European Journal of Surgical Oncology xxx (2018) 1e7

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European Journal of Surgical Oncology

journal homepage: www.ejso.com

Neoadjuvant systemic treatment for breast cancer in Italy: The Italian

Society of Surgical Oncology (SICO) Breast Oncoteam survey
E. Vicini a, *, A. Invento b, M. Cuoghi c, A. Bafile d, C. Battaglia e, N. Biglia f, M. Busani g,
R. Bussone h, E. Cianchetti i, F. Caruso j, M.C. Cucchi c, M. Dessena k, F. Di Filippo l, N. Fabi l,
S. Folli m, D. Friedman n, G. Macellari o, P. Mainente p, R. Murgo q, A. Neri r, G.P. Pollini b,
D. Palli s, F. Ricci t, G. Scalco u, M. Taffurelli v, M. Trunfio w, V. Galimberti a, the Italian
Society of Surgical Oncology (SICO) Breast Oncoteam
a
Division of Breast Surgery, European Institute of Oncology, Milan, Italy
b
U.O.C. Breast Unit AOUI Borgo Trento, Verona, Italy
c
U.O.S.D. Chirurgia Senologica Breast Unit Bellaria USL Bologna, Italy
d
Division of Breast Surgery, Ospedale San Salvatore Coppito, L'Aquila, Italy
e
Unit of Senology Ospedale Civile di Sanremo, Italy
f
di Torino, Osp. Mauriziano Umberto I, Torino, Italy
Universita
g
SSD di Chirurgia Senologica, Az. Osp. " C. Poma ", Mantova, Italy
h
Chirurgia Senologica-Breast Unit, Ospedale Cottolengo, Torino, Italy
i
Chirurgia generale a indirizzo Senologico, Ospedale Gaetano Bernabeo, Ortona, CH, Italy
j
Breast Centre Humanitas, Catania, Italy
k
S.C. Chirurgia Sperimentale, Ospedale Oncologico, Azienda Ospedaliera Brotzu, Cagliari, Italy
l
Regina Elena National Cancer Institute, Roma, Italy
m
AUSL Romagna, Ospedale GB Morgagni S.C. di Senologia, Forlì, FC, Italy
n
U.O. Chirurgia Senologica, Ospedale Policlinico San Martino, Genova, Italy
o
Breast Centre Ospedale S. Giuseppe, Milano, Italy
p
UOS Senologia c/o S.C. di Chirurgia Generale, Ospedale "Alto Vicentino" - ULSS 7 PEDEMONTANA e Santorso, Vicenza, Italy
q
UOC di Chirurgia Senologica, Ospedale IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
r
Centro Senologico AOU Senese, Policlinico Le Scotte, Siena, Italy
s
U.O.S.D. di Chirurgia Senologia-Breast Unit Ospedale "Guglielmo da Saliceto", Piacenza, Italy
t
Breast Unit "S. M. Goretti" Hospital, ASL-Latina/Sapienza University of Rome, Polo Pontino, Latina, Italy
u
U.O.S. di Senologia Chirurgica, U.O.C. di Chirurgia Generale, Ospedale San Bortolo, Vicenza, Italy
v
Dipartimento di Medicina e Chirurgia (DIMEC), Universita
di Bologna, Policlinico di Sant’Orsola, Bologna, Italy
w
Dipartimento di Senologia Chirurgica, Azienda Ospedaliera A. Cardarelli, Napoli, Italy

a r t i c l e i n f o a b s t r a c t

Article history: The Italian Society of Surgical Oncology (SICO) Breast Oncoteam developed a survey to explore the state
Accepted 20 March 2018 of the art of neoadjuvant treatment for breast cancer in Italy, specifically focusing on cases treated during
Available online xxx the two-year period 2014e2015.
A questionnaire was sent to Italian Breast Units with a minimum of 150 new breast cancer cases
Keywords: treated/year according to the Senonetwork directory and to the SICO Breast Oncoteam Breast Unit
Neoadjuvant
network.
Breast cancer
A total of 23/107 Breast Units submitted the survey, reporting a total amount of 20156 cases of breast
Multidisciplinary
Breast surgery
carcinoma (17241 invasive, 2915 in situ) treated in the biennium, corresponding approximately to 20% of
Pathological complete response newly diagnosed breast cancers in Italy.
In the United States, medical treatment before surgery for breast cancer is indicated in about 22.7% of
newly diagnosed cases according to the National Cancer Database, while a German study reported
approximately 20% of cases treated with neoadjuvant therapy. In our survey, a total of 1673/17241 cases
(9.7%) were treated with neoadjuvant therapy, ranging from 2.9% to 23.6% according to different centres,

Abbreviations: NAT, NeoAdjuvant systemic Treatment; SICO, Italian Society of Surgical Oncology; DTMP, Diagnostic Therapeutic and Healthcare Management Protocol;
QoL, Quality of Life; Fig, Figure.
* Corresponding author.
E-mail address: elisa.vicini@hotmail.it (E. Vicini).

https://doi.org/10.1016/j.ejso.2018.03.018
0748-7983/© 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Please cite this article in press as: Vicini E, et al., Neoadjuvant systemic treatment for breast cancer in Italy: The Italian Society of Surgical
Oncology (SICO) Breast Oncoteam survey, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.03.018
2 E. Vicini et al. / European Journal of Surgical Oncology xxx (2018) 1e7

showing heterogeneity in neoadjuvant treatment indications, even in multidisciplinary breast units.

Better resources should be engaged to achieve a standardised quality indicator for neoadjuvant treat-
ment, and this indicator could be included among the European Society of Breast Cancer Specialists
(EUSOMA) quality indicators. In the near future, we plan to develop a second survey to better test im-
provements in the employment of neoadjuvant therapy after the expiry of the 2016 European Parliament
deadline and after the 2017 St. Gallen Conference recommendations.
© 2018 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical
Oncology. All rights reserved.

Introduction
Initially developed as a treatment option for locally advanced
breast tumours, the concept of neoadjuvant systemic treatment
(NAT) has, over the years, been translated into the setting of early
breast cancer [1,2].
NAT can be employed to downstage a tumour and therefore to
achieve loco-regional disease control allowing breast surgery in
initially unresectable neoplasms [3].
The rationale of primary systemic treatment for operable breast
cancers is the opportunity to test in vivo chemosensitivity, instead
of administering adjuvant treatment after tumour removal [4]. In
fact, recent meta-analyses have shown how pathologic complete
response (pCR) after NAT can occur in around 20% of cases and how
it is associated with a better prognosis [5,6].
Primary systemic treatment can convert a surgical indication for
mastectomy into a conservative option (breast conservative sur-
gery, nipple/skin sparing mastectomies with immediate recon-
struction) [7,8] and can downstage axillary node-positive disease to
node-negative [9,10].
In order to select those patients most likely to respond to NAT
and thus avoid unnecessary aggressive treatments, molecular bio-
markers are required.
The wide range of responses to NAT is related to histotype
(ductal/lobular/other types), to molecular subtypes of breast cancer
(Luminal A, Luminal B, HER2-enriched, and triple negative) and to
the proliferation index. Triple negative and even more HER2-
enriched subtypes, particularly in the absence of hormone recep-
tor expression, show a higher rate of pCR, while luminal B/HER2-
negative subtypes demonstrates a lower rate of pCR [5,11]. Only a
minority of patients affected by Luminal A subtypes and lobular
histotype achieve pCR [11,12].
Pre-surgical systemic treatment can include chemotherapy
regimens (in the majority of cases), associated with anti-HER2
targeted agents in HER2-overexpressed tumours, or endocrine
therapy that could represent an option in clinical trials for hor-
monal sensitive cancers [13].
The aim of the present survey is to estimate the current
employment of NAT for breast cancer treatment in Italy and the
current modalities.
Materials and methods
In July 2016, the Italian Society of Surgical Oncology (SICO)
Breast Oncoteam developed a questionnaire involving various as-
pects of NAT and specifically referred to cases treated during the
two-year period 2014e2015. The questionnaire was divided into 7
sections: general information, clinical records, indications, diag-
nosis, surgical treatment, radiation therapy, and final consider-
ations (Table 1). It was sent by e-mail to all the Italian Breast Units
which handle a minimum of 150 new breast cancer cases treated
per year, according to the Senonetwork directory [14] and to the
SICO Breast Oncoteam Breast Unit network. The authors certify that
ethical approval was not required for the study.
Descriptive analysis was carried out as appropriate.
Results
A total of 23/107 (21,4%) Breast Units completed and submitted
the survey to the SICO Breast Oncoteam, reporting a total of 20156
cases of breast carcinoma (17241 invasive carcinoma, 2915 in situ)
treated in the 2014e2015 biennium. A total of 1673 of 17241 cases
(9.7%) were treated with NAT, ranging from 2.9% to 23.6% according
to different centres.
Unfortunately, it was not possible to report T and N status before
NAT, due to the lack of information from many centres. Breast
pathological response was complete (ypT0 and ypTis in the defin-
itive histological examination) in 538 from 1673 cases (32,1%), 410/
1673 (24,5%) ypT0 and 128/1673 (7,6%) ypTis respectively (Fig. 1).
In 859 cases, pathological nodal status after NAT was negative,
ypN0 and ypN0sn, with a total of 21 (91.3%) centres performing
sentinel node biopsy in clinically node-negative patients pre-NAC
and 14 (60.8%) centres performing sentinel node biopsy in pa-
tients with nodal involvement pre-NAC who showed a complete
radiological response. A total of 17 (73.9%) centres reported a
sentinel node detection rate >90% post NAT, 2 centres <90%. In 15
(65.2%) centres, the tracer employed is 99Tc only, 4 centres employ
the double tracer technique with 99Tc and blue dye, one centre uses
indocyanine green, while 3 (13%) centres did not respond to the
question.
In all centres, a Diagnostic, Therapeutic and Healthcare Man-
agement Protocol (DTMP) is active and the final planning decision
is discussed during multidisciplinary meetings. The major indica-
tion reported for NAT is biological subtype (86.4%), as shown in
Fig. 2 and, in relation to the biological subtypes, all the 23 Breast
Units indicate NAT for HER2þ tumours, 21 (91.3%) for triple-
negative tumours, 15 (65.2%) for luminal B cancers, while only 5
(21.7%) multidisciplinary groups indicate NAT for luminal A cancers
(Fig. 3). In 14 centres, HER2 status is considered crucial for preop-
erative treatment indication in all cases, while in the remaining 9
centres it is considered only for selected cases. Among the 1673
reported cases treated with NAT, 527 (31.5%) were HER2 positive
cases. In 17 breast units, neoadjuvant endocrine therapy is
employed.
Regarding diagnostic procedures, although there may be some
concerns regarding the actual need for staging in asymptomatic
patients according to the recent guidelines [15], we enquired about
the procedures employed. We found that 54.5% of centres perform
a CT total body and a skeletal scintigraphy; the other centres re-
ported that they conduct positron emission tomography only
(17.4%), positron emission tomography and skeletal scintigraphy
(13%), positron emission tomography or CT total body (8.7%), or CT
total body only (4.3%).
Also regarding breast diagnostic procedures, in 17 breast
units, pre- and post-NAT Breast MRI is performed for every

Please cite this article in press as: Vicini E, et al., Neoadjuvant systemic treatment for breast cancer in Italy: The Italian Society of Surgical
Oncology (SICO) Breast Oncoteam survey, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.03.018
 E. Vicini et al. / European Journal of Surgical Oncology xxx (2018) 1e7 3

Table 1
Questionnaire.

General Information Date of completion Centre Principal Investigator

Clinical Records How many new breast cancer cases were How many cases were treated with How do you routinely stage patients before
treated at your Centre? How many DCIS? NAT? NAT? (choose at least 1 option)
N … new breast cancers treated N … PET þ skeletal scintigraphy
N … comprehensive of DCIS CT total body
PET
CT total body þ skeletal scintigraphy
Skeletal Scintigraphy
Divide the number of cases treated with How many HER2 positive cases were
NAT by pathological response (ypT) treated with NAT?
Complete response ypT0 þ ypTis N … N …
ypT2 N …
ypT3 N …
ypT4 N …
Indications Is a Diagnostic, Therapeutic and Healthcare Do you discuss NAT indication during Which factors do you consider as determinant
Management Protocol (DTMP) active in multidisciplinary meetings? to indicate NAT? (choose at least 1 option)
your Centre? y/n Tumour dimension (>2.5 cm)
y/n Conversion mastectomy/conservative
Nodal involvement
Tumour biology
Outcome benefit (PFS)
Outcome benefit (OS)
You indicate NAT for: (choose at least 1 Is HER2 status crucial for you to Do you employ neoadjuvant endocrine
option) prescribe NAT? therapy?
HER 2 positive Yes, for all patients y/n
Triple negative Only for selected cases
Luminal A No, we consider other factors
Luminal B
Diagnosis Do you perform pre- and post-NAT Breast Do you perform pre and post NAT Do you perform pre and post NAT
MRI? (choose only 1 option) Breast UltraSound? (choose only 1 Mammogram? (choose only 1 option)
For all cases option) y/n
Never y/n
For multifocal or multicentric disease
How do you perform biopsies? (choose only Is biopsy site marked? If marked, how?
1 option) y/n Clip
Tru-Cut Tattoo
Incisional biopsy Picture of skin clinical mapping
Do you routinely perform axillary Do you perform FNAC/biopsy of any Do you perform clinical/radiological monitoring
UltraSound? suspicious axillary node? during NAT?
y/n y/n y/n
If yes, do you mark it with a clip?
y/n
Surgery Is surgery performed within 30 days after In node-negative patients do you In node-positive patients converted to node
the completion of NAT? perform sentinel node biopsy before or negative on imaging after NAT do you perform
y/n after NAT? sentinel node biopsy?
Before y/n
After
What is your sentinel node detection rate What tracer do you use for sentinel What type of breast surgery after NAT?
after NAT? node biopsy after NAT? (choose only 1 Conservative N …
>90% option) Demolitive N …
<90 99Tc
Blue dye
99Tc þ Blue dye
Indocyanine green
In the case of conservative surgery do you In the case of mastectomy, do you If radiation therapy is planned, do you perform
excise an area corresponding to the initial perform nipple-sparing technique after reconstruction?
tumour size? NAT? y/n
y/n y/n If yes, what type of reconstruction?
In what percentage of cases? … % Expander
Expander þ lipofilling
Adjuvant Therapy You base radiation therapy indication on: After surgery, do you prescribe In what percentage of cases?
Pre-NAT status additional chemotherapy? …%
Post-NAT status y/n Please specify indications …
Final Considerations In your opinion, what are the major
limitations to NAT?
Quality of Life (QoL) impact
Treatment delay
Progression risk
Organisation difficulties
Patient compliance

patient, while the remaining 7 centres employ MRI only when with suspected node cytology/histology in 21 centres. In 2 cen-
there is a suspicion of multifocal/multicentric disease. Pre- and tres a clip is placed in the suspected node before NAT and in 20
post-NAT mammogram and breast US are performed in 18 and 20 centres a clinical/radiological monitoring is conducted during
centres respectively; routine axillary US is reported in 21 centres, NAT. Marking before NAT is reported in 22/23 centres, using a clip

Please cite this article in press as: Vicini E, et al., Neoadjuvant systemic treatment for breast cancer in Italy: The Italian Society of Surgical
Oncology (SICO) Breast Oncoteam survey, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.03.018
4 E. Vicini et al. / European Journal of Surgical Oncology xxx (2018) 1e7

Fig. 1. Breast pathological response to NAT.

in 11 centres, a tattoo in 9 centres, a picture of skin clinical Timing for surgery in all centres was adequate according to the
mapping in 2 cases. Three centres employ clip or tattoo. A total of current literature [16,17], within 30 days after the completion of
21 centres perform core biopsy, while in the remaining 2 centres NAT. Among the whole group of patients treated with NAT, 40.4%
an incisional biopsy is performed. received conservative surgery, while 59.6% underwent a

Fig. 2. NAT indications in the 23 reported centers.

Please cite this article in press as: Vicini E, et al., Neoadjuvant systemic treatment for breast cancer in Italy: The Italian Society of Surgical
Oncology (SICO) Breast Oncoteam survey, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.03.018
 E. Vicini et al. / European Journal of Surgical Oncology xxx (2018) 1e7 5

Fig. 3. Indications for NAT according to molecular subtypes in different centres.

mastectomy. According to the 2017 St. Gallen conference, regarding Resolution on Breast Cancer [23,24]. Recent data shows how im-
conservative surgery, the tendency to excise an area corresponding provements in survival have been achieved, with a slight difference
to the initial tumour size should decrease in the future in the remaining between the north and south of Italy [25].
absence of microcalcifications or scattered residual disease [18]; We decided to focus our survey to the specific topic of neo-
there were found to be 7 centres that still excise an area corre- adjuvant chemotherapy because the whole process requires orga-
sponding to the initial tumour size. Nipple-sparing mastectomy nisation, support, excellent communication skills, specialised
after NAT is offered in 21 breast units, in line with the 2017 St. services and qualified professionals. It could offer a good surrogate
Gallen Conference statements and the diffusion of the technique endpoint to effectively sample the quality of a multidisciplinary
[18,19]. team, despite the limitations due to the arbitrary nature of inter-
As the role played by post-mastectomy radiation therapy and preting a multiple-choice questionnaire. Moreover, controversies
regional nodal irradiation after NAT is still a matter of controversy
in the medical literature, with several trials ongoing [20], the
centres were asked about indications for radiation therapy. In 15
centres radiation therapy was reported to be based on pre-NAC
status.
We asked about issues pertaining to reconstruction, considering
that radiation therapy represents a risk factor for complications
which can affect the quality of results in both the immediate and
the delayed setting: 20 centres perform immediate reconstruction
if radiation therapy is planned after surgery, 12 of them with an
expander, 8 with an expander plus lipofilling. The authors agree
that immediate reconstruction could be considered an available
option consistent with a personalised approach based on the pa-
tient's medical history and expectations [21].
Additional chemotherapy after surgery in patients with an
incomplete response and who are at a high risk of recurrence, in the
absence of hormone receptor expression, could be considered
(Capecitabine is a possible option) [22] and eleven (47.8%) centres
prescribe it.
The answers to the final question “what are the major limita-
tions to NAC?” are reported in Fig. 4.

Discussion

During the past decade, Italy has devoted considerable and

sustained effort to establishing certified multidisciplinary breast
units nationwide, in accordance with the European Parliament Fig. 4. Clinicians’ opinion regarding limitations to primary systemic treatment.

Please cite this article in press as: Vicini E, et al., Neoadjuvant systemic treatment for breast cancer in Italy: The Italian Society of Surgical
Oncology (SICO) Breast Oncoteam survey, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.03.018
6 E. Vicini et al. / European Journal of Surgical Oncology xxx (2018) 1e7
regarding the issue of neoadjuvant treatment are still present in the
guidelines [15,26]. It is currently a matter of discussion and debate
at key international conferences, particularly during the 2017 St.
Gallen International Conference (tumour biology, breast and axil-
lary surgery, radiation therapy, additional chemotherapy in pa-
tients with partial pathological response) [18,22,27]. Our survey
provided data regarding approximately 20% of the total breast
cancers treated in Italy in the 2014e2015 biennium.
In the United States, medical treatment before surgery for breast
cancer is indicated in about 23% of newly diagnosed cases accord-
ing to the National Cancer Database (2010e2011) [28]. A German
study reported approximately 20% of cases treated with NAT in the
years 2009e2011 from a cohort of 39570 patients [29], while in our
survey, primary systemic treatment is employed in 9.7% of cases
(range 2.9%e23.6% according to different centres), showing het-
erogeneity in NAT indications.
Regarding limitations to pre-surgical treatment, clinicians were
of the opinion that no concerns were warranted in 23% of cases,
while in 77% of cases, Quality of Life (QoL impact), treatment delay,
progression risk, organisation difficulties and patient compliance
were considered obstacles to treatment. These data suggest a cul-
tural and organisational problem underlying the poor use of NAT,
even in multidisciplinary breast units with a DTMP where all cases
are discussed during multidisciplinary meetings, and where the
main indicator identified for NAT is tumour biology, in line with the
standard of care proposed by national and international guidelines.
Only 5/23 centres indicate neoadjuvant treatment for luminal A
tumours, while 23/23 centres indicate preoperative treatment for
HER2þ tumours. We understand that the question was conceivably
confounding because staging was not specified. According to
guidelines, the authors consider NAT as a routine treatment in IIIB,
IIIC and inflammatory tumours [15,26,30]. pCR was reported in
one-third (32%) of the treated cases, probably due to selection of
HER2 positive and triple-negative cases [31].
Diagnosis, staging, imaging [32,33] and marking are performed
according to the guidelines [15,26] and only two centres perform
incisional biopsy instead of percutaneous biopsy for diagnosis.
Some concerns remain regarding the fact that 30% of centres
excise the whole initial tumour area in cases of conservative sur-
gery, 2 centres perform axillary clearance without sentinel node
biopsy in patients node negative pre-NAC and 9 centres in patients
with nodal involvement pre-NAC who showed a complete radio-
logical response. However, the reported detection rate is over 90%
in 73.9% of centres, with only four centres employing the double-
tracer technique, suggesting good skills in sentinel node biopsy
mandatory to apply the latest recommendation (least three
sentinel nodes should anyway be excised) [18]. New approaches
include clipping of metastatic nodes before chemotherapy [34] but
at present only two centres apply it.
Further studies could shed light on how to better select patients
who would benefit from adjuvant treatment and on testing more
effective therapies, according to different tumour subtypes. Future
research should focus on de-escalating overtreatment in patients
who show an early response and on providing effective further
targeted adjuvant treatment in patients with an incomplete or
absent pathological response to NAT.
Better resources should be engaged to achieve a standardised
quality indicator for NAT that could be employed for around 20% of
all new cases. This could be included among the European Society
of Breast Cancer Specialists (EUSOMA) quality indicators [35]. The
data presented are at least two years old; in the near future, we plan
to develop a second survey to better test improvements in the
employment of NAT therapy after the expiry of the 2016 European
Parliament deadline, and subsequent to the 2017 St. Gallen Con-
ference recommendations.
Please cite this article in press as: Vicini E, et al., Neoadjuvant systemic treatment for breast cancer in Italy: The Italian Society of Surgical
Oncology (SICO) Breast Oncoteam survey, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.03.018
Conflict of interest statement
We wish to confirm that there are no known conflicts of interest
associated with this publication and there has been no significant
financial support for this work that could have influenced its
outcome.
Acknowledgments
The authors thank Maria Carla Massa for data processing and
William Russell-Edu and Maria Grazia Villardita for constructive
criticism of the manuscript.
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Please cite this article in press as: Vicini E, et al., Neoadjuvant systemic treatment for breast cancer in Italy: The Italian Society of Surgical
Oncology (SICO) Breast Oncoteam survey, European Journal of Surgical Oncology (2018), https://doi.org/10.1016/j.ejso.2018.03.018