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Table: 1657P
TH BV + TH
HR (95% CI) Interaction p value a
Subgroup Events/pts, n Median, mo Events/pts, n Median, mo
All 64/82 11.2 66/80 16.5 0.78 (0.56–1.11)
E-selectin L H 31/44 32/37 16.4 8.2 30/36 35/43 16.5 16.6 1.01 (0.61–1.68) 0.57 (0.35–0.92) 0.241
IL-8 L H 35/45 28/36 13.6 8.4 28/35 37/44 16.4 17.8 0.84 (0.51–1.40) 0.74 (0.45–1.22) 0.506
ICAM-1 L H 30/45 33/36 16.4 10.3 29/35 36/44 16.5 16.2 1.13 (0.68–1.89) 0.49 (0.30–0.80) 0.017
bFGF L H 32/41 31/40 13.3 11.1 33/39 32/40 16.4 19.1 0.80 (0.49–1.30) 0.80 (0.49–1.32) 0.837
PDGF-C L H 29/40 35/42 17.1 8.5 32/41 34/39 16.5 16.6 0.87 (0.52–1.44) 0.72 (0.45–1.16) 0.342
VEGF-A L 33/45 13.6 30/36 16.5 0.83 (0.50–1.36) 0.795
H 31/37 8.5 35/43 16.6 0.70 (0.43–1.14)
VEGF-C L H 35/42 29/40 13.5 9.6 32/39 34/41 14.8 19.1 0.70 (0.43–1.15) 0.92 (0.56–1.51) 0.649
VEGFR-1 L H 30/40 33/41 11.1 13.3 33/40 32/39 16.2 16.6 0.76 (0.46–1.25) 0.84 (0.52–1.37) 0.982
VEGFR-2 L H 35/44 28/37 11.2 11.0 30/36 35/43 13.7 19.2 0.95 (0.58–1.55) 0.67 (0.40–1.10) 0.174
VEGFR-3 L H 35/48 28/33 12.2 11.0 25/32 40/47 15.3 16.6 0.88 (0.52–1.47) 0.65 (0.40–1.06) 0.051
a Model includes prognostic factors.
Disclosure: L. Gianni: LG acts as a Consultant and has sat on Advisory Boards for Roche,
Genentech, GSK, Novartis, Pfizer, Boehringer Ingelheim, Astra Zeneca, and Celgene. A.
Chan: AC has acted as a Consultant, sat on Advisory Boards, and received honoraria and
research funding from Roche. X. Pivot: XP has acted as a Consultant and sat on Advisory
Boards for Roche, Eisai and GlaxoSmithKline, and has received honoraria from Sanofi. R.
Greil: RG has acted as a Consultant for, sat on Advisory Boards for, and received
honoraria and research funding from Roche. L. Provencher: LP has received a travel grant
and honoraria from Roche.S. Prot: SP is an employee of F Hoffmann-La Roche Ltd. N.
Moore: NM is an employee and holds stock in F Hoffmann-La Roche Ltd. S.J. Scherer: SS
is an employee of Genentech. C. Pallaud: CP is an employee of F Hoffmann-La Roche Ltd.
.All other authors have declared no conflicts of interest.
1658P DIFFUSE REFLECTANCE SPECTROSCOPY; TOWARDS
CLINICAL APPLICATION IN BREAST CANCER
T.J.M. Ruers 1 , D. Evers 1 , R. Nachabé 2 , M.J. Vranken Peeters 1 , J. van der Hage 1 ,
H. Oldenburg 1 , E. Rutgers 1 , G. Lucassen 2 , B. Hendriks 2 , J. Wesseling 3
1 Surgery, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital,
Amsterdam, NETHERLANDS, 2 Minimally Invasive Healthcare, Philips Research,
Eindhoven, NETHERLANDS, 3 Pathology, The Netherlands Cancer Institute
Antoni van Leeuwenhoek Hospital, Amsterdam, NETHERLANDS
Background: Diffuse reflectance spectroscopy (DRS) is a promising new technique
for breast cancer diagnosis. During DRS tissue is illuminated by a selected light
spectrum. By specific absorption and scattering characteristics of the tissue an
‘optical fingerprint’ is obtained which represents specific morphological information.
In this way DRS is able to differentiate normal tissue from tumor tissue. Here we
compared the diagnostic accuracy of DRS in a cohort of patients and each patient
individually to the pathology analysis of normal and malignant breast tissue.
Methods: Breast tissue from 47 female patients was analysed ex-vivo by DRS. A total
of 1073 optical spectra were collected from fat, glandular tissue and fibroadenoma
lesions as well as from (pre)-malignant tissue samples. These spectra were analyzed
for each patient individually as well as for all patients collectively. Results were
compared to the pathology analysis of biopsies from each measurement location.
Results: Collective patient data analysis for discrimination between normal and
malignant breast tissue resulted in a sensitivity of 90%, a specificity of 88% and an
overall accuracy of 89%. For individual analysis all measurements per patient were
categorized as either benign or malignant. The discriminative accuracy of this individual
analysis was nearly 100%. When an arbitrary threshold was used of a 90% agreement
between all DRS measurements and the pathology analysis for each individual patient to
ascertain a diagnosis, only in one patient the diagnosis was classified as uncertain.
Conclusions: Our results demonstrate that diffuse reflectance spectroscopy can be
considered as an important new optical sensing technique that could improve the
diagnostic workflow in breast cancer.
Disclosure: All authors have declared no conflicts of interest.
1659P EFFECTS OF SRC INHIBITION ON SURVIVAL, MIGRATION
AND INVASION OF HUMAN BREAST CANCER CELLS
RESISTANT TO LAPATINIB
L. Nappi, L. Formisano, R. Rosa, V. Damiano, T. Gelardi, C. D’Amato,
V. D’Amato, R. Marciano, A.P. De Maio, R. Bianco
Medical Oncology, University Federico II, Napoli, ITALY
Background: HER2, a member of the HER family, is a transmembrane tyrosine
kinase receptor overexpressed in almost 30% of breast cancer patients. Lapatinib is a
small molecule HER2 inhibitor approved in metastatic breast cancer patients after
Annals of Oncology
trastuzumab failure. Unfortunately, the resistance against lapatinib is observed even
in responding patients. Src is an intracellular kinase involved in tumor growth,
angiogenesis and migration and it is related to trastuzumab resistance in human
breast cancer cell lines.
Materials and methods: We used different HER2 expressing human breast cancer
cell lines, such as MDA-MB-361, MDA-MB-231 and BT474 (sensitive to lapatinib)
JIMT-1 and KPL-4 (low sensitivity against lapatinib), and MDA-MB-361-LR
(acquired resistance to lapatinib). We performed survival, migration and invasion
assays and WB analysis in all cell lines treated with lapatinib, saracatinib (a Src
inhibitor) or the combination. We also used nude mice xenografted with JIMT-1
cells and in vivo artificial metastatic assay.
Results: We observed that the combination treatment of lapatinib plus saracatinib is
able to inhibit survival, migration and invasion in vitro and to regulate several
proteins such as Src, Akt, MAPK, paxillin and FAK in all cancer cell lines tested. In
nude mice xenografted with JIMT-1 cells, the combined treatment reduced tumor
growth, prolonged survival and strongly decreased the incidence of lung metastases.
Interestingly, we observed that Src preferentially binds to HER2 in lapatinib sensitive
cells and with EGFR in resistant ones. EGFR inhibition, through the use of
cetuximab or siRNA silencing, strongly enhanced the effect of lapatinib on the
growth of resistant cancer cells. The combined treatment of lapatinib and cetuximab,
moreover, significantly reduced the activation of several intracellular transducers.
Conclusions: We demonstrated that Src plays an important role in the development
of resistance to lapatinib in breast cancer cell lines, in particular affecting invasion
and migration, and that EGFR may mediate its activation. These results may suggest
the clinical development of lapatinib and cetuximab combination in patients resistant
to lapatinib.
Disclosure: All authors have declared no conflicts of interest.
1660P EPIGENETIC SILENCING OF ARGININO-SUCCINATE
SYNTHASE (ASS1) DEFINES ARGININE DEPLETION
THERAPY AS A NOVEL TREATMENT STRATEGY FOR
BREAST CANCER
F. Cavicchioli 1 , A. Shia 1 ,K.O’Leary 1 , V. Haley 1 , C. Palmieri 2 ,N.Syed 3 ,
T. Crook 4 , A.M. Thompson 5 , C. Lo Nigro 6 , P. Schmid 7
1 Oncology, Brighton and Sussex Medical School, Brighton, UNITED KINGDOM,
2 Hammersmith Campus, Charing Cross HospitalImperial College Healthcare
NHS Trust, London, UNITED KINGDOM, 3 Faculty of Medicine, Imperial College
of London, London, UNITED KINGDOM, 4 Dundee Cancer Centre, University of
Dundee, Dundee, UNITED KINGDOM, 5 Surgery and Molecular Oncology,
University of Dundee, Dundee, UNITED KINGDOM, 6 Oncology, S. Croce General
Hospital, Cuneo, ITALY, 7 Clinical Investigation and Research Unit, Brighton and
Sussex Medical School, Brighton, UNITED KINGDOM
Background: Loss of argininosuccinate synthetase (ASS1) or lyase (ASL) expression,
critical for the biosynthesis of arginine in normal tissues, due to
methylation-dependent silencing sensitises ovarian or glioblastoma cells to arginine
depletion therapy (ADT). Cells not expressing sufficient levels of ASS1 or ASL
become auxotrophic for arginine and require exogenous supply. Arginine deiminase
(ADI), a novel arginine-degrading enzyme, can eliminate arginine from the
circulation and has shown activity in cancers with low ASS1 and/or ASL activity.
This study was performed to establish whether ASS1 or ASL are subject to
methylation-dependent silencing in breast cancer to validate ADT as a novel
therapeutic strategy for breast cancer.
Methods: Methylation of ASS1 and/or ASL was analysed by pyrosequencing and
methylation-specific PCR (MSP) using primer sets validated by bisulphite
sequencing. We used a panel of 19 breast cancer cell lines and two independent
series of stage I-III primary breast cancers with linked mature clinical outcome that
ix532 | Abstracts Volume 23 | Supplement 9 | September 2012