Partial breast irradiation La IORT: TARGIT Il punto di vista del chirurgo

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1 IL CARCINOMA DELLA MAMMELLA NEL 2010: Il chirurgo generale tra demolizione, ricostruzione e radioterapia Udine, 23 ottobre 2010 Partial breast irradiation La IORT: TARGIT Il punto di vista del chirurgo Dott. Samuele Massarut, C.R.O. Aviano Oncologia Chirurgica Senologica C.R.O. Aviano

Partial breast irradiation La IORT: TARGIT Il punto di vista del

2 TARGIT: il punto di vista del chirurgo 1. Facilità di esecuzione 2. Assenza di effetti indesiderati maggiori 3. Buon risultato estetico 4. Ottimo controllo locale di malattia 5. Studio delle interazioni tra intervento chirurgico e tumore mammario

3 Results (1) 114 patients assessed Median age at randomisation 62 years (IQR 56 to 68). Median tumour size o 10 (IQR 8-15) mm 42% upper outer quadrant Photographs taken at 1, 2 & 3 years after initial breast conserving surgery None had subsequent breast surgery S. M. Udine 23 Ottobre 2010

4 Results (2) A higher proportion of patients achieved Excellent or Good cosmesis in the TARGIT group than in the EBRT group (Log Rank test p=0.0244). The largest difference was seen in the first year; 74.6% (SEM 5.7%) versus 56.4% (SEM 6.7%). S.M. Udine 23 Ottobre 2010

5 Results (3) Excellent/Good cosmetic outcome Proportion EBRT TARGIT Year after surgery S.M. Udine 23 Otobre 2010

7 TARGIT A: CRITERI DI INCLUSIONE Età > 45 anni Tumore unifocale < 2,5 cm. Istotipo non lobulare Assenza di metastasi linfonodali ascellari clinicamente evidenti Assenza di EIC Assenza di trattamenti neoadiuvanti Altri criteri a discrezione dei singoli Centri, predefiniti e concordati con l ISC S.M. Udine 23 Ottobre 2010

evidenti Assenza di EIC Assenza di trattamenti neoadiuvanti Altri criteri a

8 Centres are listed in the order that they joined the trial. The patients randomised from each country were: UK 469 (21%), Germany 571 (26%), Denmark 302 (14%), Australia 296 (13%), Italy 293 (13%), USA 207 (9%), Poland 41 (2%), Switzerland 40 (2%), Canada 13 (1%).

Germany 571 (26%), Denmark 302 (14%), Australia 296 (13%), Italy

11 INTRODUCTION THE PREMISE In Breast Carcinomas 90% of recurrences after wide local excision occur in the index quadrant despite the fact that tumour multi-centricity is present in around 60% of cases and that wide free margins are often obtained with surgery S.M. Udine 13 Ottobre 2010

tumour multi-centricity is present in around 60% of cases and that

12 INTRODUCTION THE QUESTION Is that due only to cancer cells left in the tumour bed? (conventional hypothesis) OR is it maybe due also to the ability of the surgical wound to induce the recurrence? (new hypothesis) S.M. Udine 13 Ottobre 2010

13 EXPERIMENTAL EVIDENCES A normal microenvironment can preserve the tissue architecture even in the presence of predisposed cells; An aberrant microenvironment can promote the mutated cells to form tumors. Mina J. Bissell and Mark A. LaBarge Cancer Cell :

aberrant microenvironment can promote the mutated cells to form

14 EXPERIMENTAL EVIDENCES Tumour activated fibroblasts stimulate cancer cell growth by producing specific growth factors and chemokines Orimo, et al. Cell :

15 EXPERIMENTAL EVIDENCES Tumour microenvironment stiffness favours cancer cell growth Paszek, et al. Cancer Cell :

16 CLINICAL EVIDENCES 90% of recurrences occur in the index quadrant S.M. Udine 23 Ottobre 2010

17 CLINICAL EVIDENCES Surgery modifies the growth kinetics of breast cancer micrometastasis S.M. Udine 23 Ottobre 2010

18 CLINICAL EVIDENCES Axillary wound fluid derived from breast cancer pts. induced proliferation of Her2- expressing breast carcinoma cells in vitro, an effect that can be abrogated by trastuzumab S. M. Udine 23 Ottobre 2010

19 CLINICAL EVIDENCES Residual tumour after conservative surgery has a much higher level of Mib-1 (proliferation index) than the primary tumour S. M. Udine 23 Ottobre 2010

20 CLINICAL EVIDENCES The absolute effect of radiotherapy in reducing the risk of local recurrence increases with increasing risk of local recurrence. Thus, the proportional reduction of the risk by radiotherapy remains constant S. M. Udine 23 Ottobre 2010

21 Distribution of fibroadenomas by age and according to modality of diagnosis Age HD F CDF Total Cases % Cases % Cases % Total Abbreviations : HDF - hystologically diagnosed fibroadenomas ; CDF- clinically diagnosed fibroadenomas. Ciatto S et al. Ann of Oncol 8: ;1997

22 Distribution of person-years (PY), expected (EBC) and observed (OBC) breast cancers, standardized incidence ratio (SIR) and 95% confidence interval (95% CI), according to calendar year and modality of diagnosis Period PY EBC OBC SIR 95% CI HDF Total CDF Total Ciatto S et al. Ann of Oncol 8: ;1997

23 INTRODUCTION Tumors growing in preirradiated beds in rodents show a prolonged latency period and a reduced volumetric growth rate. This classic phenomenon is known since 1914 and was called in 1955 Tumor Bed Effect Rofstad, et al. Cancer Res :

24 Serum Collection The day prior to surgery the patient received a blood drawing; At the end of the surgery (with or without IORT) drainage fluid from breast surgical wound was collected for 24 hours; Drawing of Presurgery Serum Drainage of Postsurgery Serum Both the Pre-surgery serum and the Post-surgery serum (drainage fluid) were promptly sent to the Experimental Oncology Dept. where they were processed, aliquoted and stored at -80 C until analysed. Exp.Onc.Dept. processing centrifuging and storage.

25 TARGIT treatment impairs the wound fluid - induced cancer cell growth in 3D-matrices HMEC in MATRIGEL MCF-7 in MATRIGEL

26 TARGIT impairs the wound fluid-induced cancer cell migration and invasion HMEC MDA-MB 231 SFM NIH CM PRE Sera WF UNTR PRE Sera WF TARGIT MDA-MB 231 MDA-MB 453 SFM NIH CM PRE Sera WF UNTR PRE Sera WF TARGIT PRE-Sera WF UNTR. WF TARGIT PRE-Sera WF UNTR. WF TARGIT

27 TARGIT alters the proteomic profile of the wound fluid PRE-Sera WF untreated WF TARGIT HGF IL-10 IL-13

28 CONCLUSIONS 1. Wound Fluids trigger breast cancer cell proliferation (but not that of normal cells) 2. Wound Fluids stimulate migration and invasion of breast cancer cells (but not of normal cells); 3. Both these effects are counteracted by TARGIT; 4. Wound Fluids from TARGIT-treated patients display a different molecular profile from other WF; 5. Altogether these results suggest that TARGIT could act not only by killing residual tumor cells present in the tumor bed after surgery, but also by rendering the tumor microenvironment less favorable to breast cancer cell local invasion, which could, eventually, translate into a decreased recurrence rate. S.M. Udine 23 Ottobre 2010

33 ACKNOWLEDGEMENTS CRO National Cancer Institute -Aviano- Italy Department of Experimental Oncology Gustavo Baldassarre, MD Barbara Belletti, PhD Sara D andrea, Tech Alfonso Colombatti, MD Department of Pathology Tiziana Perin, MD Vincenzo Canzonieri, MD Antonino Carbone,MD Department of Breast Surgical Oncology Samuele Massarut, MD Mario Mileto,MD Ezio Candiani, MD Department of Radiation Oncology Mario Roncadin, MD Giovanna Sartor, Phy Mauro Trovò, MD

How TARGIT Intra-operative Radiotherapy can help Older Patients with Breast cancer

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