinical Oncology, Faculty of Medicine,
Ain Shams University, Cairo, Egypt
Keywords
Timing of surgery · Neoadjuvant chemotherapy · Breast
cancer · Survival implications of time to surgical treatment
Abstract
Background: There is a paucity of literature examining the
impact of timing of surgery after neoadjuvant chemothera-
py. Objective: This study aimed to analyze the impact of the
time taken to initiate surgical treatment following comple-
tion of neoadjuvant chemotherapy on patients’ outcomes
by evaluating their pathological response, overall survival
(OS), and disease-free survival (DFS). Methods: This is a ret-
rospective review of 611 patients diagnosed with stage II
and III breast cancer that received neoadjuvant chemother-
apy and surgery between January 2004 and December 2014.
The data was collected from a prospectively gathered regis-
try. The patients were stratified into three cohorts according
to the time of surgery after neoadjuvant chemotherapy: <4
weeks, 4–7 weeks, or ≥8 weeks. Outcomes were assessed us-
ing Kaplan-Meier curves, and the variables were compared
using log-rank statistics. Results: The 5-year OS rate was
89.6% and the 5-year DFS rate was 74%. OS and DFS were not
significantly different when stratified according to timing of
© 2020 S. Karger AG, Basel
E-Mail karger@karger.com
www.karger.com/ocl
Received: November 1, 2019
Accepted: November 7, 2019
Published online: January 9, 2020
surgery; however, the trends of OS and DFS were poor when
surgery was delayed for ≥8 weeks. Median OS and median
DFS have not yet been reached. Of the 17% of patients that
had surgery after ≥8 weeks, 12.9% had pathological com-
plete response (pCR), while among those that received sur-
gery 4–7 weeks and <4 weeks after neoadjuvant chemother-
apy, 26% and 21% had pCR, respectively (p = 0.02). ER+/HER-
2+ patients had a statistically significant decrease in pCR if
surgery was performed after ≥8 weeks. Conclusion: Our pa-
tients showed improved pCR if surgery was performed with-
in 8 weeks, especially for ER+/HER-2+ patients. All patients
had better OS and DFS trends if surgery was performed be-
tween 4 and 7 weeks after neoadjuvant chemotherapy.
© 2020 S. Karger AG, Basel
Introduction
Surgical resection is regarded as one of the main treat-
ment options in treating breast cancer [1]. The optimal
time of surgical intervention in breast cancer varies de-
pending on whether surgery is the initial treatment after
diagnosis or it follows neoadjuvant chemotherapy.
193.51.85.197 - 1/10/2020 10:16:02 AM
Prof. Kausar Suleman
Oncology Center, King Faisal Specialist Hospital and Research Center
Zahrawi St, Al Maather
Riyadh 12713 (Kingdom of Saudi Arabia)
Université de Paris
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E-Mail ksuleman @ kfshrc.edu.sa
 A review of the literature on the timing of treatment
after diagnosis found that delays have an impact on dis-
ease-free survival (DFS), disease-specific survival, and
overall survival (OS) [2]. The review concluded that the
optimal time from diagnosis to surgery should be <90
days, while the optimal time for initiating chemotherapy
after the time of diagnosis ought to be <120 days [2].
Neoadjuvant chemotherapy has become an option for
locally advanced breast cancer as a means of downstaging
the tumor to allow for breast conservation, or in assessing
the efficacy of systemic therapy by the tumor response
[3]. It was further seen that patients with triple-negative
breast cancer (TNBC) who received neoadjuvant chemo-
therapy had higher rates of pathological complete re-
sponse (pCR), and had excellent survival rates when com-
pared to those of non-TNBC patients [4].
Furthermore, a pooled analysis of 7 randomized trials
of patients receiving neoadjuvant chemotherapy that
looked at long-term outcomes of 6,377 patients found
that pCR, defined as no residual invasive or in situ disease
in both the breast and the axilla, was seen to have a posi-
tive prognostic impact on survival in patients with lumi-
nal B/Her2–, Her2+, or triple-negative disease [5]. This
highlights the importance of the biology of the disease
and pCR for the outcome of breast cancer.
Several studies were done assessing the impact of initiat-
ing adjuvant chemotherapy after surgery, and they showed
that delays affected survival outcomes [6, 7]. A retrospective
review that looked at 2,594 patients found that relapse-free
survival and OS of patients were worse if chemotherapy was
started >12 weeks after definitive surgery [8]. A meta-anal-
ysis and systematic review found that a 31- to 60-day delay
of starting adjuvant chemotherapy after surgery led to
worse OS among TNBC patients, but had no effect in the
case of hormone receptor-positive breast cancer [9].
While there are many studies analyzing the impact of
a delay in starting adjuvant chemotherapy, there is a pau-
city of literature examining the impact of timing of sur-
gery after neoadjuvant chemotherapy. A recent retro-
spective study that analyzed data on 1,101 patients found
that patients who underwent surgery after 8 weeks had
worse outcomes [10]. Another retrospective review of
319 patients found that if surgery was performed 21 days
after neoadjuvant chemotherapy, then the patients had
worse OS and relapse-free survival [11].
In this context, the aim of this study was to retrospec-
tively analyze the impact of the timing of surgery after
neoadjuvant chemotherapy on outcomes such as DFS
and OS, and to assess whether a certain subset of patients
would benefit from earlier surgery.
2 Oncology
DOI: 10.1159/000504964
Subjects and Methods
This is a retrospective review of data collected from a prospec-
tively gathered registry at King Faisal Specialist Hospital on breast
cancer patients treated between January 2004 to December 2014.
Patients included were female breast cancer patients diagnosed
with stage II and III, locally advanced breast cancer over the age of
18 years who had been initially treated with neoadjuvant chemo-
therapy. The neoadjuvant chemotherapy treatment regimen was
FEC (5-FU, epirubicin, and cyclophosphamide) and Taxotere ±
Herceptin (depending on the HER-2 status of the disease). Patients
were excluded from the study if they had undergone adjuvant che-
motherapy, had stage IV disease, or had undergone surgical exci-
sion of the primary tumor at an outside institution. A total of 611
patients were included in the analysis.
Breast cancer patient’s medical records were reviewed, and data
were collected according to a predesigned data sheet. The clinical
data included patient age, clinical stage, neoadjuvant chemothera-
py regimen, and the surgical procedure performed on the patient.
The histopathological data included histological type, grade, lymph
node status, hormonal status, pathological nodal stage, and patient
survival data.
The patients were stratified into three cohorts. The first cohort
(A) comprised patients who received surgery following neoadjuvant
chemotherapy within ≤4 weeks, the second cohort (B) received it
within 4–7 weeks, and the third cohort (C) after ≥8 weeks. The sig-
nificance of the timing of surgery was evaluated on the basis of path-
ological response, OS, and DFS. Furthermore, we differentiated
pathological response and outcome depending on the receptor sta-
tus: ER+/HER-2–, ER–/HER-2–, ER+/HER-2+, and ER–/HER-2+.
OS was defined as the time from administration of treatment to
the death of the patient (or loss to follow-up). DFS was defined as
the time from diagnosis to the development of metastatic disease
assessed via radiological intervention. pCR was defined as no re-
sidual invasive or in situ disease in both the breast and the axilla.
OS and DFS were evaluated using Kaplan-Meier curves, and the
variables were compared using log-rank statistics. The time from
the last dose of neoadjuvant therapy to the time of surgery was re-
corded in weeks. Variables were selected based on statistical and
clinical significance, and this included the hormone receptor status
and pCR. All p values were two-tailed and considered statistically
significant at <0.05. Statistical analysis was performed using SPSS
version 20.
Results
A total of 611 patients were identified; of these, 94 pa-
tients (15.4%) had had surgery within the first 4 weeks,
424 patients (69.4%) within 4–7 weeks, and 93 patients
(15.2%) after ≥8 weeks. Within the time period of this
study, 93 patients died from any cause.
The patient and tumor characteristics are summarized
in Table  1. The median age at diagnosis was 44 years
(range, 23–83). Most patients (99.7%) had invasive ductal
carcinoma. Of the 611 patients in the study, 261 (42.7%)
were ER+/HER-2–, 108 patients (17.7%) were ER–/HER-
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Suleman et al.
Université de Paris
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Table 1. Patient, clinical, and treatment characteristics at baseline stratified by time to surgery after neoadjuvant chemotherapy

All patients <4 weeks 4–7 weeks ≥8 weeks p value

(N = 611) (n = 94) (n = 434) (n = 93)
n % n % n % n %

Age
<40 years 219 35.8 30 31.9 156 36.8 33 35.5 0.219
40–50 years 238 39.0 36 38.3 158 37.3 44 47.3
>50 years 154 25.2 28 29.8 110 25.9 16 17.2
Clinical tumor stage
T1 6 1.0 1 1.1 3 0.7 2 2.2 0.590
T2 155 25.4 21 22.3 111 26.2 23 24.7
T3 220 36.0 37 39.4 156 36.8 27 29.0
T4 227 37.2 35 37.2 151 35.6 41 44.1
Tx 3 0.5 0 0.0 3 0.7 0 0.0
Clinical stage
IIA 30 4.9 6 6.4 20 4.7 4 4.3 0.822
IIB 141 23.1 19 20.2 101 23.8 21 22.6
IIIA 191 31.3 30 31.9 137 32.3 24 25.8
IIIB 245 40.1 38 40.4 163 38.4 44 47.3
Unstageable 4 0.7 1 1.1 3 0.7 0 0.0
Histopathological grade
G1 7 1.1 3 3.2 4 0.9 0 0.0 0.321
G2 293 48.0 49 52.1 199 46.9 45 48.4
G3 286 46.8 40 42.6 201 47.4 45 48.4
Gx 25 4.1 2 2.1 20 4.7 3 3.2
Hormone receptor status
ER+/PR+ 294 48.1 37 39.4 215 50.7 42 45.2 0.304
ER+/PR– 78 12.8 11 11.7 51 12.0 16 17.2
ER–/PR+ 7 1.1 2 2.1 4 0.9 1 1.1
ER–/PR– 232 38.0 44 46.8 154 36.3 34 36.6
HER2– 392 64.2 55 58.5 280 66 57 61.3 0.319
HER2+ 219 35.8 39 41.5 144 34.0 36 38.7
ER+/HER2– 261 42.7 33 35.1 189 44.6 39 41.9 0.355
ER–/HER2+ 108 17.7 24 25.5 67 15.8 17 18.3
ER+/HER2+ 111 18.2 15 16.0 77 18.2 19 20.4
ER–/HER2– 131 21.4 22 23.4 91 21.5 18 19.4
Type of treatment received
Anthracyclines 392 64.2 55 58.5 280 66.0 57 61.3 0.319
Anthracyclines + trastuzumab 219 35.8 39 41.5 144 34.0 36 38.7

2+, 111 patients (18.2%) were ER+/HER-2+, and 131
(21.4%) were ER–/HER-2–.
The median time to surgery from diagnosis was 27
weeks, and the median time to surgery following comple-
tion of neoadjuvant chemotherapy was 5 weeks.
Among all patients, the OS rate at 5 years was 89.6%
(Fig. 1a) and the DFS rate at 5 years was 74% (Fig. 1c).
Median OS and median DFS have not yet been reached;
OS and DFS were not significantly different when strati-
fied according to the time of surgery; however, the trends
of DFS and OS were poor when surgery was delayed for
≥8 weeks. The median duration of follow-up was 62
months, with a range of 40–92 months. The 5-year OS
rate was estimated to be 88.8%, 85.9%, and 70% among
the patients who had surgery within the first 4 weeks,
within 4–7 weeks, and after ≥8 weeks, respectively. How-
ever, the difference between rates was not statistically sig-
nificant. Figure 1b and d indicates the Kaplan-Meier es-
timates of OS and DFS for the three different groups.
Only 12.9% of the patients who received surgery after
≥8 weeks had pCR; this is in comparison to a pCR of 26%
among the patients who received surgery within 4–7
weeks after completion of neoadjuvant chemotherapy
(p = 0.02) (Table 2).
193.51.85.197 - 1/10/2020 10:16:02 AM

Timing of Surgery in Breast Cancer Oncology 3

Patients DOI: 10.1159/000504964
Université de Paris
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 Color version available online
Cumulative overall survival probability Cumulative disease-free survival probability

1.0 1.0

0.8 0.8
Cumulative survival

Cumulative survival
OS = 89.6%
0.6 0.6
DFS = 74%

0.4 0.4

0.2 0.2

0 0

0 50 100 150 200 0 50 100 150 200

a Time, months c Time, months

Cumulative overall survival probability Cumulative disease-free survival probability

1.0 1.0 <4 weeks
<4 weeks
4–7 weeks 4–7 weeks
≥8 weeks ≥8 weeks

0.8 0.8
Cumulative survival

Cumulative survival

0.6 0.6

0.4 0.4

0.2 0.2

p value = 0.5 p value = 0.3

0 0

0 50 100 150 200 0 50 100 150 200

b Time, months d Time, months

Fig. 1. Kaplan-Meier curves comparing cumulative overall survival in all three cohorts (a) and in the subgroups
(b), as well as disease-free survival in all three cohorts (c) and in the subgroups (d).

In terms of receptor status, a Pearson χ2 test performed Discussion

for ER+/HER-2+ patients was found to be statistically sig-
nificant for this subgroup of patients. They had a de-
creased pCR if surgery was performed ≥8 weeks after neo-
adjuvant chemotherapy (Table  3). However, the ER+/
HER-2–, ER–/HER-2+, and ER–/HER-2– patients had
no statistically significant difference in pCR.
Timing of adjuvant chemotherapy has been shown
to affect outcome in breast cancer patients, and a clear
window of time has been defined. However, the win-
dow of time for surgery after neoadjuvant chemothera-
py still remains to be defined. In our review, we found
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4 Oncology Suleman et al.

DOI: 10.1159/000504964
Université de Paris
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Table 2. pCR among patients who received surgery <4 weeks, 4–7
weeks, and ≥8 weeks following neoadjuvant chemotherapy
Patients <4 weeks 4–7 weeks ≥8 weeks p value
No pCR 74 (78.7%) 313 (73.8%) 81 (87.1%) 0.020
pCR 20 (21.3%) 111 (26.2%) 12 (12.9%)
Total 94 (100%) 424 (100%) 93 (100%)
pCR, pathological complete response.
that all patients had better OS and DFS trends if surgery
was performed between 4 and 7 weeks after neoadju-
vant chemotherapy. It was also seen that the pCR rates
were higher if surgery was performed within 8 weeks,
especially for ER+/HER-2+ patients.
Several factors determine scheduling for surgery;
this could be related to the time needed to recover from
the toxicity of the systemic therapy to withstand sur-
gery, patient comorbidities, and coordination with re-
constructive surgeons. All these factors may cause pa-
tients to experience anxiety and to consider this wait
time a delay in their treatment plan. However, these
wait times may be necessary and may not impact the
patients’ outcome in the setting after neoadjuvant che-
motherapy.
In a SEER review of 95,544 patients that analyzed the
time from diagnosis to breast cancer surgery before sys-
temic therapy, Bleicher et al. [12] demonstrated that a
delay of over 60 days led to lower OS among patients
with stage I and II disease but not among those with
stage III disease. However, a possible reason for the dif-
ference in findings in stage III patients could be that
these patients tend to receive neoadjuvant rather than
adjuvant chemotherapy as the first modality of treat-
ment, hence explaining the findings seen in this article.
This suggests that the timing of starting definitive treat-
ment – whether surgery or systemic therapy – impacts
survival.
The median time to surgery following completion of
neoadjuvant chemotherapy was 5 weeks in our cohort.
This is similar to what was found in a review of the im-
pact of surgery time after neoadjuvant chemotherapy on
survival that was conducted by Sanford et al. [10]; the
majority of their cohort had had surgery between 4 and
6 weeks after neoadjuvant chemotherapy. Furthermore,
in their multivariate analysis, they found equivalent OS,
locoregional recurrence-free survival, and relapse-free
Timing of Surgery in Breast Cancer
Patients
Table 3. pCR in relation to ER+/HER-2+ biological subtype pa-
tients who received surgery <4 weeks, 4–7 weeks, and ≥8 weeks
following neoadjuvant chemotherapy
Patients <8 weeks ≥8 weeks p value
No pCR 61 (66.3%) 17 (89.5%) 0.044
pCR 31 (33.7%) 2 (10.5%)
Total 92 (100%) 19 (100%)
pCR, pathological complete response.
survival rates between patients with surgery <4 weeks,
4–6 weeks, and >6 weeks after neoadjuvant chemothera-
py [10].
In contrast, another study that looked at the impact of
surgery after neoadjuvant chemotherapy among 319 pa-
tients divided the patients into two groups: 61 patients in
group A who received surgery within 21 days, and 258
patients in group B that had surgery after 21 days, with
the majority of the patients having surgery within 5 weeks
[11]. It was seen that OS (hazard ratio = 3.1, 95% CI 1.1–
8.6, p = 0.03) and relapse-free survival (hazard ratio = 3.1,
95% CI 1.3–7.1, p = 0.008) was significantly lower among
the patients who received surgery after 21 days (group B)
than among those in group A [11]. One of the limitations
of that study, however, is the division of the cohort, with
81% being in group B [11].
In our analysis, all patients showed a better pCR rate,
as well as improved OS and DFS trends, if surgery was
performed before 8 weeks, especially for ER+/HER-2+ pa-
tients, with pCR indirectly translating into improved OS
in some subtypes of breast cancer. Delaying surgery for >8
weeks showed a lower pCR, as was demonstrated not only
in our study but also in the MD Anderson Cancer Center
review of the impact of time of surgery after neoadjuvant
chemotherapy [10]. A study done by Wagner et al. [13]
that looked at the effect of time to primary surgery follow-
ing breast cancer diagnosis showed that delays in surgery
were not associated with tumor size progression.
However, a recent study analyzing the impact of time
to starting adjuvant chemotherapy after surgery found
that delaying the start of adjuvant chemotherapy by >120
days after diagnosis was associated with worse OS (hazard
ratio = 1.29, p < 0.001) [14].
Furthermore, a clinical feasibility study was done eval-
uating omitting surgery for patients with pCR for neoad-
juvant chemotherapy [15]. That study has led to a clinical
trial that is enrolling patients with triple-negative disease
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Oncology 5
DOI: 10.1159/000504964
Université de Paris
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and her2/neu+ disease who receive neoadjuvant chemo-
therapy and attained complete radiological and biopsy-
proven pathological response to omit surgery [15].
While the timing of surgery for breast cancer from the
time of diagnosis until definitive surgery is important,
multiple studies have shown that the time of starting (ei-
ther adjuvant or neoadjuvant) chemotherapy from diag-
nosis affects OS. This suggests that the biology of breast
cancer is important and that the timing of starting sys-
temic therapy is more relevant to survival than the timing
of surgery, in the neoadjuvant setting.
gery was performed before 8 weeks, especially for ER+/
HER-2+ patients.
Statement of Ethics
The study was carried out in compliance with the principles
laid down in the Declaration of Helsinki. The study was initiated
only after all required legal documentation was reviewed and ap-
proved by the respective institutional review board/independent
ethics committee and competent authority according to national
and international regulations.

Limitations Disclosure Statement

This study is retrospective in nature and was conducted
at a single large tertiary care center. The patients’ initial dis- The authors have no conflict of interest nor funding to declare
related to this study.
ease status could have been the reason for the response ob-
served, and not necessarily the timing of surgery. Finally,
our study did not take into consideration the new chemo- Funding Sources
therapy protocols, which include dose-dense and weekly
chemotherapy where recovery of the bone marrow is faster. The authors received no funding for this study.

Conclusion
All patients had better OS and DFS trends if surgery
was performed between 4 and 7 weeks after neoadjuvant
chemotherapy. Higher pCR rates were observed if sur-
Author Contributions
The authors are fully responsible for all content and editorial
decisions, were involved in all stages of manuscript development,
and have approved the final version of the paper.

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