Clinical Imaging 71 (2021) 24–28

Contents lists available at ScienceDirect

Clinical Imaging
journal homepage: www.elsevier.com/locate/clinimag

Breast Imaging

Timing to imaging and surgery after neoadjuvant therapy for breast cancer
Ahuva Grubstein a, *, Yael Rapson a, Salomon M. Stemmer b, Tanir Allweis c, Meirav Wolff-Bar d,
Sara Borshtein a, Sivan Eden a, Shlomit Tamir a, Eli Atar a, Eran Sharon e, Tzippy Shochat f,
Rinat Yerushalmi b
a
Radiology Department, Rabin Medical Center, Beilinson, Petah Tikva affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
b
Oncology Department, Rabin Medical Center, Beilinson, Petah Tikva affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
c
Surgery Department, Kaplan Medical Center, Rehovot affiliated to Hadassah Medical School, the Hebrew University, Jerusalem, Israel
d
Pathology Department, Rabin Medical Center, Beilinson, Petah Tikva affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
e
Surgery Department, Rabin Medical Center, Beilinson, Petah Tikva affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
f
Statistical Department, Rabin Medical Center, Beilinson, Petah Tikva affiliated with the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

A R T I C L E I N F O A B S T R A C T

Keywords: Neoadjuvant therapy (NAT) is increasingly used in breast cancer (BC), yet, the recommended time interval
Breast cancer between NAT completion, preoperative imaging assessment, and breast surgery is not clearly defined. This
Breast MRI single-center retrospective study investigated tumor growth between NAT completion and surgery. The analysis
Neoadjuvant therapy
included 106 BC patients who received NAT (69% chemotherapy alone, 31% chemotherapy plus anti-HER2
Pathologic report
Surgery
therapy), had post-NAT breast MRI, and definitive surgery between 2012 and 2019. The median time interval
Tumor size between end-of-treatment and surgery was 6 weeks; 90% had surgery within 8 weeks of NAT completion, and
10% had surgery 8–12 weeks after NAT completion. No significant correlation was found between any of the
time intervals (i.e., NAT completion-to-surgery, NAT completion-to-MRI, post-NAT MRI to surgery) and the
tumor size as captured in the pathology report. The only parameter that was significantly correlated with
pathological tumor size was tumor size as measured on the post NAT MRI (P < .0001). The difference in tumor
size between post NAT MRI and surgical pathology did not correlate with the time interval between end-of-
treatment and surgery. The ratio between residual tumor size on post-NAT MRI and the time interval from
the end-of-treatment to surgery, significantly correlated with the tumor size on surgical pathology (P < .0001)
suggesting that NAT has a beneficial effect weeks after end-of-treatment. In conclusion, our results suggest that
for patients undergoing neoadjuvant chemotherapy, surgery within 4–8 weeks of completing NAT is reasonable,
and is unlikely to result in a clinically significant change in residual tumor size.

1. Introduction
Neoadjuvant therapy (NAT) has become an increasingly common
strategy for breast cancer patients. NAT has been shown to decrease
tumor size, enabling a smaller volume of resection and facilitating breast
conservation, with survival rates comparable to those of adjuvant
therapy [1]. In addition, NAT enables direct observation of therapeutic
efficacy, and tumor response to NAT provides prognostic information
[2,3]. Surgery is planned based both on the extent of the disease at
diagnosis, as well as the extent of residual disease after NAT [4,5]. Breast
magnetic resonance imaging (MRI) is the most accurate imaging mo­
dality for the assessment of response and the evaluation of residual
disease [6]. The optimal timing of MRI after completion of NAT, and the
acceptable time interval from NAT completion to the definitive surgery
have not been clearly defined and are still being debated [4,5]. Breast
cancer subtypes, different NAT protocols, and different rates of
response, all contribute to the uncertainty.
The purpose of the current study was to investigate tumor growth in
the interval between NAT completion and surgery by comparing tumor
size as determined by imaging post-NAT to tumor size as captured in the
surgical pathology report.

* Corresponding author at: Radiology Department, Rabin Medical Center, Beilinson, Petah Tikva, Israel affiliated with the Sackler School of Medicine, Tel Aviv
University, Tel Aviv, Israel.
E-mail address: ahuvag@clalit.org.il (A. Grubstein).

https://doi.org/10.1016/j.clinimag.2020.10.043
Received 27 July 2020; Received in revised form 8 October 2020; Accepted 26 October 2020
Available online 5 November 2020
0899-7071/© 2020 Elsevier Inc. All rights reserved.
A. Grubstein et al. Clinical Imaging 71 (2021) 24–28

Fig. 1. Post contrast dynamic T1W and subtraction axial images, measurement of the largest residual focus (white arrowhead).

Fig. 2. Two examples of inadequate tumor size measurements.

A. Pre NAT (a) and post NAT (b) breast MRI, demonstrating complete resolution of the pathological enhancement. In the pathology analysis (c), residual invasive
carcinoma cells are seen in small groups within the thin fibrous tissue, mostly surrounding intact normal duct, showing a characteristic retraction artifact, mimicking
vascular invasion. H&E stain at X40 and X200 original magnification. B. Pre and post NAT MRI (a, b) demonstrating vague residual enhancement, pathology analysis
(c,d) showing residual invasive lobular carcinoma. Single cells scattered across the tumor bed, with scant fibrous background, some dispersed within the adipose
tissue. On the left of the photomicroscopy, residual in situ component is also noted. H&E stain at X40 original magnification The residual tumor cells are highlighted
by the cytokeratin stain. CK-MNF-116 stain at X40 original magnification.

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A. Grubstein et al. Clinical Imaging 71 (2021) 24–28

Table 1 2.2. MRI technique

Patient demographics and tumor/treatment characteristics.
All Patients treated with Patients treated Breast MRI was carried out with a 3T or 1.5T machine (3T Ingenia
patients chemotherapy and with and 1.5T Achieva, Philips Medical Systems, Best, Netherlands), using a
N = 106 anti-HER2 therapy chemotherapy bilateral, 16-channel breast coil (Mammotrak, Philips Medical Systems)
n = 33 n = 73
[7].
Mean (SD) age, years 52 (12) 51 (12) 52 (13)
Tumor Histology, n 2.3. Image interpretation
(%) 105 32 (97%), 73 (100%)
IDC (99%) 1 (3%)
ILC 1(1%) Residual disease was retrospectively assessed on the post-NAT MRI
Tumor subtype, n (%) scans by 2 breast radiologists (A.G and Y.R). Radiologic interpretation of
HER2-enriched 13 13 (39%) 0 (0%) MRI images included assessment of lesion size, shape, extent, and dis­
ER+ PR+ HER2- (12%) 20 (61%) 33 (45%)
tribution. Readings were blinded to the surgical pathology at first, and a
negative 53 0 (0%) 40 (55%)
Triple negative (50%) second reading was performed comparing the pathology report to each
40 MRI reading. The longest diameter (-LD) of the dominant enhancing
(38%) focus or mass was measured on the post contrast dynamic T1W and
Mean (SD) tumor size 40.1 (2) 44 (23) 40 (20) subtraction images (Fig. 1). In cases of multiple foci and masses, the
at baseline MRI, mm
Mean (SD) tumor size 10 (14) 5 (8) 11 (15)
largest focus or mass was measured on the MRI, and compared to the
on post treatment largest tumor on pathology.
MRI, mm Cases where tumor size measurement was inadequate (i.e. vague,
Mean (SD) tumor size 8 (13) 2 (6) 8 (14) non-measurable, non-mass like enhancement on the MRI, and isolated
on pathology
tumor cells within the tumor bed on the pathology report) were
specimen, mm
Mean (SD) difference 2.2 (8) 2 (5) 3 (7) excluded from the correlations calculations (Fig. 2).
in size between the
MRI and the 2.4. Statistical analysis
pathology report,
mm
Median (range) 38 38 (2–85) 38 (0–76)
Continuous variables were presented as median (range). Categorical
duration from end- (0–76) variables were presented as N (%). Pearson correlation coefficient and
of-treatment to regression analysis were used to examine the association between
surgery, days ordinal variables and ordinal or continuous variables. All analyses were
Median (range) 7 (0–63) 6 (0–50) 8 (0–63)
performed using SAS (version 9.0, SAS Institute, Cary, NC). P < .05 was
duration from end-
of-treatment to MRI, considered statistically significant.
days
Median (range) 35 40 (2− 110) 31 (2–121) 3. Results
duration from post- (2− 121)
treatment MRI to
surgery, days
Of 125 patients treated with NAT over the abovementioned time
period, 19 (15%) received neoadjuvant hormonal therapy and were
ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; IDC, excluded from the analysis;106 (85%) received chemotherapy or
invasive ductal carcinoma; ILC, invasive lobular carcinoma; MRI, magnetic
chemotherapy plus biological therapy and are included in the current
resonance imaging; PR, progesterone receptor.
analysis. Patient demographics and tumor characteristics are presented
in Table 1. Overall, 73 patients (69%) received neoadjuvant chemo­
2. Methods therapy, and 33 patients (31%) also received anti-HER2 therapy. The
size measurements in the post-NAT MRI (blinded to the pathology) were
2.1. Study design and patient population strongly correlated between the 2 readers (r = 0.88, P < .0001). After
excluding 4 cases of tumor size measurement uncertainty (cases of vague
This was a single-center retrospective analysis that included all pa­ non-mass like enhancement on the MRI, and isolated tumor cells within
tients with breast cancer who received NAT and underwent post-NAT the tumor bed on the pathology report), the post NAT MRI tumor size
breast MRI and definitive surgery at our institution between 2012 and measurement was highly correlated to the tumor size as captured in the
2019. The diagnostic baseline MRI study, when available, was retrieved surgical pathology report (r = 0.94, P < .0001).
as well. Patient demographics, clinical and pathology report at diag­ Time intervals between NAT completion, MRI, and definitive surgery
nosis, and final surgical pathology results including tumor size, nodal are also presented in Table 1. The median time interval between end-of-
status, breast cancer subtype, tumor grade, proliferative index (Ki-67), treatment and surgery was 6 weeks. Longer intervals between end-of-
and NAT regiments were retrieved from the digital patient records. treatment and surgery were recorded more frequently for regimens
Patients with missing data were excluded. Patients who received neo­ containing anti-HER2 therapy. The vast majority of patients (90%) un­
adjuvant endocrine therapy were also excluded (because endocrine derwent surgery within 8 weeks of completing NAT, and the remaining
therapy is administered pre and post operatively, without a break 10% underwent surgery 8–12 weeks after completing their NAT. The
period). NAT regimens included in the analysis were categorized into longest time interval between end-of-treatment and surgery was 85
chemotherapy, and chemotherapy plus biological treatment (targeting days.
human epidermal growth factor receptor 2 [HER2]). Time from the end- The median time from the end of treatment to the post NAT MRI was
of-treatment to the date of post NAT MRI and the date of surgery was 7 days (6 days) for patients treated with chemotherapy and anti-HER2
measured in days. therapy, and 8 days for patients treated with chemotherapy, therefore
The study protocol was approved by Rabin Medical Center review was not suspected to affect the pathology results.No significant direct
board, which waived the need for informed consent due to the retro­ correlation was found between any of the time intervals (i.e., time from
spective nature of the study. NAT completion to surgery, from NAT completion to MRI and from the
post-NAT MRI to surgery) and the tumor size as captured in the pa­
thology report. The only parameter that was significantly correlated

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Table 2 similar with respect to recurrence and survival rates when the interval
Pearson’s correlation coefficient between time intervals, tumor characteristics, was <8 weeks, whereas beyond that, survival outcomes were compro­
and tumor size as captured in the pathology report. mised [9]. Similar results were reported by Ladd et al. [10] In contrast,
Parameter correlated to pathology tumor size Correlation P-value Lin and Anna found that longer time from end-of-treatment to surgery
coefficient resulted in a higher recurrence rate, but did not impact overall survival
Baseline MRI tumor size (longest diameter) 0.2 0.06 [11]. Notably, the question of a delayed surgery after NAT has also been
Preoperative MRI tumor size (longest 0.94 <0.0001 examined in other cancer types. For example, in rectal cancer even a
diameter) subtle interval of 2 weeks was evaluated, with no clear-cut results [12].
Time from preoperative MRI to surgery 0.2 0.016
Our results are consistent with those by Stanford et al., [9] and Ladd
Tumor size in preoperative MRI − 0.021 0.02
Time from end-of-treatment to preop MRI − 0.01 0.86 et al.,[10] as the vast majority of our patients were treated within 8
Time from end-of-treatment to surgery − 0.01 0.37 weeks of NAT completion. We defined the tumor size as measured on the
Ki 67 From the pathology report − 0.3 0.0054 post-NAT MRI, as a point-of-reference for the best estimated residual
tumor size [6,13–16]. As tumor response to NAT varies, a pathological
report of residual tumor bed measuring several centimeters could
with pathological tumor size was tumor size as measured on the post
represent isolated tumor cells. For standardization, and since our goal
NAT MRI (r = 0.94, P < .0001). The calculated difference in tumor size
was to find differences in size between post-NAT MRI and surgery, we
between post NAT MRI and surgical pathology did not correlate with the
based our measurement in the post-NAT MRI, on the longest diameter of
time interval between end-of-treatment and definitive surgery (Table 2).
the largest tumor focus corresponding to the largest tumor focus
Nonetheless, the ratio between residual tumor size on post-NAT MRI and
measured within the tumor bed, in the pathology report [16,17]. We
the time interval from the end-of-treatment to surgery, significantly
found that the MRI measurements and the tumor size as captured in the
correlated with the tumor size on surgical pathology (r = 0.82, P < .0001
pathology reports were well correlated, and that longer time intervals
for chemotherapy; r = 0.7, P < .0001 for chemotherapy with anti-HER2
between end-of-NAT and imaging or surgery did not impact tumor size
therapy) (Fig. 3).
significantly. Since most of our patients underwent definitive surgery
within 8 weeks of NAT completion, our results confirm those of prior
4. Discussion
reports, and lessen the concern that a longer interval to surgery (up to 8
weeks), would have a detrimental effect on tumor growth in the interval.
The recommended time interval between completion of NAT, pre­
Moreover, the positive correlation between tumor size on pathology and
operative imaging assessment, and breast surgery is not clearly defined
the ratio between the residual tumor seen in the MRI and the time in­
[4,5]. In the adjuvant setting (without NAT), Bleicher et al. reported that
terval to surgery pointing towards smaller residual tumor are either due
each 60-day interval from diagnosis to surgery is associated with lower
to smaller tumors initially, or longer time duration from the end of
overall and disease-specific survival (subdistribution hazard ratio [sHR]
treatment to surgery, suggests that the beneficial effect of NAT may
of 1.26; 95% confidence interval [CI], 1.02–1.54; P = .03) [8]. In the
resonate even weeks after the end-of-treatment.
neoadjuvant setting, it could be argued that the control of micro-
Our study is limited by its design (retrospective, single-center, rela­
metastatic disease by NAT may mitigate the significant impact of sur­
tively small sample size). Another major limitation is that no clinical
gical timing on survival. Stanford et al. compared 3 groups of patients
outcomes were collected. Tumor size difference was the only parameter
who received NAT (chemotherapy, n = 1442; chemotherapy plus anti-
correlated to, and was considered as a surrogate for tumor staging dif­
HER2 treatment, n = 7) according to the time interval between end-
ference based on prior previously published data [3]. Also, the
of-treatment and surgery: <4, 4–6, and >6 weeks. The 3 groups were

Fig. 3. Pearson’s correlation between the ratio of the tumor size as determined in the MRI post-NAT treatment (chemotherapy, red; chemotherapy plus anti-HER2
treatment, blue) and the tumor size as captured in the surgical pathology report. (For interpretation of the references to color in this figure legend, the reader is
referred to the web version of this article.)

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A. Grubstein et al.
variability in time from end-of-treatment to definitive surgery was
limited, as the majority of patients underwent surgery within 6 weeks,
and the rest underwent surgery within 6–8 weeks. It is possible that
longer time intervals would be associated with a significant difference in
tumor size between end-of-treatment and surgery. Nonetheless, our re­
sults provide reassurance that delaying surgery for up to 8 weeks is
probably not associated with tumor growth (survival parameters were
not evaluated in this study).
5. Conclusions
Our study results suggest that for patients undergoing neoadjuvant
chemotherapy, scheduling the surgery within 4–8 weeks of completing
NAT is reasonable, and is unlikely to result in a clinically significant
change in residual tumor size. Further research is warranted with a
larger sample size and assessment of survival outcomes.
Acknowledgments
Disclosures - all authors disclosed no relevant relationships.
Compliance with ethical standards
This study was not funded.
Ethical approval
This article does not contain any studies with human participants or
animals performed by any of the authors and is in accordance with the
ethical standards of the institutional and/or national research commit­
tee and with the 1964 Helsinki declaration and its later amendments or
comparable ethical standards.
Declaration of competing interest
All authors disclosed no relevant relationships, did not recived any
grant and has no conflict of interest.
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Clinical Imaging 71 (2021) 24–28
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