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

(1)

IL CARCINOMA DELLA MAMMELLA NEL 2010:

Il chirurgo generale tra demolizione,

ricostruzione e radioterapia

Udine, 23 ottobre 2010

Dott. Samuele Massarut, C.R.O. Aviano

Oncologia Chirurgica Senologica C.R.O. Aviano

Partial breast irradiation

La IORT: TARGIT

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TARGIT: il punto di vista del chirurgo



1 . Facilità di esecuzione



2. Assenza di effetti indesiderati maggiori

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3. Buon risultato estetico

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4. Ottimo controllo locale di malattia



5. Studio delle interazioni tra intervento

chirurgico e tumore mammario

(3)

Results (1)

o

• 114 patients assessed

– Median age at randomisation 62 years (IQR 56 to 68).

– Median tumour size 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

(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%).

(5)

Results (3)

Excellent/Good cosmetic outcome

0.0 0.2 0.4 0.6 0.8 1.0 0 1 2 3

Year after surgery

P ropor ti on EBRT TARGIT S.M. – Udine 23 Otobre 2010

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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

(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%).

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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

(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)

(13)

• 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.

EXPERIMENTAL EVIDENCES

(14)

Tumour activated fibroblasts stimulate cancer cell growth by producing specific growth factors and chemokines

Orimo, et al. Cell 2005 121: 335-348

(15)

Paszek, et al. Cancer Cell 2005 8: 241-254.

Tumour microenvironment stiffness favours cancer cell growth

(16)

CLINICAL EVIDENCES



90% of recurrences occur in the index

quadrant

(17)

CLINICAL EVIDENCES



Surgery modifies the growth kinetics of

breast cancer micrometastasis

(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

(19)

CLINICAL EVIDENCES



Residual tumour after conservative surgery

has a much higher level of Mib-1

(proliferation index) than the primary

tumour

(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

(21)

Distribution of fibroadenomas by age and

according to modality of diagnosis

Age HD F CDF Total

Cases % Cases % Cases %

30-39 591 44.3 314 12.0 905 23.0 40-49 556 41.6 918 35.2 1474 37.4 50-59 134 10.1 890 34.2 1024 26.9 60-69 54 4.0 481 18.6 535 13.6 Total 1335 100.0 2603 100.0 3938 100.0 Abbreviations‘:

HDF - hystologically diagnosed fibroadenomas ; CDF- clinically diagnosed fibroadenomas.

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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 1978-81 6.546 10.03 21 2.14 0.8-3.2 1982-85 6.015 7.82 17 2.17 1.2-3.5 1986-89 1.751 2.01 2 1.00 0.1-3.6 1990-93 530 0.63 1 1.59 0.1-8.8 Total 14.842 20.43 41 2.00 1.4-2.7 CDF 1978-81 4.964 10.58 6 0.57 0.2-1.2 1982-85 3.545 6.42 4 0.62 0.2-1.6 1986-89 4.351 7.52 4 0.53 0.1-1.4 1990-93 4.804 7.31 17 2.33 1.3-3.7 Total 17.664 31.83 31 0.97 0.7-1.4

(23)

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

INTRODUCTION

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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;

•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. Drawing of Pre -surgery Serum Drainage of Post -surgery Serum Exp.Onc.Dept.

(25)

TARGIT treatment impairs the wound fluid

-induced cancer cell growth in 3D-matrices

HMEC in MATRIGEL

(26)

HMEC MDA-MB 231

MDA-MB 231 _{MDA-MB 453}

PRE-Sera WF

UNTR. TARGITWF PRE-Sera

WF

UNTR. TARGITWF

PRE

Sera UNTRWF TARGITWF NIH

CM

SFM PRE

Sera

TARGIT impairs the wound fluid-induced

cancer cell migration and invasion

PRE

Sera UNTRWF TARGITWF NIH

CM

SFM PRE

(27)

PRE-Sera WF untreated WF TARGIT

HGF IL-10 IL-13

TARGIT alters the proteomic profile

of the wound fluid

(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.

(29)

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ACKNOWLEDGEMENTS

Department of Experimental Oncology

Gustavo Baldassarre, MD Barbara Belletti, PhD

Sara D’andrea, Tech Alfonso Colombatti, 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

Department of Pathology Tiziana Perin, MD

Vincenzo Canzonieri, MD Antonino Carbone,MD