BackgroundIntraoperative radiotherapy (IORT) is a new treatment approach for early stage breast cancer. This study reports on the effects of IORT on radiation-related quality of life (QoL) parameters.MethodsTwo hundred and thirty women with stage I-III breast cancer (age, 31 to 84 years) were entered into the study. A single-center subgroup of 87 women from the two arms of the randomized phase III trial TARGIT-A (TARGeted Intra-operative radioTherapy versus whole breast radiotherapy for breast cancer) was analyzed. Furthermore, results were compared to non-randomized control groups: n = 90 receiving IORT as a tumor bed boost followed by external beam whole breast radiotherapy (EBRT) outside of TARGIT-A (IORT-boost), and n = 53 treated with EBRT followed by an external-beam boost (EBRT-boost). QoL was collected using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaires C30 (QLQ-C30) and BR23 (QLQ-BR23). The mean follow-up period in the TARGIT-A groups was 32 versus 39 months in the non-randomized control groups.ResultsPatients receiving IORT alone reported less general pain (21.3 points), breast (7.0 points) and arm (15.1 points) symptoms, and better role functioning (78.7 points) as patients receiving EBRT (40.9; 19.0; 32.8; and 60.5 points, respectively, P < 0.01). Patients receiving IORT alone also had fewer breast symptoms than TARGIT-A patients receiving IORT followed by EBRT for high risk features on final pathology (IORT-EBRT; 7.0 versus 29.7 points, P < 0.01). There were no significant differences between TARGIT-A patients receiving IORT-EBRT compared to non-randomized IORT-boost or EBRT-boost patients and patients receiving EBRT without a boost.ConclusionsIn the randomized setting, important radiation-related QoL parameters after IORT were superior to EBRT. Non-randomized comparisons showed equivalent parameters in the IORT-EBRT group and the control groups.

scheel@helmholtz-muenchen.de and 39 Martin R. Sprick, m.sprick@Dkfz-Heidelberg.de and 40 Andreas Trumpp, a.trumpp@Dkfz-Heidelberg.de 41 42 Running title: 43 Epithelial gene expression in EMT is required for breast cancer metastasis. 44 45 Abstract 48Despite important advances in the treatment of breast cancer, the 5-year survival rate 49 for patients with distant metastasis remains less than 30%. Metastasis is a complex, 50 multi-step process beginning with local invasion and ending with the outgrowth of 51 systemically disseminated cells into actively proliferating metastases that ultimately 52 cause the destruction of vital organs. It is this last step that limits patient survival and, 53 at the same time, remains the least understood mechanistically. Here, we focus on 54 understanding determinants of metastatic outgrowth using metastatic effusion biopsies 55 from stage IV breast cancer patients. By modelling metastatic outgrowth through 56 xenograft transplantation, we show that tumour initiation potential of patient-derived 57 metastatic breast cancer cells across breast cancer subtypes is strongly linked to high 58 levels of EPCAM expression. Breast cancer cells with high EPCAM levels are highly 59 plastic and, upon induction of epithelial-mesenchymal transition (EMT), readily adopt 60 mesenchymal traits while maintaining epithelial identity. In contrast, low EPCAM levels 61 are caused by the irreversible reprogramming to a mesenchymal state with 62 concomitant suppression of metastatic outgrowth. The ability of breast cancer cells to 63 retain epithelial traits is tied to a global epigenetic program that limits the actions of 64 EMT-transcription factor ZEB1, a suppressor of epithelial genes. Our results provide 65 direct evidence that maintenance of epithelial identity is required for metastatic 66 outgrowth while concomitant expression of mesenchymal markers enables plasticity. 67In contrast, loss of epithelial traits is characteristic of an irreversible mesenchymal 68 reprogramming associated to a deficiency for metastatic outgrowth. Collectively, our 69 data provide a framework for the intricate intercalation of mesenchymal and epithelial 70 traits in metastatic growth. 71Other studies emphasize that a transient, rather than permanent expression of EMT-87 transcription factors is crucial for the outgrowth of metastases 4,6,7 . This is supported by 88 the finding that most macroscopic metastases generated by carcinomas display an 89 epithelial morphology 8 . However, a strict requirement for EMT at any time during the 90 metastatic process is called into question by the finding that overexpression of micro 91RNAs that inhibit EMT does not affect metastasis 9 and loss of Twist1 and Snai1 92 expression in a pancreatic cancer mouse model does not change invasion and disease 93 progression 10 . 94More complication has recently arisen from the observation that tumour cells with an 95 intermediate, often termed hybrid epithelial-mesenchymal phenotype, are the most 96 competent in colonization and metastasis fo...

Intraoperative radiotherapy (IORT) with low-energy x-rays is increasingly used in breast-conserving therapy (BCT). Previous non-randomized studies have observed mammographic changes in the tumor bed to be more pronounced after IORT. The purpose of this study was to reassess the postoperative changes in a randomized single-center subgroup of patients from a multicenter trial (TARGIT-A). In this subgroup (n = 48) 27 patients received BCT with IORT, 21 patients had BCT with standard whole-breast radiotherapy serving as controls. Overall 258 postoperative mammograms (median follow-up 4.3 years, range 3-8) were retrospectively evaluated by two radiologists in consensus focusing on changes in the tumor bed. Fat necroses showed to be significantly more frequent (56% versus 24%) and larger (8.7 versus 1.6 sq cm, median) after IORT than those in controls. Scar calcifications were also significantly more frequent after IORT (63% versus 19%). The high incidence of large fat necroses in our study confirms previous study findings. However, the overall higher incidence of calcifications in the tumor bed after IORT represents a new finding, requiring further attention.