The Breast 20 (2011) 199e204

Contents lists available at ScienceDirect

The Breast
journal homepage: www.elsevier.com/brst

Review

Breast sarcomas: Current and future perspectives

Ioannis A. Voutsadakis*, Khalil Zaman, Serge Leyvraz
Centre Pluridisciplinaire d’Oncologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

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

Article history: Breast sarcomas are rare neoplasms of the breast that need to be clearly distinguished from the very
Received 5 November 2010 common breast carcinomas and treated in a multidisciplinary manner modelled after treatment para-
Received in revised form digms in other sarcoma locations. An increasing need to differentiate sarcoma sub-types based on
4 February 2011
molecular characteristics that will also be depicted in differential treatment sensitivities and develop-
Accepted 14 February 2011
ment of specifically targeted therapies are equally valid in sarcomas in general and in breast sarcomas in
particular.
Keywords:
Of special interest in breast are sarcomas developing after breast irradiation for a previous breast
Breast
Sarcoma
carcinoma, a scenario that is increasingly common, given the increasing trends of breast conservation in
Molecular lesions the surgical treatment of breast carcinoma that necessitates the adjuvant use of radiotherapy.
Post-irradiation sarcomas Ó 2011 Elsevier Ltd. All rights reserved.
Targeted therapies

Sarcomas of the breast are heterogeneous neoplasms derived sarcoma) have been described as smaller percentages of case series or
from non-epithelial elements of the gland. Although they represent as case reports.2e7
comparatively rare neoplasms, comprising less than 1% of breast A main risk factor for the development of breast sarcomas is
cancers and less than 5% of all location sarcomas, their incidence previous radiation treatment for a breast carcinoma. An additional
may increase in the years to come as a result of increasing use of risk factor is chronic lymphoedema. Professional exposure to vinyl-
breast radiation after breast-conserving treatment of breast cancer. chloride and artificial implants constitute debatable risk factors.8,9
In addition, sarcomas are very important to differentiate from Sarcomas are part of the LieFraumeni syndrome tumour spectrum
breast carcinomas because treatment of the two entities differs. and, thus, breast sarcomas may develop in these patients carrying
In this article, data on specific sub-types of breast sarcomas will a mutation in p53. The majority of breast sarcomas present without
be reviewed and implications for treatment will be discussed. an identifiable aetiologic factor.
Carcinosarcomas, which have a prominent epithelial component Radiation-induced sarcomas (RIS) of the breast develop after
and should be treated as carcinomas, and cystosarcomas phylloides, a wide range of time from radiation treatment. A cumulative inci-
which are a heterogeneous group of tumours with differing dence of 0.3% at 15 years after radiation treatment has been
malignancy potential1 will be excluded from this discussion. reported in a series of patients diagnosed between 1973 and 1997,
some of whom had been treated before this interval.10 This means
that about 1 patient in 300 receiving radiotherapy for a breast
Sub-types, aetiologic factors, diagnosis, staging, pathogenesis
cancer can be expected to develop a sarcoma during the 15 years
and prognosis
that follow. Whether this incidence will decrease with newer
radiation equipment and techniques remains to be seen and could
The whole complement of sarcoma sub-types have been reported
be the subject of a study comparing the RIS incidence of patients,
to occur in breast. The most common sub-types are malignant
who received radiation therapy by traditional versus conformal
fibrohistiocytoma (MFH), (myxo)-fibrosarcoma, angiosarcoma and
techniques.
spindle cell sarcoma. Several other sub-types (leiomyosarcoma,
Various histologies have been reported in RIS but angiosarcomas
liposarcoma, rhabdomyosarcoma, haemangiopericytoma, synovial
appear to be the most common histologic sub-type.10,11 Angio-
sarcoma, osteosarcoma, chondrosarcoma, neurosarcoma and stromal
sarcomas after previous radiation treatment occur in older patients
than primary angiosarcomas.12 The clinical presentation of primary
* Corresponding author. Centre Pluridisciplinaire d’Oncologie, BH06, Centre
and secondary angiosarcomas may be similar,13,14 although
Hospitalier Universitaire Vaudois, Bugnon 46, Lausanne 1011, Switzerland. secondary tumours tend to present more often as a rash while
E-mail address: ivoutsadakis@yahoo.com (I.A. Voutsadakis). primary tumours more often as a mass.13,15,16 The median latency of

0960-9776/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.breast.2011.02.016
200 I.A. Voutsadakis et al. / The Breast 20 (2011) 199e204

secondary angiosarcomas after radiation treatment in different Liposarcomas constitute another example of a histologic type of
series is 5e8 years,14,17,18 with a wide range of 1e16 years. In rare sarcoma in which specific molecular lesions define different sub-
cases, sarcoma development several decades after irradiation types. Myxoid/round cell liposarcomas are characterised by trans-
treatment of a breast carcinoma has been reported. Both primary location t(12;16) (q13;p11) fusing genes FUS at 16p11 and CHOP
and secondary angiosarcomas have to be distinguished from more at 12q13 or, rarely, translocation t(12;22) (p13;q12) fusing CHOP
benign, atypical, vascular lesions.19 Osteosarcomas are the most with EWSR1. By contrast, the other common sub-type of liposar-
common post-irradiation sarcomas in general.20 After breast radi- comas, well-differentiated or dedifferentiated liposarcomas display
ation therapy, osteosarcomas constitute also a common histology amplifications of chromosome locus 12q13e15 that includes genes
but arise mostly from adjacent bone structures (sternum and ribs) encoding for mdm2 and CDK4. Myxoid/round cell liposarcomas
and are, thus, not real breast sarcomas.11 Nevertheless, true extra- tend to be more aggressive and arise almost exclusively from
osseous osteosarcomas occur in the breast both primary and post extremities, so that some authors advocate a search for a primary
irradiation.21e24 site if a supposedly primary retroperitoneal myxoid/round cell
Diagnosis of breast sarcomas is made histologically with liposarcoma with the t(12;16) (q13;p11) translocation is diag-
a percutaneous biopsy. Core biopsy is preferred to fine needle nosed.38 The well-differentiated/dedifferentiated sub-type is less
aspiration (FNA), which results in lower material yield and offers aggressive initially and can be treated by excision alone. After
lower diagnosis rates.25 For local staging, the three methods used multiple recurrences, it can eventually progress to highly malig-
are mammography, ultrasound and breast magnetic resonance nant dedifferentiated histology with significant metastatic poten-
imaging (MRI). In mammography, microcalcifications are less often tial. Dedifferentiated liposarcomas may also present de novo,
present in sarcomas than in breast carcinomas. MRI may aid in especially in the retroperitoneum. Both types of liposarcomas have
differentiating malignant versus benign tumuors.26 Nevertheless, been reported in the breast.39,40
a biopsy is always needed. As molecular sarcoma lesions are sub-type and not location
Tumour, node, metastasis (TNM) staging of breast sarcomas specific, breast sarcomas probably contain lesions of their respec-
differs from that of breast carcinomas in that grading is taken into tive histologic sub-type, although there are few published specific
account in defining stage with grade 1 (well-differentiated) molecular studies pertaining to the breast. In a case study,
tumours considered as stage I and grade 2 and 3 (intermediate and a monomorphic synovial sarcoma developing after radiation
poorly differentiated) tumours considered as stage II and III. treatment of the breast was reported to contain the t(X;18)
Regional lymph node involvement from a tumour of any grade is (p11;q11) translocation.41 With the increasing recognition of
also considered now as stage III disease in the most recent Amer- different prognosis and response to treatment of various sarcoma-
ican Joint Committee on Cancer (AJCC) classification.27 associated molecular lesions, these lesions should be sought in
The molecular pathogenesis of sarcomas varies according to cases of breast sarcomas as in other location sarcomas.
histologic type, independently of primary location. In some cases, Ten-year overall survival of breast sarcomas was 62% in one
even within the same histologic type, specific molecular lesions series,42 and the 5- and 10-year relapse-free survival was 47% and
characterise groups with different prognosis. For example, rhab- 42% in another series where, only initially, patients with localised
domyosarcomas (RMSs) are divided into two major groups: disease were included.3 Outcomes of the larger and most recent
embryonal with a better prognosis and alveolar with a worse series of breast sarcomas are provided in the Table 1. Prognosis of
prognosis. Alveolar RMSs are characterised by translocations fusing breast sarcomas has been found to depend on factors common to
genes PAX3 or PAX7 with transcription factor FOXO1. Nevertheless, other locations, such as the tumour size and grade, although the
histologically, alveolar RMSs that lack these fusions behave clini- evidence is derived from smaller series.2,6,42 The third main prog-
cally like embryonal RMS.28 nostic variable in sarcomas in general, deepness of the tumour, is
Synovial sarcomas bear also a specific translocation t(X;18) evidently irrelevant in breast sarcomas, which are considered
(p11;q11), which fuses gene SYT at chromosome 18q11 with either of superficial tumours. Histology is also a prognostic factor in breast
two related genes SXX1 or SXX2 at chromosome Xp11. Two histo- sarcomas, with angiosarcomas having a worse prognosis than other
logic variants of synovial sarcomas exist: monophasic with histologic sub-types.4,42 The negativity of surgical margins is also
a monotonous spindle cell morphology and biphasic with epithelial important for increased survival, while the extent of surgery
cells lining gland-like spaces in a spindle cell background. Almost all (mastectomy vs. more conservative excision) is not.3,5 Post-irradi-
synovial sarcomas with biphasic morphology bear the SYTeSXX1 ation soft-tissue sarcomas have also been found to have a worse
translocation while the SYTeSXX2 translocation is associated almost prognosis than primary sarcomas.44 If this holds true for the breast,
exclusively with monophasic morphology. Although the morpho- localisation has not been irrefutably proven but some series data
logic sub-type of synovial sarcoma does not correlate with prog- support this hypothesis. Grade and surgical margin status are
nosis, the type of translocation present was found to be a prognostic important prognostic determinants also in cases of post-irradiation
factor for metastases-free survival in localised disease in some sarcomas.45
series, with SYTeSXX2-bearing synovial sarcomas having a better
metastases-free survival than SYTeSXX1-bearing ones.29e31 By Treatment
contrast, other groups have provided contradictory results with no
prognostic value derived from the type of translocation.32e34 This The treatment paradigm for breast sarcoma is built upon
may be due to different populations studied and techniques used, treatment of sarcomas in general and should be planned by
and the question of prognostic significance remains open.35 Syno- a multidisciplinary team. The primary treatment of sarcomas is
vial sarcomas may arise from sites unrelated to joints and have been surgery. Thus, localised breast sarcomas should be treated by
reported to arise in breast in rare cases.36,37 Nevertheless, some of complete surgical excision, which offers a chance for long-term
the sarcomas classified as spindle cell sarcomas of the breast survival. Mastectomy is generally performed for more sizeable
without further specifications could, in reality, be synovial tumours, but lumpectomy obtains equivalent oncologic results, if
sarcomas. Thus, a molecular characterisation of these tumours with technically feasible. Obtaining negative surgical margins is more
a search for the translocations characterising synovial sarcomas important than the type of surgery.46 In some larger tumours
could be useful for better defining these entities and, possibly in the where lumpectomy is still technically feasible, cosmetic results are
future, for treatment if specific therapies become available. often inferior to mastectomy and reconstruction and thus, this last
 I.A. Voutsadakis et al. / The Breast 20 (2011) 199e204 201

Table 1
Most recent series with 25 or more patients with localised breast sarcomas.

Ref. No of pts Pathology (%) Prognostic factors (outcome) Outcome

47
59 MFH/FS/SS (54), AS (29) Size, surgical margins (LF) LF: 25% (with adj. RTx)
OSa (5), Other (12) 60% (without RTx)
2
25 FS (24), AS (24), PS (24), Size (OS) OS 5yrs: 66%
MFS (12), LMS (8), OSa (4)
4
103 AS (41), MFH (14), FS (12), Grade, tumor necrosis, residual OS 5yrs: 55%
LPS (7), LMS (6), RMS (6), tumor post-treatment, DFS 5yrs: 44%
SCS (6), OSa (2), Other (6) AS histology (DFS)
7
44 AS (38), SCS (13), LPS (7), Surgical margins, AS histology (OS) OS 1 yr: 68%
FS (7), OSa (5), LMS (5), OS 3 yr: 60%
Other (25)
3
41 SS (34), AS(20), FS (17), Surgical margins (LRFR) CSS 10yrs: 48%
LPS (10), Other (19) RTx>48 Gy (CSS)
42
83 MFH (70), AS (10), LPS (8), Size, grade (DFS) OS 10yrs: 62%
NS (2), Osa (2), RMS (2), grade, AS histology (OS) DFS 10yrs: 50%
LMS (2)
11
27 AS (48), Osa (11), US (19), FS (3), OS 5yrs: 36%
(RIS) LMS (7), MFH (3), RMS (3)
43
55 AS (33), MFH (20), SS (15), Median OS: 58 months
LPS (7), LMS (7), OSa (5),
FS (4), Other (9)

AS: Angiosarcoma, CSS: Cause specific survival, FS: Fibrosarcoma, LF: Local failure, LMS: Leiomyosarcoma, LRFR: Local relapse-free rate, LPS: Liposarcoma, MFH: Malignant
Fibrohistiocytoma, MFS: Myxofibrosarcoma, OS: Overall survival, OSa: Osteosarcoma, RIS: Radiation-induced sarcoma, RTx: Radiation Therapy, SCS: Spindle cell sarcoma,
SS: Stromal sarcoma, US: Undifferentiated sarcoma.

strategy should be preferred.25 Metastatic spread through the that data for the breast-specific location are limited. Classic
lymph node route is not the norm in sarcomas and thus, axillary sarcoma regimens containing doxorubicin, ifosfamide or combi-
lymph node dissection is not generally viewed as part of breast nations may be used in the initial treatment of breast sarcomas.52,53
sarcoma surgery. In a retrospective series that included 34 lymph Combinations obtain higher response rates but their superiority
node dissections for breast sarcomas, none was positive.47 Never- over single agents in increasing overall survival is marginal. Other
theless, angiosarcomas may metastasise to regional lymph nodes. regimens with activity include the combination of gemcitabine
In a series of 28 breast angiosarcoma patients, who underwent an with docetaxel54,55 or vinorelbine56 as well as trabectedin, which is
axillary lymph node dissection as part of their surgery, two (7%) had particularly active in myxoid/round cell liposarcomas and leio-
pathologically positive lymph nodes.48 Thus, axillary lymph node myosarcomas57 and probably also in synovial sarcomas.58
dissection or sentinel lymph node biopsy should be considered in Angiosarcomas are particularly sensitive to taxanes and lipo-
patients with this histology, especially if other risk factors of somal doxorubicin.59e61 This appears to be true also for breast
advanced disease, such as a voluminous primary, are present. angiosarcomas given that some reports have confirmed responses
Positron emission tomography/computed tomography (PET/CT) to these agents.62 As a result, weekly paclitaxel or liposomal
scanning may be helpful in the investigation of the axilla in doxorubicin may be considered as a valid alternative to standard
angiosarcomas to guide the need for dissection.49 ifosfamide/anthracycline treatment for this particular histology in
In locally advanced cases not amenable to primary resection, view also of their manageable adverse effect profile and ease of
neo-adjuvant chemotherapy or radiotherapy is advised in an administration.
attempt to decrease tumour size and subsequently perform Whether the treatment of localised post-irradiation breast
a surgery with negative margins.50 Neo-adjuvant chemo- (radio-) sarcomas should be different from primary sarcomas is debatable.
therapy can also be administered with the aim of avoiding Excision with negative pathologic margins is always of paramount
a mastectomy, a rationale analogous to its use in extremities’ importance.63 The role of chemotherapy is analogous to primary
sarcomas to avoid amputation. sarcomas.64 A high proportion of sarcomas occurring post irradia-
In the absence of specific data on breast sarcoma, the indication tion are angiosarcomas, and the type of chemotherapy should be
for the use of adjuvant chemotherapy and radiation therapy in this adjusted accordingly. Most clinicians are reluctant to include radi-
location should follow the indications for soft-tissue sarcomas in ation treatment in the therapy plan because of surrounding healthy
general.47 These include tumours with higher grade (II or III), size tissue radiation limits even years after the initial radiotherapy.
>5 cm and resection with positive margins that cannot be re- Nevertheless, a small retrospective series of 13 patients with radi-
excised. Chemotherapy and radiation therapy are usually given ation-induced angiosarcomas, who received hyper-fractionated
sequentially, but concomitant schemas with radio-sensitising or accelerated radiotherapy, showed that this mode of treatment is
full chemotherapy doses have been proven feasible. Adjuvant well tolerated and provides local control in nearly 60% of patients.65
radiotherapy decreased local failure from 34% to 13% in a series of Patients in these series received a median of 60 Gy total with three
59 patients, although this did not reach statistical significance fractions of 1 Gy per day at least 4 h apart, and had surgery before or
probably due to the small number of patients.47 after radiation. Their 5-year overall survival was 86%.
Palliative chemotherapy is the mainstay of treatment in meta-
static disease. Surgical resection of metastatic masses could be Novel treatments
considered in selected cases, while radiation therapy can be used
for palliation of localised symptoms. Novel treatments are needed to improve the prognosis of
The choice of chemotherapeutic drugs to be used in the adju- metastatic breast sarcomas. New investigational chemotherapeutic
vant and palliative treatment of breast sarcomas must also rely on agents in sarcomas include palifosfamide and eribulin. Pal-
the experience from soft-tissue sarcomas in other locations,51 given ifosfamide, a DNA cross-linking analogue of ifosfamide, was
202 I.A. Voutsadakis et al. / The Breast 20 (2011) 199e204

compared in combination with doxorubicin to doxorubicin alone in (PI3 K/akt/mTOR) pathway, leading to cell survival and proliferation.
a randomised phase II study of 67 patients with unresectable or In many sarcomas sub-types, IGF axis activity is up-regulated by
metastatic soft-tissue sarcomas.66 The combination produced changes produced by genetic lesions involved in these malignan-
a median progression-free survival of 7.8 months versus 4.4 months cies.77 Inhibiting the pathway with monoclonal antibodies bind-
for doxorubicin monotherapy with no significant increase in ing the receptor is a strategy undergoing investigation in sarcomas.
toxicity. The drug of this type in most advanced clinical development is
Eribulin, a tubulin-targeting derivative of marine sponges, was figitumumab (also known as CP-751, 871). This antibody has shown
studied in a phase II single-arm investigation of advanced soft- single-agent activity mainly in Ewing sarcoma, and also in cases of
tissue sarcomas progressing after one or two lines of chemo- synovial sarcoma and fibrosarcoma.78 Other antibodies and small
therapy.67 It was found to produce responses in various sub-types molecule inhibitors of IGF-1R are in less advanced development.
with the higher percentage of responses in leiomyosarcomas and mTOR, a down-stream intracellular target of the IGF pathway
adipocyte sarcomas. (but also of other signal transduction pathways), has been
Excellent results with agents that target various molecular successfully targeted in the treatment of renal cell carcinoma where
lesions and pathways have been obtained in diverse malignancy two inhibitors, temsirolimus and everolimus, are already in the
types. In sarcomas, targeted treatment of gastroIntestinal stromal clinic. In soft-tissue sarcomas, initial clinical investigations have
tumors (GISTs) with c-kit inhibitor imatinib has been very effective shown limited single-agent activity.79 A combination regimen of
and second-line inhibitors have significant activity even in imati- everolimus with fugitumumab, inhibiting the IGF pathway at two
nib-resistant cases.68,69 Other sarcoma types have been proven less levels, has shown the feasibility of administering the two drugs at
amenable to targeted therapeutics up to present but preclinical and full doses.80
clinical investigations continue. Inhibitors of other tyrosine kinases Other drugs in various phases of investigation in soft-tissue
are already in clinical use in other malignancies, and have been sarcomas include histone deacetylase inhibitors81 and tumour
studied in sarcomas, although no specific data on breast sarcomas necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor
are available. agonists.72 Finally, another avenue to explore is combinations of
The vascular endothelial growth factor (VEGF) pathway is classic chemotherapeutics with targeted agents, such as ifosfamide
important for angiogenesis. VEGF exerts its actions through ligation with sorafenib.82
of its surface receptors VEGFR1e3, which then transduce intracel-
lular signals for cell survival, proliferation and angiogenesis. VEGF is
Conclusions
expressed in soft-tissue sarcomas and may correlate with prog-
nosis.70 VEGFR1 and 2 have also been found to be expressed in
Treatment of breast sarcoma follows the model of sarcomas of
angiosarcomas.71 In addition, activating mutations of VEGFR2 are
other locations and must be planned in a multidisciplinary fashion.
detected in a minority of these tumours, all of which were breast
For localised disease, surgery is the primary treatment but adjuvant
angiosarcomas, both primary and secondary, after radiotherapy.
or neo-adjuvant chemotherapy and radiotherapy should be
These activated mutants VEGFR2 were inhibited by VEGFR inhibi-
considered in high-risk cases. For locally advanced inoperable or
tors sorafenib and sunitinib in vitro.71
metastatic disease, chemotherapy is the mainstay of treatment.
VEGF pathway inhibition in cancer has been obtained with the
Disease response or prolonged disease stabilisation is obtained in
use of small inhibitors of the kinase activity of the receptors
a significant minority of cases but most often is of short duration,
VEGFR1e3 and with monoclonal antibodies against the ligands. In
necessitating treatment with an alternative type of palliative
the former category belong kinase inhibitors sunitinib, sorafenib
chemotherapy, if the patient’s condition allows. Excision of meta-
and pazopanib, already in clinical use for renal cell carcinoma.
static sites can be discussed in a multidisciplinary manner, espe-
These are multi-functional inhibitors that inhibit other receptors in
cially in cases of chemotherapy-resistant histologic sub-types and
addition to VEGFRs. Sunitinib is also a c-kit, platelet-derived
a prolonged natural history of the disease. Even multiple metas-
growth factor receptor (PDGFR) and neurotrophic factor receptor
tases may be resected in selected cases. Radiotherapy for symptoms
inhibitor, sorafenib inhibits PDGFR and Raf kinase,72 while pazo-
relief is also an additional option.
panib inhibits also PDGFR, fibroblast growth factor receptor 1
Development of novel treatments should be based upon the
(FGFR-1) and c-fms.73 In soft-tissue sarcomas, these inhibitors have
increasing understanding of tumour biology, and should attempt to
shown activity in initial clinical trials. Disease stabilisation is seen
address the heterogeneity of sarcomas depicted in their respective
in a significant percentage of sarcoma patients with all these drugs.
genetic lesions. Solid preclinical data should always precede clinical
By contrast, partial or complete responses are rare. Angiosarcomas
development to maximise the probability of success.
seem to be more sensitive to pazopanib, while liposarcomas were
the sub-type the more resistant to it.74
Bevacizumab, a monoclonal antibody against VEGF, inhibits the Conflict of interest statement
same pathway and has single-agent activity against angiosarcoma
None declared.
with a clinical benefit rate (partial responses and stable disease) of
63%.72
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