Review Article

Breast Care 2017;12:109–113 Published online: February 7, 2017

DOI: 10.1159/000454673

Intraoperative Radiotherapy of Breast Cancer and

Its Biological Effects
Igor Piotrowski a, b Katarzyna Kulcenty a, b Mateusz Wichtowski c Dawid Murawa c
Wiktoria Suchorska a, b
a Radiobiology ’ Poland;
Laboratory, Department of Medical Physics, Greater Poland Cancer Centre, Poznan,
b Department ’ Poland;
of Electroradiology, University of Medical Sciences, Poznan,
c ’ Poland
Oncological and General Surgery Department I, Greater Poland Cancer Centre, Poznan,

Keywords Introduction
Breast cancer · Radiotherapy · Molecular biology ·
Intraoperative radiotherapy For almost a century, radical mastectomy was the treatment of
choice for breast cancer patients. At the end of the last century,
Summary mastectomy was replaced by breast-conserving surgery followed by
Conservative breast cancer surgery followed by radia- external beam radiation therapy (EBRT) delivered in fractioned
tion therapy is the standard treatment for this type of doses, which significantly reduced the risk of local recurrence [1].
cancer. Numerous studies demonstrate that 90% of local Even though EBRT achieves good results without inducing a high
recurrences after traditional surgery occur in the same risk of side effects, the duration of this treatment is a major down-
quadrant as the primary cancer. The published data sug- side. Many patients who cannot attend a radiation center for sev-
gest that the wound healing process after surgery alters eral weeks of radiotherapy, receive mastectomy instead. Intraoper-
the area surrounding the original tumor and the modi- ative radiotherapy (IORT) administered in 1 dose during surgery
fied microenvironment is more favorable for the tumor could be a solution to the problem of radiotherapy duration. The
to recur. The majority of metastases within scar initiated idea of using partial breast irradiation instead of whole breast irra-
much research, and the consequences of these studies diation derives from the fact that a great majority of intra-breast
led to clinical trials aimed at assessing whether localized tumor reoccurrences arise in the same quadrant of the breast in
radiotherapy, such as intraoperative radiotherapy (IORT), which the primary tumor appeared [1]. Results of several ongoing
would be more effective in inhibiting formation of local IORT clinical trials show that IORT might be a viable alternative to
recurrence than the standard postoperative whole breast EBRT for a specific group of patients. The effects of radiation and
radiotherapy. IORT involves irradiation of diseased tis- surgical procedures on tumor bed are still largely unknown. Re-
sue directly during surgery. The rationale for this ap- searchers point out that the wound healing process and inflamma-
proach is the fact that the increase in the radiation dose tion induced by the surgical procedure might stimulate the growth
increases local tumor control, which is the primary goal of residual cancer cells after tumor excision [2]. Recent discoveries
of radiation therapy. The biological basis of this process indicate that this stimulatory effect might be reduced by radiation
are still not thoroughly understood. Gaining new knowl- [3]. Better understanding of interactions occurring between breast
edge about the recurrence formation at the molecular cancer cells and tumor environment after radiation therapy might
level could serve as a starting point for further analysis open the way for finding new targets for breast cancer therapy.
and to create an opportunity to identify new targets of
therapy, and possibly new therapeutic agents.
© 2017 S. Karger GmbH, Freiburg Intraoperative Radiation Therapy Trials

Different concepts of IORT have been adapted into therapy.

IORT can be utilized as a boost and followed by irradiation of the

© 2017 S. Karger GmbH, Freiburg Dr. Katarzyna Kulcenty

Radiobiology Laboratory, Department of Medical Physics
Fax +49 761 4 52 07 14 Greater Poland Cancer Centre
[email protected] Accessible online at: Garbary 15 Street, Poznań, Poland
www.karger.com www.karger.com/brc katarzyna.kulcenty @ wco.pl
whole breast, which has provided promising results in local recur- TARGIT-A
rence control [4]. A different approach of IORT is the usage of in- The TARGIT-A trial is a randomized IORT trial comparing the
sertion techniques like MammoSite [5]. A disadvantage of this sys- effects of IORT performed with an intrabeam device to EBRT [7].
tem is inhomogeneous irradiation of tumor bed. The trials that The device used in TARGIT-A has a low-energy x-ray source pro-
yielded the most promising results are electron intraoperative ra- viding an isotropic dose of radiation by accelerating electrons into
diotherapy (ELIOT) and targeted intraoperative radiotherapy a gold target at the end of a 10-cm probe. The energy of the pho-
(TARGIT) [6, 7]. tons produced is 50 keV, and the depth-dose of the x-rays thus falls
off rapidly [11]. With 20–45-min radiation, the tumor bed receives
ELIOT dose of 20 Gy that attenuates to 5–7 Gy at a depth of 1 cm [12]. The
ELIOT is an electron IORT technique developed at the Euro- surgical procedure starts with a wide local excision and axillary
pean Institute of Oncology (Milan, Italy) [6]. In this trial electrons clearance. After insertion of the appropriate applicator into the
are administered to tumor bed in a single session by a linear accel- breast cavity, the breast tissue at risk is brought to the applicator by
erator: NOVAC 7 or Liac. The NOVAC 7 accelerator is able to de- inserting a purse-string suture and irradiated [13].
liver collimated electron beams at energies of 3, 5, 7 and 9 MeV [8]. Of the 3,451 patients aged 45  years or older with early breast
In the preliminary study by Veronesi et al. [9], doses of 10, 15, 17, cancer enrolled, 1,721 (49.87%) were randomized to TARGIT and
19 and 21 Gy were administered to patients. Using a linear-quad- 1,730 (50.13%) to EBRT. 239 of 1,571 patients receiving TARGIT
ratic surviving fraction model, scientists estimated that a single (15.2%) required supplemental EBRT. Additional EBRT was rec-
dose of 20–22 Gy is equivalent to 60 Gy delivered in 30 fractions of ommended when final pathology report showed 1 of 3 features: a
2 Gy, which is an accepted method of treatment following breast- positive margin of > 1 mm, an extensive in-situ component, or in-
conserving surgery. vasive lobular carcinoma. The primary outcome of the trial was
In the ELIOT trial, 1,305 patients between 48 and 75  years of local recurrence in the conserved breast [7].
age with tumors up to 2.5  cm in diameter were randomized [6]. Risks of local recurrences in the conserved breast and other re-
654 patients were assigned to external radiotherapy and 651 pa- currences for patients who received TARGIT were 3.3% and 4.9%,
tients were assigned to ELIOT. For this trial, ipsilateral breast respectively, compared with 1.3% and 4.4% in EBRT group. There
tumor recurrences (IBTR) included recurrences at the site of sur- was no significant difference between breast cancer-related deaths
gery and new carcinomas appearing in the same quadrant of the in TARGIT (2.6%) and EBRT (1.9%), but the TARGIT group
breast. 35 cases (4.4%) of IBTR were observed in the ELIOT group showed fewer non-breast cancer deaths (1.4%) than EBRT group
compared to 4 cases (0.4%) in the EBRT group. Patients in the (3.5%). Patients who received both TARGIT-A and EBRT had a 3
IORT group developed IBTR at much higher rates. Characteristics times lower chance of developing local recurrence (0.9%) and
that correlated with the highest IBTR rate (above 10%) were: tumor showed increased breast cancer mortality (8%) in comparison with
size > 2 cm, the presence of 4 or more positive nodes, tumor poorly patients who received only TARGIT-A [7]. Median follow-up for
differentiated, estrogen receptor-negative tumor and triple nega- the whole cohort at the end of trial was 29 months.
tive tumor. Authors concluded that patients with a tumor size of Silverstein et al. [14] in a critical review of the trial deemed
>  2  cm, 4 or more positive lymph nodes, poorly differentiated 29 months of follow-up as too short a time to observe breast recur-
tumor or triple negative tumor could potentially benefit from ad- rences. The authors of the TARGIT-A trial emphasize the impor-
ditional whole breast irradiation after IORT, administrated as a tance of selection of patients, and point out that a pre-pathology
boost of 10 Gy [9]. It is worth mentioning that patients with a lu- approach and risk-adapted design are crucial to allow the best re-
minal A-subtype tumor had results similar to those of EBRT pa- sults in patients.
tients [10]. Even though both TARGIT-A and ELIOT trials have already
The ELIOT group also showed a higher rate of true local relapse shown great promise in breast cancer therapy, it is necessary to sig-
(21 cases, 2.5%) at 5 years than patients in the EBTR group (4 cases, nificantly extend the follow-up. The results suggest that with
0.4%). Distant metastases and primary cancers at other sites oc- proper selection of patients, these techniques will yield results sim-
curred with similar frequency in both groups. Overall 5-year sur- ilar to those of EBRT, while greatly reducing therapy time for the
vival was similar between the ELIOT and EBRT groups (96.8% and patients’ convenience.
96.9%, respectively).
Side effects of the therapy with IORT were assessed in 876 pa-
tients (464 in the ELIOT group and 412 in EBRT group). There Biological Aspects of IORT
were no significant differences in occurrence of mammary fibrosis,
mammary retraction, pain and burning between the 2 groups. The Even though recent results of IORT application in breast tumor
IORT group suffered less often from skin-related side effects like treatment show great promise, our knowledge of biological and mo-
erythema, dryness, hyper-pigmentation and pruritus compared to lecular effects of this therapy on tumor cells and tumor environ-
the EBRT group. More cases of liponecrosis were seen in the ment is still limited. Recently, direct effects of ionizing radiation on
ELIOT than in the EBRT group. gene expression of luminal A breast cancer cell line MCF7 have
been described [15–17]. The cells irradiated with 9 Gy and 23 Gy

110 Breast Care 2017;12:109–113 Piotrowski/Kulcenty/Wichtowski/Murawa/

Suchorska
(IORT as boost and exclusive treatment, respectively) showed a se- gesting that cancer cells remaining in tumor bed after surgery
nescence phenotype increasing with dose. Irradiation also caused might be responsible for that. The changes in the tumor microen-
double-strand breaks in a dose-dependent manner. Irradiated vironment, such as inflammation and wound healing initiated by
MCF-7 cells also showed an increased expression of proteins in- surgery, might promote growth of breast cancer cells [29]. A recent
volved in stress and survival responses, but no evidence of apoptotic study conducted by Beletti et al. [3] indicated that IORT modifies
pathway activation. Radiation has been proven to increase NF-kB properties of surgical wound fluids (WF). Breast cancer cells cul-
binding activity, leading to changes in cell-cycle regulation and to tured with WF harvested from IORT-treated patients showed sig-
apoptosis suppression [18], which was also confirmed in the irradi- nificantly reduced ability to grow in 3D culture, together with im-
ated MCF-7 cells. These results show how the response of breast paired motility and cell invasion in comparison to culture with
cancer cells differs depending on the administered radiation dose. surgical WF from patients who had not undergone IORT. The pro-
Kim et al. [19] described molecular effects of a radiation dose of teomic analysis of WF and WF from IORT-treated patients showed
6 Gy on an MCF-7 cell line. Irradiated cells showed morphological a decrease in molecules involved in tumor growth and motility in
changes increasing with dose, indicating senescence. The senescent IORT WF. These results indicate the effect of radiation-induced
phenotype also induced retardation in cell proliferation. Recent re- changes in the microenvironment on breast cancer cells.
ports suggest that ‘accelerated senescence’ might be a major factor Surgical WF are also known to stimulate breast cancer cell
in loss of reproductive capacity by solid tumors [20]. Changes in growth, but the mechanisms of this stimulation remain largely un-
the expression profile after irradiation resulted in cell cycle arrest at known [29]. Recently, Segatto et al. [30] showed that stimulation of
S and G2/M phases. Suppression of mitotic activity was also re- breast cancer cells with WF collected from patients after breast
flected by the fact that exposure of breast cancer cells to irradiation tumor excision induces the Signal Transducer and Activator of
resulted in down-regulation of expression of the genes responsible Transcription 3 (STAT3) pathway in those cells. STAT3 plays a
for microtubule structure and for spindle organization and biogen- role in the transcriptional regulation of genes responsible for cell
esis [19]. proliferation, survival, self-renewal, differentiation and apoptosis
The direct effect of cell irradiation, especially the DNA damage, [31] and has been proven to influence growth and progression of
has already been thoroughly described [21, 22]. In addition to the breast cancer cells [32, 33]. These authors have shown that cell
direct effect, ionizing radiation can also affect non-irradiated cells lines representing different pathological subtypes (basal MDA-
neighboring the irradiated cells. This effect is called ‘bystander ef- MB-231 and MDA-MB-468, luminal MCF-7, HER-2 positive BT-
fect’ and is mediated through cell-to-cell gap junctions and se- 474) displayed higher mammosphere-forming efficiency (MFE)
creted cytokines and chemokines [23]. Several mechanisms for the and formed spheres bigger in size when stimulated with WF than
‘bystander effect’ have already been described. It seems that induc- after stimulation with epidermal growth factor (EGF), which is
tion of oxidative DNA damage by inflammatory response is an im- used as a standard sphere-forming agent. The authors confirmed
portant factor [24]. Although the changes in microenvironment that STAT3 mediates the effect of WF on mammosphere forma-
can inhibit tumor growth, researchers point out that mediators of tion by showing that cells stimulated with WF in presence of
the ‘bystander effect’ can also induce tumor growth [25]. The radi- STAT3 inhibitors had decreased MFE. Taken together with a fact
ation-mediated ‘bystander effect’ increases with dose, but reaches that WF stimulation enriched the population of cancer cells with
plateau at relatively low doses [23, 26]. The effect of ionizing radia- tumor-initiating cells, these results suggest that WF might be a po-
tion on carcinoma cells growing in a mammary stromal microenvi- tent factor inducing local recurrence[34]. Stimulation of breast
ronment and on the microenvironment itself has been demon- cancer cells with WF in vitro also caused an increase in CD44+/
strated. Researchers have investigated interactions in 3-dimen- CD24-/low population, which is more tumorigenic and shows stem
sional (3D) co-culture between fibroblasts exposed to chronic low- cell-like properties [35]. The effect of WF stimulation on the puta-
dose radiation with non-irradiated breast cancer cells tive stem cell phenotype of breast cancer cells was also investigated
(MDA-MB-231) and with untransformed mammary epithelial cells by Zaleska et al. [36]. Although stimulation with both WF and WF
MCF-10A. Results show that irradiated fibroblasts exhibited char- from patients after IORT treatment induced ALDH1 activity in
acteristics of replicative senescence. Irradiated fibroblasts also dis- breast cancer cells (a marker connected with cancer-stem like phe-
rupted development of MCF-10A into ductal structures. In co-cul- notype [35, 37]), WF collected from patients after surgery alone
ture with MDA-MB-231 cells, senescence-like fibroblasts induced stimulated the ALDH1 activity more strongly than WF after IORT
growth and invasion of breast carcinoma cells. It was concluded treatment. The effect of WF stimulation on expression of CD44
that irradiated fibroblasts secreted matrix-degrading metallopro- and CD24 varied significantly depending on the cell line. These re-
teinases, which effect the invasive growth of breast cancer cells. sults indicate that surgical procedure can influence the putative
The authors pointed out that accumulation of senescence-like fi- stem cell phenotype of breast cancer cells.
broblasts in breast stroma might create environment that promotes Another important factor in tumorigenesis is the activity of the
breast cancer progression [27]. 70-kDa ribosomal protein S6 kinase (p70S6K), a serine/threonine
Local relapse is often pointed out as the most important risk kinase involved in regulation of cell growth, survival and metabo-
factor in survival of breast cancer patients [28]. Most local recur- lism [38]. In primary breast cancer, amplification of the region
rences occur within the same quadrant as the primary cancer, sug- 17q23 containing the gene encoding p70S6K has been observed in

Biology of Intraoperative Radiotherapy Breast Care 2017;12:109–113 111

12.5% cases [39]. Robust activity of this protein has been connected T cells [41]. It is important to note that changes in tumor microen-
to survival of residual cancer cells after surgery [34]. Experiments vironment induced by irradiation may exert pro- and anti-tumor
on breast cancer cell lines showed that stimulation with WF in- effects, since many cytokines and chemokines have unknown
duced activity of p70S6K. In an in vivo model, breast cancer cells effects.
with impaired p70S6K formed tumors later and showed reduced Application of IORT in breast cancer treatment has shown great
invasion of surrounding tissue in comparison to control cells. Inhi- promise not only by giving similar results to the widely used EBRT,
bition of p70S6K in breast cancer cells growing in vitro impaired but also by providing a treatment method that is less time and
their proliferation, survivability and growth even with WF stimula- money consuming. This relatively new therapy is already used in
tion [40]. The role of p70S6K in apoptosis escape, survival in hos- many radiation centers around the world as an alternative to EBRT
tile conditions and primary tumor growth makes it a viable target in the treatment of early breast carcinomas.
in breast cancer therapy. Interfering with its activity in cancer cells
might be an important step in reducing locoregional recurrences.
Acknowledgement

Summary This work was supported by the National Science Centre (grant
number: 2015/19/D/NZ5/02190).
Recent discoveries in the field of tumor microenvironment
might help provide a better understanding of its importance in
tumor growth and progression. High-dose radiation has been Disclosure Statement
shown not only to directly induce damage on DNA but also to pro-
mote anti-tumor T cell immunity and expansion of activated The authors indicate that there is no conflict of interest.

References
1 Veronesi U, Marubini E, Mariani L, et al.: Radiother- 11 Kraus-Tiefenbacher U, Steil V, Bauer L, et al.: A novel 20 Gewirtz DA, Holt SE, Elmore LW: Accelerated senes-
apy after breast-conserving surgery in small breast car- mobile device for intraoperative radiotherapy (IORT). cence: An emerging role in tumor cell response to
cinoma: Long-term results of a randomized trial. Ann Onkologie 2003; 26: 596–598. chemotherapy and radiation. Biochem Pharmacol
Oncol 2001; 12: 997–1003. 12 Vaidya JS, Joseph DJ, Tobias JS, et al.: Targeted intra- 2008; 76: 947–957.
2 Troester MA, Lee MH, Carter M, et al.: Activation of operative radiotherapy versus whole breast radiother- 21 Goodhead DT: Initial events in the cellular effects of
host wound responses in breast cancer microenviron- apy for breast cancer (TARGIT-A trial): An interna- ionizing radiations: Clustered damage in DNA. Int J
ment. Clin Cancer Res 2009; 15: 7020–7028. tional, prospective, randomised, non-inferiority phase Radiat Biol 1994; 65: 7–17.
3 Belletti B, Vaidya JS, D’Andrea S, et al.: Targeted intra- 3 trial. Lancet 2010; 376: 91–102. 22 Henner WD, Grunberg SM, Haseltine WA: Sites and
operative radiotherapy impairs the stimulation of breast 13 Vaidya JS, Tobias JS, Baum M, et al.: TARGeted Intra- structure of gamma radiation-induced DNA strand
cancer cell proliferation and invasion caused by surgical operative radiotherapy (TARGIT): An innovative ap- breaks. J Biol Chem 1982; 257: 11750–11754.
wounding. Clin Cancer Res 2008; 14: 1325–1332. proach to partial-breast irradiation. Semin Radiat 23 Mothersill C, Seymour CB: Radiation-induced by-
4 Reitsamer R, Sedlmayer F, Kopp M, et al.: The Salz- Oncol 2005; 15: 84–91. stander effects – implications for cancer. Nat Rev Cancer
burg concept of intraoperative radiotherapy for breast 14 Silverstein MJ, Fastner G, Maluta S, et al.: Intraopera- 2004; 4: 158–164.
cancer: results and considerations. Int J Cancer 2006; tive radiation therapy: A critical analysis of the ELIOT 24 Sprung CN, Ivashkevich A, Forrester HB, et al.: Oxida-
118: 2882–2887. and TARGIT trials. Part 2 – TARGIT. Ann Surg Oncol tive DNA damage caused by inflammation may link to
5 Thompson N, Cogen C, Forman D, Londerville S: 2014; 21: 3793–3799. stress-induced non-targeted effects. Cancer Lett 2015;
MammoSite Radiation Therapy System. Clin J Oncol 15 Bravata V, Minafra L, Russo G, et al.: High-dose ioniz- 356: 72–81.
Nurs 2005; 9: 375–377. ing radiation regulates gene expression changes in the 25 Park B, Yee C, Lee KM: The effect of radiation on the
6 Veronesi U, Orecchia R, Maisonneuve P, et al.: Intra- MCF7 breast cancer cell line. Anticancer Res 2015; 35: immune response to cancers. Int J Mol Sci 2014; 15:
operative radiotherapy versus external radiotherapy 2577–2591. 927–943.
for early breast cancer (ELIOT): A randomised con- 16 Subik K, Lee JF, Baxter L, et al.: The expression pat- 26 Lara PC, Lopez-Penalver JJ, Farias Vde A, et al.: Direct
trolled equivalence trial. Lancet Oncol 2013; 14: 1269– terns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR and bystander radiation effects: A biophysical model
1277. by immunohistochemical analysis in breast cancer cell and clinical perspectives. Cancer Lett 2015; 356: 5–16.
7 Vaidya JS, Wenz F, Bulsara M, et al.: Risk-adapted tar- lines. Breast Cancer (Auckl) 2010; 4: 35–41. 27 Tsai KK, Chuang EY, Little JB, Yuan ZM: Cellular
geted intraoperative radiotherapy versus whole-breast 17 Yan W, Chen Y, Yao Y, et al.: Increased invasion and mechanisms for low-dose ionizing radiation-induced
radiotherapy for breast cancer: 5-year results for local tumorigenicity capacity of CD44+/CD24- breast can- perturbation of the breast tissue microenvironment.
control and overall survival from the TARGIT-A ran- cer MCF7 cells in vitro and in nude mice. Cancer Cell Cancer Res 2005; 65: 6734–6744.
domised trial. Lancet 2014; 383: 603–613. Int 2013; 13: 62. 28 Huston TL, Simmons RM: Locally recurrent breast
8 Veronesi U, Gatti G, Luini A, et al.: Intraoperative ra- 18 Veeraraghavan J, Natarajan M, Aravindan S, et al.: Ra- cancer after conservation therapy. Am J Surg 2005;189:
diation therapy for breast cancer: technical notes. diation-triggered tumor necrosis factor (TNF) alpha- 229–235.
Breast J 2003; 9: 106–112. NFkappaB cross-signaling favors survival advantage in 29 Tagliabue E, Agresti R, Carcangiu ML, et al.: Role of
9 Veronesi U, Orecchia R, Luini A, et al.: A preliminary human neuroblastoma cells. J Biol Chem 2011; 286: HER2 in wound-induced breast carcinoma prolifera-
report of intraoperative radiotherapy (IORT) in lim- 21588–21600. tion. Lancet 2003; 362: 527–533.
ited-stage breast cancers that are conservatively 19 Kim BC, Han NK, Byun HO, et al.: Time-dependently 30 Segatto I, Berton S, Sonego M, et al.: Surgery-induced
treated. Eur J Cancer 2001; 37: 2178–2183. expressed markers and the characterization for prema- wound response promotes stem-like and tumor-initi-
10 Esserman LJ, Alvarado MD, Howe RJ, et al.: Applica- ture senescence induced by ionizing radiation in MCF7. ating features of breast cancer cells, via STAT3 signal-
tion of a decision analytic framework for adoption of Oncol Rep 2010; 24: 395–403. ing. Oncotarget 2014; 5: 6267–6279.
clinical trial results: Are the data regarding TARGIT-A
IORT ready for prime time? Breast Cancer Res Treat
2014; 144: 371–378.

112 Breast Care 2017;12:109–113 Piotrowski/Kulcenty/Wichtowski/Murawa/

Suchorska
31 Bromberg J: Signal transducers and activators of tran- 35 Al-Hajj M, Wicha MS, Benito-Hernandez A, et al.: 38 Fenton TR, Gout IT: Functions and regulation of the
scription as regulators of growth, apoptosis and breast Prospective identification of tumorigenic breast cancer 70kDa ribosomal S6 kinases. Int J Biochem Cell Biol
development. Breast Cancer Res 2000; 2: 86–90. cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988. 2011; 43: 47–59.
32 Marotta LL, Almendro V, Marusyk A, et al.: The JAK2/ 36 Zaleska K, Suchorska WM, Przybyła A, Murawa D: Ef- 39 Monni O, Barlund M, Mousses S, et al.: Comprehen-
STAT3 signaling pathway is required for growth of fect of surgical wound fluids after intraoperative elec- sive copy number and gene expression profiling of the
CD44(+)CD24(-) stem cell-like breast cancer cells in tron radiotherapy on the cancer stem cell phenotype in 17q23 amplicon in human breast cancer. Proc Natl
human tumors. J Clin Invest 2011; 121: 2723–2735. a panel of human breast cancer cell lines. Oncol Lett Acad Sci USA 2001; 98: 5711–5716.
33 Chang Q, Bournazou E, Sansone P, et al.: The IL-6/ 2016; 12: 3707–3714. 40 Segatto I, Berton S, Sonego M, et al.: p70S6 kinase me-
JAK/Stat3 feed-forward loop drives tumorigenesis and 37 Croker AK, Goodale D, Chu J, et al.: High aldehyde diates breast cancer cell survival in response to surgical
metastasis. Neoplasia 2013; 15: 848–862. dehydrogenase and expression of cancer stem cell wound fluid stimulation. Mol Oncol 2014; 8: 766–780.
34 Segatto I, Berton S, Sonego M, et al.: Inhibition of markers selects for breast cancer cells with enhanced 41 Kaur P, Asea A: Radiation-induced effects and the im-
breast cancer local relapse by targeting p70S6 kinase malignant and metastatic ability. J Cell Mol Med 2009; mune system in cancer. Front Oncol 2012; 2: 191.
activity. J Mol Cell Biol 2013; 5: 428–431. 13: 2236–2252.

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