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number of biomarkers have been tried with varying results. Minichromsome
Maintenance Proteins (MCMs) play a regulatory role in eukaryotic DNA
replication and are expressed as normal cells progress from G0 into G1/S phase
of the cell cycle. Over expression has been demonstrated in neoplasia in many
sites including urothelium. The aim of the study was to evaluate use of MCM2
in urine cytology and tissue specimens to differentiate high grade from low
grade UC.
Methods: epithelial cells retrieved from urine samples of 114 patients were stained
with MCM2 using an immunocytochemical technique. MCM2 was similarly applied
to 13 archived urothelial tumour specimens. MCM positive cell counts were
performed on all cytology specimens and results correlated to the different grades of
UC. Tumor specimens were evaluated for MCM2 staining intensity, distribution and
percentage of positive cells.
Results: 26 of 114 patients were found to have UC. In cytology specimens the
MCM mean and median cell counts increased with grade of cancer (Table 1).
Non cancerous urines had mean and median MCMs of 232 and 14
respectively. In urothelial solid tissue tumour specimens, MCM2 showed
strong nuclear staining characteristics where the percentage of positive cells
was related to tumor grade. The lowest percentage MCM stained cells was
noted in grade 1 tumours, the highest percentage in grade 3. Staining
distribution was predominantly in the basal zone of the urothelium in grade 1
tumours, basal and middle epithelial zones in grade 2, and more diffusely
distributed in grade 3 tumours. Table 1: MCM cell count with increasing grade
of urothelial cancer.
Grade
Number
of cases Mean
Standard
Deviation Median
G1 3 3207 5026 600
G2 9 8177 15975 3000
G3 13 14795 14167 10000
CIS 1 40000 - 40000
Total 26
Conclusion: MCM2 could be a useful biomarker in differentiating low grade from
high grade UC both in cytology and biopsy tissue specimens.
Disclosure: All authors have declared no conflicts of interest.
242 GENERATION OF A SOMATIC MUTATIONS BRAF
IN MELANOMA DATABASE (WWW.
SOMATICMUTATIONS-BRAFMELANOMA.NET)
H. Linardou 1 , S. Murray 2 , F. Siannis 3 , D. Bafaloukos 1
1 1st Department of Medical Oncology, Metropolitan Hospital, Athens, GREECE,
2 Oncology, GeneKor SA, Athens, GREECE, 3 Department of Mathematics,
University of Athens, Athens, GREECE
Background: Somatic mutations of BRAF are correlated with improved outcomes in
patients with melanoma treated with the anti-BRAF tyrosine kinase inhibitor
Vemurafenib. The frequency and spectrum of these mutations is currently not well
classified within melanoma or amongst melanocytic lesions. A systematic
compendium of BRAF mutations in human tumors may better clarify issues related
to incidence and spectrum.
Methods: Using a broad search string including “BRAF”, “RAS”, “Melanoma”,
“Cancer” and associated synonyms we identified 3,879 abstracts from inception
through to 23/12/2011 in MEDLINE (PubMed). Sub-searches for Melanoma or
melanocytic lesions (naevi) identified 175 articles. Data extraction was conducted
by two investigators. Fields included: incidence, melanoma subtype, AJCC stage,
gender, sun exposure, site, Breslow status amongst others split by mutational
status.
Results: With a total of 14,019 screened patients, 5,606 were identified to harbor
a mutation (40.0%). Cumulative data indicated that there were no significant
differences according to gender (55.2% male, 57.8% female), ulceration (46.4%
with, 44.6% without), stage (46.6% I, 52.7% IV), metastatic and primary
cutaneous melanoma (39.7% vs 41.1%). Differences in incidence were seen
between sun exposure (36.2% exposed, 44.8% non-), site [except ocular/ uveal]
(10.5% mucosal, 44.6% other) and between benign and Spitz nevi (52.5%
versus 5.5%).
Conclusions: This compendium of datasets allows the investigation of several trends
in melanoma and melanocytic lesions. Technical and intra-inter-tumor
dis-concordance issues were highlighted. A comprehensive analysis of
clinicopathological correlations will be presented.
Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
243 IMPACT OF PIK3CA MUTATIONS AND P95HER2 EXPRESSION
ON THE OUTCOME OF HER2-POSITIVE METASTATIC BREAST
CANCER PATIENTS TREATED WITH A TRASTUZUMAB-BASED
THERAPY
I. Stasi 1 , A. Fontana 2 , G. Allegrini 3 , C. Mazzanti 4 , S. Lucchesi 5 , E. Bona 2 ,
I. Ferrarini 2 , B. Salvadori 2 , A. Falcone 6 , K. Zavaglia 4
1 Medical Oncology, Azienda Ospedaliero Universitaria S.Chiara, Pisa, ITALY,
2 Oncologia Medica Ii, Polo Oncologico, Ospedale S. Chiara, AOUP, Pisa, ITALY,
3 Medical Oncology Unit, Pontedera Hospital, Pontedera, ITALY, 4 University of
Pisa and Pisa University Hospital, Section of Molecular Pathology, Division of
Surgical, Molecular, and Ultrastructural Pathology, pisa, ITALY, 5 Oncologia
Medica, Ospedale "F. Lotti", Pontedera, ITALY, 6 Oncologia, Trapianti E Nuove
Tecnologie In Medicina, Polo Oncologico - Azienda Ospedaliero-Universitaria
Pisana - Istituto Toscano Tumori, Pisa, ITALY
Background: Currently, no biomarkers of Trastuzumab (T) clinical resistance have
been validated. The aim of this pilot study was to evaluate the impact of PIK3CA
mutations and p95HER2 (pHER2 truncated form) expression on the efficacy of a
T based-therapy in a HER2-positive metastatic breast cancer (MBC) patients (pts).
Methods: 107 HER2-positive MBC pts, treated in the last 10 years, were evaluated.
Median age was 54 years (25-79); ECOG performance status was 0 in 56% of pts; all
pts received several lines of treatment including T; biomarkers molecular analysis was
performed in 70 tumor specimens. The IHC expression of p95HER2 was evaluated
by a monoclonal antibody that specifically recognizes only the HER2 external
domain; the HER2 integrity was defined by the presence of a homogeneous
membrane staining (moderate or intense) in at least 30% of the cells, otherwise the
HER2 was defined as p95HER2 positive. PIK3CA mutations in exons 9 and 20 were
detected by automated sequencing. The molecular data were correlated to Time to
progression (TTP) of the first line treatment including T and the Overall Survival
(OS) by using the Kaplan-Meir method and the log-rank-test.
Results: p95HER2 positive pts and PIK3CA mutations in exon 9 or 20 were detected
in 42% and 22% of tumor specimens, respectively. p95HER2 positive tumors showed
a shorter TTP and OS that did not reach statistical significance; PIK3CA mutations
correlated with a worse TTP (median 7,6 vs 11,3 months) and OS (median 20,1 vs
41,0 months, p= 0,046).
Conclusions: These preliminary results suggest a possible role of PIK3CA mutational
status in predicting the outcome of MBC pts treated with T.
Disclosure: All authors have declared no conflicts of interest.
244 DETECTION OF CIRCULATING TUMOUR CELLS IN
PERIPHERAL BLOOD OF PATIENTS WITH MALIGNANT
PLEURAL MESOTHELIOMA
J. Raphael 1 , C. Massard 2 ,F.Farace 3 , G. Le Teuff 4 , J. Margery 5 , F. Billiot 3 ,
B. Besse 1 , A. Hollebecque 2 , J. Soria 1 , D. Planchard 1
1 Thoracic Group, Inserm U981, Institut Gustave Roussy, Villejuif, FRANCE,
2 Department of Medical Oncology, Institute Gustave Roussy, Villejuif, FRANCE,
3 Laboratory of Translational Research, Institut Gustave Roussy, Villejuif, FRANCE,
4 Department of Statistics and Epidemiology, Institut Gustave Roussy, Villejuif,
FRANCE, 5 Pulmonary Department, Percy Hospital, Paris, FRANCE
Background: The independent prognostic value of Circulating Tumour Cells (CTC)
level has been demonstrated in patients with advanced breast, prostate and colorectal
cancers. There is currently few data on Malignant Pleural Mesothelioma (MPM) and
CTC. We investigated whether the presence of CTC was correlated with prognosis
factors and treatment efficacy in MPM patients.
Methods: Patients (pts) with MPM in progression were enrolled before any new line of
treatment in a prospective monocentric study. CTC detection was made on peripheral
blood samples (7.5ml) using the “CellSearch” assay according to the manufacturer’s
protocol. The correlation between the presence of CTC and known worse prognosis
factors was assessed using the X2 test. Progression Free Survival (PFS) was defined as the
time from diagnosis until first progression (PFS1) and as the time from CTC measure
until progression or death (PFS2). Comparison of PFS according to CTC detection was
performed using the log-rank test. The cut-off date of the analysis was May 2012.
Results: Twenty-five MPM pts with a median follow-up of 4.2 months were included.
The median age and sex ratio (M/F) were 65 years old and 2.1 respectively. Eighty-four
percent of pts had an epithelioid MPM, 64% had a stage 4 disease, 60% had an anemia,
a thrombocytosis or a leucocytosis at the time of inclusion. All pts except one had an
Eastern Cooperative Oncology Group performance status (ECOG) < 2 and 64% received
more than one line of chemotherapy. CTC were detected in 48% of pts (n = 12) with a
median level of 1.5 (0-36). No significant correlation was observed between the presence
of CTC and a metastatic disease, an ECOG ≥ 1, the presence of anaemia, leucocytosis, or
thrombocytosis and the non-epithelioid type. The median PFS (1 and 2) were 17.9 (95%
CI= [10.1-24.0]) and 2.5 (95%CI= [1.3-3.5]) months respectively. CTC detection was
not a significant predictor of PFS 2 (p = 0.27).
Conclusion: Detection of CTC has been done in a small cohort of MPM patients. It
could be an important tool though we were not able to demonstrate a significant
prognostic value or a difference in PFS between CTC levels. The "Cellsearch" assay
might not be the best technique to use in this setting. Further analyzes are in
progress, and updated results will be presented in September.
Disclosure: All authors have declared no conflicts of interest.
ix94 | Abstracts Volume 23 | Supplement 9 | September 2012