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\begin{document}

\title{``Unplanned breast-conserving surgery after systemic therapy in locally
advanced breast cancer: the results of level II oncoplastic techniques''}



\author[1]{mehmet gulcelik}%
\author[2]{Lütfi Doğan}%
\affil[1]{Universty of health sciences Gulhane medical school}%
\affil[2]{Dr Abdurrahman Yurtaslan Onkoloji Eğitim ve Araştırma Hastanesi}%


\vspace{-1em}



  
  \date{June 15, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
BACKGROUND: In patients with breast cancer for whom neoadjuvant
chemotherapy (NAC) is planned, it is recommended to mark the primary
tumor before treatment (planned surgery). However, surgeons may have to
perform breast-conserving surgery on patients whose tumors are not
marked (unplanned surgery). This study focused on the results obtained
with planned and unplanned level II oncoplastic surgery (OPS) techniques
applied to patients after NAC. METHODS: Patient groups who underwent
planned, unplanned OPS and mastectomy after NAC were compared. Surgical
margin status, re-operation and re-excision requirements, ipsilateral
breast tumor recurrence (IBTR) and axillary recurrence rates recorded.
Long-term local recurrence-free survival (LRFS), disease-free survival
and overall survival were evaluated. RESULTS: There was no significant
difference between the planned and unplanned OPS groups in terms of
surgical margin status, re-excision requirement, and mastectomy rates.
During an average follow-up period of 43 months, 5.3\% and 4\% of the
patients in the planned OPS group developed IBTR and axillary
recurrence, respectively, whereas these rates were 6.6\% and 5.3\% in
the unplanned OPS group. In the mastectomy group, the rates of IBTR and
axillary recurrence were found to be 4.1\% and 3.8\%, respectively.
There was no significant difference between the three groups in terms of
IBTR (p: 0.06) and axillary recurrence (p: 0.08) rates. CONCLUSION:
Breast conserving surgery can be applied using level II OPS techniques
with the post-NAC radiological examination and marking even if primary
tumor marking is not done in the pre-NAC period.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION:}

One of the goals of neoadjuvant therapy is to make the tumor
volume-to-breast ratio suitable for breast-conserving surgery (BCS) by
reducing the tumor size in patients with large tumors (1). Randomized
controlled trials have shown that neoadjuvant therapy increases the
rates of BCS and presented suggestions for performing BCS after
neoadjuvant chemotherapy (NAC) in patients who are not suitable
candidates for BCS at the time of presentation (2,3). The concepts of
marking both the primary tumor and the metastatic axillary lymph node in
the pre-NAC period, and targeted primary tumor and axillary surgery in
the post-NAC period have been developed (4). Concepts regarding surgical
margins in patients, who underwent breast surgery after NAC, have become
clearer over time, and concerns on this issue have decreased (5,6).
There is a consensus that with appropriate surgical intervention, local
control can be achieved without mastectomy after NAC (7,8). The main
point is to obtain adequate surgical margins with the accurate
localization of the tumor.

It is known that BCS was not planned in a group of patients before NAC,
therefore tumor marking was not performed, but BCS was thought after NAC
(unplanned BCS). It is not possible to perform BCS due to tumor
localization problems particularly in patients achieving good clinical
response. In some cases, pre-NAC tumor marking cannot be performed due
to technical issues. The literature review has shown that there are
studies presenting the results obtained from unplanned BCS after NAC.
Conventional BCS techniques were used in these studies. Furthermore,
they are relatively old studies, and therefore, neoadjuvant therapy
criteria for patients included in these studies are unclear (9,10).
Oncoplastic surgery (OPS) is known to ensure larger tissue excision
compared to the conventional BCS and provides the opportunity to obtain
wider surgical margins (11). It can be advantageous in unplanned BCS.
This study focused on the results obtained with planned and unplanned
level II OPS techniques applied to patients after NAC.

\textbf{MATERIALS and METHODS:}

This study examined a retrospective series of patients with breast
cancer who underwent surgical treatment after NAC between 2012 and 2017.
The planned OPS group consisted of patients who were scheduled to
undergo OPS before NAC between the specified dates. Tumors of patients
in the planned OPS group were marked with metallic clips before
neoadjuvant therapy. The unplanned OPS group consisted of patients who
underwent OPS after NAC although OPS was not scheduled. Therefore, tumor
marking was not performed in these patients. Patients undergoing
mastectomy after NAC constituted the mastectomy group. Anthracycline-
and taxane-based chemotherapies were applied to patients receiving NAC.
Patients with HER2-positive breast cancer received NAC with trastuzumab.
For local staging; mammography (MG), breast ultrasonography (USG),
axillary USG were performed as standard in the pre-NAC period. Magnetic
Resonance Imaging (MRI) was used in the pre and post NAC period in the
unplanned OPS group. Post-NAC clinical response was classified as
unresponsive, partial, and complete clinical response. Absence of
radiological and clinical signs of tumor in the breast and axilla was
considered a complete response. A reduction of more than 50\% compared
to pre-NAC was considered as a partial response whereas a reduction of
less than 50\% was considered a stable condition.

Patients with minimal edema or skin shrinkage around the tumor were
considered to have T4 breast cancer and they had the opportunity to
undergo OPS after NAC. Mastectomy was performed in patients who were
considered to be at the T4 stage due to diffuse edema, ulceration, peau
d'orange appearance, and chest wall invasion. The most common reasons
for mastectomy were patient's request, inadequate response to
chemotherapy, multicentricity, tumor-to-breast ratio mismatch, complete
radiological disappearance of the tumor, and no residual radiological
findings. Although OPS was not scheduled initially, it was possible to
be performed after NAC in patients with palpable tumors or radiological
(MG, MRI, or USG) residual disease (e.g. structural distortion or
microcalcification). Patients with radiological residual disease in the
unplanned OPS group were operated on after these areas were marked with
a wire. Tumors were labeled with titanium clips before the NAC was
initiated in the planned OPS group. Fine needle aspiration biopsy (FNAB)
was performed for radiologically suspicious axillary lymph nodes.
Surgical margins in patients in the unplanned OPS group were determined
considering the areas containing microcalcification and structural
distortion (residual radiological disease) surrounding the tumor, which
were identified through the local staging investigations performed
following NAC. If necessary, the areas to be resected were marked with a
wire before surgery. Radio-guided occult lesion localization (ROLL)
method was used for this purpose in some patients. After resection,
specimen radiographs were taken in all patients to determine whether
adequate resection was achieved. Routine frozen section examination was
not performed for surgical margins; however, when deemed necessary,
additional resections were made from the suspicious margins. Sentinel
lymph node biopsy (SLNB) was performed in patients without clinical
signs of metastasis in axillary lymph nodes before and/or after NAC. The
closest surgical margins were used to calculate the average length of
the surgical margins. No tumor on ink was considered a negative surgical
margin.

Level II OPS techniques were used for the planned and unplanned OPS
groups. Techniques were chosen according to tumor localization and
tumor-to-breast volume. Racquet and fusiform mammoplasty techniques were
used for tumors located in the upper outer quadrant. Radial
mammoplasties were preferred for inner quadrant tumors. Vertical
mammoplasty techniques were used for tumors located in the upper or
lower midline. Furthermore, reduction mammoplasty techniques with
superior or inferior flap (wise pattern) were applied to patients who
required reduction. Superior flap techniques were used for lower
quadrant tumors whereas inferior flap techniques were used for upper
quadrant tumors. Batwing and round block techniques were most commonly
used for tumors close to the areola. Patients undergoing OPS received
radiotherapy (RT) with 5 Gy + 1 Gy boost dose to the tumor bed. The RT
needs of patients who underwent mastectomy were also discussed in the
tumor board. Patients were invited for follow-ups at three-month
intervals for the first two years and at six-month intervals for the
next three years. After five years, the patients were followed at
one-year intervals. In addition to physical examinations, annual MG and
breast USG examinations were performed as standard. Breast MRI was
performed when needed.

Age, body mass index (BMI), menopause status, and tumor characteristics
(stage, grade, hormone receptor status, and CerbB2 status) of the
patients were recorded. Surgical margin status, re-operation and
re-excision requirements, axillary intervention results, ipsilateral
breast tumor recurrence (IBTR), and axillary recurrence rates were also
recorded. Long-term local recurrence-free survival (LRFS), disease-free
survival (DFS), and overall survival (OS) were evaluated. The IBTR
(invasive or in-situ) and regional recurrence were accepted as the
events that ended LRFS.

\textbf{STATISTICAL ANALYSIS:} :

Statistical analyses were performed using SPSS version 25 (SPSS Inc;
Chicago, IL, USA). Mann-Whitney U test was used for inter-group
comparisons. Qualitative data for each group were analyzed using the
Student's t-test. Chi-square test was used for quantitative data.
Kaplan-Meier analysis was used to determine recurrence rates, LRFS, and
OS. A p value of \textless{}0.05 was considered statistically
significant.

\textbf{RESULTS:}

There were 150 patients in the planned OPS group, 75 patients in the
unplanned OPS group, and 340 patients in the mastectomy group.
Thirty-eigth patients in the unplanned OPS group completed their NAC in
external centers, and no preoperative tumor marking was performed in
these patients. Although 32 patients did not accept BCS in the
pre-treatment period, they requested BCS after NAC. Tumor marking with a
titanium clip before neoadjuvant treatment could not be performed in
five patients due to technical reasons. When all three groups were
evaluated in terms of patient and tumor characteristics, the patients in
the mastectomy group were found to be significantly older and the number
of those in the postmenopausal period was higher. There was no
difference between the groups in terms of pre-NAC stage, grade, and
biological characteristics of the tumor. Patient and tumor
characteristics of the groups are summarized in Table 1.

In the planned OPS group, complete clinical response was observed in 40
(26\%) of the patients whereas 110 (74\%) achieved a partial response.
These numbers were 29.3\% and 70.7\% in the planned OPS group,
respectively. Twenty-six patients (7.6\%) in the mastectomy group were
considered to be stable after NAC. Complete clinical response was
achieved in 72 patients (21.2\%) whereas 242 (71.2\%) patients achieved
a partial response in the mastectomy group. Mastectomy was performed in
10 patients who were scheduled for OPS before NAC but achieved an
inadequate response. Pathologic complete response rate was 9.4\% in the
whole series.

In the planned OPS group, re-excision was required in 16 (10.6\%)
patients due to positive or close surgical margins. Eight (5.3\%)
patients were required re-operation and mastectomy. In the unplanned OPS
group, nine (12\%) and six (8\%) patients underwent re-excision and
mastectomy, respectively. The mean distance between the tumor and
closest surgical margin was 14\selectlanguage{ngerman}±0.6 mm in the planned OPS group and
18±0.4 mm in the unplanned OPS group. There was no significant
difference between the groups in terms of surgical margin status,
re-excision requirement, and mastectomy rates (Table 2).

Axillary dissection was performed in patients with positive SLNB and
patients with clinical suspicious lymph nodes after neoadjuvant therapy.
While axillary dissection was performed in 110 (74\%) patients in the
planned OPS group, 77\% of the patients in the unplanned OPS group
underwent axillary dissection whereas SLNB alone was performed in 13\%.
In the mastectomy group, 79\% of patients underwent axillary dissection.
There was no significant difference between the groups.

During an average follow-up period of 43 months, 5.3\% and 4\% of the
patients in the planned OPS group developed IBTR and axillary
recurrence, respectively, whereas these rates were 6.6\% and 5.3\% in
the unplanned OPS group, respectively. In the mastectomy group, the
rates of IBTR and axillary recurrence were found to be 4.1\% and 3.8\%,
respectively. There was no significant difference between the three
groups in terms of IBTR (p: 0.06) and axillary recurrence (p: 0.08)
rates. The rate of patients developing distant metastasis during the
follow-up period was 26\%, 29.3\%, and 25.2\% in the planned, unplanned
OPS, and mastectomy groups, respectively (p: 0.2) (Table 2). The mean
five-year LRFS was 90.1\% in the planned OPS group whereas it was 91.2\%
in the unplanned OPS group and 93\% in the mastectomy group. There was
no significant difference between the groups in terms of LRFS (p: 0.6)
(Figure 1). Five-year OS was found to be 92\% in the planned OPS group,
90.3\% in the unplanned OPS group, and 89.8\% in the mastectomy group.
There was no significant difference between the groups in terms of OS
(p: 0.9).

\textbf{DISCUSSION:}

The excision volume required to safely perform BCS can be reduced by
neoadjuvant therapy (12). Regardless of the administration of
neoadjuvant therapy, poor cosmetic outcomes are obtained in cases where
large excisions are required to perform BCS (13). Furthermore, surgical
margin positivity and re-excision rates are quite high after BCS (14).
Oncoplastic surgery allows larger volume excision without impairing
cosmetic outcomes and reduces re-excision rates (15). Primary tumor size
decreases after neoadjuvant therapy. In such cases, the success of the
treatment in terms of local control depends on the accurate tumor
localization. It is aimed to excise the accurate area at sufficient
volume after NAC by marking the tumor in the pre-NAC period, determining
localization by means of seeds containing radioactive material, and
applying intraoperative USG. However, pre-NAC marking cannot adequately
guide the clinician for tumors showing non-concentric shrinkage
patterns. Intraoperative localization techniques may remain inadequate
in this regard (16,17). In tumors that shrink into fragments, the
residual radiological disease should be evaluated and, if necessary,
marked after NAC. At this point, the question of whether unplanned
surgery can provide safe oncological results should arise. The answer to
this question has been investigated in patients who primarily underwent
BCS. In the National Surgical Adjuvant Breast and Bowel Project (NSABP)
Protocol B-18 trial, the local recurrence rate was reported to be 15.9\%
in unplanned surgery and 9.3\% in planned surgery. The difference was
statistically significant (2). The European Organization for Research
and Treatment of Cancer (EORTC) 10920 trial reported higher local
recurrence rates with unplanned surgery (3). In a study by Shin et al.
(10) involving patients with stage III breast cancer, the results of
planned BCS, unplanned BCS, and mastectomy were compared in patients
with a tumor size of less than 4 cm after NAC. The authors reported that
five-year LRFS was 90.9\% in patients undergoing unplanned surgery,
while this rate was 96.3\% in patients undergoing mastectomy (10). In
the series published by Fitzal et al. (9), BCS was performed in 110 of
221 patients scheduled for mastectomy before NAC. While unplanned
surgery was observed to have no disadvantage in terms of local control
in patients with a good response to NAC, local recurrence rates were
found to be higher in the unplanned surgery arm in patients with an
insufficient response. The technique used in all these studies was BCS,
but the neoadjuvant therapy criteria were not standard. It should be
kept in mind that the number of patients receiving neoadjuvant therapy
and the rate of responses to treatment have increased at the present
time. Furthermore, advanced imaging techniques may increase the
possibility of localization after NAC.

More than 20\% of breast volume and a significant amount of breast skin
is excised in Level II techniques and simultaneous reconstruction is
performed with more complicated and sophisticated glandular flap
methods. On the other hand, less than 20\% of the total breast volume is
excised and the volume excision is limited in Level I techniques.
Youssef et al. (18) presented post-NAC OPS results in a series of 70
patients. In this series where tumor marking was not performed before
NAC, the rate of IBTR was reported as 4.2\% and Level I OPS techniques
were applied to \%57 of the patients. The mean surgical margin distance
was found to be wider in patients for whom Level II techniques were
applied (25 mm vs. 10 mm). In the present series, Level II OPS
techniques were applied to all of our patients. Although not
statistically significant, the mean surgical margin distance was found
to be wider in the unplanned surgery group (18 mm vs. 14 mm). Surgeons
likely tend to excise more tissue to provide a firm surgical margin in
unmarked patients. In a study by Chauhan et al. (19), patients who
underwent OPS and BCS after NAC were compared. In the whole series,
reduction in the form of fragmentation was detected at a rate of 44\%
and the tumor bed was marked with a clip in all patients before NAC.
Skin tattooing was performed, if necessary, to promote localization
after NAC. While the mean specimen volume and mean surgical margin
distance were larger in patients undergoing OPS, the ratio of involved
margin and IBTR was lower. In the literature, IBTR rates in patients
undergoing planned OPS after NAC were observed to range from 6\% to 10\%
(20,21). A matching case-control study comparing patients who underwent
BCS and OPS after NAC was reported from Brazil. Planned surgery was
applied to all patients. In this series, the majority of which consisted
of patients with T3 tumors, the volume of the excised specimen and mean
surgical margin distance were larger in the OPS group. During an average
follow-up of 67 months, the rate of IBTR was found to be 10.2\%. In this
series, Level I OPS techniques were applied to nearly half of the
patients in the OPS group. Longer follow-up time and non-standardized
surgical techniques may explain the high local recurrence rates in this
series (22). Similar results were reported by Mazouni et al. (23) from
France. Pre-NAC primary tumor marking was not standard in this series.
Post-NAC tumor size and specimen volume were found to be larger in
patients undergoing OPS. The re-excision rate was reported to be 2\% in
patients undergoing OPS whereas it was 9\% in patients undergoing BCS.
The requirement for mastectomy was 24\% vs 18\%, respectively, in
patients who underwent BCS and OPS (23). In our series, there were no
patients who underwent conventional BCS. Although re-excision rates in
patients who underwent OPS were found to be higher in our series
compared to the said study, the requirement for mastectomy was found to
be lower in patients undergoing planned and unplanned OPS. Five-year 5\%
local recurrence rates, on the other hand, were found to be similar to
our series.

In the present series, mastectomy was performed after systemic treatment
in the presence of extensive skin involvement, skin edema, chest wall
involvement, and diffuse microcalcification. Performing mastectomy in
patients with any of these conditions is currently considered as
standard treatment. However, we were able to successfully perform OPS
after systemic therapy in our patients in the presence of minimal edema
and skin shrinkage around the tumor. This feature makes the present
study different from others.

Tumor shrinkage after NAC in locally advanced breast cancer may occur in
three ways. First, a complete clinical response can be seen in the
tumor. In this case, pre-NAC tumor marking makes the planning of
surgical treatment easier; however, the previous tumor bed can be still
displayed in post-NAC radiological examinations. Surgery can be planned
by taking this area as the center. Secondly, tumor sizes can be reduced
and a concentric response can be achieved, and no tumor nodules may be
seen in the periphery of the tumor. In this case, surgery can be planned
by taking residual tumor as a basis in the post-NAC period. The third
shrinkage pattern is called the mosaic pattern, where the tumor shrinks
by breaking into small pieces. In this case, pre-NAC marking of the
tumor is not sufficient to perform the surgery safely. The margins of
the nodules located in the periphery of the tumor should be known or
marked in the post-NAC period. Secondary surgical intervention is
mandatory for patients with involved resection margins, resulting in
poor cosmetic outcomes or loss of the breast. It further means increased
costs and psychological stress for the patient. The marking of the tumor
in both pre- and post-NAC periods is likely to be more meaningful.
Figures 2 and 3 present images related to OPS performed with post-NAC
wire localization on the patient with a tumor that shrank concentrically
with NAC.

This study has shown that BCS can be applied using level II OPS
techniques with the post-NAC radiological examination and marking even
if primary tumor marking is not done in the pre-NAC period. The rates of
re-excision and mastectomy requirement similar to the patients
undergoing planned OPS and mastectomy have been obtained in those
undergoing post-NAC unplanned OPS. Furthermore, long-term local control
rates are similar. The absence of pre-NAC primary tumor marking is not a
condition that necessarily requires a mastectomy. Moreover, localized
skin involvement and localized edema should not be considered a
contraindication for OPS.

\textbf{A} \textbf{cknowledgements: None}

\textbf{Statement of Ethics} : This study was conducted with the
permission of the local ethics committee. Ethics committee approval
number: AOH/125/12

\textbf{InformedConsent:} Written informed consent was obtained from
patients who participated in this study.

\textbf{The authors have no conflicts of interest to declare.}

\textbf{Funding Sources: None}

\textbf{Financial Disclosure:} The authors declare that this study has
received no financial support

\textbf{Availability of data and materials} : The data sets used and/or
analyzed during the current

study are available from the corresponding author on reasonable request.

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\textbf{Table and Figure Legends}

Table-1. Patient and tumor characteristics of groups

Table-2. Surgical margin, need for re-intervention and recurrence status
of groups.

Figure-1. Loco-regional free survival curves of three groups

Figure 2. A. Tumor close to the areola in the upper outer quadrant of
the left breast, skin shrinkage, and minimal edema (pre-NAC image). B.
Structural distortion and focal asymmetric density in the post-NAC tumor
bed. C. Wire-guided marking of this area D. Complete excision of
radiological residual area on specimen radiography.

Figure 3. Postoperative image of the patient.

\textbf{List of abbreviations}

Oncoplastic surgery: OPS

Neoadjuvant chemotherapy: NAC

Surgical margin: SM

Locoregional recurrence-free survival: LRFS

Overall survival: OS

Breast-conserving surgery: BCS

Ultrasonography: USG

Magnetic resonance imaging: MRI

Ipsilateral breast tumor recurrence: IBTR

Radio-guided occult lesion localization: ROLL

Sentinel lymph node biopsy: SLNB

Body-mass index: BMI

Breast conserving Surgery: BCS

Mammography: MG

Fine-needle aspiration biopsy: FNAB

Disease-free survival: DFS

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