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Journal of Plastic, Reconstructive & Aesthetic Surgery (2017) xx, 1e10

Impact of adjuvant anti-estrogen therapies

(tamoxifen and aromatase inhibitors) on
perioperative outcomes of breast
reconstruction*
Raphaëlle Billon a, Romain Bosc a,b,*, Yazid Belkacemi b,c,
Elias Assaf b,d, Mounia SidAhmed-Mezi a, Barbara Hersant a,
Jean-Paul Meningaud a

a
Department of Plastic, Reconstructive, Aesthetic and Maxillo-Facial Surgery, Henri Mondor University
Hospital, UPEC, University Paris-Est Créteil, Créteil, France
b
Centre Sein Henri Mondor, Henri Mondor University Hospital, Créteil, France
c
Department of Radiation Therapy and Oncology, Henri Mondor University Hospital, UPEC, University
Paris-Est Créteil, INSERM U 955 Eq07, Créteil, France
d
Department of Oncology, Henri Mondor University Hospital, UPEC, University Paris-Est Créteil,
Créteil, France

Received 12 February 2017; accepted 24 May 2017

KEYWORDS Summary Purpose: Hormone (anti-estrogen) therapy (HT) plays a major role in hormone
Adjuvant hormone receptor-positive breast cancer management. The latest guidelines propose to extend the
therapy; duration of adjuvant treatment from 5 to 10 years. The association between HT and thrombo-
Tamoxifen; embolic or microvascular complications during breast reconstruction has been investigated.
Aromatase inhibitors; However, while estrogens play a crucial role in wound healing, no study has assessed the
Wound healing; impact of tamoxifen or aromatase inhibitors on other postoperative complications, including
Breast reconstruction wound healing complications. This study aimed to assess the impact of HT on surgical outcomes
after breast reconstruction.
Methods: All patients who underwent breast reconstruction between January 2012 and
December 2013 were reviewed. Rates of wound healing complications, prosthesis complica-
tions, microvascular thrombosis, flap failures, and venous thromboembolism were retrospec-
tively compared between patients treated and not treated with HT at the time of surgery.

*
Meetings: Part of this work was presented at the 61st National meeting of the SoFCPRE (Société Française de Chirurgie Plastique,
Reconstructrice et Esthétique) at Beffroi de Montrouge (Paris), 24th November 2016, France.
* Corresponding author. Department of Plastic, Reconstructive, Aesthetic and Maxillo-Facial Surgery, Henri Mondor University Hospital, 51
avenue du Maréchal de Lattre de Tassigny, 94000 Créteil, France. Fax: þ33 01 49 81 25 32.
E-mail address: romainbosc@gmail.com (R. Bosc).

http://dx.doi.org/10.1016/j.bjps.2017.05.046
1748-6815/ª 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Billon R, et al., Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on
perioperative outcomes of breast reconstruction, Journal of Plastic, Reconstructive & Aesthetic Surgery (2017), http://dx.doi.org/
10.1016/j.bjps.2017.05.046
 + MODEL
2 R. Billon et al.

Results: A total of 233 operations were performed: 78 free flaps, 12 autologous latissimus dorsi
flaps, 47 implants, 42 lipofilling, and 54 secondary symmetrization. At the time of surgery, 38%
of patients were treated with HT. Those who received HT experienced significantly more
wound healing complications (61% versus 28%; p < 0.001), including fat necrosis (26% versus
8.3%; p < 0.001), infections (15% versus 2.8%; p < 0.001), delayed wound healing (49% versus
13%; p < 0.001), and grade III/IV capsular contracture (55% versus 9.1%; p Z 0.001). No signif-
icant difference was observed in the occurrence of microvascular thrombosis and venous
thromboembolism.
Conclusions: HT seems to be associated with an increased risk of wound healing complications.
Currently, there is no guideline on perioperative HT discontinuation. Further investigations are
required.
ª 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Else-
vier Ltd. All rights reserved.

Introduction Some studies have examined the use of tamoxifen and

Personalized adjuvant treatments and therapeutic in-
novations have improved the long-term outcome of breast
cancer.1 Depending on the clinical and anatomopatho-
logical prognostic factors, adjuvant treatments can be
indicated after surgery. Adjuvant treatments include radi-
ation therapy, chemotherapy, targeted therapies with
trastuzumab, and/or hormone therapy.
Approximately 75% of breast cancers overexpress hor-
mone receptors (HRs) such as estrogen receptors (ERs) and
progesterone receptors (PRs).2 Hormone-sensitive tumors
must be treated with adjuvant hormone therapy for at least
5 years, and recent trials have proven that 10 years of
hormone therapy further improve rates of recurrence and
mortality.3 In pre- or perimenopausal women, adjuvant
therapy consists of selective estrogen receptor modulators
(SERMs) such as tamoxifen associated with ovarian sup-
pression in higher risk patients.4,5 In postmenopausal
women, adjuvant therapy is based on aromatase inhibitors
(AIs) such as anastrozole (Arimidex), letrozole (Femara),
and exemestane (Aromasin).6 Fulvestrant is only used as a
second-line treatment.7 These treatments have been
proven to reduce recurrence rates and improve overall
survival.8e10
However, these therapies have many side effects. Both
anti-estrogen therapies can cause menopausal symptoms
such as hot flashes, vaginal dryness, and libido disorders.
Tamoxifen is associated with an increased risk of endome-
trial cancer and venous thromboembolic events
(VTEs).3,11,12 AIs and ovarian suppression are associated
with a risk of osteoporosis, joint pain, and cardiovascular
diseases.13
Owing to the advancement of surgical techniques, the
demand for breast reconstruction has dramatically
increased over the past decade. Hormone therapy is usually
initiated after adjuvant chemotherapy and radiation ther-
apy when indicated. Consequently, the reconstruction is
usually performed during hormone therapy administration.
Given that the majority of women demonstrate HR-positive
breast cancer and newer guidelines increasing treatment
duration, it is essential for reconstructive surgeons to
familiarize themselves with these agents.
AIs as a VTE risk factor and as a potential microvascular
thrombotic risk factor following free flap breast recon-
struction, but results are contradictory.14e19
Estrogens are known to be implicated in the normal
wound healing process, and by blocking their effects, anti-
estrogen therapies could also affect healing.20 However, no
study has evaluated the effect of hormone therapy on
postoperative wound healing in breast reconstruction. This
study was designed to assess these shortcomings. This study
aimed to evaluate the effect of hormone therapy on sur-
gical outcomes, especially on the risk of wound healing
complications, in patients undergoing postmastectomy
breast reconstruction.
Materials and methods
Data collection
A retrospective cohort study of all patients who underwent
breast reconstruction between January 2012 and December
2013 was conducted. All patients who underwent autolo-
gous or prosthetic breast reconstruction (immediate or
delayed) and secondary surgery for symmetrization and
remodeling were included. Data were collected prospec-
tively from the electronic medical record shared by on-
cologists and surgeons. For patients included in the study,
the following parameters were collected: age; body mass
index (BMI); menopausal status; osteoporosis history;
thromboembolic history; comorbidities including hyper-
tension, dyslipidemia, diabetes, smoking status, the pres-
ence of chronic obstructive pulmonary disease, peripheral
vascular disease, and coronary artery disease; and corti-
costeroid therapy exposition. Oncological history was
recorded including cancer type, HR and HER2 expression
status, previous lumpectomy or mastectomy, axillary node
dissection, trastuzumab, and hormone therapy status with
its exposure duration, drugs-related adverse events, pre-
operative chemotherapy and radiation therapy, and the
type of breast reconstruction procedure. Patients receiving
SERM or AIs at the time of reconstruction were compared to
those not receiving hormone therapy.

Please cite this article in press as: Billon R, et al., Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on
perioperative outcomes of breast reconstruction, Journal of Plastic, Reconstructive & Aesthetic Surgery (2017), http://dx.doi.org/
10.1016/j.bjps.2017.05.046
 + MODEL
Impact of adjuvant anti-estrogen therapies on perioperative outcomes of breast reconstruction
Classification of complications
Complications were defined as intraoperative, early post-
operative when they occurred within 3 weeks post-
operatively, and late postoperative when they occurred
later on the follow-up.
Intraoperative vascular complications were recorded for
free flaps including arterial or venous thrombosis and the
need to reperform anastomosis during the procedure.
Specific early postoperative wound healing complica-
tions examined included skin necrosis, nippleeareolar
complex (NACi) necrosis, wound infection requiring oral or
IV antibiotics, seroma, and hematoma or delayed wound
healing. NAC necrosis was defined as full-thickness necrosis
that required surgical debridement, delayed repair, or skin
grafting. Delayed wound healing was defined by the need
for care or dressings for more than 3 weeks at the breast or
flap donor site. The other early postoperative complica-
tions examined included, postoperative thrombosis for free
flaps, flap loss (total or partial defined by a loss of <50% of
the flap), occurrence of a VTE (deep vein thrombosis or
pulmonary embolism), need for a second emergency sur-
gery, and hospital stay length.
Late complications recorded were fat necrosis, hyper-
trophic scar, and prosthesis complications (infection,
exposure, rupture, capsular contracture, and implant loss).
Fat necrosis was defined as a firm palpable nodule at the
breast or visible on imaging during the follow-up after
ruling out a cancer recurrence.
Statistical analyses
Patients treated with hormone therapy at the time of sur-
gery were compared to those who were not treated with
hormone therapy (i.e., controls) by using univariate ana-
lyses and then a multivariate model. Both groups were
compared in terms of comorbidities, cancer characteristics,
reconstruction type, and rates of complications. Chi-square
or Fisher’s exact tests and t-test and ManneWhitney tests
were used respectively for categorical and continuous
variables. P values of 0.05 were considered statistically
significant. Multivariate logistic regression models were
then developed to adjust these results and remove con-
founding factors such as preoperative chemotherapy and
radiation therapy that are expected in higher rates in the
hormone therapy group. Thus, adjusted odds ratios were
obtained. All statistical analyses were performed using the
R software version 3.2.4 (GNU General Public License).
This retrospective cohort study was designed to comply
with the STROBE guidelines.
Results
Patient characteristics and side effects of hormone
therapy
A total of 233 consecutive breast reconstructions were
performed between January 2012 and December 2013. The
following types of breast reconstruction were performed:
78 free flaps [77 deep inferior epigastric perforator (DIEP)
Please cite this article in press as: Billon R, et al., Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on
perioperative outcomes of breast reconstruction, Journal of Plastic, Reconstructive & Aesthetic Surgery (2017), http://dx.doi.org/
10.1016/j.bjps.2017.05.046
3
flaps and 1 superior gluteal artery perforator flap], 21
pediculated latissimus dorsi flaps (12 autologous and 9 with
implant), 38 breast implants, 42 lipofilling, and 54 sec-
ondary reconstruction (flap remodeling, NAC reconstruc-
tion, and contralateral breast symmetrization). The median
follow-up period was 37 months (interquartile range, 31e45
months). The median age of patients was 52 years (inter-
quartile range, 45e61 years).
Distribution of hormone therapy administrated is
detailed in Table 1. A total of 88 patients (38%) were
treated with hormone therapy at the time of breast
reconstruction. Among them, 55% received tamoxifen and
44% received an AI (51% on anastrozole, 31% on letrozole,
and 18% on exemestane). Only one patient (1.1%) received
fulvestrant because of AI intolerance.
The median duration of exposure to hormone therapy at
the time of analysis was 18 months (interquartile range,
12e27 months). Most patients (63%) were receiving hor-
mone therapy for less than 2 years at the time of breast
reconstruction. The main reported side effects of tamox-
ifen were hot flushes (29%), joint pain (21%), breakthrough
bleeding (10%), and weight gain (8.3%). Only one patient
treated with tamoxifen had a history of pulmonary embo-
lism (2%). With regard to AIs, the reported side effects were
osteoporosis (31%), joint pain (15%), weight gain (7.7%), and
hot flushes (7.7%).
Table 2 summarizes patient and tumor characteristics.
Patients treated with hormone therapy had fewer comor-
bidities. There were significantly fewer patients with
obesity (p Z 0.008), hypertension (p Z 0.014), diabetes
(p Z 0.012), chronic obstructive pulmonary disease
(p Z 0.015), VTE history (p Z 0.021), and a shorter median
duration of menopause (p Z 0.032) in the group treated
with hormone therapy than in the group not receiving
hormone therapy. However, more patients underwent
axillary node dissection (93.2% versus 45.5%, p < 0.001),
preoperative chemotherapy (76.1% versus 52.4%,
p Z 0.001), and radiation therapy (83% versus 59.3%,
p < <0.001) in the group treated with hormone therapy.
This is explained by the fact that invasive carcinomas
Table 1 Distribution of hormone therapy at the time of
breast reconstruction.
No. (%)
Total no. of breast 233
reconstruction performed
No hormone therapy 145 (62.2)
Hormone therapy 88 (37.8)
SERM (Tamoxifen) 48 (54.6)
Aromatase inhibitors 39 (44.3)
Anastrozole (Arimidex) 20 (51.3)
Letrozole (Femara) 12 (30.8)
Exemestane (Aromasin) 7 (17.9)
Fulvestrant 1 (1.1)
Exposure time (mo); median [IQR] 18.00 [12.00, 27.25]
Exposure time <24 mo 55 (62.5)
Exposure time 24 mo 33 (37.5)
SERM, selective estrogen receptor modulator; IQR, interquartile
range.
 + MODEL
4 R. Billon et al.

Table 2 Baseline patient and breast cancer characteristics depending on the treatment group.
Overall no. (%) No hormone Hormone therapy p
therapy no. (%) no. (%)
No. of breast reconstruction performed 233 145 (62.2) 88 (37.8)
Patient characteristics (comorbidities)
Age (year); median [IQR] 52.00 [45.00, 61.00] 51.00 [44.00, 61.00] 52.00 [45.75, 60.25] 0.757
Age 65 year 26 (11.2) 18 (12.4) 8 (9.1) 0.571
BMI (kg/m2); median [IQR] 25.00 [22.00, 29.00] 25.00 [22.50, 30.00] 25.00 [22.00, 27.00] 0.244
Obesity (BMI 30 kg/m2) 41 (17.6) 33 (22.8) 8 (9.1) 0.008
Hypertension 44 (18.9) 35 (24.1) 9 (10.2) 0.014
Dyslipidemia 45 (19.3) 30 (20.7) 15 (17.0) 0.609
Diabetes 19 (8.2) 17 (11.7) 2 (2.3) 0.012
Chronic obstructive pulmonary disease 10 (4.3) 10 (6.9) 0 (0.0) 0.015
Coronary artery disease 6 (2.6) 6 (4.1) 0 (0.0) 0.086
Peripheral vascular disease 17 (7.3) 13 (9.0) 4 (4.5) 0.300
Active smoking 27 (11.6) 20 (13.8) 7 (8.0) 0.255
Corticosteroid therapy 11 (4.7) 11 (7.6) 0 (0.0) 0.008
Personal history of thromboembolism 17 (7.3) 15 (10.3) 2 (2.3) 0.021
Menopause 110 (47.2) 67 (46.2) 43 (48.9) 0.796
Menopause duration (year); median [IQR] 10.00 [5.00, 15.00] 11.00 [6.00, 16.00] 8.00 [4.00, 12.00] 0.032
Osteoporosis 33 (14.2) 20 (13.8) 13 (14.8) 0.989
Breast cancer features
Type of breast cancer
Ductal carcinoma in situ (DCIS) 63 (27.0) 60 (41.4) 3 (3.4) <0.001
Invasive ductal carcinoma (IDC) 135 (57.9) 73 (50.3) 62 (70.5) 0.003
Lobular carcinoma in situ (LCIS) 3 (1.3) 3 (2.1) 0 (0.0) 0.292
Invasive lobular carcinoma (ILC) 21 (9.0) 4 (2.8) 17 (19.3) <0.001
Invasive mixed ductal/lobular 8 (3.4) 2 (1.4) 6 (6.8) 0.056
carcinoma (IDC/ILC)
Paget’s disease of the nipple 1 (0.4) 1 (0.7) 0 (0.0) 1.000
Breast sarcoma 2 (0.9) 2 (1.4) 0 (0.0) 0.528
Hormone receptor status
HR-positive tumor 122 (52.4) 34 (23.4) 88 (100.0) <0.001
HER2-positive tumor 38 (16.3) 18 (12.4) 20 (22.7) 0.060
Cancer treatment before breast reconstruction
Mastectomy 223 (95.7) 139 (95.9) 83 (95.3) 0.703
Tumorectomy 10 (4.3) 6 (4.1) 4 (4.5) 1.000
Axillary lymph node dissection 148 (63.5) 66 (45.5) 82 (93.2) <0.001
Preoperative chemotherapy 143 (61.4) 76 (52.4) 67 (76.1) 0.001
Time since the last chemotherapy (mo); 35.00 [18.00, 72.00] 20.00 [14.50, 30.50] 0.001
median [IQR]
Preoperative radiation therapy 159 (68.2) 86 (59.3) 73 (83.0) <0.001
Time since the last radiation therapy (mo); 68.50 [26.50, 132.25] 24.00 [15.00, 40.00] <0.001
median [IQR]
IQR, interquartile range; BMI, body mass index; HR, hormone receptors; HER2, Human Epidermal Growth Factor Receptor-2.

(ductal or lobular) were significantly more common in the
group treated with hormone therapy (p Z 0.003 and
p < 0.001), whereas intraductal carcinomas were more
common in the group not treated with hormone therapy
(p < 0.001).
Table 3 shows a homogeneous distribution of different
procedures between the two groups. However, more pa-
tients underwent immediate breast reconstruction in the
group that did not receive hormone therapy (p < 0.001).
Complication rates: univariate analyses
Complication rates are presented in Table 4. In the univariate
analysis, patients treated with hormone therapy were
significantly more likely to experience wound healing com-
plications than those not treated with hormone therapy (61%
versus 28%, OR Z 4.17 (95% CI, 2.39e7.39), p < 0.001).
Among them, rates of fat necrosis (26% versus 8.3%,
OR Z 3.92 (95% CI, 1.87e8.62), p < 0.001), wound infection

Please cite this article in press as: Billon R, et al., Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on
perioperative outcomes of breast reconstruction, Journal of Plastic, Reconstructive & Aesthetic Surgery (2017), http://dx.doi.org/
10.1016/j.bjps.2017.05.046
 + MODEL
Impact of adjuvant anti-estrogen therapies on perioperative outcomes of breast reconstruction 5

Table 3 Types of breast reconstruction depending on the treatment group.

Overall no. (%) No hormone Hormone therapy p
therapy no. (%) no. (%)
No. of breast reconstruction performed 233 145 88
Immediate reconstruction 46 (19.7) 41 (28.3) 5 (5.7) <0.001
Bilateral reconstruction 7 (3.0) 4 (2.8) 3 (3.4) 1.000
Type of reconstruction
Free flaps (DIEP, SGAP) 78 (33.5) 48 (33.1) 30 (34,1) 0.938
Latissimus dorsi flap 12 (5.2) 8 (5.5) 4 (4.5) 1.000
Tissue expander/implant 47 (20.2) 31 (21.4) 16 (18.2) 0.716
Autologous fat grafting 42 (18.0) 24 (16.6) 18 (20.5) 0.485
Second stages 54 (23.2) 34 (23.4) 20 (22.7) 1.000
DIEP, deep inferior epigastric perforator; SGAP, superior gluteal artery perforator.

(15% versus 2.8%, OR Z 6.11 (95% CI, 2.08e22.29),
p Z 0.001), and delayed wound healing (49% versus 13%,
OR Z 6.34 (95% CI, 3.39e12.22), p < 0.001) were significantly
increased. The mean wound healing time was 38.5 days in the
group treated with hormone therapy versus 17.3 days in the
group not treated with hormone therapy (p < 0.001). There
were also more patients with capsular contracture (Baker’s
grade III or IV) in patients with implant and treated with
hormone therapy than in those not treated with hormone
therapy (55% versus 9.1%, OR Z 12.22, p Z 0.001).
With regard to the vascular complications, no signifi-
cant difference was observed in the occurrence of

Table 4 Comparison of perioperative complications depending on the treatment group.

Complications Total No hormone Hormone therapy Univariate
no. (%) therapy no. (%) no. (%) OR (95% CI) p
Any intraoperative 9 (11.5) 7 (14.6) 2 (6.7) 0.42 (0.08e2.20) 0.469
vascular complication
Intraoperative arterial thrombosis 3 (3.8) 2 (4.2) 1 (3.3) 0.79 (0.05e7.08) 1.000
Intraoperative venous thrombosis 2 (2.6) 1 (2.1) 1 (3.3) 1.62 (0.08e31.36) 1.000
Re-performed arterial anastomosis 5 (6.4) 4 (8.3) 1 (3.3) 0.38 (0.03e2.53) 0.644
Re-performed venous anastomosis 3 (3.8) 2 (4.2) 1 (3.3) 0.79 (0.05e7.08) 1.000
Postoperative thrombosis 6 (7.7) 5 (10.4) 1 (3.3) 0.30 (0.02e2.44) 0.397
Flap loss
Total 9 (6.1) 7 (11.3) 2 (5.4) 0.45 (0.09e2.27) 0.477
Partial 2 (2.0) 2 (3.2) 0 (0.0) 0.00 (0.00e3.62) 0.527
Any wound healing complication 94 (40.3) 40 (27.6) 54 (61.4) 4.17 (2.39e7.39) <0.001
Skin flap necrosis 5 (2.1) 2 (1.4) 3 (3.4) 2.52 (0.50e14.39) 0.369
Nippleeareolar complex loss 9 (3.9) 4 (2.8) 5 (5.7) 2.12 (0.61e7.06) 0.304
Fat necrosis 35 (15.0) 12 (8.3) 23 (26.1) 3.92 (1.87e8.62) <0.001
Wound infection 17 (7.3) 4 (2.8) 13 (14.8) 6.11 (2.08e22.29) 0.001
Delayed wound healing 62 (26.6) 19 (13.1) 43 (48.9) 6.34 (3.39e12.22) <0.001
Mean wound healing time (days) 17.3 38.5
Median [IQR] 15.00 [10.00, 20.00] 20.50 [15.00, 31.50] <0.001
Hematoma 13 (5,6) 8 (5.5) 5 (5.7) 1.03 (0.37e3.40) 1.000
Seroma 22 (9.4) 10 (6.9) 12 (13.6) 2.13 (0.93e5.19) 0.140
Hypertrophic scar 13 (5.6) 9 (6.2) 4 (4.5) 0.72 (0.24e2.37) 0.771
Thromboembolic event (any) 4 (1.7) 2 (1.4) 2 (2.3) 1.66 (0.26e10.74) 0.634
Deep vein thrombosis 0 (0.0) 0 (0.0) 0 (0.0)
Pulmonary embolism 4 (1.7) 2 (1.4) 2 (2.3) 1,66 (0.26e10.74) 0.634
Unplanned revision surgery 36 (15.5) 22 (15.2) 14 (15.9) 1.06 (0.49e2.21) 1.000
Tissue expander/implant complications
Implant loss 16 (30.2) 9 (27.3) 7 (35.0) 1.44 (0.44e4.38) 0.775
Implant infection 8 (15.1) 6 (18.2) 2 (10.0) 0.50 (0.10e2.42) 0.695
Implant extrusion 6 (11.3) 6 (18.2) 0 (0.0) 0.00 (0.00e0.83) 0.072
Implant rupture 3 (5.7) 1 (3.0) 2 (10.0) 3.56 (0.38e52.86) 0.549
Implant capsular contracture 14 (26.4) 3 (9.1) 11 (55.0) 12.22 (3.08e63.59) 0.001
IQR, interquartile range.

Please cite this article in press as: Billon R, et al., Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on
perioperative outcomes of breast reconstruction, Journal of Plastic, Reconstructive & Aesthetic Surgery (2017), http://dx.doi.org/
10.1016/j.bjps.2017.05.046
 + MODEL
6 R. Billon et al.

Table 5 Comparison of perioperative complications between patients treated with tamoxifen and patients not treated with
hormone therapy.
Complications No hormone therapy no. (%) Tamoxifen no. (%) OR (95% CI) p
Any intraoperative vascular complication 7 (14.6) 0 (0.0) 0.00 (0.00e2.01) 0.330
Intraoperative arterial thrombosis 2 (4.2) 0 (0.0) 0.00 (0.00e7.50) 1.000
Intraoperative venous thrombosis 1 (2.1) 0 (0.0) 0.00 (0.00e30,86) 1.000
Re-performed arterial anastomosis 4 (8.3) 0 (0.0) 0.00 (0.00e3.73) 0.566
Re-performed venous anastomosis 2 (4.2) 0 (0.0) 0.00 (0.00e7.50) 1.000
Postoperative thrombosis 5 (10.4) 0 (0.0) 0.00 (0.00e2.44) 0.579
Flap loss
Total 7 (11.3) 0 (0.0) 0.00 (0.00e1.98) 0.340
Partial 2 (3.2) 0 (0.0) 0.00 (0.00e7.51) 1.000
Any wound healing complication 40 (27.6) 29 (60.4) 4.01 (1.97e8.14) <0.001
Skin flap necrosis 2 (1.4) 2 (4.2) 3.11 (0.47e20.13) 0.258
Nippleeareolar complex loss 4 (2.8) 3 (6.3) 2.35 (0.57e8.98) 0.368
Fat necrosis 12 (8.3) 12 (25.0) 3.69 (1.60e8.48) 0.005
Wound infection 4 (2.8) 6 (12.5) 5.04 (1.25e16.24) 0.017
Delayed wound healing 19 (13.1) 23 (47.9) 6.10 (2.80e12.93) <0.001
Mean wound healing time (days) 17.3 27.7
Median [IQR] 15.00 [10.00, 20.00] 20.50 [15.00, 30.00] <0.001
Hematoma 8 (5.5) 2 (4.2) 0.74 (0.15e3.23) 1.000
Seroma 10 (6.9) 5 (10.4) 1.57 (0.57e4.56) 0.533
Hypertrophic scar 9 (6.2) 3 (6.3) 1.01 (0.28e3.96) 1.000
Thromboembolic event (any) 2 (1.4) 2 (4.2) 3.11 (0.47e20.13) 0.258
Deep vein thrombosis 0 (0.0) 0 (0.0)
Pulmonary embolism 2 (1.4) 2 (4.2) 3.11 (0.47e20.13) 0.258
Unplanned revision surgery 22 (15.2) 4 (8.3) 0.51 (0.18e1.55) 0.330
Tissue expander/implant complications
Implant loss 9 (27.3) 1 (8.3) 0.24 (0.02e1.65) 0.246
Implant infection 6 (18.2) 0 (0.0) 0.00 (0.00e1.44) 0.171
Implant extrusion 6 (18.2) 0 (0.0) 0.00 (0.00e1.44) 0.171
Implant rupture 1 (3.0) 1 (8.3) 2.91 (0.14e56.68) 0.467
Implant capsular contracture 3 (9.1) 6 (50.0) 10.00 (2.01e41.61) 0.006
IQR, interquartile range.

intraoperative or early postoperative thrombosis of
microvascular anastomoses or in flap failures. Four pa-
tients experienced pulmonary embolism: two patients not
treated with hormone therapy 2 and 4 days after a DIEP
flap, one patient treated with tamoxifen 2 days after a
DIEP flap, and one patient treated with tamoxifen expe-
rienced a bilateral massive pulmonary embolism with
cardiogenic shock during a symmetrization mammoplasty.
No significant difference was observed in the occurrence
of VTE or in the need for a second emergency surgery or in
hospital stay length.
These results were similar when patients treated with
tamoxifen or AIs were compared separately to patients not
treated with hormone therapy. In addition, there was an
increased rate of implant loss in the case of prosthetic
reconstruction during treatment with AIs (Tables 5 and 6).
Multivariate analyses
History of axillary node dissection, preoperative chemo-
therapy, and radiation therapy were then included in our
multivariate logistic regression models. The differences
remained statistically significant after adjustment for these
potential confounding factors (Table 7). Hormone therapy
was therefore an independent risk factor associated with
the occurrence of these complications. In addition, the
complications were more significant within the first 2 years
of treatment exposure.
Immediate breast reconstruction followed by
hormone therapy
We also sought to determine whether these complications
occurred for patients who underwent immediate recon-
struction and subsequently started hormone therapy.
Among the 12 patients who underwent immediate
reconstruction followed by hormone therapy, only one pa-
tient experienced a wound healing complication, which was
a seroma after an autologous latissimus dorsi flap. These
patients had a significantly lower rate of complications than
patients who had a delayed reconstruction and were
treated with hormone therapy at the time of the surgery.
The rate of wound healing complications was 8.3% for im-
mediate reconstruction and 61.4% for delayed reconstruc-
tion (p Z 0.001). There were no wound infection
(p Z 0.356) and no delayed wound healing (p Z 0.001).
Neither fat necrosis (p Z 0.063) nor capsular contracture
(p Z 0.024) occurred later on follow-up.

Please cite this article in press as: Billon R, et al., Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on
perioperative outcomes of breast reconstruction, Journal of Plastic, Reconstructive & Aesthetic Surgery (2017), http://dx.doi.org/
10.1016/j.bjps.2017.05.046
 + MODEL
Impact of adjuvant anti-estrogen therapies on perioperative outcomes of breast reconstruction 7

Table 6 Comparison of perioperative complications between patients treated with Aromatase Inhibitors and patients not
treated with hormone therapy.
Complications No hormone Aromatase OR (95% CI) p
therapy no. (%) inhibitors no. (%)
Any intraoperative vascular complication 7 (14.6) 2(12.5) 0,84 (0.00e84) 1.000
Intraoperative arterial thrombosis 2 (4.2) 1(6.3) 1.53 (0.10e13.80) 1.000
Intraoperative venous thrombosis 1 (2.1) 1(6.3) 3.13 (0.16e60.55) 0.441
Re-performed arterial anastomosis 4 (8.3) 1(6.3) 0.73 (0.06e5.17) 1.000
Re-performed venous anastomosis 2 (4.2) 1(6.3) 1.53 (0.10e13.80) 1.000
Postoperative thrombosis 5 (10.4) 1(6.3) 0.57 (0.05e5.09) 1.000
Flap loss
Total 7 (11.3) 2 (11.1) 0.98 (0.19e4.37) 1.000
Partial 2 (3.2) 0 (0.0) 0.00 (0.00e7.51) 1.000
Any wound healing complication 40 (27.6) 24 (61.5) 4.2 (1.97e9.09) <0.001
Skin flap necrosis 2 (1.4) 1 (2.6) 1.88 (0.13e16.45) 0.513
Nippleeareolar complex loss 4 (2.8) 2 (5.1) 1.91 (0.35e8.41) 0.609
Fat necrosis 12 (8.3) 11 (28.2) 4.35 (1.74e10.57) 0.002
Wound infection 4 (2.8) 6 (15.4) 6.41 (1.69e20.76) 0.007
Delayed wound healing 19 (13.1) 19 (48.7) 6.3 (2.80e13.40) <0.001
Mean wound healing time (days) 17.3 50.7
Median [IQR] 15.00 [10.00, 20.00] 20.00 [15.00, 52.50] <0.001
Hematoma 8 (5.5) 2 (5.1) 0.93 (0.19e4.08) 1.000
Seroma 10 (6.9) 7 (18.0) 2.95 (1.12e7.76) 0.056
Hypertrophic scar 9 (6.2) 1 (2.6) 0.40 (0.04e2.60) 0.691
Thromboembolic event (any) 2 (1.4) 0 (0.0) 0.00 (0.00e8.07) 1.000
Deep vein thrombosis 0 (0.0) 0 (0.0)
Pulmonary embolism 2 (1.4) 0 (0.0) 0.00 (0.00e8.07) 1.000
Unplanned revision surgery 22 (15.2) 9 (23.1) 1.68 (0.70e3.82) 0.238
Tissue expander/implant complications
Implant loss 9 (27.3) 6 (75.0) 8.00 (1.43e42.03) 0.035
Implant infection 6 (18.2) 2 (25.0) 1.50 (0.26e8.61) 0.642
Implant extrusion 6 (18.2) 0 (0.0) 0.00 (0.00e2.34) 0.323
Implant rupture 1 (3.0) 1 (12.5) 4.57 (0.21e88.89) 0.356
Implant capsular contracture 3 (9.1) 5 (62.5) 16.67 (2.15e81.00) 0.003
IQR, interquartile range.

Discussion
This study shows that tamoxifen and AIs seem to be asso-
ciated with an increased risk of wound healing complica-
tions (fat necrosis, infection, and delayed wound healing),
regardless of the type of breast reconstruction performed,
and with an increased risk of Baker’s grade III or IV capsular
contracture in the case of prosthetic reconstruction. Hor-
mone therapy did not seem to significantly increase the risk
of microvascular thrombosis or VTE for breast
reconstruction.
Early and late complications occurred more frequently
in patients who were receiving hormone therapy at recon-
struction. This can be explained by the fact that hormone
therapy may adversely affect the wound healing process.
Tamoxifen and AIs decrease the exposure of tumor cells
to estrogen through different mechanisms. Tamoxifen is a
SERM that acts by competitive antagonism with estrogens in
the breast. SERMs are indicated in nonmenopausal women
whose ovarian estrogen production is maintained. They also
have agonist effects in other tissues. These tissue-
dependent estrogenic or anti-estrogenic effects are deter-
mined not only by the different expression of the two ER
isoforms, ERa and ERb, depending on tissues but also by the
various coactivators and corepressors present in the envi-
ronment.21 AIs inhibit the transformation of adrenal an-
drogens into estrogens in peripheral tissues, the only source
of estrogens in postmenopausal women. Therefore, AIs are
not equal in estrogenic depletion. Indeed, letrozole re-
duces plasma estrogen level to a significantly greater
extent than anastrozole.22,23
The skin is one of the estrogen target tissues. In the
elderly, estrogen deficiency is responsible for skin aging and
may cause healing disorders. Estrogens maintain the skin
collagen and elastic fiber content; they thus help maintain
skin thickness and prevent the appearance of wrinkles.
They also maintain skin hydration by increasing glycosami-
noglycans and hyaluronic acid in the skin.20 In addition to
these effects on skin aging, estrogens play a role in healing
by regulating the level of a cytokine, the transforming
growth factor-beta 1 (TGF-b1), which is involved in cell
proliferation, differentiation, and matrix production.24 Es-
trogens activate the proliferation and migration of
different components of the skin by acting on dermal
fibroblast ER.25 Topical or systemic estrogen therapy could
improve wound healing in this population.26,27 Variations in

Please cite this article in press as: Billon R, et al., Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on
perioperative outcomes of breast reconstruction, Journal of Plastic, Reconstructive & Aesthetic Surgery (2017), http://dx.doi.org/
10.1016/j.bjps.2017.05.046
 + MODEL
8 R. Billon et al.
Table 7 Adjusted estimates of the odds ratio of complications.
Univariate
OR (95% CI)
Any wound complication 4.17 (2.39e7.39)
Exposure time <24 mo 5.87 (3.02e11.80)
Exposure time >24 mo 2.47 (1.13e5.38)
Fat necrosis 3.92 (1.87e8.62)
Wound infection 6.11 (2.08e22.29)
Delayed wound healing 6,34 (3.39e12.22)
Implant capsular contracture 12.22 (3.08e63.59)
OR, odds ratio; CI, confidence interval.
hormone levels during the menstrual cycle may affect
wound healing.28
Therefore, by blocking the effects of estrogens, hor-
mone therapy may also affect the healing process. Data on
the subject are limited and contradictory. An in vivo study
conducted in ovariectomized mice has shown that tamox-
ifen accelerated wound healing.29 Conversely, tamoxifen
delays human fibroblast proliferation in vitro and thereby
reduces the formation of keloid scars.30,31 The authors of
another comparative study conducted in rats have reported
delayed healing with significant dehiscence on tamoxifen.32
This discrepancy could be caused because SERMs are partial
antagonists or agonists depending on tissues and could act
differently depending on the cellular context (concentra-
tion of coregulators). The aggravating effect of tamoxifen
in association with radiation therapy on subcutaneous
fibrosis increases and is accompanied by delayed wound
healing with extended axillary drainage when it is admin-
istered perioperatively during axillary node dissection.33,34
All these phenomena seem to be related to the growth
factor TGF-b1. Animal studies have also shown that AIs
delay wound healing, although to date no human study has
been conducted to confirm this assumption.35
In our study, we found that the administration of an
adjuvant hormone therapy was associated with significant
delays in wound healing independently of other risk factors
such as radiation therapy (adjusted OR Z 6.64, 95% CI
1.88e28.32; p Z 0.005). Nearly one in two patients treated
with hormone therapy required local care and dressings for
more than 3 weeks (49% versus 13%, mean healing duration
of 38.5 days versus 17.3 days; p < 0.001). Similarly, the risk
of infection was significantly increased in patients treated
with hormone therapy (adjusted OR Z 15.77, 95% CI
3.61e97.09; p < 0.001). An increased risk of fat necrosis
was found both after flap reconstruction and after lipo-
filling (adjusted OR Z 11.26, 95% CI 3.58e42.85;
p < 0.001).
In addition to the discomfort caused, morphological re-
sults of breast reconstruction may be impaired. Eventually,
fat necrosis results in firm nodules on palpation, and its
main differential diagnosis is the recurrence or appearance
of a second cancer. Performing a biopsy is sometimes
required to confirm their benign nature.
We found Baker’s grade III or IV capsular contracture in
more than half the patients in the group treated with
Please cite this article in press as: Billon R, et al., Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on
perioperative outcomes of breast reconstruction, Journal of Plastic, Reconstructive & Aesthetic Surgery (2017), http://dx.doi.org/
10.1016/j.bjps.2017.05.046
Multivariate
p Adjusted OR (95% CI) p
<0.001 8.12 (2.38e33.06) 0.002
<0.001 9.85 (2.13e53.70) 0.005
0.022 6.94 (1.63e33.57) 0.011
<0.001 11.26 (3.58e42.85) <0.001
0.001 15.77 (3.61e97.09) <0.001
<0.001 6.64 (1.88e28.32) 0.005
0.001 23.2 (3.85e235.98) 0.002
hormone therapy (55% versus 9.1%, adjusted OR Z 23.2,
95% CI 3.85e235.98, p Z 0.002), most often requiring
revision surgery with capsulectomy and implant change or
reconstruction failure due to pain or a major alteration of
the morphological result. The pathophysiology of capsular
contracture is unclear. It is a physiological response of the
body to the presence of a foreign body. The importance of
this response varies from one patient to another but is
increased by a local inflammation and during prosthesis
irradiation.36 Hormone therapy could also activate these
periprosthetic inflammatory phenomena. Our study shows
that hormone therapy, regardless of a possible radiation
therapy, could increase the risk of capsular contracture and
could therefore lead to the failure of reconstruction.
Despite a limited sample, patients who had immediate
reconstruction and subsequently started hormone therapy
had less complications than patients who had delayed
reconstruction and were treated with hormone therapy at
the time of surgery. Starting the hormone therapy after the
wound healing process could decrease early and late com-
plications. Recently, there has been a rise in the use of
immediate breast reconstruction, which may have impli-
cations on the multidisciplinary management of the dis-
ease.37 Our findings further suggest that it would be better
to perform immediate reconstruction whenever possible to
decrease the complications associated with hormone
therapy.
We found that the complications were more significant
within the first 2 years of treatment exposure (OR Z 5.9 in
the first 2 years; OR Z 2.5 after 2 years). It is well known
that many medication effects vary with duration.38 In other
studies, the first 2 years of therapy with tamoxifen appear
to be the period during which the risk of VTE is the high-
est.39 This decreased risk of VTE over time with sustained
use is consistent with our findings. This issue remains
understudied, and existing published reports have not
provided consistent conclusions.39,40 Our findings suggest
that the first 2 years after the initiation of hormone therapy
may be the most crucial time for monitoring wound healing
complications.
Despite a known risk of VTE that is 2.3 times higher with
tamoxifen, we did not find any significant difference in our
study.41 This could be explained by the lack of power of our
study. A risk of arterial thrombosis has also been reported in
several studies.42,43 Unlike in the study by Kelley et al., we
 + MODEL
Impact of adjuvant anti-estrogen therapies on perioperative outcomes of breast reconstruction
did not observe a higher rate of microvascular thrombosis in
cases of free flaps performed on patients receiving hor-
mone therapy.16 The biases of this study have already been
discussed by Disa and reported by Mirzabeigi et al.: a higher
rate of microvascular complications for nonabdominal free
flaps that are less commonly performed (superior and
inferior gluteal artery perforator flaps), a higher rate of
preoperative irradiation, and a grouping of heterogeneous
complications.17,19 In a study conducted in rats, tamoxifen
has been associated with intimal hyperplasia with a pro-
pensity to inflammation without real thrombotic effect on
microsurgical arterial anastomoses.32
To limit the increased risk of VTEs and the uncertain risk
of microvascular complications, some teams have sug-
gested pausing tamoxifen 3 weeks before and after breast
reconstruction, although there is no consensus on this
subject.44 Our study suggests that temporary discontinua-
tion of tamoxifen or AIs could help limit wound healing
complications as well. No study has shown that the peri-
operative discontinuation of hormone therapy was respon-
sible for an increased risk of relapse or a decrease in
patient overall survival. Such studies are, however, essen-
tial before proposing guidelines on the perioperative mod-
ulation of hormone therapy for breast reconstruction.
Our study does suffer from several limitations. First, it is
a retrospective study with limited sample sizes of different
types of autologous and implant-based reconstruction.
Moreover, there were some differences between the two
groups. It should be noted, however, that patients treated
with hormone therapy had fewer comorbidities (they were
thinner, with less hypertension and diabetes) than those
not treated with hormone therapy. Despite fewer comor-
bidities, complications were significantly more common
among them. The main disparity between the two groups is
a higher number of invasive carcinomas with a higher rate
of axillary node dissection and adjuvant chemotherapy and
radiation therapy in the group treated with hormone ther-
apy. Integrating these factors into the multivariate logistic
regression models allowed overcoming this bias. Hormone
therapy remained associated with increased rate of com-
plications, independent of other contributing factor. Yet,
despite these limitations, we believe that our results
demonstrate important findings to the reconstructive sur-
geon. This study lends support for further investigations
with a prospective design, assessing flaps and implants
separately and excluding patients with previous radio-
therapy. The issue of capsular contracture also deserves to
be explored.
Conclusion
In our study, hormone therapy, including tamoxifen and AIs,
appeared to be associated with a higher risk of post-
operative wound healing complications and capsular
contracture.
Our study suggests that temporary discontinuation of
tamoxifen or AIs could help limit wound healing complica-
tions that may sometimes lead to the failure of the
reconstruction, especially in the case of prosthetic recon-
struction. A prospective cohort study should, however, be
conducted to confirm our findings.
Please cite this article in press as: Billon R, et al., Impact of adjuvant anti-estrogen therapies (tamoxifen and aromatase inhibitors) on
perioperative outcomes of breast reconstruction, Journal of Plastic, Reconstructive & Aesthetic Surgery (2017), http://dx.doi.org/
10.1016/j.bjps.2017.05.046
9
Ethical statement
Compliance with ethical standards.
Funding
None.
Conflicts of interest
None.
Acknowledgments
Henri Mondor Clinic Research Unit.
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