International Journal of

Molecular Sciences

Review
Clinical and Molecular Insights of Radiation-Induced Breast
Sarcomas: Is There Hope on the Horizon for Effective Treatment
of This Aggressive Disease?
Stefania Kokkali 1,2, *, Jose Duran Moreno 3 , Jerzy Klijanienko 4 and Stamatios Theocharis 1

1 First Department of Pathology, Medical School, National and Kapodistrian University of Athens,
75 Mikras Asias Street, 11527 Athens, Greece; stamtheo@med.uoa.gr
2 Oncology Unit, 2nd Department of Medicine, Medical School, National and Kapodistrian University of Athens,
Hippocratio General Hospital of Athens, V. Sofias 114, 11527 Athens, Greece
3 Hellenic Group of Sarcoma and Rare Cancers, G. Theologou 5, 11471 Athens, Greece;
duranmoreno.jose@gmail.com
4 Department of Pathology, Institut Curie, 26 Rue d’Ulm, CEDEX 05, 75248 Paris, France;
jerzy.klijanienko@curie.fr
* Correspondence: stefkokka@med.uoa.gr; Tel.: +30-6932326547

Abstract: Radiation-induced breast sarcomas (RIBS) are rare entities representing <1% of all primary
breast malignancies, limiting most reports to small retrospective case series. They constitute a
heterogeneous group of neoplasms, with high-grade angiosarcoma being the most common subtype.
Other sarcoma histotypes, such as undifferentiated pleomorphic sarcoma and leiomyosarcoma, can
also be identified. Radiation-induced breast angiosarcoma (RIBA) has an incidence of approximately
0.1% after breast-conserving therapy and arises mainly from the dermis of the irradiated breast.





 MYC gene amplification is highly indicative of secondary breast angiosarcomas. Their clinical
Citation: Kokkali, S.; Moreno, J.D.; presentation often mimics benign port-radiation lesions, leading to a delay in diagnosis and a lost
Klijanienko, J.; Theocharis, S. Clinical window of opportunity for cure. Surgery with negative margins is the mainstay of treatment of
and Molecular Insights of Radiation- localized RIBS. In the case of angiosarcoma, technical difficulties, including multifocality, infiltrative
Induced Breast Sarcomas: Is There margins, and difficulty in assessing tumor margins, render surgical treatment quite challenging.
Hope on the Horizon for Effective
A limited number of studies showed that adjuvant radiation therapy reduces local recurrences;
Treatment of This Aggressive
therefore, it is proposed by many groups for large, high-grade tumors. Chemotherapy has been
Disease? Int. J. Mol. Sci. 2022, 23,
evaluated retrospectively in a small subset of patients, with some evidence supporting its use in
4125. https://doi.org/10.3390/
angiosarcoma patients. Approximately half of patients with RIBA will show local recurrence. In the
ijms23084125
advanced setting, different therapeutic options are discussed in the review, including chemotherapy,
Academic Editor: Shinji Miwa antiangiogenic therapy, and immunotherapy, whereas the need for further research on molecular
Received: 3 March 2022 therapeutic targets is pointed out.
Accepted: 1 April 2022
Published: 8 April 2022 Keywords: breast sarcoma; angiosarcoma; radiation-induced sarcoma; radiotherapy

Publisher’s Note: MDPI stays neutral

with regard to jurisdictional claims in
published maps and institutional affil-
1. Introduction on Breast Sarcomas
iations.
Breast cancer represents the most common cancer in women and the second most
common cancer-related cause of death [1]. The vast majority of invasive breast cancers
are adenocarcinomas, arising from the terminal duct lobular unit. Breast sarcomas (BS),
Copyright: © 2022 by the authors. on the other hand, are very rare histologically heterogeneous nonepithelial malignancies,
Licensee MDPI, Basel, Switzerland. arising from the mesenchymal breast tissue. They should be differentiated from malignant
This article is an open access article phyllodes tumor and metaplastic breast carcinoma [2]. The rarity of such tumors limits
distributed under the terms and most studies to small retrospective case series and case reports, most of which have limited
conditions of the Creative Commons long-term follow-up.
Attribution (CC BY) license (https://
The median age at diagnosis of BS varies between 45 and 55 years [3–6]. The median
creativecommons.org/licenses/by/
size of the primary tumor is approximately 5 cm, which is larger than epithelial breast
4.0/).

Int. J. Mol. Sci. 2022, 23, 4125. https://doi.org/10.3390/ijms23084125 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2022, 23, 4125 2 of 18

carcinoma (BC), whereas nodal involvement is very uncommon. The most common sub-
types of BS are angiosarcoma, stromal sarcoma, liposarcoma, fibrosarcoma, osteosarcoma,
chondrosarcoma, leiomyosarcoma, undifferentiated pleiomorphic sarcoma, and Kaposi
sarcoma [7–9], with the most common being angiosarcoma. Factors identified to have a
prognostic significance, associated with either overall survival (OS) or disease-free survival
(DFS), are tumor grade, angiosarcoma histology, surgical margins, and tumor size.
A clear distinction exists between the de novo developing primary breast sarcomas
(PBS) and secondary breast sarcomas (SBS) developing after radiation therapy (RT), or in the
setting of chronic lymphedema, similarly to secondary sarcomas of the arm (Stewart-Treves
syndrome) after axillary lymph node dissection [6,10–12]. Both are rare, representing <1%
of all primary breast malignancies and <5% of all sarcomas [13]. The annual incidental
rate for breast sarcoma varies in the literature according to the histotypes included in the
different series. A retrospective analysis of the Swedish cancer registry identified an overall
incidence of 1.5–2 cases per million per year [14]. Radiation-induced BS (RIBS) comprises
approximately one-third of BS, with angiosarcoma being the most common subtype. The
cumulative incidence of RIBS was estimated at 0.3% at 15 years post-RT [15]. Karlsson et al.
reported a standardized incidence ratio of 1.9 for BS in women treated for BC [16].
The modified criteria, proposed by Cahan et al. [17] for radiation-induced bone sarco-
mas, are also used to define RIBS and include: different histological features between the
primary tumor and the present sarcoma; the development of sarcoma in a previously irra-
diated field; a latent period typically >5 years; and histological confirmation of the second
malignancy as sarcoma. These criteria were further modified by Arlen et al. in 1971, in-
cluding tissues adjacent to the irradiated field and a shorter latency period (3–4 years) [18].
The latency period is necessary to distinguish RIBS from PBS, but the minimum required
interval has been controversial among authors [19,20].
Common breast imaging studies, including mammography and ultrasound, are not
specific for BS in demonstrating a suspicious mass. Fine-needle aspiration cytology is
not very helpful, as adequate sampling is required for accurate preoperative diagnosis.
Therefore, core biopsy is the gold standard, coupled with histological examination by
an expert sarcoma pathologist, to distinguish BS from metaplastic carcinoma and malig-
nant phyllodes tumor [21]. Breast magnetic resonance imaging (MRI) is indicated for
planning appropriate surgery. The staging system of the American Joint Committee on
Cancer/International Union Against Cancer is the most commonly used, just as for soft
tissue sarcomas (STS) arising in other sites.
In the current review, the clinical and histopathological characteristics of RIBS will
be discussed, as well as their management and prognosis, emphasizing their distinct
characteristics versus PBS.

2. Histological Findings in Radiation-Induced Breast Sarcomas—Focus on Angiosarcoma

BS is a heterogeneous group of tumors, with angiosarcoma comprising approximately
50% of the cases of RIBS, corresponding to the most common histotype [12,15,22]. Never-
theless, other histotypes have also been described, including undifferentiated pleomorphic
sarcomas (formerly referred to as malignant fibrous histiocytomas), leiomyosarcomas, fi-
brosarcomas, osteosarcoma etc. [11,19,23–25]. Figure 1 presents cytologic and histologic
findings of radiation-induced osteosarcoma of the breast. In this case, cytological smears
showed clustered or isolated spindle and pleomorphic sarcomatous cells associated with a
pinkish/orange osteoid. Corresponding surgical sections showed a spindle-shaped and
epithelioid proliferation with a foci of osteogenesis. Most of the reported cases of RIBS were
diagnosed before 2010, and a large number of them before 2000, when diagnostic molecular
techniques were not available. Therefore, accurate histological classification is questioned.
Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 3 of 19

Int. J. Mol. Sci. 2022, 23, 4125 3 of 18

2000, when diagnostic molecular techniques were not available. Therefore, accurate his-
tological classification is questioned.

A B

Figure1.1.Radiation-induced
Figure Radiation-induced osteosarcoma.
osteosarcoma. (A):(A): smears
smears showing
showing clustered
clustered spindlespindle and pleo-
and pleomorphic
morphic sarcomatous cells associated with pinkish/orange osteoid (May-Grunwald–Giemsa, 400×;
sarcomatous cells associated with pinkish/orange osteoid (May-Grunwald–Giemsa, 400×; Merck,
Merck, Darmstadt, Germany); (B): corresponding surgical sections of spindle-shaped and epitheli-
Darmstadt, Germany); (B): corresponding surgical sections of spindle-shaped and epithelioid pro-
oid proliferation showing osteogenesis (Hematoxylin-Eosin-Safran,200×; Merck, Darmstadt, Ger-
liferation showing osteogenesis (Hematoxylin-Eosin-Safran,200×; Merck, Darmstadt, Germany).
many). Schemes follow the same formatting.
Schemes follow the same formatting.
Αngiosarcomas are rare but aggressive tumors that account for less than 5% of all
Angiosarcomas are rare but aggressive tumors that account for less than 5% of all soft
soft tissue sarcomas (STS). They arise from the endothelial cells of blood vessels (he-
tissue sarcomas (STS). They arise from the endothelial cells of blood vessels (hemangiosar-
mangiosarcoma) or lymphatics (lymphangiosarcoma), either sporadically (as primary
coma) or lymphatics (lymphangiosarcoma), either sporadically (as primary neoplasms) or
neoplasms) or secondary to chronic lymphedema and previous irradiation. In this re-
secondary to chronic lymphedema and previous irradiation. In this review, only breast
view, only breast hemangiosarcoma will be discussed. Primary breast angiosarcoma
hemangiosarcoma will be discussed. Primary breast angiosarcoma (PBA) occurs in breast
(PBA) occurswhereas
parenchyma, in breast parenchyma, whereas
radiation-induced radiation-induced
breast angiosarcoma (RIBA)breast
involvesangiosarcoma
mainly the
(RIBA) involves mainly the dermis and may or may not infiltrate
dermis and may or may not infiltrate breast parenchyma. Contrary to Stewart–Treves breast parenchyma.
Contrary to Stewart–Treves
angiosarcoma, RIBA usuallyangiosarcoma,
lacks lymphedema RIBAchanges
usually lacks
[26]. lymphedema changes [26].
Before RT became a common practice for breast cancer,
Before RT became a common practice for breast cancer, treatment-related treatment-related angiosar-
angiosar-
comas were
comas were usually
usually lymphangiosarcomas,
lymphangiosarcomas, arising arising inin the
the lymphedematous
lymphedematous breast breast and
and
upper arm following mastectomy and axillary dissection, and
upper arm following mastectomy and axillary dissection, and associated with chronic associated with chronic
lymphedema[27].
lymphedema [27].The
Theintroduction
introductionof ofbreast
breastconserving
conservingsurgery
surgery(BCS)
(BCS)andandsentinel
sentinellymph
lymph
node sampling has led to a decrease in treatment-related lymphedema
node sampling has led to a decrease in treatment-related lymphedema and consequent and consequent
lymphangiosarcoma, while
lymphangiosarcoma, while atat the
the same
same time,
time, toto an
an increase
increase inin the
theincidence
incidenceofofRIBA.
RIBA.
RIBA typically
RIBA typically exhibits
exhibits aa vasoformative,
vasoformative,and andless
lesscommonly,
commonly, a solid growth
a solid growthpattern
pat-
[26,28].
tern An analysis
[26,28]. of 27 of
An analysis cases of RIBA
27 cases demonstrated
of RIBA a vasoformative
demonstrated patternpattern
a vasoformative of growth of
combined with sieve-like or solid pattern areas, mainly high-grade
growth combined with sieve-like or solid pattern areas, mainly high-grade nuclear fea- nuclear features (16
grade(16
tures 3, grade
8 grade3, 2,8 grade
3 grade2, 1), high mitotic
3 grade 1), highrate, and rate,
mitotic rarely,
and necrosis
rarely, [26]. The [26].
necrosis predomi-
The
nance of high-grade angiosarcoma is reported in all studies of RIBA
predominance of high-grade angiosarcoma is reported in all studies of RIBA with available with available his-
tological data
histological data [29–33].
[29–33].Furthermore,
Furthermore,RIBA RIBAisismore
moreoften
oftenmulti-focal,
multi-focal, and the macroscopic
macroscopic
aspectisisshown
aspect shownininFigure
Figure 2. 2. Cytologic
Cytologic findings
findings andand corresponding
corresponding histological
histological sections
sections are
are shown
shown in Figure
in Figure 3. Cytological
3. Cytological smearssmears
showedshowednumerous numerous spindle-shaped
spindle-shaped sarcomatoussarcoma-
cells
tous cells mild
exhibiting exhibiting mild cyto-nuclear
cyto-nuclear pleomorphism. pleomorphism.
Numerous naked Numerousnucleinaked nuclei and a
and a hemorrhagic
hemorrhagic background were also found. Histological sections
background were also found. Histological sections showed a typical angiosarcoma, showed a typical angi-
rich in
osarcoma,
vascular rich in
spaces vascular
bordered byspaces bordered by
spindle-shaped spindle-shaped
sarcomatous cells. sarcomatous cells.
RIBA should be differentiated from atypical vascular lesion (AVL), a cutaneous vascu-
lar lesion arising in patients who have received RT for breast carcinoma. This entity, first
described by Fineberg and Rosen in 1994 [34], has been attributed to lymphatic obstruction
secondary to surgery and/or RT [35,36]. A constant finding of AVL is a variable degree of
chronic inflammatory infiltrate, and most of them resemble benign lymphangioendothe-
lioma and/or lymphangioma circumscriptum. Although most authors consider AVLs as
benign, a number of cases progressing to angiosarcoma have been reported, raising the
concern of whether AVLs are premalignant or not [35–38]. Differential diagnosis between
AVL and well-differentiated angiosarcoma can be extremely difficult in small biopsies [39].
Features that favor diagnosis of AVL include relative circumscription, bloodless spaces,
and delicate projections of endothelial-lined stroma into vessel lumens, while infiltrative
 Int. J. Mol. Sci. 2022, 23, 4125 4 of 18

t. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW

pattern, prominent dissection of dermal collagen, hemorrhage, extravasated red blood cells,
blood lakes, and cytologic atypia are the characteristics of angiosarcomas [36].

Int. J. Mol. Sci. 2022, 23, x FOR PEER REVIEW 4 of 19

Figure 2. Surgical
Figure mammary
2. Surgical specimen of radiation-induced
mammary specimen of breastbreast angiosarcoma. Note
radiation-induced violet, angio
breast
Figure 2. Surgical
congestive skin andmammary
subcutaneousspecimen of radiation-induced
tumoral angiosarcoma.
infiltration. Morphological Note
cytologic and violet,
histologic
congestive
congestive skin
skin and and subcutaneous
subcutaneous
findings are shown in Figure 3.
tumoral
tumoral infiltration. infiltration.
Morphological cytologicMorphological
and histologic cy
findings are shown in Figure 3.
findings are shown in Figure 3.

A B

Figure 3.
Figure Thesame
3. The samecase
caseofof radiation-induced
radiation-induced breast
breast angiosarcoma
angiosarcoma fromfrom
thethe Figure
Figure 2. (A):
2. (A): cyto-
cytologic
smears showing
logic smears numerous
showing spindle-shaped
numerous sarcomatous
spindle-shaped cells exhibiting
sarcomatous mild cyto-nuclear
cells exhibiting pleo-
mild cyto-nuclear
morphism.
pleomorphism. Note the presence
Note the presence of nuclei
of naked nakedandnuclei and background
hemorrhagic hemorrhagic background
(May-Grunwald–
(May-Grunwald–Giemsa
Giemsa 400×; Merck, Darmstadt, Germany). (B): Corresponding surgical sections showingsections
400×; Merck, Darmstadt, Germany). (B): Corresponding surgical
showing typical angiosarcoma A
rich inbordered
vascularbyspaces bordered by spindle-shaped
typical
sarcomatous
angiosarcoma rich in vascular spaces spindle-shaped sarcomatous cells (Hematoxylin-
cells (Hematoxylin-Eosin-Safran, 400×; Merck, Darmstadt, Germany).
Eosin-Safran, 400×; Merck, Darmstadt, Germany).

RIBA should be differentiated from atypical vascular lesion (AVL), a cutaneous

3.Figure
Genetic3. Alterations
The same in Radiation-Induced
case ofwho Breast Sarcomas
radiation-induced
vascular lesion arising in patients have received RT forbreast angiosarcoma
breast carcinoma. from the F
This entity,
Some
smears
first genetic
showing
described factors have been
numerous
by Fineberg associated with
and Rosenspindle-shaped a higher risk of developing
sarcomatous
in 1994 [34], has been attributed to cellsa radiation-
lymphaticexhibiting
ob- m
induced sarcoma
struction secondary(RIS).
to In patients
surgery with
and/or RTLi–Fraumeni
[35,36]. A syndrome
constant (TP53
finding of mutation),
AVL is a an in-
variable
morphism. Note the presence of naked nuclei and hemo
creased risk of BS following RT for breast carcinoma has been reported. A 33% risk of RIBS
degree of chronic inflammatory infiltrate, and most of them resemble benign lymphan-
(May-Grunwald–Giemsa 400×; Merck, Darmstadt, Germany). (B): Correspon
gioendothelioma and/or lymphangioma circumscriptum. Although most authors con-
showing
sider AVLs as typical
benign,angiosarcoma
a number of cases rich in vascular
progressing spaces bordered
to angiosarcoma have beenby re- spindl
cells (Hematoxylin-Eosin-Safran,
ported, raising the concern of whether AVLs400×; Merck, Darmstadt,
are premalignant Germany).
or not [35–38]. Differential
diagnosis between AVL and well-differentiated angiosarcoma can be extremely difficult
Int. J. Mol. Sci. 2022, 23, 4125 5 of 18

in patients with Li–Fraumeni syndrome and a history of breast carcinoma was reported by
Heyman et al. [40], whereas a recent study found a much lower risk of 6% [41]. Alterations
of the tumor suppressor gene TP53 were also identified in a large proportion of AVLs and
RIBA, suggesting that the two entities are the extremes of a morphological continuum [42].
The TP53 gene is considered a guardian of the genome, as it is involved in DNA repair,
the regulation of cell cycle checkpoints, etc. TP53 mutations have been associated with
impaired repair of DNA damages induced by RT in some studies, and its use is avoided in
patients with Li–Fraumeni syndrome [43].
A very limited number of RIBS cases in BRCA mutation carriers have been reported,
raising the question of a possible association between BRCA mutation and secondary
sarcomas [44]. BRCA proteins, encoded by the tumor suppressor genes BRCA1 and BRCA2,
regulate DNA double-strand breaks repair. Ionizing radiation induce mainly double strand
breaks of DNA, and BRCA mutations may lead to impaired radiation response, raising
concerns about the use of RT in these patients [45]. However, the largest study of breast
cancer patients with BRCA mutations treated with RT, which included 230 women in Israel
(of whom 80% with an Ashkenazi Jewish founder mutation), found no increased risk of
RIBS [46]. Thus, RT can be administered in BRCA-associated breast carcinoma.
Carriers of the retinoblastoma (Rb) germline mutation have a strong predisposition
to cell cycle dysregulation, and an increased risk of STS post-radiation for retinoblastoma
has been established, in a dose-dependent manner [47]. However, there is no data on the
susceptibility to breast sarcoma. Similar to BRCA and TP53 mutations, concerns have been
expressed about a deleterious role of RT in patients carrying Rb mutations [48].
In angiosarcomas in particular, recent comparative genomic hybridization studies
revealed genetic differences between primary and secondary tumors. MYC gene amplifica-
tion as a result of recurrent genetic alterations on chromosome 8q24.21 is highly indicative
of secondary angiosarcoma [49–51]. However, there is a small subset of primary angiosar-
comas harboring also MYC amplification [52]. Further research on MYC in secondary
angiosarcomas, AVL and other RIS revealed high levels of MYC amplification by fluores-
cence in situ hybridization (FISH) only in secondary angiosarcomas, as opposed to AVL
cases or AVL lesions adjacent to RIBA [51,53]. Moreover, incidence of MYC alteration
was low in radiation-induced non-breast angiosarcomas [52], or absent in RIS without
angiosarcoma morphology [54]. The incidence of MYC amplification, detected by FISH,
in radiation- or lymphedema-induced angiosarcomas, ranges between 54% and 100% of
studied cases [49,50,54]. A high concordance between MYC gene amplification and pro-
tein expression by immunohistochemistry (IHC) was reported in subsequent studies in
secondary mammary angiosarcomas, AVLs, and primary mammary AS [50,55].

4. Pathophysiology
For RIBS, RT is likelythe main causative factor, although a clear dose–response rela-
tionship has not yet been established. Childhood high-dose fractionated radiation exposure
(10+ Gy) has been linked to an increased risk of bone and STS, and a linear relationship
was found between dose and risk [56]. Such a dose–response relationship has also been
described in women receiving RT for BC [57]. According to an earlier report, a direct dose–
risk relationship between RT dose and sarcoma risk was observed until 150–200 Joules [16].
Apart from the dose, the techniques of radiotherapy also seem to play a role in the de-
velopment of secondary tumors in cancer survivors. Technological efforts during the last
two decades aiming at a better radiation distribution and a reduction of normal tissue
damage are expected to reduce the incidence of these neoplasms. The combination of RT
and alkylating chemotherapy agents is also considered a risk factor for BS [58,59].
A large single-institution study of 13,472 patients who received RT for breast cancer at
the Curie Institute reported a cumulative incidence of 0.48% for RIBS at 15 years [22]. In
another large Canadian population-based study, the standardized incidence ratio was 26.2
for RIBA and 2.5 for RIBS [12]. The estimated incidence of RIBA after breast-conserving
therapy ranges from 0.05% to 0.1% [15,60,61].
Int. J. Mol. Sci. 2022, 23, 4125 6 of 18

The clear role of RT in SBS reflects different hypotheses regarding its exact patho-
physiological mechanism. The first hypothesis supports a direct effect of RT due to tissue
damage [62]. On the other hand, a central role of lymphedema, as a result of lymphatic
channels obstruction from RT or surgery, has also been speculated to be the principal
causative factor of SBS [26]. In support of the second hypothesis, there are several reports of
SBS in patients who underwent surgery for breast carcinoma without adjuvant RT [12,15],
likely related to surgical sequelae, prior chemotherapy, and other environmental factors. In
addition, a large Swedish study of secondary sarcomas post-treatment for BC found that
the risk of STS, other than angiosarcomas, correlated with RT dose, whereas angiosarcomas
risk correlated only with lymphoedema [16]. Furthermore, lymphangiosarcomas develop
in patients with chronic lymphedema, even in the absence of RT [63]. Cases of out-of-field
sarcomas have also been described in patients who underwent RT for BC [15]. Finally,
radiation-induced angiosarcomas also occur in female reproductive organs after RT for
previous cancers, raising the question of a possible association with female hormones [64].

5. Clinical Presentation of Radiation-Induced Breast Sarcomas

RIBS represent a distinct entity compared to other radiation-induced STS. The latency
period between RT and the diagnosis of SBS is typically shorter in RIBS than in other
STS [65]. The median latency period varies between 4.9 and 8.8 years in the different
retrospective series, whereas SBS diagnosis is not established earlier than one year post
RT [10,11,22,25]. The risk of BS after RT reaches its peak at 10years and then, although it
declines, remains elevated for more than 20 years [66]. Therefore, while patients with PBS
are usually in their fifth or sixth decade of life at the time of presentation [2,6,30], patients
diagnosed of RIBS are usually older (Table 1). RIBA is likely distinct from radiation-
induced angiosarcoma of other locations, as depicted by the difference in the latency period
in several studies, which is shorter in the former (approximately 7 years versus 10–30 years,
respectively) [31,67,68]. A more recent comparative study reported a mean latency of
6.7 versus 20.9 years for breast and non-breast angiosarcoma, respectively [28].

Table 1. Clinicopathological differences between primary and radiation-induced breast sarcoma.

Primary Breast Sarcoma Radiation-Induced Breast Sarcoma

Frequency Rare Rare
Depends on first cancer age and
Age 5th–6th decade
latency period
Young age of RT, long latency period,
Unknown, genetic
Risk factors high radiation dosage, alkylating
predisposition
agents, genetic predisposition
Unilateral breast lump, discoloration,
purplish-red nodules, thickening or
Clinical presentation Unilateral breast lump
elevation of the skin, and a diffuse
pattern of extension
Histology UPS, FS, AS AS
Prognosis Poor Poor

The clinical presentation of RIBS is analogous to PBS. Most patients present with a
unilateral, painless breast lump arising within the irradiated region, with a median diameter
of approximately 5 cm in most series (Table 2). Irradiated fields may be more fibrotic or
sclerotic, rendering physical examination and evaluation of the lesion more difficult. RIBA
have distinct clinical findings, including discoloration, purplish-red nodules, thickening or
elevation of the skin, and a diffuse pattern of extension. There is often a delay in diagnosis,
as typical lesions mimic ecchymosis, eczema, and benign post-radiation skin changes [69].
Consequently, the window of opportunity for timely treatment can be lost. Multifocality is
another common feature of RIBA, combined with microsatellite lesions, in some cases. An
Int. J. Mol. Sci. 2022, 23, 4125 7 of 18

initial indolent phase corresponding to low-grade RIBA is possible, followed by a sudden

local progression coupled with high-grade histology [33].

Table 2. Clinicopathological findings of retrospective studies including ≥10 cases of radiation-induced

breast sarcoma (excluding bone sarcomas). The mean value of age at diagnosis and primary tumor
diameter (T) is reported instead of the median, when the latter is not available. NA: Not available.

Year of Treatment Median Age Latency Period

Author Total N AS (%) Median T (cm)
Publication Period (Years) (Years)
Karlsson 1998 1958–1992 67 47.8 NA NA NA
Lagrange 2000 1975–1995 14 42.9 65.5 NA NA
Blanchard 2002 1975–2001 34 35.3 62.3 (mean) 12.7 (mean) NA
Billings 2004 <2004 27 100 70 4.9 4
Kirova 2005 1984–2005 18 72.2 66.5 7.3 NA
Sher 2007 1965–2002 13 100 72 7 NA
Hodgson 2007 1981–2000 31 100 72.9 (mean) 5.2 (mean) NA
Palta 2010 1997–2006 14 100 66.5 7.7 NA
Pencavel 2011 1996–2006 19 78.9 61 (mean) NA NA
Seinen 2012 1990–2009 35 100 67 7 4
Fraga-Guedes 2012 1999–2009 20 100 66 7.5 2.8
Torres 2013 1993–2011 95 100 71 7 5
Linthorst 2013 2000–2011 23 100 70 8.8 NA
D’Angelo 2013 1982–2011 79 100 68 7 4.2
Cohen-Hallaleh 2017 2000–2014 49 100 72 7.5 5
Gervais 2017 1994–2014 20 100 71 8 5–10
Yin 2017 1973–2012 173 100 70–74 NA NA
Abdou 2019 1990–2015 13 100 71 7.8 6.9
Rombouts 2019 1989–2017 209 100 73 8 NM
Gutkin 2020 1998–2019 34 100 72 6.9 5.6 (mean)

AVL, on the other hand, arises in irradiated skin as solitary or multiple well-circumscribed,
small, flesh-colored/reddish papules, or small erythematous patches/plaques, with a
mean diameter of 8 mm (1–60 mm). Usually, these lesions are limited to superficial and
middermis, although cases extending into the deep dermis and subcutis have also been
described [36,38]. In one study, angiosarcomas presented as larger lesions compared to
AVLs (median diameter of 7.5 cm versus 0.5 cm) [70]. The latency period of AVL is shorter,
ranging from 3.5 to 6 years [36–38,70].
Similar to BS in general, mammography and ultra-sound findings of RIBS are not
specific. False negative results can be obtained in the case of breast angiosarcoma, since
both post-RT, and angiosarcoma-related skin changes may be mammographically indis-
tinct [71,72]. According to available data, around 33% of angiosarcomas are not detected
in mammography [73]. MRI can accurately detect tumor extension. Pronounced skin en-
hancement is a constant MRI finding of RIBA [74]. A large retrospective study of RIBA [71]
reported diffuse T2 high-signal skin thickening, with persistent enhancement and rapidly
enhanced T1-weighted images in all patients. Seven out of sixteen patients showed nodular
foci of rapid, early arterial enhancement with washout hypointense lesions on T2-weighted
images. Only four patients displayed distinct intraparenchymal masses.

6. Management of Early Disease

As for all STS, the optimal management of RIBS should be discussed by a multi-
disciplinary team following biopsy, in order to plan the best therapeutic strategy. The
cornerstone of the treatment of localized disease is surgery, while the beneficial effect of
adjuvant therapies in resectable disease remains unclear. The tumor growth pattern and
involvement of the surrounding tissues will determine the correct therapeutic strategy,
taking into consideration the previous treatment modalities of these patients.
Int. J. Mol. Sci. 2022, 23, 4125 8 of 18

6.1. Surgery
Positive surgical margins have been consistently reported to have a detrimental impact
in overall survival [4,23,30,75] and a higher risk of local recurrence [76], turning this into
the most important prognostic factor. Closer margins have also been associated with a
higher risk of local recurrence when compared to wider margins [76], although this issue
may be discussed, since McGowan et al. [30] concluded, after the analysis of a large breast
sarcoma cohort with 26 RIS, that negative margins are adequate, irrespective of how close
they are, but the tendency for satellite deposits of RIBA suggests that margins of 2 to 5 cm
are preferable [33,77,78].
Prior RT-related tissue changes and the diffusively infiltrative margins of angiosarcoma
make the complete excision of the tumor a surgical challenge, mandating the performance
of surgery at experienced, high-volume centers. Pencavel et al. [3] retrospectively analyzed
a large series of breast sarcomas, including both PBS and SBS, and indicated a better
prognosis when the primary surgery was performed in a high-volume tertiary sarcoma
center, when compared to patients who were referred to complete their treatment after
a primary surgery with margin involvement. Unfortunately, these data support that
wide local excision (WLE) may only be an option for low-grade tumors of up to 5 cm
of diameter. The excision of all irradiated tissues should be preferred, and mastectomy
more often achieves negative margins compared to WLE [78]. In most series, the majority
of patients underwent mastectomy [3,22,31,32,78–80], providing a robust base of data for
recommending this approach.
As with other STS, BS rarely metastasize to regional lymph nodes. In most series,
only anecdotal cases of nodal metastases are reported [81]. According to a large Surveil-
lance, Epidemiology, and End Results (SEER) database study, approximately 40% of breast
sarcoma patients undergo some degree of lymphadenectomy, with only 6/246 positive
cases [82]. In most studies with RIBS, the incidence of nodal metastasis is not mentioned or
not investigated, while those reporting any regional lymph-node involvement corroborate
the low incidence indicated by the SEER. However, only one series of 20 RIBA patients
from Brazil [83] reports a higher frequency of axillary nodal involvement, with two patients
initially diagnosed with axillary metastases and another four with axillary recurrence.
The available data support that sentinel lymph node biopsy, or systematic lymph-node
dissection, is not indicated as part of the treatment of RIBS.
Approximately one out of two patients will present local recurrence, despite an initial
wide surgical treatment. Resection of local recurrence improves local control and survival,
with an estimated benefit in overall survival of over two years (34 versus 6 months) [78].

6.2. Radiation Therapy

The natural history of RIBS, in conjunction with the fact that surrounding or underlying
tissues have probably received the maximum tolerated dose of radiation, render clinicians
reluctant to include radiation in the therapeutic plan. In contrast, the aggressiveness of
RIBS and especially angiosarcomas, as manifested by the high local recurrence rate, fosters
the interest in evaluating additional treatment modalities, such as RT. In most series, only a
small percentage of patients with resected disease underwent adjuvant RT without being
associated with a better prognosis (Table 3). The rationale of patient selection for RT is not
always clear and depends on the local practice and the experience of each group. Therefore,
we cannot draw any definite conclusions on the role of RT in the management of RIBS.
A limited number of studies have shown a meaningful clinical benefit of the use
of adjuvant RT. A large systematic review analyzed the role of adjuvant RT in RIBA;
17% of the patients received reirradiation, which was associated with local recurrence-free
survival (LRFS) prolongation (5-year LRFS 57% versus 34% in patients who did not undergo
adjuvant RT) [84]. Modesto et al. reported a trend for OS benefit in patients who received
adjuvant RT for RT-induced sarcomas in general [85]. Lastly, an improved prognosis was
demonstrated by two studies that included both primary and secondary tumors with
adjuvant RT in breast angiosarcomas in general [30,86]. On the contrary, a detrimental
Int. J. Mol. Sci. 2022, 23, 4125 9 of 18

effect of reirradiation on survival emerged by multivariate analysis in a population-based

USA cohort study using the SEER database [87]. Whether this finding reflects patients’
vulnerability to RT damage or is due to confounding factors has yet to be defined.

Table 3. Treatment modalities and prognosis of radiation-induced breast sarcoma in retrospective

studies including ≥10 cases (excluding bone sarcomas). NA: Not available.

Year of Nodal Type of Margin Adjuvant (neo)Adjuvant OS/DFS Prognostic

Author
Publication Involvem. Surgery (N) Status (N) RT (%) Chemo (%) (Years) Association
Karlsson 1998 NA NA NA NA NA NA no
2 MA,
Lagrange 2000 NA 2 R2 28.6 35.7 NA surgery
8 WLE
30/34
Blanchard 2002 NA NA 30 43 NA size
surgery
10 MA,
Billings 2004 NA NA 10 20 NA no
10 WLE
11 MA,
Kirova 2005 NA NA 5.6 5.6 mOS = 22 m no
5 WLE
12 MA,
Sher 2007 NE NA 0 NA NA size
1 WLE
25 MA,
Hodgson 2007 NA NA 0 NA NA no
1 WLE
benefit of HART in
100 5y-OS = 86%,
Palta 2010 2/14 14 MA NA 0 addition to
(HART) 5y-PFS = 64%
surgery
12 MA, mDFS = 30 m. surgery at
Pencavel 2011 0/3 NA NA NA
6 WLE 5y-DFS = 26% experienced center
amenable to
24 MA, 23 R0,
Seinen 2012 NA 3.2 3.2 mDFS = 16 m surgery for local
7 WLE 1R1, 7 R2
recurrence
Fraga-Guedes 2012 0 15 MA NA 10 50 5y-OS = 28.2% grade, prior RT
60 MA, 81 RO,
Torres 2013 0 0 52 5y-OS = 91% size
27 WLE 4 R1, 4 R2
4/11 R0, reRT +
10 MA,
Linthorst 2013 NA 6/11 R1, 34.8 0 mOS = 18 m hyperthermia
1 WLE
1/11 R2 (local control)
65 MA, 45 R0,
D’Angelo 2013 NA NA 11.4 mDSS = 3 y. age > 68 y, depth
13 WLE 12 R1, 8 R2
mOS = 37 m
Cohen-Hallaleh 2017 NE 38 MA 32/37 R0 0 19.1 size, resectability
(resectable)
19 MA,
Gervais 2017 NA 18 R0 35 50 mOS = 51 m no
1 WLE
Yin 2017 NA NA NA 12.7 NA mOS = 32 m age, tumor spread
Abdou 2019 NA 9 MA NA 7.7 61.5 mOS = 64.2 m no
Rombouts 2019 NA NA NA 9.1 1.4 5y-OS = 40.5% no
27 MA,
Gutkin 2020 0 12 R0, 6 R1 8.8 44.1 mOS = 16.9 y chemotherapy
4 WLE

Hyperfractionated accelerated RT (HART) may be of particular benefit to RIBS. It

has been evaluated as neoadjuvant or adjuvant therapy for secondary angiosarcomas.
The small fractional doses and the moderate total dose, combined with the large field
margins over a short period, provide a scientific rationale for its use in this type of highly
proliferative tumor, with a good tolerance. Fourteen patients with RIBA received HART at
the University of Florida, six after surgery and eight as the initial treatment [33,88]. The
technique consisted of three RT treatments per day, with a dose of 1 Gy per fraction, and
varying total doses depending on the risk for subclinical disease. In all seven patients that
underwent surgery after HART, a pathologic complete response was noted. The outcomes
of the whole group are very promising, with a median OS of at least 7 years, a 5-year OS of
86%, and an acceptable toxicity.
RT in combination with hyperthermia has also been proposed in the localized set-
ting, in the case of both resectable and unresectable disease. Two small studies from the
Netherlands evaluated this treatment modality in RIS and angiosarcomas of the chest
wall, reporting an improvement in local control [80,89]. In the first study, the combination
Int. J. Mol. Sci. 2022, 23, 4125 10 of 18

therapy was administered mainly in patients with unresectable disease with a response
rate of 75%, whereas in the second case, the therapy was also delivered in the adjuvant
setting. However, the median overall survival in these studies was 1–1.5 years.

6.3. Systemic Therapy (Adjuvant/Neoadjuvant Chemotherapy)

Similar to other STS, the role of adjuvant chemotherapy in breast sarcoma and RIBS,
in particular, remains uncertain. In most retrospective studies, only a small number
of patients, if any, received chemotherapy after complete surgical resection (Table 3),
with no documented impact on survival [25,26,79,83,90]. However, there are some data
supporting a benefit from adjuvant chemotherapy in angiosarcoma patients. Evidence
of OS benefit was reported by Stanford, in a small study including 34 secondary breast
angiosarcoma patients [91]. The survival benefit was not found in patients with primary
angiosarcoma. A larger study of RT-induced angiosarcoma of the breast and chest wall
from M.D. Anderson, in which approximately half of the patients were given perioperative
chemotherapy (mostly adjuvant), demonstrated a lower risk for local recurrence with
chemotherapy [31]. A small study of primary and secondary breast angiosarcoma reported
a trend towards an improved RFS with chemotherapy, which was not confirmed in a meta-
analysis of almost 1000 breast angiosarcomas [92]. Lastly, a recent nationwide analysis of
breast angiosarcomas in the USA revealed a prolonged OS in patients with large tumors
(>5 cm) who underwent adjuvant chemotherapy [93].
There is an obvious paucity of data regarding the role of adjuvant chemotherapy in
RIBS. The current studies are small, and in the larger ones, only a small subset of patients
received chemotherapy. Only a few studies separately analyze secondary breast sarcomas.
Furthermore, the selection criteria forchemotherapy are not consistent in these studies,
and only in a few cases are the criteria clearly defined. In the study from M.D. Anderson,
for example, chemotherapy was used for large or high-grade tumors in the case of close
surgical margins [31]. Likewise, in a single-institution study from Brazil, patients with
tumors larger than 2 cm or of high-grade were treated with chemotherapy [83].
The data for neoadjuvant chemotherapy are even scarcer. It is definitely an option
for locally advanced inoperable disease, with some theoretical advantages, including the
potential downsizing of the tumor and the facilitation of R0 resection [72]. In a retrospective
series of RIBA from Royal Marsden, neoadjuvant chemotherapy was delivered in the case
of seven unresectable tumors, of which three were finally operated and two had patholog-
ical complete response (pCR) [76]. In addition, the evidence on the role of neoadjuvant
chemotherapy comes from a limited number of case-reports [94–96]. It should be noted
that histotype-tailored chemotherapy regimens should be used, which was the case in the
above reports. Angiosarcoma, in comparison to other STS histotypes, seems to be more
chemosensitive, rendering neoadjuvant chemotherapy an acceptable approach.

7. Management of Inoperable/Metastatic Disease

7.1. Chemotherapy
Chemotherapy represents the standard first-line treatment in the advanced setting.
There is very limited evidence on the activity of the different drugs in RIBS in particular,
with the exception of some reports on breast angiosarcoma, and most data are extrapolated
from STS trials. Anthracyclines monotherapy, or in combination with ifosfamide, constitute
the mainstay of treatment in metastatic STS. Sher et al. reported an overall response rate
(ORR) of 48% in 29 metastatic breast angiosarcomas to first-line anthracycline-ifosfamide
or gemcitabine-taxane cytotoxic chemotherapy combination, concluding that the disease is
quite chemosensitive [79]. It should be noted, however, that anthracyclines would likely
have been used already for early breast cancer, limiting its administration to the maximum
cumulative dose.
Paclitaxel is considered active against angiosarcomas and breast angiosarcoma in par-
ticular, making it an important treatment option after anthracycline, or even in the first-line
setting. In the ANGIOTAX study, a small French phase II study of 30 angiosarcoma pa-
Int. J. Mol. Sci. 2022, 23, 4125 11 of 18

tients, of which 33% had breast angiosarcoma, the PFS at four months was 45% [24].Weekly
paclitaxel was compared with doxorubicin as a fist-line treatment in a retrospective study
of 117 metastatic angiosarcomas, of which 36 had secondary and 28 had cutaneous an-
giosarcoma [97]. The two drugs were found equal regarding PFS. Cutaneous angiosarcoma
exhibited a higher response rate to paclitaxel compared to non-cutaneous angiosarcoma,
and radiation-induced angiosarcomas exhibited more objective responses to both drugs
when compared to primary tumors. According to a retrospective series that evaluated RIBA
specifically, the median treatment time (MTT) on first-line paclitaxel was 3.5 months [98].
Both of the above drugs show dose-limiting toxic effects (cardiac and neurological).
Gemcitabine is another chemotherapeutic agent that can be used in the treatment of RIBS.
It was evaluated retrospectively as single agent in 25 angiosarcomas from the Italian Rare
Cancer Network (including eight radiation-induced angiosarcomas and seven RIBA). The
ORR was 68%, the median PFS was 7 months, and the median OS was 17 months [99]. Six
out of eight radiation-induced angiosarcomas responded to the drug. Gemcitabine can
also be combined with docetaxel, with an increased ORR, although there is no data on
breast sarcoma in particular. In addition, liposomal pegylated doxorubicin, trabectedin,
and navelbine are other therapies that can be used, based on extrapolated evidence from
STS trials.

7.2. Bevacizumab
Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are expressed
in breast angiosarcomas [100] and angiosarcomas in general [101], and they likely play a
significant role in carcinogenesis and angiosarcoma progression. VEGFR expression was
associated with grade 1 or 2 angiosarcoma of the breast [100], whereas specific data regard-
ing RIBA (usually a grade 3 tumor) are lacking. Bevacizumab is a monoclonal antibody
targeting VEGF that is approved for the treatment of different tumors. The activity of
bevacizumab monotherapy was demonstrated in a small study of epithelioid hemangioen-
dothelioma and angiosarcoma, including four patients with breast angiosarcoma [102]. Of
the 30 patients, 15 exhibited stable disease and four had a partial response. The combi-
nation of bevacizumab and paclitaxel was also compared to paclitaxel monotherapy in a
randomized phase 2 study of 49 angiosarcoma patients, of which 24 had a primary breast
tumor and 24 had a history of RT [103]. The combination was more toxic and did not
improve efficacy, although there was no separate analysis for breast sarcoma.

7.3. Tyrosine Kinase Inhibitors

In addition to VEGF/VEGFR, other receptor tyrosine kinases (RTK) have been shown
to be expressed or upregulated at the mRNA level in some STS, such as PDGFR [104].
Pazopanib is a small multi-targeted tyrosine kinase inhibitor (TKI) against VEGFR1,
VEGFR2, VEGFR3, and PDGFR, which is approved for the treatment of metastatic STS
after anthracycline-based chemotherapy, or in the first line of treatment in patients not
eligible for this therapy [105]. A retrospective EORTC study of pazopanib in advanced
vascular sarcomas revealed an ORR of 20% in 40 angiosarcoma patients, which was similar
in radiation-induced and non-radiation-induced angiosarcomas [106].
Sorafenib is another multikinase inhibitor targeting Raf, PDGF, VEGFR2, VEGFR3,
and c-Kit. In a phase 2 trial of STS, sorafenib was found active only against angiosarcoma,
with 5/37 showing at least partial response [107]. Three of the five patients who responded
to treatment had RIBA, and the remaining two had angiosarcoma of the head and neck.
However, in the phase 2 S050 trial, which evaluated sorafenib in selected STS histotypes,
including five angiosarcomas, no responses were noted according to RECIST criteria, while
a clinical benefit was observed in the majority of angiosarcoma patients [108]. The first
study, from Memorial Sloan Kettering Cancer Center (MSKCC), that evaluated systemic
therapies specifically in RIBA, used median treatment time (MTT) on the first line as an
outcome measurement and found the longest MTT of 25.1 months with sorafenib [98]. This
result may be due to MYC and FLT4 co-amplifications harbored by some RIBA [109].
Int. J. Mol. Sci. 2022, 23, 4125 12 of 18

A high positivity for Kit RTK by IHC has been demonstrated in a small study of RIS,
including RIBAs, which is not coupled with exon 11 mutations [110]. Whether Kit expres-
sion drives oncogenesis or not remains unknown. However, this observation provides a
rationale for imatinib testing in RIBS.

7.4. Immunotherapy
Immunotherapy (IO) constitutes a novel approach in the armamentarium against
cancers. The immune profile of RIS was explored in a small study of 20 cases, including
three angiosarcomas [111]. A higher mutational rate was found, compared to other cancer
types, coupled with 45% positivity to PD1/PDL1 and tumor-infiltrating lymphocytes,
whereas primary breast angiosarcomas exhibit a lower PDL1 expression [112]. In most
studies of immune checkpoint inhibitors (ICI), as a monotherapy or in combinations, for the
treatment of STS, breast sarcomas were underrepresented. It is worth mentioning that there
are some isolated responses reported in angiosarcomas, without information on tumor
location or radiation history [113,114]. In a small retrospective series of angiosarcomas,
responses to ICI have been reported for seven patients, including a patient with RIBA [115].

8. Prognosis
Prognosis of breast sarcomas is highly dependent upon histotype, histological grade,
and tumor size [25,30,31,76,116]. The extent of surgery and margin status is also an im-
portant prognostic factor. In general, RIS are considered as aggressive tumors. In a large
multivariate analysis that adjusted for age, tumor size, depth, and margin status, it was
demonstrated that RIS are associated with inferior survival rate compared to sporadic STS,
and previous radiotherapy is an independent prognostic factor [117]. For these patients,
previous treatments and subsequent side effects (i.e., bone marrow dysfunction) also reduce
therapeutic options.
Furthermore, the high frequency of angiosarcoma histology among RIBS partially
accounts for their aggressive behavior. Both primary and therapy-related angiosarcomas
have been associated with poor prognosis. Although some studies report a worse prognosis
of RIBA compared to PBA [83,86,87], it has not been confirmed in all series [32,66,81]. In
most of these studies, survival endpoints have been compared between primary and
secondary breast angiosarcomas without analyzing potential confounding factors, such as
tumor grade and stage. Only the USA comparative cohort study from the SEER database
adjusted for prognostic characteristics of patients and concluded that the worse prognosis
of RIBA was due to advanced stage, grade, and age [87].
More specifically, in the older studies, the median OS for RIBA was approximately
two to three years [78,80,83] (Table 3). Early local recurrences are reflected by a short LRFS
of 1.29 year in the MSKCC series, in which tumor depth was associated with RFS, and one
out of four patients with local recurrence died of the disease [98]. However, there are recent
data from large series reporting longer survival. A median OS of five years was reported in
a large UK study [81]. According to a recent study analyzing a national database from the
Netherlands, 5-year and 10-year OS in RIBA patients was 40.5% and 25%, respectively [61].
A higher 5-year OS of 63.5% was found in a study from Stanford, in which most patients
received total mastectomy plus wide excision of the skin [91]. This improved survival
rate is likely due to the increased awareness of RIBA and the multimodal management
of sarcomas.

9. Conclusions and Perspectives

Radiation-induced breast sarcomas represent an iatrogenic disease with distinct char-
acteristics, such as a shorter latency period compared to other RIS. Although they are very
rare, their incidence has increased in recent years, most likely due to the establishment
of breast-conserving surgery in conjunction with adjuvant RT for the treatment of BC.
Notwithstanding, their incidence is still so low that the benefits of RT for BC outweigh the
risk for SBS. The improvement of radiation techniques in the future is warranted to prevent
Int. J. Mol. Sci. 2022, 23, 4125 13 of 18

this disease. RIBS are, in general, aggressive tumors with poor prognosis, driven at least
partially by the high incidence of angiosarcoma histology and grade 3 tumors. RIBA is the
most common subtype of RIBS and has unique histological, molecular, and clinical features.
For localized disease, early diagnosis allowing for proper surgery with negative
margins is the only chance for cure. Given the high rate of local recurrence and the
challenging surgical management in RIBA, including the assessment of tumor margins, we
believe that an aggressive approach, i.e., mastectomy, is indicated. In addition, the poor
outcomes, even in series with negative margins, may suggest that surgery alone is not
curative, and maximum treatment should be offered to RIBA patients. There is limited
evidence for LRFS prolongation with adjuvant RT. Improved global outcomes have been
reported with HART, making it an interesting treatment option to evaluate further. Despite
the very limited data on adjuvant/neoadjuvant chemotherapy, we recommend its use in
fit patients. Randomized trials through international collaboration assessing the role of
adjuvant therapies should be a priority.
In the advanced setting, there are limited therapeutic options, most of which have not
been tested in RIBS or RIBA patients. The need for histotype-tailored therapies, as well as
personalized therapies based on molecular profiling, has emerged in the management of
STS. Next-generation sequencing data on RIBS and RIBA are required, as no molecular
candidates have yet been recognized to guide targeted treatments. For example, a small
study demonstrated that 10% of patients with primary and secondary angiosarcomas
uniquely to the breast exhibit activating mutations in KDR (also known as VEGFR2) [118].
VEGFR inhibitors could be studied in these tumors, based on their activity in vitro. In addi-
tion, immunohistochemical studies in angiosarcomas, including both RIBA and primary
breast angiosarcomas, have shown activation of the PIK3CA/Akt/mTOR pathway in an
important subset of the disease [97,116]. Therefore, mTOR and PIK3CA inhibitors may
be relevant targeted therapies to explore. The mTOR inhibitor sirolimus, in combination
with cyclophosphamide, was evaluated in a small study of different STS, leading to SD in
approximately 20% of patients [119]. In the study from MSKCC, one RIBA patient received
sirolimus, with a MTT of 14.9 months [98]. Finally, the relatively high levels of immunother-
apy biomarkers in RIS should be further investigated in larger studies, specifically in RIBS.
If these results are confirmed, immune checkpoint inhibitors or other IO approaches should
be tested in clinical trials.
To conclude, the current therapies which are beneficial for RIBS are very limited, both
in the early and the advanced settings. There is an urgent medical need for new therapies
to reversethe current dismal prognosis.

Author Contributions: Conceptualization, S.K. and S.T.; methodology, S.K.; validation, J.D.M. and
S.T.; formal analysis, J.K.; investigation, S.K.; data curation, J.D.M.; writing—original draft prepara-
tion, S.K.; writing—review and editing, S.T. and J.D.M.; supervision, S.T. and J.K. All authors have
read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

References
1. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer Statistics. CA Cancer J. Clin. 2020, 70, 7–30. [CrossRef]
2. Adem, C.; Reynolds, C.; Ingle, J.N.; Nascimento, A.G. Primary Breast Sarcoma: Clinicopathologic Series from the Mayo Clinic
and Review of the Literature. Br. J. Cancer 2004, 91, 237–241. [CrossRef]
3. Pencavel, T.; Allan, C.P.; Thomas, J.M.; Hayes, A.J. Treatment for Breast Sarcoma: A Large, Single-Centre Series. Eur. J. Surg.
Oncol. 2011, 37, 703–708. [CrossRef]
4. Confavreux, C.; Lurkin, A.; Mitton, N.; Blondet, R.; Saba, C.; Ranchère, D.; Sunyach, M.-P.; Thiesse, P.; Biron, P.; Blay, J.-Y.; et al.
Sarcomas and Malignant Phyllodes Tumours of the Breast—A Retrospective Study. Eur. J. Cancer 2006, 42, 2715–2721. [CrossRef]
Int. J. Mol. Sci. 2022, 23, 4125 14 of 18

5. Barrow, B.J.; Janjan, N.A.; Gutman, H.; Benjamin, R.S.; Allen, P.; Romsdahl, M.M.; Ross, M.I.; Pollock, R.E. Role of Radiotherapy in
Sarcoma of the Breast—A Retrospective Review of the M.D. Anderson Experience. Radiother. Oncol. 1999, 52, 173–178. [CrossRef]
6. Zelek, L.; Llombart-Cussac, A.; Terrier, P.; Pivot, X.; Guinebretiere, J.M.; Le Pechoux, C.; Tursz, T.; Rochard, F.; Spielmann, M.; Le Cesne, A.
Prognostic Factors in Primary Breast Sarcomas: A Series of Patients with Long-Term Follow-Up. J. Clin. Oncol. 2003, 21, 2583–2588.
[CrossRef] [PubMed]
7. Lahat, G.; Lev, D.; Gerstenhaber, F.; Madewell, J.; Le-Petross, H.; Pollock, R.E. Sarcomas of the Breast. Expert Rev. Anticancer Ther.
2012, 12, 1045–1051. [CrossRef] [PubMed]
8. Duncan, M.A.; Lautner, M.A. Sarcomas of the Breast. Surg. Clin. N. Am. 2018, 98, 869–876. [CrossRef]
9. Bousquet, G.; Confavreux, C.; Magné, N.; de Lara, C.T.; Poortmans, P.; Senkus, E.; de Lafontan, B.; Bolla, M.; Largillier, R.;
Lagneau, E.; et al. Outcome and Prognostic Factors in Breast Sarcoma: A Multicenter Study from the Rare Cancer Network.
Radiother. Oncol. 2007, 85, 355–361. [CrossRef]
10. Brady, M.S.; Garfein, C.F.; Petrek, J.A.; Brennan, M.F. Post-Treatment Sarcoma in Breast Cancer Patients. Ann. Surg. Oncol. 1994, 1,
66–72. [CrossRef]
11. Lagrange, J.L.; Ramaioli, A.; Chateau, M.C.; Marchal, C.; Resbeut, M.; Richaud, P.; Lagarde, P.; Rambert, P.; Tortechaux, J.;
Seng, S.H.; et al. Sarcoma after Radiation Therapy: Retrospective Multiinstitutional Study of 80 Histologically Confirmed Cases.
Radiology 2000, 216, 197–205. [CrossRef] [PubMed]
12. Huang, J.; Mackillop, W.J. Increased Risk of Soft Tissue Sarcoma after Radiotherapy in Women with Breast Carcinoma. Cancer
2001, 92, 172–180. [CrossRef]
13. Voutsadakis, I.A.; Zaman, K.; Leyvraz, S. Breast Sarcomas: Current and Future Perspectives. Breast 2011, 20, 199–204. [CrossRef] [PubMed]
14. Karlsson, F.; Granath, F.; Smedby, K.E.; Zedenius, J.; Bränström, R.; Nilsson, I.-L. Sarcoma of the Breast: Breast Cancer History as Etiologic
and Prognostic Factor-A Population-Based Case-Control Study. Breast Cancer Res. Treat. 2020, 183, 669–675. [CrossRef] [PubMed]
15. Yap, J.; Chuba, P.J.; Thomas, R.; Aref, A.; Lucas, D.; Severson, R.K.; Hamre, M. Sarcoma as a Second Malignancy after Treatment
for Breast Cancer. Int. J. Radiat. Oncol. Biol. Phys. 2002, 52, 1231–1237. [CrossRef]
16. Karlsson, P.; Holmberg, E.; Samuelsson, A.; Johansson, K.A.; Wallgren, A. Soft Tissue Sarcoma after Treatment for Breast
Cancer—A Swedish Population-Based Study. Eur. J. Cancer 1998, 34, 2068–2075. [CrossRef]
17. Cahan, W.G.; Woodard, H.Q.; Higinbotham, N.L.; Stewart, F.W.; Coley, B.L. Sarcoma Arising in Irradiated Bone: Report of Eleven
Cases. Cancer 1998, 82, 8–34. [CrossRef]
18. Arlen, M.; Higinbotham, N.L.; Huvos, A.G.; Marcove, R.C.; Miller, T.; Shah, I.C. Radiation-Induced Sarcoma of Bone. Cancer 1971,
28, 1087–1099. [CrossRef]
19. Cha, C.; Antonescu, C.R.; Quan, M.L.; Maru, S.; Brennan, M.F. Long-Term Results with Resection of Radiation-Induced Soft
Tissue Sarcomas. Ann. Surg. 2004, 239, 903–910. [CrossRef]
20. Mark, R.J.; Poen, J.; Tran, L.M.; Fu, Y.S.; Selch, M.T.; Parker, R.G. Postirradiation Sarcomas. A Single-Institution Study and Review
of the Literature. Cancer 1994, 73, 2653–2662. [CrossRef]
21. Al-Benna, S.; Poggemann, K.; Steinau, H.-U.; Steinstraesser, L. Diagnosis and Management of Primary Breast Sarcoma. Breast
Cancer Res. Treat. 2010, 122, 619–626. [CrossRef] [PubMed]
22. Kirova, Y.M.; Vilcoq, J.R.; Asselain, B.; Sastre-Garau, X.; Fourquet, A. Radiation-Induced Sarcomas after Radiotherapy for Breast
Carcinoma: A Large-Scale Single-Institution Review. Cancer 2005, 104, 856–863. [CrossRef] [PubMed]
23. Neuhaus, S.J.; Pinnock, N.; Giblin, V.; Fisher, C.; Thway, K.; Thomas, J.M.; Hayes, A.J. Treatment and Outcome of Radiation-
Induced Soft-Tissue Sarcomas at a Specialist Institution. Eur. J. Surg. Oncol. 2009, 35, 654–659. [CrossRef]
24. Penel, N.; Bui, B.N.; Bay, J.-O.; Cupissol, D.; Ray-Coquard, I.; Piperno-Neumann, S.; Kerbrat, P.; Fournier, C.; Taieb, S.; Jimenez, M.; et al.
Phase II Trial of Weekly Paclitaxel for Unresectable Angiosarcoma: The ANGIOTAX Study. J. Clin. Oncol. 2008, 26, 5269–5274.
[CrossRef] [PubMed]
25. Blanchard, D.K.; Reynolds, C.; Grant, C.S.; Farley, D.R.; Donohue, J.H. Radiation-Induced Breast Sarcoma. Am. J. Surg. 2002, 184,
356–358. [CrossRef]
26. Billings, S.D.; McKenney, J.K.; Folpe, A.L.; Hardacre, M.C.; Weiss, S.W. Cutaneous Angiosarcoma Following Breast-Conserving
Surgery and Radiation: An Analysis of 27 Cases. Am. J. Surg. Pathol. 2004, 28, 781–788. [CrossRef] [PubMed]
27. Stewart, F.W.; Treves, N. Lymphangiosarcoma in Postmastectomy Lymphedema; a Report of Six Cases in Elephantiasis Chirurgica.
Cancer 1948, 1, 64–81. [CrossRef]
28. Hung, J.; Hiniker, S.M.; Lucas, D.R.; Griffith, K.A.; McHugh, J.B.; Meirovitz, A.; Thomas, D.G.; Chugh, R.; Herman, J.M. Sporadic
versus Radiation-Associated Angiosarcoma: A Comparative Clinicopathologic and Molecular Analysis of 48 Cases. Sarcoma 2013,
2013, 798403. [CrossRef]
29. De Smet, S.; Vandermeeren, L.; Christiaens, M.-R.; Samson, I.; Stas, M.; Van Limbergen, E.; De Wever, I. Radiation-Induced
Sarcoma: Analysis of 46 Cases. Acta Chir. Belg. 2008, 108, 574–579. [CrossRef]
30. McGowan, T.S.; Cummings, B.J.; O’Sullivan, B.; Catton, C.N.; Miller, N.; Panzarella, T. An Analysis of 78 Breast Sarcoma Patients
without Distant Metastases at Presentation. Int. J. Radiat. Oncol. Biol. Phys. 2000, 46, 383–390. [CrossRef]
31. Torres, K.E.; Ravi, V.; Kin, K.; Yi, M.; Guadagnolo, B.A.; May, C.D.; Arun, B.K.; Hunt, K.K.; Lam, R.; Lahat, G.; et al. Long-Term
Outcomes in Patients with Radiation-Associated Angiosarcomas of the Breast Following Surgery and Radiotherapy for Breast
Cancer. Ann. Surg. Oncol. 2013, 20, 1267–1274. [CrossRef]
Int. J. Mol. Sci. 2022, 23, 4125 15 of 18

32. Hodgson, N.C.; Bowen-Wells, C.; Moffat, F.; Franceschi, D.; Avisar, E. Angiosarcomas of the Breast: A Review of 70 Cases. Am. J.
Clin. Oncol. 2007, 30, 570–573. [CrossRef] [PubMed]
33. Palta, M.; Morris, C.G.; Grobmyer, S.R.; Copeland, E.M.; Mendenhall, N.P. Angiosarcoma after Breast-Conserving Therapy:
Long-Term Outcomes with Hyperfractionated Radiotherapy. Cancer 2010, 116, 1872–1878. [CrossRef] [PubMed]
34. Fineberg, S.; Rosen, P.P. Cutaneous Angiosarcoma and Atypical Vascular Lesions of the Skin and Breast after Radiation Therapy
for Breast Carcinoma. Am. J. Clin. Pathol. 1994, 102, 757–763. [CrossRef] [PubMed]
35. Brodie, C.; Provenzano, E. Vascular Proliferations of the Breast. Histopathology 2008, 52, 30–44. [CrossRef]
36. Fraga-Guedes, C.; Gobbi, H.; Mastropasqua, M.G.; Rocha, R.M.; Botteri, E.; Toesca, A.; Viale, G. Clinicopathological and
Immunohistochemical Study of 30 Cases of Post-Radiation Atypical Vascular Lesion of the Breast. Breast Cancer Res. Treat. 2014,
146, 347–354. [CrossRef]
37. Brenn, T.; Fletcher, C.D.M. Postradiation Vascular Proliferations: An Increasing Problem. Histopathology 2006, 48, 106–114. [CrossRef]
38. Patton, K.T.; Deyrup, A.T.; Weiss, S.W. Atypical Vascular Lesions after Surgery and Radiation of the Breast: A Clinicopathologic Study of
32 Cases Analyzing Histologic Heterogeneity and Association with Angiosarcoma. Am. J. Surg. Pathol. 2008, 32, 943–950. [CrossRef]
39. Mattoch, I.W.; Robbins, J.B.; Kempson, R.L.; Kohler, S. Post-Radiotherapy Vascular Proliferations in Mammary Skin: A Clinico-
pathologic Study of 11 Cases. J. Am. Acad. Dermatol. 2007, 57, 126–133. [CrossRef]
40. Heymann, S.; Delaloge, S.; Rahal, A.; Caron, O.; Frebourg, T.; Barreau, L.; Pachet, C.; Mathieu, M.-C.; Marsiglia, H.; Bourgier, C.
Radio-Induced Malignancies after Breast Cancer Postoperative Radiotherapy in Patients with Li-Fraumeni Syndrome. Radiat.
Oncol. 2010, 5, 104. [CrossRef]
41. Le, A.N.; Harton, J.; Desai, H.; Powers, J.; Zelley, K.; Bradbury, A.R.; Nathanson, K.L.; Shah, P.D.; Doucette, A.; Freedman, G.M.; et al.
Frequency of Radiation-Induced Malignancies Post-Adjuvant Radiotherapy for Breast Cancer in Patients with Li-Fraumeni
Syndrome. Breast Cancer Res. Treat. 2020, 181, 181–188. [CrossRef] [PubMed]
42. Santi, R.; Cetica, V.; Franchi, A.; Pepi, M.; Cesinaro, A.M.; Miracco, C.; Paglierani, M.; De Giorgi, V.; Delfino, C.; Difonzo, E.M.; et al.
Tumour Suppressor Gene TP53 Mutations in Atypical Vascular Lesions of Breast Skin Following Radiotherapy. Histopathology
2011, 58, 455–466. [CrossRef] [PubMed]
43. Gondim, G.R.M.; Formiga, M.N.C.; Castro, D.G.; Silva, M.L.G.; Chen, M.; Fogaroli, R.; Ramos, H.; Coelho, T.M.; Pellizzon, A.C.A.;
Da Costa, A.A.B.A. Adjuvant radiation therapy in patients with breast cancer and Li-Fraumeni syndrome: Oncologic results and
incidence of second neoplasms. J. Clin. Oncol. 2018, 36, e12589. [CrossRef]
44. Williams, S.B.; Reed, M. Cutaneous Angiosarcoma after Breast Conserving Treatment for Bilateral Breast Cancers in a BRCA-1
Gene Mutation Carrier—A Case Report and Review of the Literature. Surgeon 2009, 7, 250. [CrossRef]
45. Sadeghi, F.; Asgari, M.; Matloubi, M.; Ranjbar, M.; Karkhaneh Yousefi, N.; Azari, T.; Zaki-Dizaji, M. Molecular Contribution of
BRCA1 and BRCA2 to Genome Instability in Breast Cancer Patients: Review of Radiosensitivity Assays. Biol. Proced. Online 2020,
22, 23. [CrossRef]
46. Schlosser, S.; Rabinovitch, R.; Shatz, Z.; Galper, S.; Shahadi-Dromi, I.; Finkel, S.; Jacobson, G.; Rasco, A.; Friedman, E.; Laitman, Y.; et al.
Radiation-Associated Secondary Malignancies in BRCA Mutation Carriers Treated for Breast Cancer. Int. J. Radiat. Oncol. Biol.
Phys. 2020, 107, 353–359. [CrossRef]
47. Wong, F.L.; Boice, J.D.; Abramson, D.H.; Tarone, R.E.; Kleinerman, R.A.; Stovall, M.; Goldman, M.B.; Seddon, J.M.; Tarbell, N.;
Fraumeni, J.F.; et al. Cancer Incidence after Retinoblastoma. Radiation Dose and Sarcoma Risk. JAMA 1997, 278, 1262–1267. [CrossRef]
48. Franken, N.a.P.; van Bree, C.; ten Cate, R.; van Oven, C.H.; Haveman, J. Importance of TP53 and RB in the Repair of Potentially
Lethal Damage and Induction of Color Junctions after Exposure to Ionizing Radiation. Radiat. Res. 2002, 158, 707–714. [CrossRef]
49. Manner, J.; Radlwimmer, B.; Hohenberger, P.; Mössinger, K.; Küffer, S.; Sauer, C.; Belharazem, D.; Zettl, A.; Coindre, J.-M.;
Hallermann, C.; et al. MYC High Level Gene Amplification Is a Distinctive Feature of Angiosarcomas after Irradiation or Chronic
Lymphedema. Am. J. Pathol. 2010, 176, 34–39. [CrossRef]
50. Fraga-Guedes, C.; André, S.; Mastropasqua, M.G.; Botteri, E.; Toesca, A.; Rocha, R.M.; Peradze, N.; Rotmensz, N.; Viale, G.;
Veronesi, P.; et al. Angiosarcoma and Atypical Vascular Lesions of the Breast: Diagnostic and Prognostic Role of MYC Gene
Amplification and Protein Expression. Breast Cancer Res. Treat. 2015, 151, 131–140. [CrossRef]
51. Mentzel, T.; Schildhaus, H.U.; Palmedo, G.; Büttner, R.; Kutzner, H. Postradiation Cutaneous Angiosarcoma after Treatment
of Breast Carcinoma Is Characterized by MYC Amplification in Contrast to Atypical Vascular Lesions after Radiotherapy and
Control Cases: Clinicopathological, Immunohistochemical and Molecular Analysis of 66 Cases. Mod. Pathol. 2012, 25, 75–85.
[CrossRef] [PubMed]
52. Huang, S.-C.; Zhang, L.; Sung, Y.-S.; Chen, C.-L.; Kao, Y.-C.; Agaram, N.P.; Singer, S.; Tap, W.D.; D’Angelo, S.; Antonescu, C.R.
Recurrent CIC Gene Abnormalities in Angiosarcomas: A Molecular Study of 120 Cases with Concurrent Investigation of PLCG1,
KDR, MYC, and FLT4 Gene Alterations. Am. J. Surg. Pathol. 2016, 40, 645–655. [CrossRef] [PubMed]
53. Fernandez, A.P.; Sun, Y.; Tubbs, R.R.; Goldblum, J.R.; Billings, S.D. FISH for MYC Amplification and Anti-MYC Immunohisto-
chemistry: Useful Diagnostic Tools in the Assessment of Secondary Angiosarcoma and Atypical Vascular Proliferations. J. Cutan.
Pathol. 2012, 39, 234–242. [CrossRef] [PubMed]
54. Guo, T.; Zhang, L.; Chang, N.-E.; Singer, S.; Maki, R.G.; Antonescu, C.R. Consistent MYC and FLT4 Gene Amplification in
Radiation-Induced Angiosarcoma but Not in Other Radiation-Associated Atypical Vascular Lesions. Genes Chromosomes Cancer
2011, 50, 25–33. [CrossRef]
Int. J. Mol. Sci. 2022, 23, 4125 16 of 18

55. Ginter, P.S.; Mosquera, J.M.; MacDonald, T.Y.; D’Alfonso, T.M.; Rubin, M.A.; Shin, S.J. Diagnostic Utility of MYC Amplification
and Anti-MYC Immunohistochemistry in Atypical Vascular Lesions, Primary or Radiation-Induced Mammary Angiosarcomas,
and Primary Angiosarcomas of Other Sites. Hum. Pathol. 2014, 45, 709–716. [CrossRef]
56. Berrington de Gonzalez, A.; Kutsenko, A.; Rajaraman, P. Sarcoma Risk after Radiation Exposure. Clin. Sarcoma Res. 2012, 2, 18. [CrossRef]
57. Rubino, C.; Shamsaldin, A.; Lê, M.G.; Labbé, M.; Guinebretière, J.-M.; Chavaudra, J.; de Vathaire, F. Radiation Dose and Risk of
Soft Tissue and Bone Sarcoma after Breast Cancer Treatment. Breast Cancer Res. Treat. 2005, 89, 277–288. [CrossRef]
58. Virtanen, A.; Pukkala, E.; Auvinen, A. Incidence of Bone and Soft Tissue Sarcoma after Radiotherapy: A Cohort Study of
295,712 Finnish Cancer Patients. Int. J. Cancer 2006, 118, 1017–1021. [CrossRef]
59. Tucker, M.A.; D’Angio, G.J.; Boice, J.D.; Strong, L.C.; Li, F.P.; Stovall, M.; Stone, B.J.; Green, D.M.; Lombardi, F.; Newton, W. Bone
Sarcomas Linked to Radiotherapy and Chemotherapy in Children. N. Engl. J. Med. 1987, 317, 588–593. [CrossRef]
60. Marchal, C.; Weber, B.; de Lafontan, B.; Resbeut, M.; Mignotte, H.; du Chatelard, P.P.; Cutuli, B.; Reme-Saumon, M.; Broussier-Leroux, A.;
Chaplain, G.; et al. Nine Breast Angiosarcomas after Conservative Treatment for Breast Carcinoma: A Survey from French
Comprehensive Cancer Centers. Int. J. Radiat. Oncol. Biol. Phys. 1999, 44, 113–119. [CrossRef]
61. Rombouts, A.J.M.; Huising, J.; Hugen, N.; Siesling, S.; Poortmans, P.M.; Nagtegaal, I.D.; de Wilt, J.H.W. Assessment of
Radiotherapy-Associated Angiosarcoma After Breast Cancer Treatment in a Dutch Population-Based Study. JAMA Oncol.
2019, 5, 267–269. [CrossRef] [PubMed]
62. Burtt, J.J.; Thompson, P.A.; Lafrenie, R.M. Non-Targeted Effects and Radiation-Induced Carcinogenesis: A Review. J. Radiol. Prot.
2016, 36, R23–R35. [CrossRef] [PubMed]
63. Sordillo, P.P.; Chapman, R.; Hajdu, S.I.; Magill, G.B.; Golbey, R.B. Lymphangiosarcoma. Cancer 1981, 48, 1674–1679. [CrossRef]
64. Virtanen, A.; Pukkala, E.; Auvinen, A. Angiosarcoma after Radiotherapy: A Cohort Study of 332,163 Finnish Cancer Patients.
Br. J. Cancer 2007, 97, 115–117. [CrossRef] [PubMed]
65. Mito, J.K.; Mitra, D.; Barysauskas, C.M.; Mariño-Enriquez, A.; Morgan, E.A.; Fletcher, C.D.M.; Raut, C.P.; Baldini, E.H.; Doyle, L.A. A
Comparison of Outcomes and Prognostic Features for Radiation-Associated Angiosarcoma of the Breast and Other Radiation-
Associated Sarcomas. Int. J. Radiat. Oncol. Biol. Phys. 2019, 104, 425–435. [CrossRef]
66. Mery, C.M.; George, S.; Bertagnolli, M.M.; Raut, C.P. Secondary Sarcomas after Radiotherapy for Breast Cancer: Sustained Risk
and Poor Survival. Cancer 2009, 115, 4055–4063. [CrossRef]
67. Vorburger, S.A.; Xing, Y.; Hunt, K.K.; Lakin, G.E.; Benjamin, R.S.; Feig, B.W.; Pisters, P.W.T.; Ballo, M.T.; Chen, L.; Trent, J.; et al.
Angiosarcoma of the Breast. Cancer 2005, 104, 2682–2688. [CrossRef]
68. Tomasini, C.; Grassi, M.; Pippione, M. Cutaneous Angiosarcoma Arising in an Irradiated Breast. Case Report and Review of the
Literature. Dermatology 2004, 209, 208–214. [CrossRef]
69. Holm, M.; Aggerholm-Pedersen, N.; Mele, M.; Jørgensen, P.; Baerentzen, S.; Safwat, A. Primary Breast Sarcoma: A Retrospective
Study over 35 Years from a Single Institution. Acta Oncol. 2016, 55, 584–590. [CrossRef]
70. Brenn, T.; Fletcher, C.D.M. Radiation-Associated Cutaneous Atypical Vascular Lesions and Angiosarcoma: Clinicopathologic
Analysis of 42 Cases. Am. J. Surg. Pathol. 2005, 29, 983–996. [CrossRef]
71. Chikarmane, S.A.; Gombos, E.C.; Jagadeesan, J.; Raut, C.; Jagannathan, J.P. MRI Findings of Radiation-Associated Angiosarcoma
of the Breast (RAS). J. Magn. Reson. Imaging 2015, 42, 763–770. [CrossRef] [PubMed]
72. Sheth, G.R.; Cranmer, L.D.; Smith, B.D.; Grasso-Lebeau, L.; Lang, J.E. Radiation-Induced Sarcoma of the Breast: A Systematic
Review. Oncologist 2012, 17, 405–418. [CrossRef] [PubMed]
73. Liberman, L.; Dershaw, D.D.; Kaufman, R.J.; Rosen, P.P. Angiosarcoma of the Breast. Radiology 1992, 183, 649–654. [CrossRef] [PubMed]
74. Alves, I.; Marques, J.C. Radiation-Induced Angiosarcoma of the Breast: A Retrospective Analysis of 15 Years’ Experience at an
Oncology Center. Radiol. Bras. 2018, 51, 281–286. [CrossRef]
75. Jallali, N.; James, S.; Searle, A.; Ghattaura, A.; Hayes, A.; Harris, P. Surgical Management of Radiation-Induced Angiosarcoma
after Breast Conservation Therapy. Am. J. Surg. 2012, 203, 156–161. [CrossRef]
76. Cohen-Hallaleh, R.B.; Smith, H.G.; Smith, R.C.; Stamp, G.F.; Al-Muderis, O.; Thway, K.; Miah, A.; Khabra, K.; Judson, I.; Jones, R.; et al.
Radiation Induced Angiosarcoma of the Breast: Outcomes from a Retrospective Case Series. Clin. Sarcoma Res. 2017, 7, 15. [CrossRef]
77. Erel, E.; Vlachou, E.; Athanasiadou, M.; Hassan, S.; Chandrasekar, C.R.; Peart, F. Management of Radiation-Induced Sarcomas in
a Tertiary Referral Centre: A Review of 25 Cases. Breast 2010, 19, 424–427. [CrossRef]
78. Seinen, J.M.; Styring, E.; Verstappen, V.; Vult von Steyern, F.; Rydholm, A.; Suurmeijer, A.J.H.; Hoekstra, H.J. Radiation-Associated
Angiosarcoma after Breast Cancer: High Recurrence Rate and Poor Survival despite Surgical Treatment with R0 Resection. Ann.
Surg. Oncol. 2012, 19, 2700–2706. [CrossRef]
79. Sher, T.; Hennessy, B.T.; Valero, V.; Broglio, K.; Woodward, W.A.; Trent, J.; Hunt, K.K.; Hortobagyi, G.N.; Gonzalez-Angulo, A.M.
Primary Angiosarcomas of the Breast. Cancer 2007, 110, 173–178. [CrossRef]
80. Linthorst, M.; van Geel, A.N.; Baartman, E.A.; Oei, S.B.; Ghidey, W.; van Rhoon, G.C.; van der Zee, J. Effect of a Combined
Surgery, Re-Irradiation and Hyperthermia Therapy on Local Control Rate in Radio-Induced Angiosarcoma of the Chest Wall.
Strahlenther. Onkol. 2013, 189, 387–393. [CrossRef]
81. Banks, J.; George, J.; Potter, S.; Gardiner, M.D.; Ives, C.; Shaaban, A.M.; Singh, J.; Sherriff, J.; Hallissey, M.T.; Horgan, K.; et al.
Breast Angiosarcoma Surveillance Study: UK National Audit of Management and Outcomes of Angiosarcoma of the Breast and
Chest Wall. Br. J. Surg. 2021, 108, 388–394. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2022, 23, 4125 17 of 18

82. Gullett, N.P.; Delman, K.; Folpe, A.L.; Johnstone, P.A.S. National Surgical Patterns of Care: Regional Lymphadenectomy of Breast
Sarcomas. Am. J. Clin. Oncol. 2007, 30, 461–465. [CrossRef] [PubMed]
83. Fraga-Guedes, C.; Gobbi, H.; Mastropasqua, M.G.; Botteri, E.; Luini, A.; Viale, G. Primary and Secondary Angiosarcomas of the
Breast: A Single Institution Experience. Breast Cancer Res. Treat. 2012, 132, 1081–1088. [CrossRef] [PubMed]
84. Depla, A.L.; Scharloo-Karels, C.H.; de Jong, M.A.A.; Oldenborg, S.; Kolff, M.W.; Oei, S.B.; van Coevorden, F.; van Rhoon, G.C.;
Baartman, E.A.; Scholten, R.J.; et al. Treatment and Prognostic Factors of Radiation-Associated Angiosarcoma (RAAS) after
Primary Breast Cancer: A Systematic Review. Eur. J. Cancer 2014, 50, 1779–1788. [CrossRef] [PubMed]
85. Modesto, A.; Filleron, T.; Chevreau, C.; Le Pechoux, C.; Rochaix, P.; Le Guellec, S.; Ducassou, A.; Gangloff, D.; Ferron, G.;
Delannes, M. Role of Radiation Therapy in the Conservative Management of Sarcoma within an Irradiated Field. Eur. J. Surg.
Oncol. 2014, 40, 187–192. [CrossRef]
86. Ghareeb, E.R.; Bhargava, R.; Vargo, J.A.; Florea, A.V.; Beriwal, S. Primary and Radiation-Induced Breast Angiosarcoma: Clinicopathologic
Predictors of Outcomes and the Impact of Adjuvant Radiation Therapy. Am. J. Clin. Oncol. 2016, 39, 463–467. [CrossRef]
87. Yin, M.; Wang, W.; Drabick, J.J.; Harold, H.A. Prognosis and Treatment of Non-Metastatic Primary and Secondary Breast
Angiosarcoma: A Comparative Study. BMC Cancer 2017, 17, 295. [CrossRef]
88. Smith, T.L.; Morris, C.G.; Mendenhall, N.P. Angiosarcoma after Breast-Conserving Therapy: Long-Term Disease Control and Late
Effects with Hyperfractionated Accelerated Re-Irradiation (HART). Acta Oncol. 2014, 53, 235–241. [CrossRef]
89. De Jong, M.A.A.; Oldenborg, S.; Bing Oei, S.; Griesdoorn, V.; Kolff, M.W.; Koning, C.C.E.; van Tienhoven, G. Reirradiation and
Hyperthermia for Radiation-Associated Sarcoma. Cancer 2012, 118, 180–187. [CrossRef]
90. Souba, W.W.; McKenna, R.J.; Meis, J.; Benjamin, R.; Raymond, A.K.; Mountain, C.F. Radiation-Induced Sarcomas of the Chest
Wall. Cancer 1986, 57, 610–615. [CrossRef]
91. Gutkin, P.M.; Ganjoo, K.N.; Lohman, M.; von Eyben, R.; Charville, G.W.; Nazerali, R.S.; Dirbas, F.M.; Horst, K.C. Angiosarcoma of
the Breast: Management and Outcomes. Am. J. Clin. Oncol. 2020, 43, 820–825. [CrossRef] [PubMed]
92. Abdou, Y.; Elkhanany, A.; Attwood, K.; Ji, W.; Takabe, K.; Opyrchal, M. Primary and Secondary Breast Angiosarcoma: Single
Center Report and a Meta-Analysis. Breast Cancer Res. Treat. 2019, 178, 523–533. [CrossRef] [PubMed]
93. McClelland, S.; Hatfield, J.; Degnin, C.; Chen, Y.; Mitin, T. Extent of Resection and Role of Adjuvant Treatment in Resected
Localized Breast Angiosarcoma. Breast Cancer Res. Treat. 2019, 175, 409–418. [CrossRef] [PubMed]
94. Arnaout, A.; Wedman, D.M.; El-Sayed, S.; Acharya, V.; Lad, S. Neoadjuvant Gemcitabine-Taxane Chemotherapy for Radiation-
Induced Angiosarcoma of the Breast: A Case Report. Breast J. 2012, 18, 276–278. [CrossRef]
95. Lewcun, J.A.; Pameijer, C.; Kass, R.; Cream, L.; Hershock, D.; Brooks, A.J.; Dodge, D.G. Doxorubicin, Paclitaxel, and Cisplatin
Based Chemotherapy for the Treatment of Angiosarcoma: Two Case Reports. Int. J. Surg. Case Rep. 2020, 68, 83–87. [CrossRef]
96. Quadros, C.A.; Vasconcelos, A.; Andrade, R.; Ramos, R.S.; Studart, E.; Nascimento, G.; Trajano, A. Good Outcome after
Neoadjuvant Chemotherapy and Extended Surgical Resection for a Large Radiation-Induced High-Grade Breast Sarcoma. Int.
Semin. Surg. Oncol. 2006, 3, 18. [CrossRef]
97. Italiano, A.; Chen, C.-L.; Thomas, R.; Breen, M.; Bonnet, F.; Sevenet, N.; Longy, M.; Maki, R.G.; Coindre, J.-M.; Antonescu, C.R.
Alterations of the P53 and PIK3CA/AKT/MTOR Pathways in Angiosarcomas: A Pattern Distinct from Other Sarcomas with
Complex Genomics. Cancer 2012, 118, 5878–5887. [CrossRef]
98. D’Angelo, S.P.; Antonescu, C.R.; Kuk, D.; Qin, L.; Moraco, N.; Carvajal, R.C.; Chi, P.; Dickson, M.A.; Gounder, M.; Keohan, M.L.; et al.
High-Risk Features in Radiation-Associated Breast Angiosarcomas. Br. J. Cancer 2013, 109, 2340–2346. [CrossRef]
99. Stacchiotti, S.; Palassini, E.; Sanfilippo, R.; Vincenzi, B.; Arena, M.G.; Bochicchio, A.M.; De Rosa, P.; Nuzzo, A.; Turano, S.; Morosi, C.; et al.
Gemcitabine in Advanced Angiosarcoma: A Retrospective Case Series Analysis from the Italian Rare Cancer Network. Ann. Oncol. 2012,
23, 501–508. [CrossRef]
100. Gennaro, M.; Valeri, B.; Casalini, P.; Carcangiu, M.L.; Gronchi, A.; Conti, A.R.; Agresti, R.; Greco, M. Angiosarcoma of the Breast
and Vascular Endothelial Growth Factor Receptor. Tumori 2010, 96, 930–935. [CrossRef]
101. Itakura, E.; Yamamoto, H.; Oda, Y.; Tsuneyoshi, M. Detection and Characterization of Vascular Endothelial Growth Factors and
Their Receptors in a Series of Angiosarcomas. J. Surg. Oncol. 2008, 97, 74–81. [CrossRef] [PubMed]
102. Agulnik, M.; Yarber, J.L.; Okuno, S.H.; von Mehren, M.; Jovanovic, B.D.; Brockstein, B.E.; Evens, A.M.; Benjamin, R.S. An Open-
Label, Multicenter, Phase II Study of Bevacizumab for the Treatment of Angiosarcoma and Epithelioid Hemangioendotheliomas.
Ann. Oncol. 2013, 24, 257–263. [CrossRef] [PubMed]
103. Ray-Coquard, I.L.; Domont, J.; Tresch-Bruneel, E.; Bompas, E.; Cassier, P.A.; Mir, O.; Piperno-Neumann, S.; Italiano, A.; Chevreau, C.;
Cupissol, D.; et al. Paclitaxel Given Once per Week with or Without Bevacizumab in Patients with Advanced Angiosarcoma: A
Randomized Phase II Trial. J. Clin. Oncol. 2015, 33, 2797–2802. [CrossRef] [PubMed]
104. Weiner, T.M.; Liu, E.T.; Craven, R.J.; Cance, W.G. Expression of Growth Factor Receptors, the Focal Adhesion Kinase, and Other
Tyrosine Kinases in Human Soft Tissue Tumors. Ann. Surg. Oncol. 1994, 1, 18–27. [CrossRef] [PubMed]
105. Van der Graaf, W.T.A.; Blay, J.-Y.; Chawla, S.P.; Kim, D.-W.; Bui-Nguyen, B.; Casali, P.G.; Schöffski, P.; Aglietta, M.; Staddon, A.P.;
Beppu, Y.; et al. Pazopanib for Metastatic Soft-Tissue Sarcoma (PALETTE): A Randomised, Double-Blind, Placebo-Controlled
Phase 3 Trial. Lancet 2012, 379, 1879–1886. [CrossRef]
106. Kollár, A.; Jones, R.L.; Stacchiotti, S.; Gelderblom, H.; Guida, M.; Grignani, G.; Steeghs, N.; Safwat, A.; Katz, D.; Duffaud, F.; et al.
Pazopanib in Advanced Vascular Sarcomas: An EORTC Soft Tissue and Bone Sarcoma Group (STBSG) Retrospective Analysis.
Acta Oncol. 2017, 56, 88–92. [CrossRef] [PubMed]
Int. J. Mol. Sci. 2022, 23, 4125 18 of 18

107. Maki, R.G.; D’Adamo, D.R.; Keohan, M.L.; Saulle, M.; Schuetze, S.M.; Undevia, S.D.; Livingston, M.B.; Cooney, M.M.; Hensley,
M.L.; Mita, M.M.; et al. Phase II Study of Sorafenib in Patients with Metastatic or Recurrent Sarcomas. J. Clin. Oncol. 2009, 27,
3133–3140. [CrossRef]
108. Von Mehren, M.; Rankin, C.; Goldblum, J.R.; Demetri, G.D.; Bramwell, V.; Ryan, C.W.; Borden, E. Phase 2 Southwest Oncology
Group-Directed Intergroup Trial (S0505) of Sorafenib in Advanced Soft Tissue Sarcomas. Cancer 2012, 118, 770–776. [CrossRef]
109. D’Angelo, S.P.; Antonescu, C.R.; Keohan, M.L.; Carvajal, R.D.; Dickson, M.A.; Gounder, M.M.; Moraco, N.H.; Singer, S.; Schwartz, G.K.;
Tap, W.D. Activity of Sorafenib in Radiation-Associated Breast Angiosarcomas Harboring MYC and FLT4 Amplifications. J. Clin. Oncol.
2012, 30, 10019. [CrossRef]
110. Komdeur, R.; Hoekstra, H.J.; Molenaar, W.M.; Van Den Berg, E.; Zwart, N.; Pras, E.; Plaza-Menacho, I.; Hofstra, R.M.W.;
Van Der Graaf, W.T.A. Clinicopathologic Assessment of Postradiation Sarcomas: KIT as a Potential Treatment Target. Clin. Cancer Res.
2003, 9, 2926–2932.
111. Malone, E.R.; Anderson, N.; Lewin, J.H.; O’Sullivan, B.; Dickson, B.; Shlien, A.; Abdul Razak, A.R. Immune Signature and
Molecular Profiling of Radiation-Induced Sarcoma (RIS). J. Clin. Oncol. 2019, 37, 11040. [CrossRef]
112. Chan, J.Y.; Lim, J.Q.; Yeong, J.; Ravi, V.; Guan, P.; Boot, A.; Tay, T.K.Y.; Selvarajan, S.; Md Nasir, N.D.; Loh, J.H.; et al. Multiomic
Analysis and Immunoprofiling Reveal Distinct Subtypes of Human Angiosarcoma. J. Clin. Investig. 2020, 130, 5833–5846.
[CrossRef] [PubMed]
113. D’Angelo, S.P.; Mahoney, M.R.; Van Tine, B.A.; Atkins, J.; Milhem, M.M.; Jahagirdar, B.N.; Antonescu, C.R.; Horvath, E.; Tap, W.D.;
Schwartz, G.K.; et al. Nivolumab with or without Ipilimumab Treatment for Metastatic Sarcoma (Alliance A091401): Two
Open-Label, Non-Comparative, Randomised, Phase 2 Trials. Lancet Oncol. 2018, 19, 416–426. [CrossRef]
114. Martin-Broto, J.; Hindi, N.; Grignani, G.; Martinez-Trufero, J.; Redondo, A.; Valverde, C.; Stacchiotti, S.; Lopez-Pousa, A.;
D’Ambrosio, L.; Gutierrez, A.; et al. Nivolumab and Sunitinib Combination in Advanced Soft Tissue Sarcomas: A Multicenter,
Single-Arm, Phase Ib/II Trial. J. Immunother. Cancer 2020, 8, e001561. [CrossRef] [PubMed]
115. Florou, V.; Rosenberg, A.E.; Wieder, E.; Komanduri, K.V.; Kolonias, D.; Uduman, M.; Castle, J.C.; Buell, J.S.; Trent, J.C.; Wilky, B.A.
Angiosarcoma Patients Treated with Immune Checkpoint Inhibitors: A Case Series of Seven Patients from a Single Institution.
J. Immunother. Cancer 2019, 7, 213. [CrossRef] [PubMed]
116. Lahat, G.; Dhuka, A.R.; Hallevi, H.; Xiao, L.; Zou, C.; Smith, K.D.; Phung, T.L.; Pollock, R.E.; Benjamin, R.; Hunt, K.K.; et al.
Angiosarcoma: Clinical and Molecular Insights. Ann. Surg. 2010, 251, 1098–1106. [CrossRef]
117. Gladdy, R.A.; Qin, L.-X.; Moraco, N.; Edgar, M.A.; Antonescu, C.R.; Alektiar, K.M.; Brennan, M.F.; Singer, S. Do Radiation-Associated
Soft Tissue Sarcomas Have the Same Prognosis as Sporadic Soft Tissue Sarcomas? J. Clin. Oncol. 2010, 28, 2064–2069. [CrossRef]
118. Antonescu, C.R.; Yoshida, A.; Guo, T.; Chang, N.-E.; Zhang, L.; Agaram, N.P.; Qin, L.-X.; Brennan, M.F.; Singer, S.; Maki, R.G. KDR
Activating Mutations in Human Angiosarcomas Are Sensitive to Specific Kinase Inhibitors. Cancer Res. 2009, 69, 7175–7179. [CrossRef]
119. Schuetze, S.M.; Zhao, L.; Chugh, R.; Thomas, D.G.; Lucas, D.R.; Metko, G.; Zalupski, M.M.; Baker, L.H. Results of a Phase II Study
of Sirolimus and Cyclophosphamide in Patients with Advanced Sarcoma. Eur. J. Cancer 2012, 48, 1347–1353. [CrossRef]